Drug Discovery and Clinical Research SK Gupta
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New Drug DevelopmentCHAPTER 1

 
INTRODUCTION TO DRUG DEVELOPMENT
Drug development is a scientific endeavor which is highly regulated due to public health concern. A promising new molecule identified in drug discovery has to go through the complex and time-consuming process of drug development before it becomes available to patients.
The discovery process begins with an understanding of the disease mechanism(s) or cause of the disease and discovery (or identification) of genes and/or proteins involved in causing certain diseases. The identification of genes/proteins responsible for the disease condition is referred to as target identification. These identified targets (gene/proteins) are the potential targets for drugs to interact and to bring about a beneficial effect in a patient. Next step is target validation, where certain studies are performed to confirm that targets (genes/proteins) are actually involved in the disease. In this stage, along with validation of the target, ability of the target to bind to a drug is identified.
After target identification and validation, a lead compound needs to be identified. A lead compound is a substance which has the greatest potential for successful interaction with the identified target. A lead compound is generally selected from libraries containing thousands of compounds. This step of the drug discovery process is known as lead identification. After the lead compound is identified it goes through an optimization process wherein the structure of the compound may be altered to make it safe and efficacious. Once this process is completed the compound is tested first in animal models (such as rats and mice), then in humans to further ascertain its properties.
It takes about ten to twelve years to develop a new drug and the cost is over ₠800 million, about 60% of which is spent on necessary rigorous clinical trials. For a variety of reasons, fewer than one or two compounds per ten thousand tested actually make it to the market and are authorized for use in patients. In view of the high cost of the drug development process, the industry has to be careful and has to look in to the factors that have significant impact on the process and should form basis for allocation of resources.
The decision to develop a new drug by a pharmaceutical company depends on the various factors and one of the key factors is to review and find out the unmet medical needs in the specific therapeutic area in which the company is interested due to strategic reasons. In some cases there may be industry – university or industry – government scientific institutes collaboration that may help to develop a new molecule.
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Table 1.1   Cost and time involved in drug discovery
Target Discovery
2.5 years ↓ 4%
Lead generation and lead optimization
3.0 years ↓ 15%
Preclinical development
1.0 year ↓ 10%
Phase I, II and III clinical trials
6.0 years ↓ 68%
FDA review and approval
1.5 years ↓ 3%
Drug to the market 14 years
₠ 880 million
Source: PAREXEL. Parexel's Pharmaceutical R & D Statistical Sourcebook, 2001; p.96
New and interesting findings may also come from university, institutes and the lead may be taken over by the pharmaceutical companies for further research.
The drug discovery and development process is designed to ensure that only those pharmaceutical products that are both safe and effective are brought to market for the benefit of the patients (Table 1.1).
 
DRUG DISCOVERY PROCESS
 
Overview of Drug Discovery Process
During the last 50 years the philosophy of valuable drugs discovery has evolved from one that was mostly based around chemistry to one that has more biological approach to treat a disease. These changes were not only driven by strategic imperative, but are enabled also by the significant changes in technology that has occurred during the past half century.
 
Historical Background
Before the existence of pharmaceutical industry, medicines were discovered by accident, and their use was passed down by written and verbal tradition. For example, digitalis is an active principal of a natural product, namely foxglove leaf, used to treat dropsy or edema in which liquids accumulate in the body and causes swelling of tissues and body cavities.
This remedy was described and used some hundred(s) of years before the isolation of the active components. In 1776, William Withering, a physician in England treated a lady who was dying of dropsy. He left her, expecting her to die shortly, but he later learned that she had recovered after taking an old cure of a garden plant called foxglove. For ten years, Withering conducted experiments to demonstrate the uses of foxglove and discovered that dropsy is actually a symptom of heart disease in which the heart does not pump 3hard enough to get rid of urine. He showed that foxglove stimulated urination by pumping more liquids to the kidneys. He published his results in 1785, but it was not until the 20th century that the cardiac glycosides, the component of the foxglove plant, were structurally and pharmacologically described.
In 1950s and 1960s, pharmaceutical industries’ success in drug discovery had their origins in serendipity, i.e. discovery by accident/chance. Lead molecules were found by chance or from screening the chemical diversity available. These were then optimized by medicinal chemists to produce candidates, which were passed to development and eventually into the market. This method led to discovery of drugs such as chlorpromazine, meprobamate, and benzodiazepines (chlordiazepoxide, diazepam) all of which have gone on to become successful medicines.
However, this approach suffered from lack of sufficient molecules with high enough structural diversity, and the common use of animal models meant that other factors such as absorption, metabolism, brain penetration, and pharmacokinetics had profound effects on the number of active molecules found. In addition, many molecules that showed activity in the models were of unknown mechanism. This greatly impeded the development of back-ups when the lead failed due to toxicity or poor pharmacokinetics.
To combat these problems, a more rational approach was developed based around the structure of the agonist (i.e. hormones and neurotransmitters) and its receptor. This was set against a background of studying biological/physiological systems in animal tissues. Thus, knowledge around molecular determinants that contribute to affinity and efficacy enabled a generation of specific and potent agonists and antagonists to be developed.
 
Steps in Drug Discovery
The advent of molecular biology, coupled with advances in screening and synthetic chemistry technologies, has allowed a combination of both knowledge around the receptor and random screening to be used for drug discovery.
The process of drug development is divided into two stages: New lead discovery and new product development (clinical development) (Fig. 1.1).
 
Target Identification
Before any potential new medicine is discovered, the disease to be treated needs to be understood, to unravel the underlying cause of the condition. Even with new tools and insights, research on disease mechanism takes many years of work and, too often, leads to frustrating dead ends. And even if the research is successful, it takes many more years of work to turn this basic understanding of what causes a disease into a new treatment.
The disease mechanism defines the possible cause or causes of a particular disorder, as well as the path or phenotype of the disease. Understanding the disease mechanism directs research and formulates a possible treatment to slow or reverse the disease process.
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Fig. 1.1: Steps in new drug development
It also predicts a change of the disease pattern and its implications.
Disease mechanisms can be broadly classified into the following groups:
  • Defects in distinct genes—genetic disorders
  • Infection by bacteria, fungi, viruses, protozoa or worms
  • Immune/autoimmune disease
  • Trauma and acute disease based on injury or organ failure
  • Multicausal disease
The identification of new and clinically relevant molecular targets for drug intervention is of outstanding importance to the discovery of innovative drugs.
It is estimated that up to 10 genes contribute to multifactorial diseases, which are linked to another 5 to 10 gene products in physiological and pathophysiological circuits which are also suitable for intervention with drugs. Environmental factors such as diet, exposure to toxins, trauma, stress, and other life experiences are assumed to interact with genetic susceptible factors to result in disease. Thus, drug targets may include molecular pathways related to environmental factors.
Current drug therapy is based on less than 500 molecular targets with potential to exploit at least 10 times the number of targets in the future. Targets for therapeutic intervention can be broadly classified into these categories:
  • Receptors
  • Proteins and enzymes
  • DNA
  • RNA and ribosomal targets.
Methods used for target identification include classical methods such as cellular and molecular biology and newer technique such as genomics and proteomics. 5
In the classical method, animal and human cell lines are used to identify the potential target of drug action. Two key research avenues involve the enzymes that metabolize the molecules (drugs) and proteins that act as receptors.
The newer methods like genomics and proteomics along with bioinformatics are aimed at discovering new genes and proteins and quantifying and analyzing gene and protein expression between diseased and normal cells.
 
Target Validation
Target validation requires a demonstration that a molecular target (such as an enzyme, gene or protein) is actually involved in a disease process, and that binding of a drug to the target is likely to have a curative effect.
The validation of a molecular target in vitro (in an artificial environment) usually precedes the validation of the therapeutic concept in vivo (in a living organism); together this defines its clinical potential. Validation involves studies in intact animals or disease-related cell-based models that can provide information about the integrative response of an organism to a pharmacological intervention and thereby help to predict the possible profile of new drugs in patients.
Targets are validated with:
  • In vitro models: RNA and protein expression analysis and cell based assays for inhibitors, agonists (substances which activate the target) and antagonists (counteracts the effect of a target). In vitro assays are more robust and cost-effective, and have fewer ethical implications than whole-animal experiments. For these reasons they are usually chosen for high-throughput screening, a process through which active compounds, antibodies or genes which modify a particular biomolecular pathway can be identified rapidly.
  • In vivo models: In vivo testing involves testing in whole animals. It assesses both pharmacology and biological efficacy in parallel. Animal models that are capable of mimicking the disease state (e.g. animals mimicking diabetes), by adding/ modifying or deleting certain genes are used. These animal models are referred to as knock-in and knock-out animal models.
Along with validation of the target it is essential to predict the “druggability” of the target. The “druggability” of a given target is defined by how well a therapeutic agent, such as small drug molecule or antibody, can access the target (i.e. ability of a target to bind to drug).
Knowledge of three-dimensional structure will help to unravel the physiological roles of target proteins and contribute to “chemical” target validation and also enable the prediction of “druggability” of the protein. One of the successfully targeted targets is G-protein coupled receptors (GPCRs), and a sizable number of drugs prescribed today hit this particular class. Therefore, the GPCR target type is considered druggable.6
In summary, target validation is one of the bottlenecks in drug discovery, as this phase is less adaptable to automation. Careful validation of target not only with respect to relevance to disease but also druggability will reduce the failure rate and increase the efficiency of drug discovery.
 
Lead Identification
In this phase, compounds which interact with the target protein and modulate its activity are identified.
The lead identification process starts with the development of an assay which will be followed by screening of compound libraries. The quality of an assay determines the quality of data. The assay used should fulfill these criteria: relevance, reliability, practicability, feasibility, automation and cost-effectiveness.
Primary screens will identify hits. Subsequently, confirmation screens and counter screens will identify leads out of the pool of hits. This winnowing process is commonly referred to as “hits-to-leads.”
The success of screening depends on the availability of compounds, as well as their quality and diversity. Efforts to synthesize, collect, and characterize compounds are an essential and costly part of drug discovery.
There are several sources for compounds:
  • Natural products (NPs) from microbes, plants, or animals. NPs are usually tested as crude extracts first, followed by isolation and identification of active compounds
  • Collections (Random) of discreetly synthesized compounds
  • Focused libraries around certain pharmacophores
  • Random libraries exploring “chemical space”
  • Combinatorial libraries.
A primary screen is designed to rapidly identify hits from compound libraries. The goals are to minimize the number of false-positives and to maximize the number of confirmed hits. Depending on the assay, hit rates typically range between 0.1 and 5 percent. This number also depends on the cutoff parameters set by the researchers, as well as the dynamic range of a given assay.
Typically, primary screens are initially run in multiplets of single compound concentrations. Readouts are expressed as percent activity in comparison to a positive (100 %) and a negative (0 %) control. Hits are then retested a second time (or more often, depending on the assays’ robustness). The retest is usually run independently of the first assay, on a different day. If a compound exhibits the same activity within a statistically significant range, it is termed a confirmed hit, which can proceed to dose-response screening.
Establishing a dose-response relationship is an important step in hit verification. It typically involves a so-called secondary screen. In the secondary screen, a range of compound concentrations usually prepared by 7serial dilution is tested in an assay to assess the concentration or dose dependence of the assay's readout. Typically, this dose-response is expressed as an IC50 in enzyme-, protein-, antibody-, or cell based assays or as an EC50 in in vivo experiments. IC50 is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug is needed to inhibit a given biological process by half. EC50 (Half maximal effective concentration) refers to the concentration of a drug or antibody which induces a response halfway between the baseline and maximum. The EC50 of a graded dose response curve therefore represents the concentration of a compound where 50% of its maximal effect is observed.
Confirmed hits proceed to a series of counterscreens. These assays usually include drug targets of the same protein or receptor family; for example, panels of GPCRs (G-protein coupled receptors,) or kinases. In cases where selectivity between subtypes is important, counterscreens might include a panel of homologous enzymes, different protein complexes, or heterooligomers. Counterscreens profile the action of a confirmed hit on a defined spectrum of biological target classes. The number and stringency of counterscreens can vary widely and depend on the drug target.
One of the goals throughout the discovery of novel drugs is to establish and confirm the mechanism of action (MOA). In an ideal scenario, the MOA remains consistent from the level of molecular interaction of a drug molecule at the target site through the physiological response in a disease model, and ultimately in the patient.
The tools used for lead identification are: High throughput screening, in-silico/virtual screening, NMR-based screening and X-ray crystallography.
  • High-throughput screening (HTS) aims to rapidly assess the activity of a large number of compounds or extracts on a given target. Entire in-house compound libraries with millions of compounds can be screened with a throughput of 10,000 (HTS) up to 100,000 compounds per day (ultra-HTS) using robust test assays.
  • Virtual (in-silico) screening sifts through large numbers of compounds based on a user-defined set of selection criteria. Selection criteria can be as simple as a physical molecular property such as molecular weight or charge, a chemical property such as number of heteroatoms, number of hydrogen-bond acceptors or donors. Selection criteria can be as complex as a three-dimensional description of a binding pocket of the target protein, including chemical functionality and solvation parameters. In-silico screening can involve simple filtering based on static selection criteria (i.e. molecular weight) or it can involve actual docking of ligands to a target site, which requires computer-intensive algorithms for conformational analysis, as well as binding energies.
  • NMR-based screening fills the gap between HTS and virtual screening. This method combines the random screening approach with the rational structure-based approach to lead discovery.
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  • X-ray crystallography: Uses X-rays to determine the structure and functioning of biological molecules. The point at which X-ray crystallography comes into the drug discovery and development process depends on the purpose for which it is used. X-ray crystallography is being increasingly used to determine the three-dimensional structure of a lead compound. The information accumulated during the process of lead identification by means of X-ray crystallography is essential for the next stage of drug development which is lead optimization.
Following are the criteria for hits to be regarded as leads:
  • Pharmacodynamic properties, e.g. efficacy, potency and selectivity in vitro and in vivo
  • Physicochemical properties, e.g. Lipinski's “rule of five”
  • Pharmacokinetic properties, e.g. permeability in the Caco-2 assays
  • Chemical optimization potential
  • Patentability.
 
Lead Optimization
Lead optimization is a complex, non-linear process of refining the chemical structure of a confirmed hit to improve its drug characteristics with the goal of producing a preclinical drug candidate. This stage constitutes the tightest bottleneck in drug discovery.
Lead optimization employs a combination of empirical, combinatorial, and rational approaches that optimize leads through a continuous, multi-step process based on knowledge gained at each stage. Typically, one or more confirmed hits are evaluated in secondary assays, and a set of related compounds, called analogs, are synthesized and screened.
The testing of analog series results in quantitative information that correlates changes in chemical structure to biological and pharmacological data generated to establish structure activity relationships (SAR).
The lead optimization process is highly iterative. Leads are assessed in pharmacological assays for their “druglikeness.” Medicinal chemists change the lead molecules based on these results in order to optimize pharmacological properties such as bioavailability or stability. At that point the new analogs are fed back into the screening hierarchy for the determination of potency, selectivity and mechanism of action.
Pharmacokinetics (PK)/pharmacodynamics (PD)/absorption, distribution, metabolism, Excretion (ADME) studies are an integral part of lead optimization. They feedback into the medicinal chemistry effort aiming to optimize the physicochemical properties of new leads in terms of minimal toxicity and side effects, as well as of maximum efficacy toward disease. PK/PD/ADME studies rely heavily on analytical methods and instrumentation.
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Fig. 1.2: Depicts use of in-silico technology in various stages of selection of a drug candidateSource:www.scfbio-iitd.res.in/image/insilicodrug.JPG
The recent innovation and progress in mass spectroscopy (whole-body) imaging, and chromatography technology (HPLC, LC-MS, MS) have tremendously increased the quantity and quality of data generated in PK/PD experiments.
These data are then fed into the next optimization cycle. The lead optimization process continues for as long as it takes to achieve a defined drug profile that warrants testing of the new drug in humans (Fig. 1.2).
 
Lead Optimization—Formulation and Delivery
Formulation development: It is the process of turning an active compound into a form and strength suitable for human use.
Formulation and delivery of drugs is an integral part of the drug discovery and development process. Indeed, formulation problems and solutions influence the design of the lead molecules; they feed back into the iterative lead optimization cycle, as well as the preclinical and clinical evaluations.
If formulation substances are not generally recognized as safe (GRAS), they become part of the safety assessment and their PK/PD/ADME behavior, as well as toxicity profile, needs to be documented in the IND (investigational new drug) application. In fact, side effects such as local irritation or allergic reactions are often attributable to drug formulation, not the active pharmaceutical ingredient (API).
Formulation substances might exhibit different biological activity than the actual drug.10
Indeed, a sizable number of drug discovery and development programs in the pharmaceutical and biotech industry are centered on new ways of formulating already known and even marketed drugs to increase their efficacy or safety profiles.
 
Stakeholders in New Drug Development
Expertise involved to achieve goal of new drug development are numerous. Once the management team sets therapeutic targets, budgets and resources, departments involved in drug discovery include:
  • Research and development: This department is responsible for finding new compounds and assuring that they are safe enough to test in humans.
  • Medicinal chemists: Their responsibilities are to prepare new chemical entities which can be screened for biological activity and to prepare compounds which have been found to be active (new leads) in quantities sufficient for advanced testing.
  • Pharmacology/molecular biology/screening: This department examines each new chemical entity (NCE) in a set of high throughput screens.
  • Safety evaluation: It demonstrates that the NCE and its metabolites do not accumulate and do not cause harm during short-term administration.
  • Formulations research: It develops a dosage form that is absorbed into the bloodstream when administered and is stable when stored for long periods of time. The concentration in the blood is an important factor in early development. The potential new drug must reach and maintain a level sufficient to sustain its biological effect; these studies are initially conducted on animals to establish the doses for human studies.
  • Process research: It manufactures the NCE in sufficient quantity for advanced testing, dosage form development.
  • Legal affairs: It writes and files the patents necessary to protect a company's inventions.
  • Research administration: It collects the material generated by all the departments and formats it into a request for exemption so that the NCE can be tested in humans. This submission is the investigational new drug (IND).
 
Need for Systematic Approach in New Drug Discovery
The pharmaceutical industry is operating in a world where medicines have to add real value in an environment in which costs are under constant pressure. This high cost is causing the evolution of the drug discovery process so that high percentages of efficient pipeline molecules are delivered to market quickly. The following needs to be considered to have a systematic approach in drug discovery.11
 
Unmet Medical Needs
A constant driver for developing new medicines has always been the unmet medical need. However, there are now strong pressures to treat the underlying cause of the disease rather than to provide symptomatic relief alone. This is reinventing the biological systems approach, but using humans rather than animals. In order to accomplish this, the investment that has already been initiated in technologies such as noninvasive imaging, clinical genetics and genomics will increase. This is now assured with the publication of the human genome.
The lack of disease models in animals in some therapeutic areas is a major driver to understand the human pathology. This is particularly relevant in the central nervous system (such as depression, bipolar disorder, schizophrenia) area. In these diseases, with no simple ways to validate the targets in the complex intact system, option left is targeting components such as receptor or biochemical systems. In these cases, the scientist is constrained to collecting a logical series of evidence that associates the target with the disease. Along with the existing imaging methods such as PET (Positron emission tomography) and fMRI (Functional magnetic resonance imaging), application of technologies like clinical genetics and genomics will strengthen the understanding of the correlation between disease and specific receptors.
Clinical genetics networks are being put into place to allow sufficient information on probands (proband denotes a particular subject (person or animal) first affected with genetics disorder) to be collected, such that associations between particular gene(s) and disease (target validation) can be made and eventually resulting in identification of a lead compound.
The advent of the human genome's publication now offers a great opportunity for the understanding of the genetic make-up of disease and will furnish specific gene products and/or pathways as new targets that would not have been previously identified. Importantly, they will be born out of human data, so again adding to the level of confidence in the validity of the target.
 
Attrition
Attrition is another driver for systematic approach in drug discovery for overall success rate. Attrition has remained static despite the investment in the new technologies. This reflects the fact that good molecules need more than potency and selectivity to be successful, and it is in these areas where technology has been concentrating in the last few years. The challenges ahead lie in reducing the risk of not obtaining efficacy in humans, and in increasing the developability of the molecules.
Efficacy: Many new mechanisms fail when they get into humans through lack of efficacy. This is one of the risks that the industry takes when developing 12such molecules. One way to diminish risk is to get better validation in humans (proof-of-concept, i.e. proof of efficacy) as soon as possible. The use of imaging, genetics, and genomics has already been discussed earlier as a way to help build early confidence in the target.
It is now recognized that fast decision making saves money and allows resources to be more effectively used. Proof-of-concept is generally obtained in phase III. Killing compounds in phase III is extremely costly; therefore, it is a disadvantage to obtain proof of concept at such a late stage. Thus, simple proof-of-concept studies (POCs) are being sought in phase I or phase II. If POC, were to be obtained during phase I and phase II instead of phase III, it will provide sponsors with sufficient evidence which can be used to assess the clinical and commercial potential of the drug and, in turn, eliminate potential failures from the drug discovery pipeline.
In addition, diagnostics will play a greater role in helping to choose patient populations, at least initially to show that the mechanism works. This will see greater use of imaging, proteomics and genetics in helping to identify the right patient group.
In the meantime, a better balance of novel molecules and those that are precedented will be seen in the drug discovery portfolio. This will mean that a higher proportion of molecules will not fail for efficacy. However, this strategy creates its own problems in that to be successful in the marketplace the molecule will need to be differentiated from those already present. To do this in the clinic will add to the cost and to the overall cycle time, thus these problems will need to be addressed much earlier in the process.
Developability: A large proportion of molecules fail due to of lack of developability. Prentis et al suggest that this proportion is as high as 69%, broken down as toxicity (22%), poor biopharmaceutical properties (41%) and market reasons (6%). This is not a new revelation, and efforts have been actively followed to automate and miniaturize methods to measure solubility, stability, pKa (value which describes the acid and basic properties of a substance), bioavailability, brain penetration, and various toxicity. These methods (combinatorial lead optimization) are being applied to leads during optimization, but need to be developed further and applied even earlier to maximize their impact. This is particularly true for toxicity screens, where it can be predicted that a great deal of effort will be done in the next few years.
Great extent of work is being done in the field of predictive algorithms, and Pfizer has developed tool known as the “rule of 5”. This is an awareness tool for medicinal chemists that suggests that there will be poor absorption if a molecule has two or more of the following: more than 5 H-bond donors; a molecular weight > 500; c log P > 5; the sum of Ns and Os (a rough measure of H-bond acceptors) >10.
While it is inherently costly to try to fix poor developability by formulation, pharmaceutical development will become more actively engaged in alternative formulations and delivery systems during the lead optimization 13phase. The trend towards higher potency compounds, that reduces cost of goods, also allows, due to the smaller dose, alternative delivery systems such as inhalation, nasal, buccal and sublingual absorption.
 
Cycle Times
The need to speed up the delivery of molecules to the market is another driver to have systematic approach in drug discovery. The regulatory environment and the growing complexity of drug development affect the time taken for a drug to reach the market.
Screening automation and combinatorial chemistry have greatly reduced the time to candidate selection. This will almost certainly decrease again by further application of techniques like chemoinformatics to aid library design, both for those to be used for random screening and those within the process of lead optimization. As mentioned above, continual automation of developability criteria will also speed up the process by selecting compounds with a high probability of succeeding. This raises the concept that speed in each phase should not always be the major driver. A candidate for development goes forward with all of its associated baggage. Fixing problems become costly and may lead to a suboptimal product that cannot fulfill its medical and commercial potential. Thus, spending time choosing the right candidate will have major benefits downstream, both in terms of speed and value. The same concept applies to development candidates in phase III. Differentiation may not be obvious if the mechanism is precedented with another marketed product. Thus, differentiation will become a challenge, which potentially will increase the time in phase III. To aid in this process and help in choosing which differentiators to pursue, this problem will need to be addressed much earlier. This might stimulate automated assays for common side effects of drugs as part of the candidate selection criteria during the lead optimization stage.
 
Economic Value
There is growing internal pressure to increase productivity while controlling costs. This has led to the drive for high-value molecules in diseases with high unmet need. An extension of this concept is the “blockbuster” approach where projects that deliver medicines with potential peak sales greater than 1 billion pounds are given the highest priority. This means that portfolio management will become even more important with an associated greater interaction between R & D and the commercial functions.
Thus, new portfolio tools will also be major contributors to the future process of drug development. The real value of medicines to the health of society is only now beginning to be recognized. It has taken many years of persuasion that medicines can have profound economic benefit.
The push to raise health, economic and quality-of-life issues has produced a counter response from some regulators that the industry demonstrates 14added value in its novel medicines. Thus, committees like National Institute for Clinical Excellence (NICE) in the UK will put pressure on the process to produce medicines that have significant value for society. This will mean that in the future more outcome studies will be needed to demonstrate quality-of-life and economic benefit.
 
PRECLINICAL DRUG DEVELOPMENT
 
Introduction to Preclinical Drug Development
Preclinical drug development is a stage that begins before clinical trials (testing in humans) during which important safety and pharmacology data are collected. Clinicians and regulators need to be reassured that information concerning all of these different aspects is available to enable clinical trials to progress and ultimately to support regulatory decisions on whether a new drug can be approved for marketing. Most regulatory toxicity studies are conducted in animals to identify possible hazards from which an assessment of risk to humans is made by extrapolation. Regulatory agencies request studies in a rodent (e.g. rat) and a nonrodent (e.g. dog). The choice of animal species is based on the similarities of its metabolism to humans or the applicability of desired pharmacological properties to humans. It is not possible or ethical to use animals in large numbers, to compensate for the same it is assumed that increasing the dose and prolonging the duration of exposure will improve both sensitivity and predictivity of the tests.
Preclinical research includes synthesis, purification and animal testing which is done to measure the biological activity and safety of an investigational drug or device. Preclinical research is conducted by pharmaceutical companies early in the process of new drug development. This research takes place in either the part or whole animal to determine important information, including therapeutic effects the drug may have, potential side effects and toxicities and metabolism and clearance of the drug in the body. Good results in the preclinical or animal stage do not necessarily mean that similar results will be found when the drug is given to healthy volunteers or patients.
The main goals of preclinical studies are to determine a drug's pharmacodynamics (PD), pharmacokinetics (PK) and toxicity through animal testing. These data allow researchers to estimate a safe starting dose of the drug for clinical trials in humans.
The goals of the nonclinical safety evaluation include:
  • Categorization of toxic effects with respect to target organs, dose dependence, relationship to exposure, and potential reversibility. This information is important for the estimation of an initial safe starting dose for the human trials
  • The identification of specific parameters for clinical monitoring for potential adverse effects
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  • The nonclinical safety studies, although limited at the beginning of clinical development, should be adequate to characterize potential toxic effects.
The need for nonclinical information including toxicology, pharmacology and pharmacokinetics to support clinical trials is addressed in the ICH (International Conference on Harmonization) Safety guidelines. Typically, both in vitro and in vivo tests will be performed. Studies of a drug's toxicity on organs targeted by that drug, as well as any long-term carcinogenic effects or toxic effects on mammalian reproduction will be estimated in preclinical studies.
 
Types of Preclinical Studies
  • In vitro studies
  • In vivo studies
  • Ex vivo studies.
 
In Vitro Studies
In vitro studies are done for testing of a drug or chemical's effect on a specific isolated tissue or organ maintaining its body functions. Basic instruments used for isolated tissue experiments are organ baths, recording devices.
Few examples of in vitro studies include:
Langendroff's heart preparation: The objective is to study the effect of drugs like noradrenaline, acetylcholine and isoprenaline on the coronary blood flow and heart rate and force of contraction using rat isolated heart.
  • Ileum preparation: The objective is to record the effect of drugs like histamine and antihistamine by using segment of ileal portion of Guinea pig.
  • Rectus abdominus muscle preparation: The objective is to record the effect of drugs like d-tubocurarine by using rectus abdominus muscle of frog.
 
In Vivo Studies
In in vivo studies, in vivo is a Latin term meaning (with) “in the living”. It indicates the use of a whole organism/animals (for an experiment). Researchers use laboratory animals as models of humans or some other target species to achieve long-term objective, such as developing a new drug for a particular disease, screening a particular compound for human toxicity, studying a gene or mutation found in both animals and human; to achieve short-term objective to find out how the animal responds to the treatment. If it is a faithful model of humans, then humans should respond in the same way. Animals and other models, are used because the research cannot be done on humans for practical or ethical reasons.
Purpose of models: A specific model is chosen because it is believed to be appropriate to the condition being investigated and is thought likely to respond in the same way as humans to the proposed treatment(s) for the character being investigated.16
Having chosen the model it is essential that any experiments in which it is used are well designed, i.e. are capable of demonstrating a response to a treatment. If the model happens to be insensitive or the experiments are badly designed so that they are incapable of distinguishing between treated and control groups, say as a result of using too few animals, then the model is not appropriate to its purpose.
Animal models are used to define a new molecule's:
  • Therapeutic potential
  • Toxicity potential
  • Pharmaceutical properties and metabolic pathways
  • Mechanism and specificity of action (lead molecules).
In vivo studies are preferred over in vitro studies for the following reasons:
  • Greater similarity to human studies when compared to in vitro screening
  • Drug effects modified by physiological mechanisms can be studied
  • ADME of drugs that modifies drug effects are also factored
  • Most animal systems are similar to human systems
  • Effect of drug is studied on complete systems rather than tissues and organs
  • Drugs acting on central nervous system, cardiovascular system, gastro-intestinal system, and other systems can be studied
  • Results easier to interpret and extrapolate.
Some of the examples of in vivo studies are:
  • Noninvasive method—rat tail cuff method
  • Invasive methods—BP recording in anesthetized dog or cat.
Transgenic animal models: Partly due to the low speed and high cost of conventional animal models (typically rodents) and the relatively high number of preliminary hits from HTS (high throughput screening), alternative small-animal models have emerged. The small size, high utility, and experimental tractability (i.e. easy to manage) of these animals enable cost-effective and rapid screening of numerous compounds. Technologies for engineering the mouse genome have made it possible to create various disease models for use in screening corresponding therapeutic compounds. Knockout mouse models have been shown to be highly predictive of the effects of drugs that act on target specific gene-sequence alterations or manipulate the levels and patterns of target-gene expression. Using these techniques, researchers can generate specific disease models to validate targets as therapeutic intervention points and screen drug candidates. Transgenic technology represents an attractive approach to reduce the attrition rate of compounds entering clinical trials by increasing the quality of the target and compound combinations making the transition from discovery into development. Some of the transgenic animal models are Obese Zucker rats for testing obesity-related hypertension, genetically epilepsy-prone rats for testing antiepileptic drugs, etc.17
 
Ex Vivo Studies
In ex vivo, experiment is performed in vivo and then analyzed in vitro. The organs of the animals are detached from the body and replaced once an experiment is performed. Then the animals are kept under observation and findings recorded for a set duration.
 
General Requirements for Conducting Preclinical Studies
  • Toxicity studies should comply with good laboratory practice (GLP).
  • These studies should be performed by suitably trained and qualified staff employing properly calibrated and standardized equipment, done as per written protocols.
  • Standard operating procedures (SOPs) should be followed.
  • Test substances and test systems (in vitro or in vivo) should be properly characterized and standardized.
  • All documents belonging to each study, including its approved protocol, raw data, draft report, final report, and histology slides and paraffin tissue blocks should be preserved for a minimum of 5 years after marketing of the drug.
 
Animal Pharmacology Studies
Safety pharmacology studies are studies that investigate potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure within the therapeutic range or above. Specific pharmacological actions are those which demonstrate the therapeutic potential for humans.
Based on the individual properties and intended uses of an investigational drug, specific studies that need to be conducted and their design will vary. Only scientifically validated methods should be used.
The essential safety pharmacology is to study the effects of the test drug on vital functions. Vital organ systems such as cardiovascular, respiratory and central nervous systems should be studied.
In addition to the essential safety pharmacological studies, additional supplemental and follow-up safety pharmacology studies may need to be conducted as appropriate. These depend on the pharmacological properties or chemical class of the test substance, and the data generated from safety pharmacology studies.
Specific and essential pharmacological studies should be conducted to support use of therapeutics in humans. Essential safety pharmacology studies may be excluded or supplemented based on scientific rationale. Also, the exclusion of certain test(s) or exploration(s) of certain organs, systems or functions should be scientifically justified. Supplemental Safety Pharmacology Studies are required to investigate the possible adverse pharmacological effects that are not assessed in the essential safety pharmacological studies and are a cause for concern. 18
The following factors are to be considered when specific tests are to be conducted:
  • Mechanism of action
  • Class-specific effects
  • Ligand binding or enzyme assay suggesting a potential for adverse events.
Safety pharmacology studies are usually not required when:
  • Product is to be used for local application, e.g. dermal or ocular
  • The pharmacology of the investigational drug is well known, and/or
  • Systemic absorption from the site of application is low.
Safety pharmacology testing is also not necessary, in case of a new derivative having similar pharmacokinetics and pharmacodynamics. For biotechnology-derived products that achieve highly specific receptor targeting, it is often sufficient to evaluate safety pharmacology end-points as a part of toxicology and/or pharmacodynamic studies; therefore, safety pharmacology studies can be reduced or eliminated for these products. For biotechnology-derived products that represent a novel therapeutic class and/or those products that do not achieve highly specific receptor targeting, a more extensive evaluation by safety pharmacology studies should be considered.
In vivo safety pharmacology studies should be designed to define the dose-response relationship of the adverse effect observed. When feasible, the time course (e.g. onset and duration of response) of the adverse effect should be investigated.
In vitro studies should be designed to establish a concentration-effect relationship. The range of concentrations used should be selected to increase the likelihood of detecting an effect on the test system. The upper limit of this range may be influenced by physicochemical properties of the test substance and other assay specific factors.
 
Animal Toxicity Studies
Toxicokinetic studies should be conducted to assess the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study (Figs 1.3A and B). Other objectives of toxicokinetic studies include:
  • To relate the toxicological findings to clinical safety
  • To support in selecting species, treatment regimen and designing subsequent nonclinical toxicity studies.
Several toxicity studies need to be done before a drug goes into the clinical phase. They are as follows.
 
Systemic Toxicity Studies
Single dose study (Acute toxicity studies): Single dose studies in animals are essential for any pharmaceutical product intended for human use. The information obtained from these studies is useful in choosing doses for repeat-dose studies, providing preliminary identification of target organs of toxicity, and, occasionally, revealing delayed toxicity.
19
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Figs 1.3A and B: A researcher studies a rat being used in medical experiments
Acute toxicity studies may also aid in the selection of starting doses for phase I human studies, and provide information relevant to acute overdosing in humans.
Repeated-dose systemic toxicity studies: The primary goal of repeated dose toxicity studies is to characterize the toxicological profile of the test compound following repeated administration. This includes identification of potential target organs of toxicity and exposure/response relationships, and may include the potential reversibility of toxic effects. This information should be part of the safety assessment to support the conduct of human clinical trials and the approval of a marketing authorization.
The decision whether a developmental toxicity study needs to be performed should be made on a case-by-case basis taking into consideration historical use, product features, intended target population and intended clinical use.
 
Male Fertility Studies
Male fertility studies are designed to provide general information concerning the effects of a test substance on male reproductive system such as gonadal function.
 
Female Reproduction and Developmental Toxicity Studies
Female fertility studies are designed to provide general information concerning the effects of a test substance on female reproductive system such as ovary function and lactation (Figs 1.4A and B). These studies need to be carried out for all drugs proposed to be studied or used in women of childbearing age. 20
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Figs 1.4A and B: Depict reproductive studies done on rats
 
Teratogenicity Study
The drug should be administered throughout the period of organogenesis in animals if the test drug is intended for women of childbearing age and if women of childbearing age are to be included as subjects in the clinical trial stage.
 
Perinatal Study
This study is specially recommended if the drug is to be given to pregnant or nursing mothers for long periods or where there are indications of possible adverse effects on foetal development.
 
Local Toxicity
These studies are required when the new drug is proposed to be used by some special route (other than oral) in humans. The drug should be applied to an appropriate site (e.g. skin or vaginal mucous membrane) to determine local effects in a suitable species. If the drug is absorbed from the site of application, appropriate systemic toxicity studies will also be required. Examples of local toxicity are dermal toxicity study, vaginal toxicity study, photoallergy, rectal tolerance test, ocular toxicity studies (Fig. 1.5), inhalational toxicity studies, and hypersensitivity.
 
Genotoxicity
Genotoxicity refers to potentially harmful effects on genetic material (DNA) which may occur directly through the induction of permanent transmissible changes (mutations) in the amount or structure of the DNA within cells. In vitro (artificial environment) and in vivo (in living organisms) genotoxicity tests are conducted to detect compounds which induce genetic damage directly or indirectly. These tests should enable hazard identification with respect to damage to DNA and its fixation. Damage to DNA can occur at three levels:
  1. Point mutations
  2. Chromosomal mutations
  3. Genomic mutations.
21
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Fig. 1.5: Depicts rabbits kept ready for ocular tests
The following standard test battery is generally expected to be conducted:
  • A test for gene mutation in bacteria (Ames test)
  • An in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma assay
  • An in vivo test for chromosomal damage using rodent hematopoietic cells.
 
Carcinogenicity
Studies should be performed for all drugs that are expected to be clinically used for six months or more than six months as well as for drugs used frequently in an intermittent manner in the treatment of chronic or recurrent condition (Figs 1.6 and 1.7).
 
Limitations of Preclinical Studies
The purpose of preclinical work (animal pharmacology/toxicology testing) is to develop adequate data to undergird a decision that it is reasonably safe to proceed with human trials of the drug. Mice and rats are the most widely used host species for preclinical drug development for a variety of important reasons. First, rodents have a comparatively short life cycle. Rodent research studies can be time-compressed to evaluate disease progression with or without therapeutic intervention. The short life cycle has also lent itself to the development of many unique inbred strains. In addition, rodents, especially mice, have been thoroughly characterized genetically and were the first animal species to be genetically modified by transgenic and gene knock-out methods. The microbiology of rats and mice has been extensively studied. Sophisticated husbandry, biosecurity practices and diagnostic testing effectively control environmental conditions and adventitious infections with pathogenic microorganisms that might cloud the interpretation of experimental findings.22
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Fig. 1.6: Depicts carcinogenicity test done on mice
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Fig. 1.7: Lab mice showing one with a tumor, the other treated with toxin cancer drug
Because genetic, environmental, and microbiological variables can be comprehensively defined and carefully controlled, data from studies using rodents are invaluable for characterizing disease conditions and therapies. Also, research reagents are more widely available for biochemical testing of rodents then for testing other laboratory animal species.
However, animal studies have certain limitations:
  • Not reliably predictive of human responses due to species variation and extrapolation, poor disease models, confounding effects of laboratory confinement, stress, environment and food
  • Repeatability/reproducibility is difficult
  • Expensive, time-consuming and not amenable to high throughput. Toxicity studies are costly in terms of animals and resources. For a product 23developed for chronic oral therapy approximately 4,000 rats, 1300 mice, 100 rabbits, 50 guinea pigs and 160 dogs, a total of nearly 5,000 animals are used. If the fetus and offspring from the reproductive toxicity studies are included, the number doubles.
  • Attempting to translate research from animals to humans not as efficient as studying humans directly—92% of drugs that pass preclinical testing, almost all in vivo animal-based, fail in clinical trials.
  • Ethical issues in using animal for studies.
Predictive software and advanced in vitro technologies, have improved both the efficiency of laboratory animal experiments and the quality of data to make decisions about dosing with NCE. It is very clear that animals are not the way to explore libraries of 1 million or even 25,000 compounds. On the other hand, much can be done when the number that survives the in silico and in vitro process reaches 1000 or fewer. There are several very compelling new technologies now available that include whole-body imaging, protein biomarkers monitoring by multichannel immunoassays, flow cytometry of blood components, metabonomic component monitoring using in vivo micro dialysis and in vivo ultrafiltration, automated blood sampling for awake, freely-moving animals [pharmacokinetics (PK) and biomarkers] and parallel monitoring of physiological and electrocardiogram and psychological parameters. While not all of these data sources can be enabled simultaneously, many of them can be accomplished automatically, raising the quality of information available from animal models dramatically.
 
FDA Requirements for Preclinical Studies
It is essential to ensure the quality and reliability of safety studies and this can be achieved by adhering to good laboratory practices (GLP). The purpose of GLP is to obtain data on properties and safety of these substances with respect to human health and environment, to promote development of quality test data, such comparable data forms the basis of mutual acceptance across organizations/countries, confidence in and reliability of data from different countries will prevent duplicating tests, saves time, energy and resources.
For every 5000 drug compounds that enter preclinical testing in the United States, only about 5 will eventually be considered acceptable to test in humans. Of those final 5, only 1 drug may actually receive approval for use in patient care.
Under FDA requirements, a sponsor must first submit data showing that the drug is reasonably safe for use in initial, small-scale clinical studies.
Depending on whether the compound has been studied or marketed previously, the sponsor may have several options for fulfilling this requirement:
  • Compiling existing nonclinical data from past in vitro laboratory or animal studies on the compound
    24
  • Compiling data from previous clinical testing or marketing of the drug in the United States or another country whose population is relevant to the US population
  • Undertaking new preclinical studies designed to provide the evidence necessary to support the safety of administering the compound to humans.
At the preclinical stage, the FDA will generally ask, at a minimum that sponsors:
  • Develop a pharmacological profile of the drug
  • Determine the acute toxicity of the drug in at least two species of animals
  • Conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on the proposed duration of use of the substance in the proposed clinical studies.
Organization of Economic Cooperation and Development (OECD) framed guidelines known as good laboratory practices (GLP). GLP gives guidelines for animal testing facility (Fig. 1.8), housing the animals, responsibilities and duties of personnel conducting the animal studies, equipment, quality control, etc.
In India, the Committee for the Purpose of Control and Supervision for Experiments on Animals (CPCSEA) ensures that the animal facilities are well-maintained and experiments are conducted as per internationally accepted norms. Organizations or individuals that use animals for research, testing and teaching are required to have a code of ethical conduct which sets out the policies and procedures which must be followed when using animals for research, testing or teaching.
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Fig. 1.8: Animal testing facility according to GLP requirements
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It needs to specify provisions for compliance monitoring, the collection and maintenance of information on projects involving animals and animal management practices and facilities, and allow the fair and prompt handlings of complaints from any member of the animal ethics committee. An institutional animal ethical committee (IAEC) must be established by an institution (or group of organizations) which has an approved code of ethical conduct.
A final report shall be prepared for each nonclinical laboratory study and shall include:
  • Name and address of the facility performing the study and the dates on which the study was initiated and completed
  • Objectives and procedures stated in the approved protocol, including any changes in the original protocol
  • Statistical methods employed for analyzing the data
  • The test and control articles identified by name, chemical abstracts number or code number, strength, purity, and composition or other appropriate characteristics
  • Stability of the test and control articles under the conditions of administration
  • A description of the methods used
  • A description of the test system used. Where applicable, the final report shall include the number of animals used, sex, body weight range, source of supply, species, strain and sub strain, age, and procedure used for identification
  • A description of the dosage, dosage regimen, route of administration, and duration
  • A description of all circumstances that may have affected the quality or integrity of the data
  • The name of the study director, the names of other scientists or professionals, and the names of all supervisory personnel, involved in the study
  • A description of the transformations, calculations, or operations performed on the data, a summary and analysis of the data, and a statement of the conclusions drawn from the analysis
  • The signed and dated reports of each of the individual scientists or other professionals involved in the study
  • The locations where all specimens, raw data and the final report are to be stored
  • A statement prepared and signed by the quality assurance unit and the final report signed and dated by the study director.
 
Conclusion
Drug discovery and drug development is being revolutionized due to changes in technology. Technologies like genomics, proteomics, high throughput 26screening and structure-based design have enabled the process of drug discovery to evolve into a system where new lead molecules can be rapidly found against novel, and difficult targets. Preclinical testing of pharmaceuticals in animals has been instrumental in the development of modern therapeutic regimens. Unquestionably, human quality of life (and life expectancy) has flourished as a result of preclinical testing of drugs in animals. However, drug development remains extremely challenging, with numerous obstacles to overcome. The transition from activity in vitro (cell culture) to activity in vivo (animal model) can be especially challenging. Obtaining pharmacokinetic behavior consistent with the desired reactivity can be very difficult and the use of animals in toxicity testing has not progressed without controversy. Objections to animal testing have emphasized that the results obtained from animal tests do not always correlate well with human experience.
Attrition rates remain high, and generally only one out of ten thousand drugs tested will enter clinical development and make it all the way to regulatory approval and find a place in the market. Drugs most frequently fail in the clinic because of poor pharmacokinetics or toxicity.
Despite the fact that drug development remains a long and arduous journey, the prospect of genome-targeted individualization of therapy remains an extremely exciting one. The possibility of personalized treatments (“right drug for the right patient”) based on the genomic or proteomic readout of the particular patient is now becoming a reality.
It is envisaged that more and more strategic alliances will be formed between biotechnology and small pharmaceutical companies to make the most of all of the opportunities like human genome data.
During a new drug's early preclinical development, the sponsor's primary goal is to determine that the product is reasonably safe for initial use in humans and that compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies.
FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer) having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system (Fig. 1.9).
Before the sponsor proceeds to study a new drug in human, approval has to be obtained by IND application.27
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Fig. 1.9: The drug discovery process
 
Investigational New Drug Application
An investigational new drug (IND) application is to provide the data showing that it is reasonable to begin tests of a new drug on humans. In many ways, the IND application is the result of a successful preclinical development program. The IND application is also the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials (human trials). Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND application is the means through which the sponsor technically obtains this exemption from the FDA. The IND application shows results of previous experiments, how, where and by whom the new studies will be conducted, the chemical structure of the compound; how the compound is manufactured and any toxic effects in the animal studies.
There are two IND application categories:
  • Commercial
  • Research (noncommercial).
There are three types of IND application:
  • An Investigator IND application is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND application to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.
    28
  • Emergency Use IND application allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND application. It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist. In such a case, FDA may authorize shipment of the drug for a specified use in advance of submission of an IND application.
  • Treatment IND application is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place. A drug that is not approved for marketing may be under clinical investigation for a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug or other therapy is available. The purpose is to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible, before general marketing begins, and to obtain additional data on the drug's safety and effectiveness. In the case of a serious disease, a drug ordinarily may be made available for treatment use during phase III investigations or after all clinical trials have been completed. In the case of an immediately life-threatening disease, a drug may be made available for treatment use earlier than phase III, but ordinarily not earlier than phase II.
The IND application must contain information in three broad areas:
  • Animal pharmacology and toxicology studies: Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.
  • Manufacturing information: Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
  • Clinical protocols and investigator information: Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators who oversee the administration of the experimental compound—to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.
Sponsor files the IND application in Form 1571 to the FDA for review once successful series of preclinical studies are completed.
Along with the IND application, the sponsor submits the statement of the Investigator (Investigator's undertaking) in Form 1572.29
Once the IND application is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. If the sponsor hears nothing from CDER (Center for Drug Evaluation and Research), then on Day 31 after submission of IND application, the study may proceed as submitted. The CDER is a division of the FDA that reviews New Drug Applications to ensure that the drugs are safe and effective.
During this time, FDA has an opportunity to review the IND application for safety to assure that research subjects will not be subjected to unreasonable risk.
  • Medical review: During the IND application review process, the medical reviewer evaluates the clinical trial protocol to determine (i) if the participants will be protected from unnecessary risks; and (ii) if the study design will provide data relevant to the safety and effectiveness of the drug. Under Federal regulations, proposed phase I studies are evaluated almost exclusively for safety reasons. Since the late 1980s, FDA reviewers have been instructed to provide drug sponsors with greater freedom during phase I, as long as the investigations do not expose participants to undue risks. In evaluating phase II and III investigations, however, FDA reviewers also must ensure that these studies are of sufficient scientific quality to be capable of yielding data that can support marketing approval
  • Chemistry reviewers: They address issues related to drug identity, manufacturing control and analysis. The reviewing chemist evaluates the manufacturing and processing procedures for a drug to ensure that the compound is adequately reproducible and stable. At the beginning of the Chemistry and Manufacturing section, the drug sponsor should state whether it believes the chemistry of either the drug substance or the drug product, or the manufacturing of either the drug substance or the drug product, present any signals of potential human risk. If so, these signals should be discussed, with steps proposed to monitor for such risks. In addition, sponsors should describe any chemistry and manufacturing differences between the drug product proposed for clinical use and the drug product used in the animal toxicology trials that formed the basis for the sponsor's conclusion that it was safe to proceed with the proposed clinical study
  • Pharmacology/toxicology review: This team is staffed by pharmacologists and toxicologists who evaluate the results of animal testing and attempt to relate animal drug effects to potential effects in humans. This section of the application should contain, if known:
    • A description of the pharmacologic effects and mechanism(s) of action of the drug in animals
    • Information on the absorption, distribution, metabolism and excretion of the drug. The regulations do not further describe the presentation of these data, in contrast to the more detailed description of how to submit 30toxicology data. A summary report, without individual animal records or individual study results, usually suffices. An integrated summary of the toxicology effects of the drug in animals and in vitro the particular studies needed depend on the nature of the drug and the phase of human investigation. When species specificity, immunogenicity, or other considerations appear to make many or all toxicological models irrelevant, sponsors are encouraged to contact the agency to discuss toxicological testing.
  • Statistical analysis: The purpose of these evaluations is to give the medical officers a better idea of the power of the findings to be extrapolated to the larger patient population in the country
  • Safety review: Following review of an initial IND application submission, CDER (Center for Drug Evaluation and Research) has 30-calendar-days in which to decide if a clinical hold is necessary (i.e. if patients would be at an unacceptable risk or if CDER doesn't have the data to make such a determination).
Generally, drug review divisions do not contact the sponsor if no concerns arise with drug safety and the proposed clinical trials. If the sponsor hears nothing from CDER, then on day 31 after submission of the IND application, the study may proceed as submitted. The sponsor is notified about the deficiencies through a clinical hold. A clinical hold is issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend a clinical investigation (Flow chart 1.1).
 
Sponsor Notification
Once a clinical hold is placed on a commercial IND application, the sponsor will be notified immediately by telephone by the division director. For both individual and commercial IND applications, the division is required to send a letter within five working days following the telephone call. The letter should describe the reasons for the clinical hold and must bear the signature of the division director (or acting division director).
The grounds for imposition of clinical hold are as follows:
  • Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury
  • Clinical Investigators named in IND application are not qualified
  • Investigator Brochure is misleading, erroneous or materially incomplete
  • IND does not contain sufficient information to assess risks
  • Protocol is deficient to meet objective of trial
  • Mechanism that CDER uses when it does not believe, or cannot confirm that the study can be conducted
  • CDER will contact sponsor within 30-day initial review period.
31
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Flow chart 1.1: IND application review process
* While sponsor answers any deficiencies
The sponsor may then respond to CDER by sending an “IND CLINICAL HOLD RESPONSE” letter to the division. To expedite processing, the letter must be clearly identified as an “IND CLINICAL HOLD RESPONSE” letter.
The division then reviews the sponsor's response and decides within 30 days as to whether the hold should be lifted. If the division does not reply to the clinical hold response within 30 calendar days, the division director will telephone the sponsor and discuss what is being done to facilitate completion of the review. 32
If it is decided that the hold will not be lifted, the hold decision is automatically sent to the office director for review. The office director must decide within 14 calendar days whether or not to sustain the division's decision to maintain the clinical hold. If the decision is made to lift the hold, the division telephones the sponsor, informs them of the decision and sends a letter confirming that the hold has been lifted. The letter will be sent within 5 working days of the telephone call. However, the trial may begin once the decision has been relayed to the sponsor by telephone.
 
Sponsor will be Notified
If other deficiencies are found in an IND application that the review division determines are not serious enough to justify delaying clinical studies, the division may either telephone or forward a deficiency letter to the sponsor. In either case, the division informs the sponsor that it may proceed with the planned clinical trials, but that additional information is necessary to complete or correct the IND application file.
 
Study Ongoing
Once the CDER's 30-day initial review period expires, clinical studies can be initiated, unless a clinical hold has been placed. Beyond the 30-day review period for an IND application, subsequent clinical trials may begin immediately upon submission of the clinical protocol to the IND application (i.e. there is no 30-day waiting period for subsequent clinical trials after the submission of the first clinical trial protocol). If the sponsor was notified of deficiencies that were not serious enough to warrant a clinical hold, the sponsor addresses these deficiencies while the study proceeds.
 
Exploratory IND Studies
Exploratory IND studies are intended to provide clinical information for a new drug candidate at a much earlier phase of drug development. These studies help to identify the best candidates for continued development and eliminate those lacking promise. These clinical trials occur very early in phase I, involve very limited human exposure and have no therapeutic intent. Exploratory IND studies are conducted prior to the traditional dose escalation, safety and tolerance studies and provide important information on pharmacokinetics (PK) and bioavailability of a candidate drug.
In April 2005, the FDA released a draft guidance for exploratory IND studies that clarifies preclinical and clinical approaches that should be considered when planning exploratory IND studies in humans. As part of FDA's “Critical Path Initiative”, this process is a new tool available to the industry that enables a faster, more cost-effective path to early clinical development. 33
 
Microdosing (Phase 0 Clinical Trials)
A primary application of an Exploratory IND study is microdosing or phase 0 clinical trials. Microdosing studies permit collection of human pharmacokinetic (PK) and bioavailability data earlier in the drug development process. This human data is combined with preclinical data to select the best candidates to advance to further, more expensive and extensive clinical development. Distinctive features of phase 0 trials include the administration of single sub-therapeutic doses of the study drug to a small number of subjects (10–15) to gather preliminary data on the agent's pharmacokinetics parameters such as clearance, volume of distribution, t1/2 (half-life), etc.
A microdose is defined as less than 1/100th of the dose calculated to yield a pharmacological effect of a test substance and a maximum dose of ≤100 micrograms. Since microdosing studies are designed not to induce pharmacological effects, the potential risk to human subjects is very limited. Therefore, these studies can be initiated with less preclinical safety data (i.e. with single dose study/acute toxicity study), help reduce the number of human subjects needed and require fewer resources for selecting promising drugs candidates for further development.
Microdosing is dependent on the availability of ultrasensitive analytical methods able to measure drug and metabolite concentrations in the low pictogram to femtogram range. Nuclear physics has been applied to conduct analyses at these concentrations, viz. Accelerator Mass Spectrometry (AMS) and Positron Emission Tomography (PET). Both techniques rely on the analysis of radioisotopes incorporated into the drugs under study. In the case of AMS, [14C] is the most useful isotope for drug metabolism studies whereas for PET [11C] is proving to be the most useful isotope.
A typical human microdosing study involves the administration of microgram quantities of drug candidates, lightly-labelled with Carbon-14 (14C), to healthy volunteers. Following collection of blood, urine and feces from each subject, samples are analyzed for 14C content using AMS to determine Cmax, AUC and the terminal half-life of each compound (Fig. 1.10).
If, during the drug discovery process, a number of molecules are identified which have good pharmacological activity but similar or differing animal PK (pharmacokinetic), comparative human microdose studies can be conducted to establish human PK. Armed with this information, the human PK data can then be used to:
  • Assist in the candidate selection process
  • Determine the first dose for the subsequent phase I study on the selected candidate
  • Establish the likely pharmacological dose.
 
Advantages of Microdosing
  • Select the best lead compound supported by clinical data
  • Save time: Advance lead candidates to clinical development in months not years34
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    Fig. 1.10: Microdosing/phase 0 studies
  • Save money: Significantly reduced IND submission requirements and costs
  • Cost-effective approach to adding value to lead candidate or drug pipeline.
In conclusion, Microdosing is a technique for studying the behavior of compounds in vivo through the administration of doses so low they are unlikely to produce whole-body effects, but high enough to allow the cellular response to be studied. This works on the concept that the best model for man is man. This allows studying the pharmacokinetics of the drug with almost no risk of side effects.
Use of the technique has been provisionally endorsed by both the European Medicines Agency and the Food and Drug Administration. It is expected that by 2010, human microdosing will gain a secure foothold at the discovery-preclinical interface driven by early measurement of candidate drug behavior in humans and by irrefutable economic arguments.
 
CLINICAL DEVELOPMENT
Clinical trial/study is any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s) and/or to identify any adverse reactions to an investigational product(s) and/or to study absorption, distribution, metabolism and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. 35
Clinical trials start after the completion of required preclinical studies and IND application has been filed to the concerned regulatory authority.
The objectives of clinical trials are:
  • To identify the relationship between dose and plasma(or other) concentration—Pharmacokinetics
  • To define the shape and location of the dose/concentration/response curves for both desired and undesired effects—preliminary assessments of benefit/risk
  • On the basis of these curves, to identify the range of dosage/concentrations producing maximum benefit with fewest undesirable effects.
 
Key Players in Clinical Research
Clinical research is an integral part of drug development. Unlike in the past, today the process has gained a unique position due to the regulatory requirements and ethical guidelines available globally. Thus designing, conducting, monitoring, appropriate quality assurance and data management determine the success of the clinical research.
Listed below are the players in clinical research who are responsible for these activities:
  • Sponsor/clinical research organization
  • Medical writing team
  • Statistician
  • Clinical research associate
  • Principal investigator
  • Clinical research coordinator
  • Data management team
  • Ethics committee
  • Regulatory authority
  • Data safety monitoring board
  • Central laboratory.
 
Internal Key Players
  • Sponsor: An individual, organization or company, that is responsible for the initiation, management and/or financing of a clinical investigation.
    The sponsor is responsible for the development of the trial protocol and other study documents; selection of qualified investigators, sites and monitors; allocation of duties and responsibilities; study management, data handling and record keeping; supply, storage and handling of pharmaceutical product. It is also the sponsor's responsibility to provide all information needed to conduct investigation, ensure compliance with regulations, inform regulatory authority regarding adverse events and safety reporting, perform data analysis, report findings and submit the IND to the regulatory authority.
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  • Contract research organization (CRO): An organization which is contracted by a sponsor to perform any or all of the activities normally done by the sponsor. The sponsor is required to describe in writing exact responsibilities and obligations transferring to CRO.
  • Medical writing team: This team is involved in preparing various documents related to clinical trial, viz. protocol, investigator's brochure, clinical study report.
  • Statistician: The statistician is responsible for activities such as determination of sample size, study design, randomization and analysis of data.
  • Clinical research associate (CRA): CRA is an individual who works for the sponsor or a CRO. The CRA is responsible for the overall monitoring of the clinical trial at the trial site. The responsibilities of a CRA include evaluation of a site and initiation of the trial; he/she should ensure that regulatory requirements are met and that site personnel are qualified, trained and aware of their obligations. The CRA should monitor data and verify source records or in other words the CRA should oversee the progress of the study at site level.
  • Principal investigator (PI): According to the FDA, principal investigators should be “qualified by training and experience to be appropriate to serve as PI for a trial”. The PI is the individual who conducts, supervises and is responsible for all aspects of a clinical trial. It is the responsibility of the investigator to ensure that regulatory, GCP compliance is maintained during trial conduct. PIs are also involved in the formulation of a recruitment plan, evaluation and treatment of research subjects. The PI should supervise the medical staff participating in the study and perform timely review of all clinical and laboratory data. One of the most important responsibilities of PIs is to ensure proper reporting of all adverse events that takes place.
  • Clinical research coordinator (CRC): The CRC is a vital link between the all players and the trial site. CRC is placed at the clinical trial site and works directly under trial investigator. The CRC is responsible for coordinating all aspects of the clinical trial and day-to-day operations of the research program.
    The CRC should perform a protocol assessment and maintain adherence to the protocol and document breaches or violations and communicate the same with sponsor and the ethics committee. The CRC should help develop and maintain the study source documents at the trial site. He/she should also document all written and phone correspondence with sponsor, labs, IRB, other regulatory organizations.
  • Data management team: The data management team is responsible in the management of trial related data obtained from investigative site. Data management related activities include inputs during CRF (case report form) designing, data acquisition, validation, coding, integration and quality assurance.
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External Key Players
For a new drug/device/biologics to be tested in humans, approval from Ethics committee and regulatory authority is required.
Ethics committee—Institutional Review Board (IRB) or Independent Ethics Committee (IEC): IRB/IEC is a specially constituted board established to protect rights, safety and well-being of human subjects by providing review and oversight. The ethics committee may be a part of an institution or an independent board. The ethics committee should obtain and review trial documents such as the trial protocol, informed consent document, investigator's brochure, etc.
Regulatory authority/Licensing authority: The regulatory authority of each country is responsible for review and approval of drug applications (IND/NDA), dissemination of safety information and conducting audits or inspections of any sector of clinical research including sites, sponsors, or IRBs.
Table 1.2 shows regulatory authorities responsible for approving drug applications of a few countries.
Data Safety Monitoring Boards (DSMB): An independent committee, composed of community representatives and clinical research experts, which reviews data while a clinical trial is in progress to ensure that participants are not exposed to undue risk. DSMBs are needed when interim analyses of safety and efficacy are considered essential to ensure the safety of trial participants. A DSMB may recommend that a trial be stopped if there are safety concerns or if the trial objectives have been achieved.
 
External Key Players—Others
Central laboratory: Instead of using small, localized laboratory facilities or multiple specialty laboratories for multicentric trials, a central laboratory is used to avoid data errors, lengthened study timelines and increased study costs.
Table 1.2   Regulatory authorities
Countries
Regulatory authorities
India
DCGI (Drug Controller General of India)
USA
FDA (Food and Drug Administration)
European Union
EMEA (European Medicines Agency)
United Kingdom
MHRA (Medicines and Healthcare products Regulatory Agency)
Australia
TGA (Therapeutic Goods Administration)
Canada
Health Canada
Japan
MHLW (Ministry of Health, Labor and Welfare)
China
Ministry of Health of the People's Republic of China
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The concept of a central laboratory is based on the need for homogenous data integration to improve submission quality and reduce the timelines for data submissions. Central laboratories accomplish this by combining the use of high throughput technology with efficient internal systems that make for quick and more combinable collection of lab data.
 
Clinical Trial Design
Clinical trial may fail to achieve its aim without a good design. Before a clinical trial may proceed, it will undergo numerous reviews that will include a review of the trial design and applicability of the design to the situation. A good trial design will ensure that the trial is given approval to proceed from regulatory agencies, from ethics committees and from the investigator. A good design will ensure that the trial set-up is achievable, that the investigator will recruit subjects and that the trial will be completed—all within the target timescale. The design of any given clinical trial will depend on many factors. The fundamental factor contributing to the design is the disease for which is drug is to be tested (Target indication). The target indication will influence the objectives of the trial, the options for clinical measurement and the circumstances under which the trial should be carried out.
 
Elements to be Considered During Clinical Trial Design
Types of control: The purpose of the control group is to provide a yardstick against which to measure the efficacy and safety of the drug under investigation and the control may be an untreated group or a group receiving an active treatment or a placebo.
The choice of the comparator is influenced by objective of the study. In cases where efficacy has not yet established (phase I and phase II) it may be that a placebo is the most appropriate comparator. Assuming that the compound has been shown to possess efficacy, the objectives of later studies (phase III onwards) will be to compare the extent of efficacy and safety with that of currently used therapies.
Volunteer/subjects selection: It is important to carefully define the patient population from which the study participants will be drawn. In early phase II, the entry criteria for a study may be restrictive and throughout the development program these criteria will evolve as the drug's characteristics are discovered. For example, phase I trials will have healthy volunteers probably with a restricted age range, usually between 18 and 45 years. By the end of phase III the studies should include a population that is representative of the wider patient population who will potentially receive the licensed drug.
Number of subjects: The size of a trial is influenced by the disease to be investigated, the objective of the study and the study endpoints.
Statistical assessments of sample size should be based on:
  • The expected magnitude of the treatment effect
  • The variability of the data
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  • The specified (small) probability of error
  • The desire for information or subsets of the population or secondary endpoints.
Influence of disease indication on trial design: The onset and progression of the disease will affect the duration of the trial, the timing of each subject's treatment and the number and timing of assessments.
Acute conditions will require short treatment period and as these types of disease remit spontaneously within certain time, subjects should be entered into the study within one day of onset and assessment to be carried out more frequently to detect early signs of efficacy.
In chronic diseases, signs and symptoms of the disease will be stable for longer periods dictating study of six months or more duration, with monthly assessments carried out for efficacy.
Randomization: Randomization is a process that assigns research participants by chance, rather than by choice, to either the investigational group or the control group. In conducting a controlled trial, randomized allocation is the preferred means of assuring comparability of test groups and minimizing the possibility of selection bias. Randomization is done using a computer generated random number table (Fig. 1.11).
Randomization can be simple randomization or stratified randomization. Stratified randomization (stratification) is used when there are differences in the nature of the disease in severity or site and responses to treatment might differ due to this. For example, in analgesic trial, subjects can be stratified according to pain severity into mild, moderate and severe, where the response might differ. Each stratum can be analyzed separately, if required.
 
Blinding
Blinding is an important means of reducing the risk of biased study outcomes. A trial where the treatment assignment is not known by the study participant is known as single blind study.
zoom view
Fig. 1.11: Depicts randomization procedure
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Fig. 1.12: Depicts double-blind study
When both investigator and study participants are unaware of the treatment assignments, the study is double blind. When investigator, study participants and the sponsor staff are unaware of the treatment assignment, study is referred to as triple blind. Studies that do not utilize blinding are referred to as open label studies. Thus, all those concerned with trial are aware of the identity of the investigational medicinal product (Fig. 1.12).
It is essential to maintain blinding throughout the trial to maintain the validity of the trial data. During each monitoring visit, the monitor will verify the maintenance of blind. However, there may be a need for the investigator to know the identity of drugs administered, e.g. during emergency due to adverse event. In such a case, contingency should be provided to know the treatment by unblinding for that specific subject. Another example of requirement of contingency is, in the event of failure of effect (e.g. increased pain); in such a case rescue medication should be specified that is known not to interact with either of the blinded treatments, to avoid breaking the blind.
Types of trial design: An appropriate study design should be chosen to provide the desired information in a research study. Examples of study design include parallel group, crossover, factorial and dose escalation.
The most frequently used designs are: Parallel study and cross-over study.
In a parallel study, each subject is assigned to receive one or other treatment and subjects are studied ‘in parallel’. In a crossover study each subject will receive a course of each of the treatments under study (Figs 1.13 and 1.14).
The choice of one of these two designs over the other demands careful consideration. Crossover design may be helpful in identifying which treatment is best for a particular patient as each subject acts as his/her own control. However, results from this may not be extrapolated to general population. The choice of comparator for a crossover study must be made carefully to prevent drug interaction and sufficient washout period should be given between two treatment periods so as to avoid carry-over effect of previous treatment.
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Fig. 1.13: Depicts parallel study
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Fig. 1.14: Depicts Crossover study
The crossover design will clearly necessitate more subject visits, thus probability of subject dropping out or even not entering into trial increases. The crossover design is appropriate for less prevalent disease, as number of subjects required in crossover design is relatively less and for relatively stable disease, e.g. hypertension.
Factorial: When patients are being treated with a combination of drugs, as is current practice for HIV infection, a new drug may be evaluated by testing it in combination with other drugs rather than by itself. A factorial design trial may be used for this purpose. A simple factorial design would have one group testing therapy A, another testing therapy B, a third group testing A and B combined and a control group testing neither A nor B. Factorial designs are considered an efficient way to test medicines in combination.
Dose escalation: Also referred to as dose ranging design. The main goal of a dose escalation study is to estimate the response vs. dose given, so as to analyze the efficacy and safety of a drug. Thus, in a dose escalation study, different doses of a drug are tested against each other to establish which dose works best or is least harmful. Dose ranging design is usually chosen for a phase I or early phase II clinical trial. Typically, a dose ranging study, 42will include a placebo group of subjects and a few groups that receive different doses of the test drug. Information on the maximum tolerated dose is required to design the groups in a dose escalation study. Therefore, this type of study is usually designed after the availability of maximum tolerated dose information.
Duration of dosing: Duration of dosing is determined by factors like pharmacokinetics, mode of action and natural history of the disease being treated. In early phase II clinical trial, available toxicology data may support only a limited duration of dosing. A drug development program will include substantial chronic animal toxicology studies running in parallel with the clinical phases and results from these studies may extend the permissible duration of dosing as they become available.
Methods of clinical measurement: The assessment method must be standardized so that results from all subjects can be pooled from all centers and therefore the protocol should describe in depth method of assessments and at what time interval these assessments should be made, to obtain uniformity between centers.
The method chosen must be validated for accuracy and reproducibility. For a quantitative measurement such as blood pressure, the use of standardized equipment, e.g. the sphygmomanometer, is clearly most appropriate. For an assessment of subjective parameter, validated rating scale should be used, e.g. Hamilton Depression Rating Scale for depression.
The timing and circumstances of the assessment should be standardized. Even the quantitative measurement such as blood pressure will be influenced unless a standard procedure is specified. For example, the subject should be sitting for 10 minutes before two blood pressure readings and the mean will be used for analysis. Additionally, the time of day for the measurement may be standardized to avoid diurnal variation.
In summary, elements such as comparator, disease under study, patient population, randomization and blinding, duration of dosing and methods of clinical measurement should be considered while designing clinical study.
 
Essential Documents
Essential documents are those documents that individually and collectively evaluate the conduct of a trial and the quality of the data produced. These documents demonstrate the compliance of the investigator and sponsor with the standards of Good Clinical Practice (GCP) and all applicable regulatory requirements.
The GCP guidelines lists essential documents required for a clinical trial. The documents are grouped in three sections according to the stage of the trial:
  1. Before the clinical phase of the trial commences
  2. During the clinical conduct of the trial
  3. After completion or termination of the trial.
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Before the Clinical Phase of the Trial Commences
  • Signed and dated protocol: A document that describes the objective(s), design, methodology, statistical considerations and organization of a clinical trial
  • Protocol amendments: The changes in terms of updates or clarifications made in the protocol
  • Sample patient information sheet and informed consent form: This document provides the subjects with necessary details to participate in the study and their willingness is recorded by means of signing the document
  • Investigator's Brochure: The IB contains both clinical and nonclinical data pertaining to the description of new drug
  • Sample CRF: Case report form is the tool (a paper or electronic questionnaire) used by the sponsor of the clinical trial to collect data from each participating trial site
  • Advertisement for subject recruitment (if used): The advertisement is the proposed method of subject recruitment for the trial. It contains a brief description of the study
  • Financial agreement (where required): An agreement between the parties who are involved in conducting the clinical trial
  • Insurance/letter of indemnity (where required): Insurance or a letter guaranteeing that contractual provisions will be met, otherwise financial reparations will be made
  • Research agreement (where required): Agreement for the research/study to be conducted between the key players who are involved in the trial
  • Communication with sponsor/IRB: The communication between IRB (Institutional Review Board) and the sponsor should be done before commencing the trial
  • IRB approval: The IRB or the Ethics Committee is the independent body who approves the trial documents (protocol, CRF, ICF, etc.)
  • IRB composition (if not specified in IRB letter of approval): Documents containing the information of the details of the ethics committee quorum, name and designations of the ethics committee members
  • Investigators’ CVs—signed personally and dated: The monitor should collect the Curriculum Vitae of the investigator(s) involved in conducting the trial and present to the regulatory body concerned with the trial
  • Signature sheet and authorization sheet: This document contains the names and signatures of those who are authorized to make changes to the trial documents
  • Reference range of local labs and updates when applicable: This document will contain the reference (normal) range for various tests which are specific for the instruments available at each lab
  • Certification/accreditation of local lab: Accreditation/Certification is a process in which the competency, authority or credibility of a laboratory is presented. The accreditation must be a current one. The accreditation 44of testing laboratories and certification specialists are permitted to issue official certificates of compliance with established standards, such as physical, chemical, forensic, quality and security standards
  • Study procedures (Site SOPs): They provide a written set of instructions documenting (normally in a step by step manner) how a procedure should be performed
  • Shipping records for investigational product (IP): A record or a log is maintained for the shipping/distribution of the IP at various sites where the trial is conducted
  • Sample of IP label
  • Sealed envelope of treatment code: The treatment code is kept in a sealed envelop and should be duly checked by trial monitor for any tampering with the seal that might occur leading to unfair conduct of the trial. This envelope can be opened in case of an emergency
  • Emergency unblinding procedures (if not already described in protocol): Emergency unblinding/decoding procedure is carried out by the investigator referring the “Treatment decoding log” depending on the occurrence of the serious adverse events during a trial
  • Treatment decoding log (emergency unblinding): A record, “Treatment decoding log”, for the decoding of the code assigned to the subjects in a trial is always kept ready for emergency situation which may arise during a trial
  • Study initiation report: The study initiation report should be prepared by the monitor after the initiation of a study at a site.
 
During the Clinical Conduct of the Trial
In addition to all documents listed above, the following documents are also required during the conduct of the trial:
  • Previously-mentioned document: All previously-mentioned document updates checked before the clinical phase of the trial commences
  • Monitoring visit report: A written report from the monitor to the sponsor after each site visit. It contains all trial related communications according to the sponsor's SOP
  • Signed and dated informed consent forms: The informed consent obtained in a form from the subjects should be duly signed and dated by the investigator as well as the patient
  • Source documents: Original documents, data and records (e.g. hospital records, laboratory notes, subjects’ diaries, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, photographic negatives, magnetic media, X-rays and records kept at the pharmacy, laboratories and at medico-technical departments, etc. which are involved in the clinical trial)
  • Signed, dated and completed CRF copy: The copy of a signed, dated and completely filled case report form (CRF) is also required during the conduct of the trial
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  • Documentation of CRF correction: A documentation of the corrected CRF is required to be maintained if the CRF has undergone correction
  • AE and SAE report: A report containing all the adverse events and serious adverse events prepared by the investigator should be maintained and presented to the sponsor and the ethics committee/IRB (Investigational Review Board)
  • Sponsor's safety update: It is a document which provides regular and timely review, appraisal of safety information. Communication of this information is critical to risk management during clinical development of drugs
  • Interim/progress report to IRB/IEC: It is the progress report of the intermediate results and the evaluation based on analysis performed during the course of a trial
  • Subject screening log/screen failure log: It will contain all the details of the subjects who have been screened. This log will also contain information regarding the subjects who did not meet the eligibility criteria (Screen Failure Log)
  • Patient identification list: A unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial related data
  • Subject enrolment log: This record is maintained to document the identification of the subject who has been enrolled in the trial
  • IP accountability log: The investigational product usage/accountability should be recorded and maintained properly at the site of the trial conduction
  • Record of retained body fluids/tissue sample: To document location and identification of retained samples if tests need to be repeated.
 
Completion or Termination of the Trial
In addition to all documents listed above, the following documents are also required during the conduct of the trial:
  • Audit certificate (if available): A declaration of confirmation by the auditor that an audit has taken place
  • Documentation of IP destruction: The accountability of the investigational product (IP) usage is recorded and the left out IP is either returned to the sponsor or destroyed at the site and the process is recorded or documented
  • Study close-out report: The study close-out report is prepared by the study monitor after the completion of the trial
  • Final report by investigators to IRB: The investigator prepares the final report to be given to the concerned regulatory body (IRB) involved the trial informing the closing of the trial
  • Clinical study report: A written description of a trial/study of any therapeutic, prophylactic or diagnostic agent conducted in human 46subjects, in which the clinical and statistical description, presentations and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).
 
Phases of Clinical Trials
  • Phase I: Human pharmacology
  • Phase II: Therapeutic exploration
  • Phase III: Therapeutic confirmation
  • Phase IV: Postmarketing studies.
 
 
Phase I Clinical Trial
Phase I trials are the first stage of testing in human subjects. phase I studies are also known as Human Pharmacology studies. Normally, a small (20–80) group of healthy volunteers will be selected to participate in these studies. This phase includes trials designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a drug. Volunteers are paid an inconvenience fee for their time spent in the volunteer center.
 
Objectives of phase I studies
  • Safety and tolerability—maximum tolerated dose (the highest dose of a drug that does not cause overt toxicity in humans)
  • Pharmacokinetics
  • Pharmacodynamics.
 
Prerequisites for phase I trials
  • Preclinical safety data: Animal toxicity which needs to be completed before start of phase I studies are—single dose toxicity studies, repeated dose, safety pharmacology studies, local tolerance studies, pharmacokinetic studies, mutagenicity studies (in vitro), male reproductive system studies
  • Regulatory authority and ethics committee approval: Ethics committee approval is essential since healthy volunteers are included as subjects in this phase.
 
Conduct of the trial
  • Site: These trials are often conducted in a specialized inpatient setting called as clinical pharmacological unit/clinical trial unit, where the subject can be observed by full-time staff. The study site should be equipped to monitor all physiological functions, facilities to handle an emergency or a serious unexpected adverse event, facilities for processing blood/plasma, etc. and facilities for estimation of drug levels in biological fluids (Fig. 1.15).
 
Players
  • Investigator: usually conducted by clinical pharmacologist. The medical staff, paramedical staff should be qualified, skilled to handle emergencies; should be trained in basic life support and also advanced life support
  • Subjects: Generally healthy volunteer, sometimes patients can be included.
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Fig. 1.15: Depicts an ideal site for conducting phase I studies
WHO defines healthy subject as ‘a person who is free from any abnormality that would complicate interpretation of data or increase the sensitivity of the subject to toxic potential of a drug.’ A summary of the main points raised in favor of healthy volunteers is as follows:
  1. Scientific benefits: In healthy volunteers there are no hurdles such as the unknown parameters of disease condition and concomitant medication.
  2. Practical benefits: In healthy volunteers, physiological processes are well understood and years of experience in terms of phase I trials has established a strong infrastructure focused on facilities and healthy volunteer databases.
  3. Regulatory benefits: In terms of regulatory benefits, guidance is well established and dialogue with regulators is simpler.
Healthy volunteer studies are well understood and can act as a reference point to gain an understanding of a test compound.
There are a number of advantages for using healthy volunteers in early phase clinical trials and such studies can often provide excellent data, more quickly and at a lower cost. Healthy volunteers are more accessible, do not have diseases or take medication that needs to be considered and can remain eligible for similar studies in the future. In patient groups, the disease may not be stable over time, there is a spectrum of disease ranging from mild to severe, they are a less accessible group and most patients would prefer to obtain therapeutic benefit which is not normally anticipated in phase I studies. It can also take months to recruit sufficient patients with specific indications. In healthy volunteers, physiological processes are well understood. Healthy volunteers also show an increased acceptance of 48frequent or complex sampling as well as stricter controls such as diet and activities and there is a lower drop-out rate as compared to patient groups. Although, not a normal practice, individuals with mild but stable illness, such as hypertension or arthritis, could be considered for phase I studies considering USFDA definition of “normal subject”. FDA has defined normal subjects as those “individuals who are free from abnormalities which could complicate the interpretation of the data from the experiment or which might increase the sensitivity of the subject to the toxic potential of the drug”. Thus, according to FDA definition, subject/volunteers with mild stable illness are considered healthy if they do not have disease for which drug is being tested and the existing does not complicate with interpretation of data.
For certain disease conditions such as HIV or cancer, real patients who have end-stage disease and lack other treatment options can be included in phase I trials. Also for oncology or HIV trials, inclusion of healthy volunteers is ethically not acceptable, as these drugs are known to have toxic effects.
 
Design of phase I studies
  • Type of control: Phase I studies generally have placebo as control. Placebo as control is needed to determine variation in adverse event, laboratory value whether due to investigational agent or other influencing factor like—subject psychology (many subjects feel, since they are taking medication they should show some adverse effect), environment (light, temperature, diet, caffeine) and to evaluate common placebo symptoms like headache, dry throat, lethargy, etc.
  • Subject selection: The healthy subjects are generally recruited based on the following—
Inclusion criteria:
  • Healthy subjects
  • No clinically important abnormal physical findings.
  • Normal clinically acceptable ECG, normal BP/heart rate.
  • Body Mass Index—19 to 29 kg/m2
  • Able to communicate
  • Competent and willing to give informed consent.
Exclusion Criteria:
  • The subjects who have taken investigational drug in 0 to 45 days from the start of study
  • The subjects who have taken any prescribed medicine for 0 to 30 days/any over-the-counter drugs (0–5 days) from the start of study
  • The subjects who have donated or lost blood, 0 to 12 weeks from the start of study
  • Subjects who are unable to communicate
  • Subjects who are chronic alcoholics and smokers
  • Female subjects especially if pregnant or at risk of pregnancy or lactating
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  • Subjects suffering from asthma, neurological, neuromuscular, renal, cardiac, hepatic or psychiatric diseases
  • Subjects who are hypersensitive to drugs
  • Randomization and blinding: The allocation of subjects to either group is determined by a formal randomization procedure. The level of blinding could be either open labeled, single blinded or double blinded
  • Type of trial design: Either the parallel or crossover design is used in phase I studies. However, crossover designs are less commonly used, due to carryover effect and need for washout period
  • Dosing: The first dose to be administered in humans needs to be estimated to safeguard the safety of the volunteers. All available information has to be taken into consideration for the dose selection and this has to be made on a case-by-case basis.
Estimation of the first dose in humans: The starting dose will be determined on the basis of data from animals (two species), in particular, NOAEL (No observed adverse effect level) is the highest dose level of drug which does not produce a significant increase in adverse effects). It is determined in nonclinical safety studies performed in the most sensitive and relevant animal species, adjusted with allometric factors (various conversion steps to calculate first human dose, given by FDA) or on the basis of pharmacokinetics which gives the most important information. The relevant dose is then reduced/ adjusted by appropriate safety factors according to the particular aspects of the molecule and the design of the clinical trials.
For high-risk medicinal products, an additional approach to dose calculation should be taken. The use of ‘minimal anticipated biological effect level’ (MABEL) approach is recommended. The MABEL is the anticipated dose level leading to a minimal biological effect level in humans. Safety factors are usually applied for the calculation of the first dose in man from MABEL.
The calculation of MABEL should utilize all relevant in vitro and in vivo available information from pharmacodynamic/pharmacokinetic data such as:
  • Receptor binding and receptor occupancy studies in vitro in target cells from human and the relevant animal(s) species and in vivo in the relevant animal species
  • Concentration-response curves in vitro in target cells from human and the relevant animal(s) species and dose response in vivo in the relevant animal species
  • Exposures at pharmacological doses in the relevant species
  • When the methods of calculation (e.g. NOAEL, MABEL) give different estimations of the first dose in man, the lowest dose should be used.
Dose escalation scheme: Phase I trials include dose-ranging, also called dose escalation studies so that the appropriate dose for therapeutic use can be found. The tested range of doses will usually be a fraction of the dose that causes harm in animal testing. 50
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Fig. 1.16: Single ascending dose (SAD)
The dose ranging studies in phase I studies include—Single ascending dose and multiple ascending dose ranging studies.
  • Single ascending dose (SAD) studies: Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. The dose that is considered to be safe is about 1 to 2 percent of the maximum tolerated dose in animals (Fig. 1.16).
    Procedure:
    The subjects are screened and selected based on the inclusion/exclusion criteria. The subjects are then hospitalized, their blood and urine samples are analyzed before drug dosing. The samples obtained before dosing are referred to as trough samples. Once the subjects are dosed with the drug, the blood and urine samples are analyzed every four hours from their first dose. ECG is to be monitored for the initial 4 to 6 hours from the first dose administered. Dosing should be done at the same time for each dose increment. The final samples are collected 24 to 48 hours after dosing. The subject's posture should be standardized. The subjects before being discharged would be physically examined, ECGs repeated, blood and urine samples analyzed and asked to report for follow-up after a period of 4 to 7 days from their first dose. If they do not exhibit any adverse side effects and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated and a new group of subjects is then given a higher dose. This is continued until precalculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose)
  • Multiple ascending dose (MAD) studies: Multiple ascending dose studies start after a successful SAD result is obtained. These studies are done for a period of 14 days; however the time period can vary, some drugs can be tested for a period of 5 days or for 4 weeks depending on the indication of use. The interval between doses would be one half-life.
    Procedure:
    The screening and selection of subjects is done based on the inclusion/exclusion criteria and tests conducted are similar to the SAD, but the trough 51sample has to be analyzed before the next dose is to be administered. Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, whilst samples (of blood and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
Pharmacokinetic/Pharmacodynamics: Clinical pharmacokinetics and pharmacodynamics are indispensable source of information for drug development.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions. They are essential to establish therapeutic schedules, to evaluate their relevance or to proceed to dosage adjustments in particular patients. This particularly applies to medicinal products with a narrow therapeutic range and to those for which a close relation between plasma concentrations and therapeutic and/or toxic effects can be demonstrated or expected.
In some instances, pharmacokinetic studies may be impossible or limited, e.g. where their provision raises insuperable difficulties or would create risks for test subjects; in these cases, the use of medicinal product is partly or completely based upon pharmacodynamic and clinical studies.
This consists of two sections:
Pharmacokinetic factors to be studied which deal with:
  • Absorption
  • Distribution
  • Metabolism
  • Elimination, as well as with interactions and adverse reactions.
Methodology and conditions of study which deals with:
  • Choice of administration (route, dosage, dosage intervals)
  • Choice of subject (healthy volunteers, patients with relevant disorders, patients with other interfering conditions)
  • Choice of methodology (sampling and analysis, data processing and statistics).
A precise pharmacokinetic analysis of the entire plasma profile, including absorption, distribution and elimination, should be given since these various steps may be interrelated to a great extent. This applies particularly to special dosage forms for which delayed release of the active substance or a prolonged duration of action is claimed. Failing this, at least data on substance concentration at peak (Cmax), time to reach peak (Tmax) and area under the concentration/time curve (AUC) should be provided.52
The elimination rate for the parent compound (e.g. total body clearance, elimination half-life) should be studied in volunteers with normal elimination mechanisms. The nature of the main routes of elimination and their relative importance in regard to total elimination should be known.
The pharmacokinetic parameters of most drugs are not expected to change when different doses are administered or when the drug is given through different routes of administration or as single or multiple doses. However, for some drugs the pharmacokinetic parameters change. Hence, in such cases it is essential to determine the nonlinear kinetic properties (i.e. properties that change based on the dose of the drug) of drugs.
Pharmacodynamic studies are done to measure drug concentration related to response: dose-response relationship and also to get an idea of dosage and dosage regimen.
The procedure for conducting phase I studies would be:
  • Subject recruitment
  • Informed consent
  • Screening
  • Recording baseline parameters
  • Drug administration
  • Blood sampling
  • Recording post-treatment parameters
  • Analysis of biological samples (blood) for drug levels
  • Data collection, data analysis, statistical analysis and report generation.
Outcome from phase I studies: At the end of phase I studies the sponsor should be ready with:
  • Safe dose range (the range which indicates the amount of drug that may be prescribed safely within the framework of usual medicine practice)
  • Bioavailability data depending on Cmax (the maximum concentration of a drug in the body after dosing), Tmax (the time taken to reach maximum concentration), AUC (area under curve) is a mathematical calculation to evaluate the body's total exposure over time to a given drug. AUCs are used as a guide for dosing schedules and to compare the different drugs’ availability in the body), the half-life, metabolic pathway of the drug, metabolites, the route and rate of excretion (Fig. 1.17)
  • Nature of adverse drug reactions
  • Secondary objectives like drug activity, potential therapeutic benefits.
 
Phase I in India
Schedule Y requirements to conduct phase I in India:
  • Phase I clinical trials are done to determine the maximum tolerated dose in humans; pharmacodynamic effects; adverse reactions, if any, with their nature and intensity; as well as the pharmacokinetic properties of the drug53
    zoom view
    Fig. 1.17: Phase I
  • At least 2 subjects should be used for each dose. These studies may be carried out in one or two centers
  • According to the proposed changes of Schedule Y; apart from Indian companies, foreign companies that share intellectual property rights with an Indian based pharmaceutical company can conduct phase I trials for a new drug.
Advantages and challenges in conducting phase I clinical trial
Advantages:
  • Pharmacokinetic, pharmacodynamic and safety profile of a drug is obtained.
Challenges:
  • Ethical issues arise due to the inclusion of healthy volunteers as study subjects
  • Stringent monitoring of the subjects is required, as it is the first time humans are exposed to the new drug and unexpected drug reactions can occur.
 
Phase II Clinical Trials
Once the initial safety of the study drug has been confirmed in phase I trials, phase II trials are performed to assess how well the drug works (efficacy), as well as to continue phase I safety assessments in a large group (20–300) of patient volunteers. When the development process for a new drug fails, it is usually during phase II trials when the drug candidate does not work as intended, or has toxic effects. If the failure is due to the toxic effects of the drug, the development of the drug is abandoned. On the other hand, if the 54failure is associated with efficacy, the sponsor (R & D department) will perform further research (formulation and basic molecular research) to analyze the unfavorable effects of the drug. The sponsor can reinitiate the trial (from phase I) for the modified drug molecule.
Objectives of phase II clinical studies:
  • To explore the therapeutic efficacy and safety of the new medicinal product
  • Aim at identifying the side effects most commonly associated with the new medicinal product
  • Provide essential risk benefit assessment before more new patients are exposed to the new drug.
Additional objectives are:
  • Evaluation of potential end points
  • Therapeutic regimens
  • Target populations for further studies in phases II and III.
Prerequisites for phase II trials:
  • Preclinical safety data: Animal toxicity which needs to be completed before start of phase II studies along with those completed before phase I are— repeated dose toxicity studies in two species for a period of time equivalent to length of phase II studies, pharmacokinetic studies, mutagenicity studies (in vitro and in vivo)
  • Early phase clinical trial data: Outcome of phase I studies (preliminary safety)—generally well tolerated, no significant adverse events
  • Regulatory authority and ethics committee approval.
Types of phase II trial: Phase II studies are sometimes divided into phase IIA and phase IIB. Early phase II trials use a dosage that has been observed to be safe in phase I trials to investigate the pharmacological effects of the new medicinal product and to establish if this is a therapeutically useful intervention or not and may involve only single doses of the drug. Later phase II trials are conducted in patients to establish a safe dose regimen.
Some trials combine phase I and phase II and test both efficacy and toxicity.
Conduct of the phase II trial and players in phase II:
  • Site: Phase II studies are conducted in specialized hospital units and are closely monitored by trained investigator. There should be standard facilities to handle an emergency or a serious unexpected adverse event at the site. The medical staff, paramedical staff should be qualified, skilled to handle emergencies; should be trained in basic life support and also advanced life support. Phase IIa studies are conducted in single site but phase IIb studies are conducted at more than one center hence they are also known as multicentric studies
  • Subjects: In phase II studies around 50 to 300 participants who are patients will be administered the investigational new drug. Phase II is usually the first time that patients rather than healthy volunteers are exposed to the new drug.
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Trial design: Some phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of patients. Other phase II trials are designed as randomized controlled clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized phase II trials have far fewer patients than randomized phase III trials (as it is the first time patients are exposed to new drug in phase II, inclusion criteria will be narrow/stringent, thus the available patient pool meeting this stringent inclusion criteria will be less).
Phase IIa design components are pilot, single centric, open labeled studies conducted on small number of homogenous group of patients. Phase II A is specifically designed to asses dosing regimens, i.e. how much drug should be given.
‘Pilot studies’ refers to a smaller version of a larger study. Conducting a pilot study does not guarantee success in the main study, but it does increase the likelihood, by providing a range of important functions and valuable insights for other researchers. Thus researchers may start with “qualitative data collection and analysis on a relatively unexplored topic, using the results to design a subsequent quantitative phase of the study”.
Phase IIb studies are pivotal, single or double blind, randomized cross over, multicentric studies conducted on heterogeneous population. Phase II b is specifically designed to study efficacy, i.e. how well the drug works at the prescribed doses.
Pivotal studies are those studies which will result in important decisions being made about the medicine and are crucial to draw an inference on efficacy and safety. The results of pivotal studies are identified by the sponsor for regulatory authority to judge the efficacy and safety of the drug.
Phase II studies are comparative studies, where the comparator could be the placebo or the active comparator called the gold standard. Scientifically, comparison to a placebo is required to assess the efficacy of the new drug but a standard drug should be used as comparator if there are ethical issues (e.g. in case of a severe disease condition patient requires a treatment, as placebo has no effect it is not justified).
Procedure of phase II studies:
  • Pretrial activities are completed to prepare the site to conduct the trial
  • Suitable subjects with the target disease are identified
  • Informed consent process is completed
  • Screening procedures are carried out
  • After confirming the eligibility criteria suitable subjects are enrolled into the trial
  • Randomization procedures are done
  • Subject is given the study drug
  • Subject is recalled as per the protocol visit schedule to do the protocol required lab tests
  • Data obtained is sent to sponsor entered in Case Report Form
  • Data collected are analyzed
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  • Depending on the data obtained the sponsor decides whether it is worthwhile to proceed further.
A precise pharmacokinetic analysis of the entire plasma profile, including absorption, distribution and elimination would be evaluated. If the results of the phase II trials show that a new treatment may be as good as the existing treatment or better, it then moves on to phase III.
Outcome of Phase II trial:
  • Safe dosage schedule: It can be determined based on the safety (phase I) and efficacy (phase II) results obtained
  • Characterization of dose-response curve: The graphical representation of the responses to the test drug at different dose levels is obtained
  • Clinical benefit (Placebo/Active control): Efficacy of drug is obtained and an initial comparison of the efficacy of test drug with standard marketed drug is obtained
  • Pharmacokinetic characteristics of the drug in patients
  • Nature of adverse drug reaction: Phase II trials subjects have the disease condition that is being treated by the test drug. Therefore in this phase the possible adverse drug reactions that can be experienced by patients are identified (Fig. 1.18).
 
Phase II in India
Schedule Y requirements to conduct phase II in India:
  • Phase II clinical trials are done to determine possible therapeutic use, effective dose range and to further evaluate safety and pharmacokinetics
  • Normally, 10 to 12 patients should be studied at each dose level. These studies are usually limited to 3 to 4 centers.
  • If the application is for the conduct of clinical trials as a part of multi-national clinical development of the drug, the number of sites and patients as well as the justification for undertaking such trials in India should be provided to licensing authority along with the application.
Advantages and challenges in conducting phase II clinical trial:
Advantages:
  • Efficacy of test drug is determined. Only if a positive result is obtained in this phase, the dosing schedule for phase III is designed.
Challenges:
  • If positive results are not obtained during this phase dosage schedule cannot be determined for phase III. Most often, drug failure is seen in this phase.
 
Phase III Clinical Trials: (Therapeutic Confirmatory Trials)
Phase III studies are also known as “Therapeutic confirmatory trials”. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in phase II.
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zoom view
Fig. 1.18: Phase II
They are intended to gather additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase III studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Even at this final stage of drug development, protocol will still exclude many ‘real world’ patients, e.g. those with other serious medical conditions, women of child bearing age unless using accepted contraceptive precaution.58
Phase III studies usually include several hundred to thousand patients. Because of their size and comparatively long duration, phase III trials are the most expensive, time-consuming and difficult trials to design and conduct.
Data obtained from phase III is the major component of New Drug Application. The studies carried out in phase III complete the information needed to support adequate instructions for use of the drug (prescribing information). All features should represent regulatory requirements and proposed clinical use after marketing.
Objective(s) of phase III clinical trial: Primary objective of phase III clinical trial is to confirm the therapeutic benefit(s). They are designed to confirm the preliminary evidence accumulated in phase II that a drug is safe and effective for use in the intended indication and recipient population. In this phase, investigational product is generally compared with standard treatment.
The other objectives of phase III trial are to:
  • Determine the optimum dosage schedule for general use, safety and efficacy of the investigational product in combination with other drug(s)
  • Identification of the disease sub types for which drug is effective
  • Study on special population such as renal and hepatic insufficiency, lactating women, elderly population
  • Special studies like food/liquid interaction, drug-drug interaction
  • Study on patients of different ethnic groups
  • Phase III trials can also have HRQL (health related quality of Life) and pharmacoeconomic studies as secondary objective.
In HRQL studies, effect of investigational product on quality of life of individuals can be assessed. Pharmacoeconomic studies involve comparison of cost and outcome of medical intervention.
Prerequisites for phase III trials:
  • Preclinical safety data: Safety data will be collected throughout the development process. In the early stages reliance is placed upon understanding the class effect where other drugs belonging to the same class already exist. As development process progresses specific safety data collection becomes vital. Animal toxicity which needs to be completed before start of phase III studies along with those completed before phases I and II are chronic toxicity, carcinogenicity, in vivo genotoxicity, segment II reproductive toxicity study(if female of childbearing age to be involved in the study) and supplemental studies
  • Early phase clinical trial data: Outcome of phase I studies (preliminary safety)—generally well tolerated, no significant adverse events; outcome of phase II studies (preliminary efficacy)—dose-response relationship, no significant adverse events
  • Regulatory authority and ethics committee approval: Ethics committee approval may be rate limiting step as approval is required from each of the participating site.
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Types of phase III trials
  • Phase III a—compulsory; regulatory requirement for NDA submission; patient population in large number or in a special category
  • Phase III b—Extended trials of IIIa after NDA submission; done before launch as a marketing need. These are conducted predominantly for marketing purposes and are sometimes intended as the main support for the required cost/value arguments. Typically market leader is used as comparator, to achieve a benefit over and above that of the existing drug, thus enabling the marketing and sales groups to maximize performance after launch. Explores—new patient population, new indications, special drug features.
 
Conduct of the trial and players in phase III
  • Site: Multispeciality hospital with adequate patient attendance and laboratory facilities. Less specialized investigator.
  • Subjects: Patient population of around 250 to 1000 with broader inclusion criteria are included.
Clinical trial design: Common clinical trial design in phase III is “multicentric, randomized, controlled and blinded study”.
  • Types of control: The objective of phase III will be to compare the extent of efficacy and safety with that of currently used therapies. Placebo can be used as comparator in phase III, if there is no standard treatment for the disease or the standard treatment is ineffective.
  • When selecting active/standard comparator, countries where the study is to be carried out, registration status of the potential comparator and dosing regimens of the potential comparator should be considered.
    Control in phase III can also be concurrent control-dose comparison, wherein different dose regimens of same treatment are compared, e.g. comparison of 200 mg and 400 mg of ibuprofen for pain.
  • Patient population: Patient population included should be representative of general patient population. Factors to be considered for inclusion and exclusion criteria are:
    Nature and history of the disease: Inclusion criteria in the protocol should mention clearly patient with which disease and severity of the disease to be included, without which there could be variability in the response to treatment. For example, for an antihypertensive medication trial, inclusion criteria should be expressed in terms of diastolic blood pressure between X mm Hg and Y mm Hg.
    Concurrent disease and concomitant medication: Presence of concurrent disease and concomitant medication along with target disease may influence the study drug through metabolic interaction, which might affect the interpretation of results. As the aim of phase III is to evaluate the treatment in a situation approximating real life, inclusion of patient with concurrent disease with/without medication needs to be considered with diligence.
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  • Influence of disease indication on trial design: The duration of the trial, the timing of each subject's treatment and the number and timing of assessments will depend on whether disease is an acute condition or of chronic type.
    Acute conditions will require a short treatment period and as these types of disease remit spontaneously within certain time; subjects should be entered into the study within one day of onset and assessment to be carried out more frequently to detect early signs of efficacy.
    In chronic diseases, signs and symptoms of the disease will be stable for long periods dictating study of six months or more duration, with monthly assessments carried out for efficacy. If patients are already receiving treatment, withdrawal of current therapy must be carefully considered so as not to destabilize the subject without justification. If it, is justified, adequate wash out period must be provided to remove the effect of the previous therapy and to prevent drug-drug interaction.
    When withdrawal of current therapy is not justifiable, subjects who are newly diagnosed with the condition can be included. However, number of subjects available will be considerably less as compared to total population suffering from the disease requiring longer time to recruit the subjects.
    Need to withdraw current treatment can be avoided by designing a trial where test treatment is added to the current treatment (add-on trial). This implies that current therapy is inadequate and that measurable improvement can be gained, either in terms efficacy or safety by new drug.
  • Randomization and blinding: In phase III trial, each center acts as strata and within each center randomization like simple randomization or stratification is used. Stratification is used when there are differences in the nature of the disease in severity or site and responses to treatment might differ due to this. For example, in an analgesic trial, subjects can be stratified according to pain severity into mild, moderate and severe, where the response might differ. Each stratum can be analyzed separately if required.
    Double-blind is the preferable design in phase III trial. However, single blinding or open-label design can be used if it is appropriate.
Types of trial design: Either parallel, crossover, or factorial design
Duration of dosing: Duration of dosing is determined by factors like pharmacokinetics, mode of action and natural history of the disease being treated. The results from phase II will be the guiding factor in deciding the dosing schedule.
 
Methods of clinical measurement (refer page 42)
A central laboratory should be used in order to prevent variable results that may arise due to differences in lab procedures, for studies which have a laboratory parameter as the main efficacy assessment.61
Procedure of phase III studies:
  • Pretrial activities are completed to prepare the site to conduct the trial
  • Suitable subjects with the target disease are identified
  • Informed consent process is completed
  • Screening procedures are carried out
  • After confirming the eligibility criteria, suitable subjects are enrolled into the trial
  • Subjects are randomly allocated to different groups
  • Subjects are given the study/comparator drug
  • Individual patient in clinical trial is monitored by the investigator which may be equal to or greater than standard of care
  • Subject is recalled as per the protocol visit schedule to do the protocol required lab tests
  • Periodic monitoring from sponsor's personnel (frequency of which depends on the trial duration)
  • Data obtained is sent to sponsor in the form of completed Case Report Form
  • Depending on risk involved in the trial there can be interval protocol monitoring by independent monitoring committee
  • Data collected are analyzed.
If the results of the phase III trials show that a new treatment may be as good as the existing treatment or better, the sponsor can apply for marketing approval.
Outcome from phase III trial:
  • The efficacy of the test drug is confirmed in a more realistic population (Fig. 1.19)
  • The efficacy of test drug in special population (such as children or pregnant women) is obtained
    zoom view
    Fig. 1.19: Phase III
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  • Tolerability and safety: In this phase the preliminary results pertaining to safety, efficacy and dosage schedule obtained during phase I and II are confirmed
  • Advantages/disadvantages over standard treatment are obtained.
 
Phase III in India
Schedule Y requirements to conduct phase III in India:
  • Phase III clinical trials are done to obtain sufficient evidence about the efficacy and safety of the drug in a large number of patients generally in comparison with a standard drug and/or placebo
  • If the drug is a new drug discovered in India and/or not marketed in any other country, data should be generated on at least 500 patients distributed over 10 to 15 centers. In addition, postmarketing surveillance on large number of patients is a must for detecting adverse drug reactions
  • For new drugs approved outside India, phase III studies need to be carried out primarily to generate evidence of efficacy and safety of the drug in Indian patients when used as recommended in the prescribing information. Data should be generated in at least 100 patients over 3 to 4 centers
  • Prior to conduct of phase III studies in Indian subjects, licensing authority may require pharmacokinetic studies to be undertaken to verify that the data generated in Indian population is in conformity with the data already generated abroad
  • If the application is for the conduct of clinical trials as a part of multi-national clinical development of the drug, the number of sites and patients as well as the justification for undertaking such trials in India should be provided to Licensing Authority along with the application.
Advantages and challenges in conducting phase III clinical trial
Advantages
  • Therapeutic confirmation of the investigational product
  • Due to less stringent inclusion and exclusion criteria, recruitment of subject is relatively easy
  • Simultaneous generation of large data
  • Results from phase III trial are generalizable.
Challenges: Phase III trial is conducted at multiple centers with a single protocol. Thus, the protocol needs to be designed accordingly. Following are the challenges faced during conduct of phase III trial:
  • IEC/IRB approval should be obtained for each site/center involved, which might lead to unexpected delay
  • Patient recruitment—requires large and heterogeneous population, leading to longer duration and greater cost
  • Arranging investigators’ meet
  • Training of staff and monitoring the trial
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  • Clinical trial supplies—to be supplied on time to all centers taking into consideration the expiry date and stability data of the new drug
  • Central laboratory—sample supply to laboratory
  • Centralized data management and analysis
  • Different study outcomes—difficult to interpret
  • Drafting of a common final report and publication issues.
Once a drug has proven to be satisfactory, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details and shelf-life. This collection of information makes-up the “regulatory submission” that is provided for review to the appropriate regulatory authorities in different countries so they can then grant the sponsor approval to market the drug.
 
NDA Application
 
New Drug Application (NDA) Review Process
The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the US. The data gathered during animal studies and human clinical trials of an investigational new drug (IND) becomes part of the NDA. Once the sponsor has completed phase IIIa successfully and is ready with the clinical study report the application to market drugs can be filed through an NDA application. Following the completion of all three phases of clinical trials, the company analyses all the data and files an NDA with FDA in the form of a dossier.
The clinical study report is a document containing the description of the trial, this when submitted as part of the NDA must comply with requirements as given in ICH E3 when sponsor has to make the submission to USFDA, EMEA, MHLW. The sponsor has to follow the requirements listed in Appendix II of Schedule Y to submit the clinical study reports to the regulatory authority of India. The NDA must contain all the scientific information, safety and efficacy data collected during the trials. The NDAs typically run 100,000 pages or more. By law, FDA is allowed to take around six months to review an NDA.
The ICH M4 guideline is for the organization of Common technical document (CTD) which refers to the application format—a dossier/research binder for regulatory submission for marketing approval of a drug. CTD helps the sponsor as it provides a common format for the preparation of technical documentation to support a NDA that will be submitted to the regulatory authorities. CTD also reduces time and resources needed to compile the dossier for different regulatory submissions.
CTD has 5 modules which are as follows:
  1. Administrative and prescribing information
  2. Overview and summary of modules 3 to 5
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  3. Quality (pharmaceutical documentation)
  4. Safety (toxicology studies)
  5. Efficacy (clinical studies).
The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:
  • Whether the drug is safe and effective in its proposed use(s) and whether the benefits of the drug outweigh the risks
  • Whether the drugs proposed labeling (package insert) is appropriate and what it should contain
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality and purity.
 
NDA Content and Format Requirements
The documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body and how it is manufactured, processed and packaged. The following resources provide summaries on NDA content, format and classification, plus the NDA review process.
As outlined in Form FDA-356h, Application to Market a New Drug for Human Use or as an Antibiotic Drug for Human Use, NDAs consist of as many as 15 different sections:
  1. Index
  2. Summary
  3. Chemistry, manufacturing and control
  4. Samples, methods validation package and labeling
  5. Nonclinical pharmacology and toxicology
  6. Human pharmacokinetics and bioavailability
  7. Microbiology (for antimicrobial drugs only)
  8. Clinical data
  9. Safety update report (typically submitted 120 days after the NDA's submission)
  10. Statistics
  11. Case report tabulations
  12. Case report forms
  13. Patent information
  14. Patent certification
  15. Other information.
Although the exact requirements are a function of the nature of a specific drug, the NDA must provide all relevant data and information that a sponsor has collected during the product's research and development.
CDER classifies new drug applications with a code that reflects both the type of drug being submitted and its intended uses. The numbers 1 through 7 are used to describe the type of drug:65
  1. New molecular entity
  2. New salt of previously approved drug (not a new molecular entity)
  3. New formulation of previously approved drug (not a new salt OR a new molecular entity)
  4. New vombination of two or more drugs
  5. Already marketed drug product-duplication (i.e. new manufacturer)
  6. New indication (claim) for already marketed drug (includes switch in marketing status from prescription to OTC)
  7. Already marketed drug product—no previously approved NDA
The following letter codes describe the review priority of the drug:
S—Standard review for drugs similar to currently available drugs.
P—Priority review for drugs that represent significant advances over existing treatments.
After a NDA is received by the agency, it undergoes a technical screening generally referred to as a completeness review. This evaluation ensures that sufficient data and information have been submitted in each area to justify “filing” the application, i.e. justifying initiating CDER's formal review of the NDA.
NDA's that are incomplete become the subject of a formal “refuse-to-file” action. In such cases, the applicant receives a letter detailing the decision and the deficiencies that form its basis. This decision must be forwarded to the sponsor within 60 calendar days after the NDA is initially received by CDER.
Medical reviewers are responsible for evaluating the clinical sections of submissions, such as the safety of the clinical protocols in an IND or the results of this testing as submitted in the NDA.
Biopharmaceutical reviewers evaluate the rate and extent to which the drug's active ingredient is made available to the body and the way it is distributed in, metabolized by and eliminated from the human body.
Statisticians evaluate the statistical relevance of the data in the NDA with the main tasks of evaluating the methods used to conduct studies and the various methods used to analyze the data.
Each review division employs a team of chemists responsible for reviewing the chemistry and manufacturing control sections of drug applications related to drug identity, manufacturing control and analysis.
The clinical microbiology information is required only in NDAs for anti-infective drugs. Since these drugs affect microbial, rather than human physiology, reports on the drug's in vivo and in vitro effects on the target microorganisms are critical for establishing product effectiveness.
CDER uses advisory committees to obtain outside advice and opinions from expert advisors so that final agency decisions will have the benefit of wider national expert input. Committee recommendations are not binding on CDER, but the agency considers them carefully when deciding drug issues. During the course of reviewing an application, CDER usually communicates often with sponsors about scientific, medical and procedural issues that arise during the review process.
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Communications may take the form of telephone conversations, letters, faxes or meetings (either face-to-face or via video conferencing) (Flow chart 1.2).
 
Notification of Easily Correctable Deficiencies
CDER makes every effort to communicate promptly to applicants easily correctable deficiencies found during the review of an application. CDER also informs applicants of the need for more data or information, or for 67technical changes in the application needed to facilitate the agency's review. This type of early communication would not ordinarily apply to major scientific issues, which require consideration of the entire pending application by agency final decision makers as well as by reviewing staff. Instead, major scientific issues are usually addressed in an action letter at the end of the initial review process.
 
End of Review Conference
At the conclusion of CDER's review of an application, there are three possible action letters that can be sent to the sponsor:
  1. Not approvable letter: lists the deficiencies in the application and explains why the application cannot be approved.
  2. Approvable letter: signals that, ultimately, the drug can be approved. It lists minor deficiencies that can be corrected, often involves labeling changes, and possibly requests commitment to do postapproval studies.
  3. Approval letter: states that the drug is approved. It may follow an approvable letter, but can also be issued directly.
In some cases, an applicant may seek to augment the information provided in the original NDA during the review process. For example, the applicant may submit a new analysis of previously submitted data or information needed to address a deficiency in the drug application. Any such information provided for an unapproved application is considered an NDA amendment. The submission of a significant amendment may result in an extension of FDA's time line for application review.
When an NDA nears approval, agency reviewers evaluate draft package labeling for accuracy and consistency with the regulatory requirements for applicable prescription or over-the-counter drugs. Each element of the proposed labeling, including indications, use instructions, and warnings, is evaluated in terms of conclusions drawn from animal and human testing. All claims, instructions, and precautions must accurately reflect submitted clinical results. The labeling “negotiation process,” through which a drug's final approved labeling is agreed upon, can take a few weeks to many months. The length of the process depends upon the number of agency comments and an applicant's willingness to reach agreement.
There is also extensive communication between review team members. If a medical reviewer's reanalysis of clinical data produces results different from those of the sponsor, e.g. the reviewer is likely to forward this information to the statistical reviewer with a request for a statistical reanalysis of the data. Likewise, the pharmacology reviewer may work closely with the statistical reviewer in evaluating the statistical significance of potential cancer-causing effects of the drug in long-term animal studies.
When the technical reviews are completed, each reviewer develops a written evaluation of the NDA that presents their conclusions and their recommendations on the application. The division director or office director then evaluates the reviews and recommendations and decides the action that the division will take on the application.
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Table 1.3   Labeling requirement to be met for approved product
Description
: Proprietary and established name of drug, dosage form, ingredients, chemical name, and structural formula.
Clinical pharmacology
: Summary of the actions of the drug in humans, in vitro and in vivo actions in animals if pertinent to human therapeutics, pharmacokinetics.
Indications and usage
: Description of use of drug in the treatment, prevention or diagnosis of a recognized disease or condition.
Contraindications
: Description of situations in which the drug should not be used because the risk of use clearly outweighs any possible benefit.
Warnings
: Description of serious adverse reactions and potential safety hazards, subsequent limitation in use and steps that should be taken, if they occur.
Precautions
: Information regarding any special care to be exercised for the safe and effective use of the drug. Includes general precautions and information for patients on drug interactions, carcinogenesis/mutagenesis, pregnancy rating, labor and delivery, nursing mothers, and pediatric use.
Adverse reactions
: Description of undesirable effect(s) reasonably associated with the proper use of the drug.
Drug abuse/dependence
: Description of types of abuse that can occur with the drug and the adverse reactions pertinent to them.
Over dosage
: Description of the signs, symptoms and laboratory findings of acute overdosage and the general principles of treatment.
Dosage/administration
: Recommendation for usage dose, usual dosage range, and, if appropriate, upper limit beyond which safety and effectiveness have not been established.
How supplied?
: Information on the available dosage forms to which the labeling applies.
The result is an action letter that provides an approval, approvable or non-approvable decision and a justification for that recommendation. Once the FDA approves the NDA, the new medicine becomes available for physicians to prescribe. The company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality control records. The FDA requires additional studies (phase IV) to evaluate long-term effects (Table 1.3).
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Electronic Records for NDA
Regulatory agencies are rapidly moving toward requiring submissions in electronic format because electronic submissions allow regulatory reviewers to rapidly and efficiently search and navigate marketing applications and other submissions, facilitating and potentially shortening the time to approval.
An electronic application for a new chemical entity, i.e. NDA, is submitted as an archival copy.
The archival copy is divided into five or six sections containing technical information. Each technical section of the review copy will go to the reviewer in charge of that specific section. Thus, the archival copy is intended to serve as a reference source for FDA reviewers to locate information not contained in the section of the review copy assigned to them. After approval, the archival copy is retained by the FDA and serves as the sole file copy of the approved application.
All documents and datasets for the electronic archival copy should be placed in a main folder using the NDA number (e.g. N123456) as the folder name. Sponsor should obtain the NDA number prior to submission. Inside the main folder, all of the documents and datasets should be organized by the NDA items described on page 2 of FDA form 356h.
The files and folders in folder N123456 contain the following examples:
  1. Folder structure for an NDA submission.
  2. Table of contents for the NDA.
  3. Table of contents with bookmarks for CMC, nonclinical pharmtox, Clinstat, CRT, CRT datasets, CRT profiles, CRF.
  4. Table of contents for Hpbio and micro (no bookmarks).
  5. Study report bookmarks (clinstat/pneumo/1234.pdf).
  6. Document information fields for labels and CRF, publications (pharmtox and Clinstat).
  7. Full text index (crf/crfindex.pdx).
  8. Data definition file for nonclinical data (pharmtox/datasets/101/define.pdf).
  9. Dataset for tumors from a carcinogenicity study (pharmtox/datasets/101/tumor.xpt).
  10. Data definition file for clinical data (crt/datasets/1234/define.pdf).
  11. Dataset for efficacy data (crt/datasets/1234/efficacy.xpt).
  12. Partial bookmarks for CRF (crf/101/001/112.pdf).
The US FDA and the EMEA currently accept the CTD in electronic format. The table of contents of the eCTD is consistent with that of the CTD. The eCTD is not limited to transfer of information alone, it also has provisions for creation, review, life cycle management and archival of electronic submission.
The eCTD is a message specification for the transfer of files from a submitter to a receiver. The primary technical components are:
  • A high level folder structure
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  • An XML backbone file which consists of a comprehensive table of contents and provides corresponding navigation aid
  • PDF files.
The eCTD therefore consists of PDF documents stored in the high level folder structure, which is accessed through the XML backbone.
In summary, NDA includes an integrated summary of efficacy (ISE) and of safety (ISS). When evaluating NDAs, regulatory agencies look at:
  • Validity of pivotal studies
  • Replicability of pivotal studies (consistency across studies)
  • Generalizability across populations (demographic groups, concomitant medications, intercurrent diseases, geographic regions, and even cultural groups)
  • Establishment of supportable dosage and dose regimen(s)
  • Clinical relevance of efficacy results
  • Clinical seriousness of safety profile (in context of seriousness of condition being treated)
  • Overall usefulness of drug (risk/benefit ratio).
In the US, the FDA does not actually approve the drug itself for sale. It approves the labeling—the package insert (as given in Figure 1.20, final outcome of a new drug application review is the label-package insert. All the information pertaining to new drug should be reproduced as label/package insert complying with FDA label requirement (refer Table 1.3 for labeling requirement) and this will be reviewed and approved by FDA reviewers so that product will carry the truthfully and accurate information as was submitted along with NDA). United States law requires truth in labeling, and the FDA assures that a drug claimed to be safe and effective for treatment of a specified disease or condition has, in fact, been proven to be so. All prescription drugs must have labeling, and without proof of the truth (Clinical studies data) of its label, a drug may not be sold in the United States.
 
Nonarchivable Electronic Records for New Drug Applications
Center policy is to encourage the submission and review of electronic NDAs as described in the guidance for industry:
  • It is Center's policy to discourage the submission of records in electronic formats that are not archivable. The only electronic records that are archivable are those provided as described in the guidance document ‘Providing Regulatory Submissions in Electronic Format – NDA (January 1999)’.
  • In the case when some records are submitted in electronic formats that are not archivable, the submission must still be accompanied by an electronic archivable version containing the same information.
  • Requests from center staff for word processing files for the purpose of copying and pasting text, figures or tables on individual pages or portions of pages are not consistent with agency policy.71
    zoom view
    Fig. 1.20: NDA review
    In most instances when such functions are needed, they can be adequately performed with archival files.
  • If a word processing file is submitted, it cannot be accepted by the Agency in lieu of the archival electronic record as described in the guidance. In other words, the Agency cannot accept a record in a word processing file format unless the record is also provided as recommended by the guidance.
  • Requests from Center staff for datasets in formats other than that described in the guidance also are not consistent with Agency policy. In most instances, staff can use the archival dataset to convert data to desired alternative formats.
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  • If datasets are requested or accepted in a format that is different from that recommended in the guidance, it cannot be accepted in lieu of the archivable electronic record as outlined in the guidance. The Agency cannot accept dataset records in a file format not described in the guidance unless the record is also provided as recommended in the guidance. For a transition period beginning in February 1999, the Agency has been making exceptions to its electronic submissions acceptance policy on a case-by-case basis in situations when a sponsor is unable to provide electronic submissions as described in the guidance.
  • If a sponsor is asked or offered to provide electronic records that will require the installation of hardware or executable software on any component of the CDER maintained information technology infrastructure, or if the use of the records requires OIT staff support beyond that needed for the electronic submission described in the guidance, advance approval from the Office of Information Technology (OIT) will be needed.
 
Role of Regulatory Bodies
In order to license/register a new chemical entity (NCE), a pharmaceutical company should develop a dossier that describes the pharmaceutical quality, safety (in animals and humans) and efficacy of the product for a specified indication.
The regulatory requirements for a pharmaceutical product would be evaluation and assessment of the pharmaceutical quality data, including: assessing that the manufacturer(s) of all components, including that of the active pharmaceutical ingredient and the finished product, are certified as meeting the international standards for Good Manufacturing Practices, standard tests for content and impurities, stability, and packaging labeling to ensure that it complies with specified standards.
Evaluation of animal (preclinical) toxicology studies in relation to acute and chronic toxicity, genetic toxicity, teratogenicity, carcinogenicity and others, including whether the studies have been carried out to international standards ICH safety guidelines, national guidelines (like Schedule Y in India) and whether the data and interpretation of the results are valid.
Evaluation of human clinical trials (either placebo or active comparator randomized controlled clinical trials) that have been carried out to define the dose, frequency and duration of treatment that is effective and safe, including assessing that the design and conduct of the trials meets international requirements like ICH GCP, that data are valid and have been interpreted correctly.
Food and drug administration: The US Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for the safety regulation of drugs, vaccines, biological products and medical devices. New drugs receive extensive scrutiny before 73FDA approval in a process called a New Drug Application (NDA). The NDA is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Recently, the FDA has mandated that NDAs submitted electronically should be done in the eCTD format.
European Medicines Agency: The European Medicines Agency (EMEA) is the regulatory agency for the evaluation of medicinal products in European Union. EMEA operates as a decentralized scientific agency. For products eligible for or requiring central approval, a pharmaceutical company submits an application for marketing authorization to the EMEA. A single evaluation is carried out through the Committee for Medicinal Products for Human Use (CHMP) if the Committee concludes that quality, safety and efficacy of the medicinal product is sufficiently proven, it adopts a positive opinion. This is sent to the European Commission to be transformed into a marketing authorization valid for the whole of the European Union. The EMEA's Committee on Orphan Medicinal Products (COMP) administers the granting of orphan drug status.
Drugs Controller General of India: The Drugs Controller General of India (DCGI) is responsible for regulatory approvals of clinical trials in India. This central authority reviews NDAs (form 44) as per the guidelines of Schedule Y. The DCGI has now classified clinical trials into two categories—A and B. Category A comprises of clinical trials for which a protocol has already been approved in specific countries such as the US, UK, Japan, Australia. The time frames for clearance of these applications are 2 to 4 weeks. All other application fall under category B. Their review will take at least 8 to 12 weeks. The DCGI has yet to set up an e-submission procedure.
Therapeutic Goods Administration: Therapeutic Goods Administration (TGA) is the regulatory authority which carries out a range of assessment and monitoring activities to ensure therapeutic goods available in Australia are of an acceptable standard. Medicines are evaluated by one of three regulatory units of the TGA. Prescription and other specified medicines are evaluated by the Drug Safety and Evaluation Branch (DSEB), OTC Medicines by the OTC Medicines Section (OTC), and complementary medicines by the Office of Complementary Medicines (OCM). One of these regulatory units evaluates the application submitted and forwards its recommendation to the Australian Drug Evaluation Committee (ADEC). The ADEC forwards its recommendation for approval or rejection to the Minister for Health.
 
ANDA Process
An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, provide for the review and ultimate approval of a generic 74drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the public.
A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).
Generic drug applications are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e. performs in the same manner as the innovator drug). One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy, volunteers. This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug.
Using bioequivalence as the basis for approving generic copies of drug products was established by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Waxman-Hatch Act. This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.
An application must contain sufficient information to allow a review to be conducted in an efficient and timely manner. Upon receipt of the application a pre-filing assessment of its completeness and acceptability is performed by a project manager within the Regulatory Support Branch, Office of Generic Drugs. If this initial review documents that the application contains all the necessary components, an “acknowledgment letter” is sent to the applicant indicating its acceptability for review and confirming its filing date.
Once the application has been determined to be acceptable for filing, the Bioequivalence, Chemistry/Microbiology and Labeling reviews may begin. If the application is missing one or more essential components, a “Refuse to File” letter is sent to the applicant. The letter documents the missing component(s) and informs the applicant that the application will not be filed until it is complete. No further review of the application occurs until the 75applicant provides the requested data and the application is found acceptable and complete.
The FDA requires an applicant to provide detailed information on a product to establish bioequivalency. Applicants may request a waiver from performing in vivo (testing done in humans) bioequivalence studies for certain drug products where bioavailability (the rate and extent to which the active ingredient or active moiety is absorbed from the drug product and becomes available at the site of action) may be demonstrated by submitting data such as (i) a formulation comparison for products whose bioavailability is self evident, for example, oral solutions, injectables or ophthalmic solutions where the formulations are identical, or (ii) comparative dissolution. Alternatively, in vivo bioequivalence testing comparing the rate and extent of absorption of the generic vs the reference product is required for most tablet and capsule dosage forms.
The Chemistry/Microbiology review process provides assurance that the generic drug will be manufactured in a reproducible manner under controlled conditions. Areas such as the applicant's manufacturing procedures, raw material specifications and controls, sterilization process, container and closure systems and accelerated and room temperature stability data are reviewed to assure that the drug will perform in an acceptable manner. Upon filing an ANDA an establishment evaluation request is forwarded to the Office of Compliance to determine whether or not the product manufacturer, the bulk drug substance manufacturer and any of the outside testing or packaging facilities are operating in compliance with current Good Manufacturing Practice (cGMP) regulations. Each facility listed on the evaluation request is evaluated individually and an overall evaluation for the entire application is made by the Office of Compliance. Furthermore, a preapproval product specific inspection may be performed on to assure data integrity of the application (Flow chart 1.3).
The Labeling review process ensures that the proposed generic drug labeling (package insert, container, package label and patient information) is identical to that of the reference listed drug except for differences due to changes in the manufacturer, distributor, pending exclusivity issues or other characteristics inherent to the generic drug product (tablet size, shape or color, etc.). Furthermore, the labeling review serves to identify and resolve issues that may contribute to medication errors such as similar sounding or appearing drug names, and the legibility or prominence of the drug name or strength.
If there are deficiencies involved in the Chemistry/Manufacturing/Controls, Microbiology or Labeling portions of the application, these deficiencies are communicated to the applicant in a facsimile. The facsimile instructs the applicant to provide information and data to address the deficiencies and provides regulatory direction on how to amend the application.
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zoom view
Flow chart 1.3: ANDA review processSource:https://secure.pharmacytimes.com/lessons/200205–01.asp
Once the above sections are found to be acceptable, as well as, the preapproval inspection and bioequivalence portion of the application, then the application moves toward approval.
After all components of the application are found to be acceptable an approval or tentative approval letter is issued to the applicant to market the generic drug product. If the approval occurs prior to the expiration of any patents or exclusivities accorded to the reference listed drug product, a tentative approval letter is issued to the applicant which details the 77circumstances associated with the tentative approval of the generic drug product and delays final approval until all patent/exclusivity issues have expired. A tentative approval does not allow the applicant to market the generic drug product.
 
Drug Application Regulatory Compliance
Guidance documents represent the Agency's current thinking on a particular subject. These documents are prepared for FDA review staff and drug sponsors to provide guidelines for the processing, content, and evaluation of applications, and for the design, production, manufacturing, and testing of regulated products. They also provide consistency in the Agency's regulation, inspection and enforcement procedures.
Following are the guidance documents available:
  1. Current Good Manufacturing Practice (cGMP) regulations: The cGMP regulations for drugs contain minimum requirements for the methods, facilities and controls used in manufacturing, processing, and packing of a drug product. FDA can issue a warning letter or initiate other regulatory actions against a company that fails to comply with Current Good Manufacturing Practice regulations.
  2. Code of Federal Regulations (CFR): The final regulations published in the Federal Register (daily published record of proposed rules, final rules, meeting notices, etc.) are collected in the CFR. The CFR is divided into 50 titles which represent broad areas subject to Federal regulations. The FDA's portion of the CFR interprets the Federal Food, Drug and Cosmetic Act and related statutes. Section 21 of the CFR contains most regulations pertaining to food and drugs. The regulations document the actions of drug sponsors that are required under Federal law.
  3. MaPPs (Manual of Policies and Procedures) are approved instructions for internal practices and procedures followed by CDER staff to help standardize the new drug review process and other activities. MaPPs define external activities as well. All MaPPs are available for the public to review to get a better understanding of office policies, definitions, staff responsibilities and procedures.
  4. Compliance Policy Programs and Guidelines
    • Compliance References: This web site from the Office of Regulatory Affairs provides links to compliance policy guides, regulatory procedures manuals, and other compliance related information.
    • Compliance Program Guidance Manual: These programs and instructions are for FDA field inspectors.
 
Post-drug Approval Activities
A vital part of CDER's mission is to monitor the safety and effectiveness of drugs that are currently available to the American people. FDA has in place 78postmarketing programs that monitor marketed human medical products for unexpected adverse events. These programs alert the Agency to potential threats to public health. Agency experts then identify the need for preventive actions, such as changes in product labeling information and, rarely, re-evaluation of an approval decision.
Post-marketing programs: FDA maintains a system of post-marketing surveillance and risk assessment programs to identify adverse events that did not appear during the drug approval process. FDA monitors adverse events such as adverse reactions and poisonings. The Agency uses this information to update drug labeling, and, on rare occasions, to re-evaluate the approval or marketing decision.
  • The adverse event reporting system (AERS) is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The ultimate goal of AERS is to improve public health by providing the best available tools for storing and analyzing safety reports. The reports in AERS are evaluated by multi disciplinary staff safety evaluators, epidemiologists and other scientists in the Center for Drug Evaluation and Research's (CDER) Office of Drug Safety.
  • The MedWatch program is for health professionals and the public to voluntarily report serious reactions and problems with medical products, such as drugs and medical devices. It also ensures that new safety information is rapidly communicated to the medical community thereby improving patient care. All data contained on the MedWatch form will be entered into the AERS database.
  • The prescription drug advertising and promotional labeling webpage provides links to an interactive chart illustrating CDER's process for reviewing and monitoring prescription drug advertising and promotional labeling.
  • Pharmaceutical industry surveillance: After a drug is approved and marketed, the FDA uses different mechanisms to assure that (i) firms adhere to the terms and conditions of approval described in the application and (ii) the drug is manufactured in a consistent and controlled manner. This is done by periodic, unannounced inspections of drug production and control facilities by FDA's field investigators and analysts. Manufacturers of prescription medical products are required by regulation to submit adverse event reports to the FDA. The Med Watch website provides information on mandatory reporting by manufacturers. In addition, drug manufacturers must submit either error and accident reports or drug quality reports when deviation from current good manufacturing practice regulations occurs.
  • FDA receives medication error reports on marketed human drugs (including prescription drugs, generic drugs and over-the-counter drugs) and nonvaccine biological products and devices. A medication error is 79“any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.”
  • Drug shortages: It is FDA's policy to attempt to prevent or alleviate shortages of medically necessary products. Drug shortages may arise from varying causes, such as the unavailability of raw materials or packaging components, marketing decisions and enforcement issues.
  • Therapeutic inequivalence reporting: In the past 10 years, FDA's Center for Drug Evaluation and Research has received an increase of reports of drug products that fail to work in patients because the product simply has no effect or is toxic. These problems are usually attributed to switching brands of drugs.
  • The following regulations apply to adverse drug event reporting. 21CFR310.305: Records and reports concerning adverse drug experiences of marketed prescription drugs for human use without approved new drug applications
  • 21CFR312.32: Investigational new drug safety reports
  • 21CFR314.80: Post-marketing reporting of adverse drug experiences.
There are guidance documents for: Postmarketing Reporting of Adverse Drug Experiences, Enforcement of the Postmarketing Adverse Drug Reporting Regulation, Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products and the Guidance document for CDER staff is CDER's Manual of Policies and Procedures (MaPPs).
Even when an NDA is approved unconditionally, regulatory scrutiny of a drug does not end. In most countries, yearly safety reports must be filed with the applicable regulatory agencies as long as a drug remains on the market, and these agencies independently monitor drug safety.
 
Post-marketing Surveillance
New drugs should be closely monitored for their safety once they are marketed. Thus post-marketing surveillance (PMS), which is systematic detection and evaluation of adverse reactions, is required for a newly marketed drug when used in clinical practice. The sponsor should furnish Periodic Safety Update Report (PSUR) by conducting PMS.
  • Periodic safety update report (PSUR): A PSUR is intended to provide an update of the worldwide safety experience of a medicinal product to competent authorities at defined time points post-authorization. Marketing authorization (MA) holders are expected to provide succinct summary information together with a critical evaluation of the risk-benefit balance of the product in the light of new or changing information. This evaluation 80should ascertain whether further investigations need to be carried out and whether changes should be made to the marketing authorization and product information.
    PSURs must be submitted for all registered products regardless of marketing status. A single report may cover all products containing the same active substance licensed by one MA holder. The report will usually include all dosage forms and formulations, as well as all indications, associated with such an active moiety. Within the PSUR, separate presentations of data for different dosage forms, indications or populations (for example, children vs. adults) may be appropriate, however an overview of the combined data should also be provided.
  • PSUR reporting cycle in INDIA, EU and USA
    • India: Schedule Y recommends that for all new products, PSURs should be submitted every 6 months for the initial 2 years and thereafter annually for the next 2 years to the Drugs Controller General of India. The reporting cycle requirements in India are similar to that of the requirements of European Union (EU).
    • European Union: PSURs are required to be submitted every 6 months for the first 2 years, annually for the three following years and every 3 years, thereafter. In EU, it is generally acceptable to the regulators that the generic companies skip the 6 monthly cycles of initial 2 years and submit the PSURs every 3 years from the date of marketing approval.
    • United States of America: Reporting requirements of US FDA are different. The US regulations require quarterly reports during the first 3 years and annual reports, thereafter.
 
Phase IV Clinical Trial
Phase IV clinical studies are defined as those studies performed with drugs that have been granted marketing authorization. The term “phase IV” is fairly standard and covers the vast majority of postregistration clinical study. Phase IV studies are not considered necessary for the granting of a marketing authorization but they are often important for optimizing the drug's use.
Phase IV studies are also referred to as “marketing studies” or “experience studies” to emphasize that they are conducted once the drug is marketed, rather than prior to its approval by the regulatory authorities. Some other terms, such as “seeding trials” or “observational studies”, have also been used, but they usually denote efforts made by marketing departments to encourage physicians to prescribe the new drug, rather than proper trials.
Phase IV studies differ from post-marketing surveillance which is observational and interventional intended mainly to monitor the safety of a marketed drug. Phase IV studies are, in fact, part of this process, but their objectives include efficacy or effectiveness in addition to safety.
Purposes: The role of Phase IV clinical trials are to extend knowledge about drug efficacy and to confirm the safety of a new drug in a wider patient 81population treated in regular medical care after the drug has been approved for marketing.
  • Effectiveness: While the efficacy of the drug has been demonstrated in a restricted patient population in phase II and III clinical trials, its effectiveness in a wider population is still largely unknown when the drug comes to the market.
    Phase III clinical trials performed for regulatory purposes usually include highly selected patients, and the results obtained do not automatically translate to the population at large. Phase IV clinical studies, in contrast, include broader patient populations which more closely reflect the reality of medical practice. A case in point is the elderly population, which has historically tended to be excluded from preregistration clinical trial programs and yet account for a substantial proportion of the patient population that consume medicines.
  • Comparison with available treatment: A second purpose of phase IV studies is to investigate the relative merit of a newly marketed drug as compared to other available treatments. The role of phase I-III trials is to demonstrate that the drug has biological activity and clinical efficacy, hence, the need to compare it, to the extent possible, to a placebo or an untreated control group. In contrast, the role of phase IV studies is to demonstrate that the drug is effective, hence, the need to compare it to alternative treatments for the disease under consideration. Examples of such comparative studies are comparing different chemical entities (e.g. methyldopa versus propranolol for hypertension), medicines within the same pharmaceutical class (e.g. captopril versus enalapril) and demonstration of efficacy in different patient groups (e.g. treatment of systolic hypertension in elderly patient).
  • Test new hypothesis: A third purpose of phase IV studies is to focus on hypotheses and questions which could not be tested and answered in preregistration trials due to the small number of patients and limited time available before filing for marketing authorization. Questions still unanswered at the phase IV stage can include the following:
    • Long-term benefit or harm of the drug
    • Impact of the drug on secondary endpoints
    • Details of drug administration schedules (such as dose fractionations),
    • Combinations with other drugs, the effect of concomitant medications or supportive care
    • Overall cost-effectiveness in routine medical practice
    • Quality of life
    • Compliance in routine medical practice.
Phase IV studies can also explore:
  • New indication for a product: Example, benefits of beta–blockers in heart failure was identified in a phase IV study (CIBIS II trial)
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  • New dosage regimen: Example, phenytoin was initially given three times a day for epilepsy management but subsequent studies demonstrated once-daily dosing to be sufficient.
  • New formulations: Example, dry powder inhaler for asthma management instead of metered-dose inhalers.
  • Introduce drug into clinical practice: Perhaps the more important purpose of phase IV studies is to introduce a new drug into routine clinical practice. The motivation for doing so is not only commercial, it also has a sound scientific and ethical basis. Indeed, valuable drugs may be underused, if clinicians are unconvinced of their merit.
Phase IV studies provide the ideal setting to further document the safety of a newly marketed drug. Because they are properly controlled (generally, phase IV studies are compared with the existing treatment or with current best practice, they are said to be controlled trial) and closely watched, such studies yield a more reliable safety profile than any method of spontaneous reporting of adverse drug reactions (ADRs), such as Yellow Cards, case reports, literature screening and so forth. In particular, the denominator is known in a prospective trial and therefore, the true incidence of ADRs can be estimated accurately. This is especially useful to study unpredictable ADRs. Phase IV trials should aim at the detection of unpredictable ADRs and should not focus on predictable, non serious adverse events or abnormal laboratory data that are not clinically important, since these add no value to what is already known from the pharmacology of the product and from preregistration trials.
While relatively common adverse events are well documented at the end of phases I-IV, rare ADRs will require the treatment of a larger number of patients to be detected.
 
Design Considerations
Approach in designing phase IV studies should be to minimize the risk of performing unnecessary trials and to ensure that trial has pragmatic and correctly balanced objectives that meet both company and external needs. It must be thoughtfully designed to properly address a serious question of interest to those health care professional who will be using and paying for the drug.
Randomization: The most crucial aspect of phase IV trials is that they should be based on a sound statistical design. Claims of effectiveness and/or efficiency can rarely be made on the basis of nonrandomized studies. Properly randomized studies of sufficient size yield a reliable and definitive answer, even if they are ultra-simple. Publication of their results may have a major impact on medical practice.
One objective of phase IV studies is to study the effectiveness of a drug in current clinical practice. This implies that the number of patients entered in such studies be large enough so as to answer the questions of interest with 83reasonable certainty. In fact, the efficacy of a new drug may be expected to be lower in phase IV studies than in phase III trials, because less responsive patients may be included in the trial, the conditions in which the patients are treated may be less tightly controlled, less experienced clinical investigators may be involved, and so on. The sample size of a phase IV study should take all these factors into account.
Broad eligibility criteria: One of the main objectives of phase IV studies is to study the drug in wide patient populations. This implies that the eligibility criteria in such studies be relaxed as compared to those of preregistration trials. Several authors have discussed the relative merits of strict versus broad eligibility criteria. As a general rule, strict criteria seem appropriate for preregistration clinical trials and broad criteria for phase IV studies. No patients should be excluded from phase IV studies except, if:
  • There is a safety concern if they receive the drug or
  • There is a sound basis for targeting certain subpopulation of patients.
The decision to enroll a patient in phase IV study is best left to the discretion of the attending physician, rather than regulating the process by means of lengthy lists of inclusion and exclusion criteria. All patients should be included unless the physician is uncertain about the benefit of either of the treatments to the patient, only then can the patient can be excluded.
Active control and equivalence trials: Many new drugs have to be compared to placebo to be granted marketing authorization even though an active treatment is known for the disease considered. Yet, the relevant medical question is not to show that the drug is biologically active as compared to placebo, but rather to prove that the drug has medical or economical benefits over the currently available treatment(s). Thus, there is an important place for phase IV studies with “active controls,” which are not required for regulatory reasons yet are essential for medical practice.
When studies use an active control group, it is often of interest to show that the new drug has the same efficacy as the control group (rather than higher efficacy), in which case these studies are called “equivalence” studies (or “active control equivalence” studies). Such trials are needed when a new drug is not expected to have better efficacy than the standard therapy, but offers a better safety profile, is more practicable, or is less expensive than the standard therapy, and should, therefore, be substituted for it in routine clinical practice. There is also an important place for phase IV “equivalence” trials with such new drugs.
 
GCP Standards
ICH-GCP is the standard applied by the vast majority of pharmaceutical companies for phase I-IV clinical trial programs, without distinction of phase or purpose of the trials.84
Simplified standards: The spirit of GCP can be maintained even if its implementation is adapted to the post registration setting. First, the intensive monitoring and site visit frequencies recommended by the GCP guidelines fall far beyond the budget of most post-registration programs. Monitoring is among the most costly aspects of trial management, and if it is required to validate data submitted to regulatory agencies, it may not be needed for studies to yield informative answers. If intensive monitoring is imposed on all trials, a well-intended sponsor might be tempted to reduce the number of patients required by a phase IV project (or perhaps to drop the project altogether) rather than to relax the GCP requirements so as to keep the budget within reasonable limits. In phase IV studies, monitoring could well be limited to an initiation and close out visit, or even in some cases to no visit at all. Second, the collection and filing of essential documents can be considerably reduced in phase IV clinical trials.
Third, quality control, which also needs to be highly detailed in a new drug application, may receive much less attention in the post-registration setting without impairing the scientific validity of the trial. For example, checking patient compliance through pill counts would be unfeasible, but also pointless in most situations of public health relevance. No measure of compliance is needed when the purpose of the study is to investigate the effect of a drug as actually taken by the patient rather than as intended by the investigator. Since in phase IV settings the drugs are used as recommended in the summary of the product characteristics, no special safety by the investigator concern should arise from their use.
Phase IV trials must aim at confirming the clinical benefit of a new product in a wide patient population and this is best achieved through large, simple, randomized clinical studies with realistic rather than exhaustive quality control.
Phase IV studies have been accepted by many companies as a part of the drug development process. These studies should still comply with ICH GCP. However, the level and nature of safety monitoring may differ compared with pre-authorization studies.
Overview of clinical trial phases is discussed in Table 1.4.
 
PHARMACOVIGILANCE
The World Health Organization in 2002 defined pharmacovigilance as‘the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems’. The principle of identifying and responding to drug safety issues apply equally to pre-marketing period but the term ‘Pharmacovigilance’ originated in the post-marketing arena. Pharmacovigilance is seen as a specialist discipline within the industry and most large pharmaceutical companies have sizable pharmacovigilance departments. Pharmacovigilance is a shared responsibility that is performed by doctors, pharmacists and pharmaceutical companies throughout the product life cycle.
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Table 1.4   Overview of clinical trial phases
Phase IV
Objectives
Determine the metabolic and pharmacological actions and the maximally tolerated dose
Evaluate effectiveness, determine the short-term side effects and identify common risks for a specific population and disease
Obtain additional information about the effectiveness on clinical outcomes and evaluate the overall risk-benefit ratio in a demographical diverse sample
Monitor ongoing safety in large populations and identify additional uses of the agent that might be approved by the FDA
Factors to be identified
• Bioavailability
• Bioequivalence
• Dose proportionality
• Metabolism
• Pharmacodynamics
• Pharmacokinetics
• Bioavailability
• Drug-disease interactions
• Drug-drug interactions
• Efficacy at various doses
• Pharmacodynamics
• Pharmacokinetics
• Patient safety
• Drug-disease interactions
• Drug-drug interactions
• Dosage intervals
• Risk-benefit information
• Efficacy and safety for subgroups
• Epidemiological data
• Efficacy and safety within large, diverse populations
• Pharmacoeconomics
Data focus
• Vital signs
• Plasma and serum levels
• Adverse events
• Dose response and tolerance
• Adverse events
• Efficacy
• Laboratory data
• Efficacy
• Adverse events
• Efficacy
• Pharmacoeconomics
• Epidemiology
• Adverse events
Design features
• Single, ascending dose tiers
• Unblinded
• Uncontrolled
• Placebo-controlled comparisons
• Active controlled comparisons
• Well-defined entry criteria
• Randomized
• Controlled
• 2–3 treatment arms
• Broader eligibility criteria
• Uncontrolled
• Observational
Duration
Up to 1 month
Several months
Several years
Ongoing (following FDA approval)
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Population
Healthy volunteers or individuals with the target disease (such as cancer or HIV)
Individuals with target disease
Individuals with target disease
Individuals with target disease as well as new age groups, genders, etc.
Sample size
20 to 80
200 to 300
Hundreds to thousands
Thousands
Example
Study of a single dose of drug X in normal subjects
Double-blind study evaluating safety and efficacy of drug X vs. placebo in patients with hypertension
Study of drug X vs. standard treatment in hypertension study
Study of economic benefit of newly-approved drug X vs. standard treatment for hypertension
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However, post-marketing surveillance is solely a sponsor initiated activity. Post-marketing surveillance is a component of pharmacovigilance.
 
Terminology
  • Adverse drug reaction (ADR): An unintended reaction to a drug taken at doses normally used in man.
  • Adverse event (AE): A negative experience encountered by an individual during the course of a clinical trial, which may or may not be associated with a drug. If an association between an AE and a drug is established the event is referred to as an adverse drug reaction.
  • Serious adverse event (SAE): Any adverse event is referred to as a serious adverse event when the event is fatal, life-threatening, permanently disabling, or which results in hospitalization.
 
Rationale and Aims of Pharmacovigilance
Events such as the thalidomide tragedy, which was caused by the drug thalidomide, taken by mothers during their pregnancy leading to limb deformities in newborns highlighted the importance of the need for a pharmacovigilance system. However, the need for a pharmacovigilance system in all countries was highlighted by the exclusive adverse reaction occurrence to the drug clioquinol in Japan.
The main reason to monitor ADR for an approved product is due to limitation of pre-marketing clinical studies to identify safety issues. Following are the reasons why pre-marketing studies are inadequate to cover all aspects of drug safety:
  • Relatively small number of patients studied as compared to large number of patients exposed after marketing.
  • The frequent exclusion of individuals who may be at greater risk of ADRs e.g. the elderly, children, pregnant women and patients with significant, concurrent disease and taking other medications.
  • The structured nature of clinical studies where drugs are given at specific doses for limited period with careful monitoring by experienced investigators. In clinical practice, a drug is unlikely to be used according to the instruction and there is less monitoring.
  • Duration of clinical studies is limited and there could be long latent period between starting the drug and the development of ADR which may not be detected in clinical studies.
Based on these observations the primary aims of pharmacovigilance programs are as follows:
  • To improve patient care and safety in relation to the use of medicines, and all medical and paramedical interventions
  • To improve public health and safety in relation to the use of medicines
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  • To contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use
  • To promote understanding, education and clinical training in pharmacovigilance and its effective communication to health professionals and the public.
 
Pharmacovigilance Process
In many countries, pharmacovigilance is part of governmental drug regulation. In several countries, it has become mandatory for pharmaceutical companies to assess case causality in case reports of adverse reactions to their own drugs.
The pharmacovigilance process includes the following steps:
  • Detecting and reporting an adverse drug reaction
  • Data collection and capture
  • Data storage and maintenance
  • Data selection, retrieval and manipulation
Pharmacovigilance relies on information gathered from the collection of individual case safety reports and other pharmacoepidemiological data. For the detection of new adverse reaction, post-marketing reports by alert individuals is the main source of information.
  • Reporting of an adverse drug reaction: A paper based, ADR (adverse drug reaction) form is filled out with patient and reaction details. Such data recorded on a paper form is later the basis for data entry into a computerized system. ADR reporting is of two types—spontaneous reporting and mandatory reporting.
    • Spontaneous reporting: This is the most common form of ADR reporting where in healthcare professionals identify and report any suspected adverse drug reaction to their national pharmacovigilance centre or to the manufacturer. Spontaneous reports are almost always submitted voluntarily.
    • Mandatory reporting: Manufacturers are required to submit reports they receive from healthcare providers to the national authority, in the form of a PSUR (Periodic Safety Update Report).
  • Data collection and capture: Data collection and capture in a database management system involves creation, update and transformation of information.
  • Data storage and maintenance: Once data have been entered into a database, it could be assumed to be a static system, in which nothing can change. However, maintaining the quality of data that has been stored poses its own challenges. The data must be secured against partial and complete loss. The integrity of the data must be protected.
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  • Data selection, retrieval and manipulation: The production of useful output involves the transformation of raw data into a refined representation which should remain truthful to the source of information and be appropriate for analysis. The common technique for selection, retrieval and aggregation of data in a database involves the use of query languages. Query commands can be executed through specially designed search interfaces.
Once the ADR data are obtained the data are sent to the WHO Uppsala Monitoring Centre where the data are stored in the central database. Based on the information in the central database a signal can be generated. The WHO definition of a pharmacovigilance signal is “reported information on a possible causal association between an adverse event and a drug, the relationship being unclear or incompletely documented previously”. Signal detection is one of the most important objectives of pharmacovigilance. The whole process of risk/benefit evaluation depends on effective detection of signals.
The process of signal detection is done by collection of adverse event reports followed by assessment of individual reports or clusters of reports in spontaneous reporting systems, observational databases and clinical trials. The detection of signals requires clinical assessment assisted by epidemiological and statistical analyses.
 
WHO and Uppsala Monitoring Centre (UMC)
The Uppsala Monitoring Centre is the field-name of the WHO Collaborating Centre for International Drug Monitoring. The UMC is responsible for the management of the WHO program for international drug monitoring.
The WHO Program for international drug monitoring provides a forum for WHO member states to collaborate in the monitoring of drug safety. Within the program, individual case reports of suspected adverse drug reactions are collected and stored in a common database.
Functions of the WHO Program for international drug monitoring include:
  • Identification and analysis of new adverse reaction signals from the case report information submitted to the National Centres and from them to the WHO database. A data-mining approach is used at the UMC to support the clinical analysis made by a panel of signal reviewers
  • Information exchange between WHO and National Centres, mainly through ‘Vigimed’, an e-mail information exchange system
  • Publication of periodical newsletters, guidelines and books in the pharmacovigilance and risk management area
  • Supply of tools for management of clinical information including adverse drug reaction case reports. The main products are the WHO Drug Dictionary and the WHO Adverse Reaction Terminology
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  • Provision of training and consultancy support to National Centres and countries establishing pharmacovigilance systems
  • Computer software for case report management designed to suit the needs of National Centres (VigiFlow)
  • Annual meetings for representatives of National Centres at which scientific and organizational matters are discussed
  • Methodological research for the development of pharmacovigilance as a science.
The functions of the UMC are as follows:
  • To co-ordinate the WHO program for international drug monitoring and its more than eighty member countries
  • To collect, assess and communicate information from member countries about the benefits, harms and risks of drugs and other substances used in medicine to improve patient therapy and public health worldwide
  • To collaborate with member countries in the development and practice of the science of pharmacovigilance.
 
Pharmacovigilance in India
The Government of India with the assistance of World Bank initiated the National Pharmacovigilance Programme in 2004. The Central Drugs Standard Control Organization (CDSCO) coordinates this country-wide pharmacovigilance program under the aegis of DGHS, Ministry of Health and Family Welfare.
India did not have a formal pharmacovigilance system in the past to detect adverse reactions of marketed drugs as very few new drugs were discovered in India. However, due to the increase in the number of new drugs being approved for marketing in India, there was a need for a vibrant pharmacovigilance system in the country. The legislative requirements of pharmacovigilance in India are guided by specifications of Schedule Y of the Drugs and Cosmetics Act, 1945. The Schedule Y also deals with regulations relating to preclinical and clinical studies for development of a new drug as well as clinical trial requirements for import, manufacture, and obtaining marketing approval for a new drug in India. The section entitled post-marketing surveillance in this schedule includes the requirement for submission of periodic safety update reports (PSURs), PSUR cycle, template for PSUR, and the timelines and conditions for expedited reporting.
As per the requirements of Schedule Y of the Drugs and Cosmetic Act, 1945, the reporting of adverse events from the clinical trials is mandatory. Schedule Y provides details of timelines for reporting adverse events by sponsor, investigator and ethics committee. These details are listed below (Fig. 1.21).
Any unexpected serious adverse event occurring during a clinical trial should be communicated by the sponsor to the Licensing authority within 14 calendar days.91
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Fig. 1.21: Flow of pharmacovigilance data in IndiaSource:http://www.ijp-online.com/temp/IndianJPharmacol393124-6222353-014342.pdf
Any unexpected serious adverse event occurring during a clinical trial should be communicated by the investigator to the sponsor within 24 hours and to the ethics committee within 7 working days.
 
Pharmacovigilance in the United Kingdom
The primary system for reporting suspected ADRs in the United Kingdom is the “Yellow Card Scheme” (YCS) which was introduced in 1964 as a result of the thalidomide tragedy. The YCS is a ‘spontaneous’ reporting system wherein health professionals voluntarily complete a card at the time a patient presents with a potential ADR. Completed Yellow Cards are submitted to the Medicine and Healthcare Products Regulatory Agency. Since 1991, data have been stored on the adverse drug reactions on-line information tracking system (ADROIT).
Until 2002, Yellow Cards were completed by doctors, dentists, coroners and pharmacists who suspected that an adverse event (AE) was related to a particular medication or combination of medications. In 2002, the YCS was extended so that nurses, midwives and health visitors could also report suspected ADRs.
EudraVigilance is a data processing network and management system for reporting and evaluating suspected adverse reactions during the development and following the marketing authorization of medicinal products in the European Economic Area (EEA).92
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Fig. 1.22: Components of Eudravigilance analysis systemSource:http://eudravigilance.emea.europa.eu/human/EVComDataAnalysisSystem.asp
EudraVigilance supports in particular (Fig. 1.22):
  • Electronic exchange of suspected adverse reaction reports (referred to as Individual Case Safety Reports) between the European Medicines Agency (EMEA), national competent authorities, marketing authorization holders, and sponsors of clinical trials in the EEA
  • Early detection of possible safety signals associated with medicinal products for human use
  • Continuous monitoring and evaluation of potential safety issues in relation to reported adverse reactions
  • Decision making process, based on a broader knowledge of the adverse reaction profile of medicinal products especially in the frame of risk management.
 
Pharmacovigilance in the United States of America
MedWatch is the reporting system for adverse events in the USA. This system provides important and timely clinical information about safety issues involving medical products, including prescription and over-the-counter drugs, biologics, medical and radiation-emitting devices, and special nutritional products.
MedWatch allows healthcare professionals and consumers to report serious problems that they suspect are associated with the drugs and medical devices they prescribe, dispense, or use. Reporting can be done on line, by phone, or by submitting the MedWatch 3500 form by mail or fax.
The FDA Form 3500 are used by healthcare professionals and consumers for voluntary reporting of adverse events noted spontaneously in the course of clinical care, not events that occur during IND clinical trials or other clinical studies. Those mandatory reports are submitted to FDA.93
 
Pharmacovigilance Software
The fast and reliable reporting of ADR (adverse drug reaction) data is an important task for pharmaceutical companies. In order to comply with regulations, good information management systems are essential. Many of the systems available are client specific.
Drug safety software applications should be simple, easy to use with functionality to comply with ADR reporting requirements, web based to enhance cross-divisional and cross affiliate work flows as well as being able to scale up with increasing demands, company growth and mergers.
Features of good ADR management tool (drug safety software):
  • ICH compliance by design including E2B reporting
  • Collect and report data to meet all common international regulations including FDA, CIOMS (Council for International Organizations of Medical Sciences), EMEA (European Medicines Agency), and MHRA (Medicines and Healthcare Products Regulatory Agency)
  • Code against standard dictionaries including current MedDRA
  • Data validation, cross-field validation checks and use of pick lists
  • FDA 21 CFR part 11 compliance
  • Duplicate check
  • Built-in query tool
  • Data export function
  • Integrated spell-checker
  • Full audit trail
  • Mandatory fields
  • Letter generation using Microsoft Word
  • Open database for use of third-party query and reporting tools
  • Use of reference dictionaries, e.g. contacts, lab tests.
 
Vigibase
From the start of the international movement for drug safety it was recognized that pooling data in a central database in order to detect signals early was essential. The creation of the WHO Collaborating Centre for International Drug Monitoring, collecting case information in an internationally agreed format has led to a high-quality, accessible data store for use by researchers from National Centres connected to the WHO Drug Monitoring Program.
Over the years, many technical modifications have been made to the ways in which data held in the WHO database were processed and retrieved. In the mid 1990s, the UMC decided to start work on a new database system for the management of WHO Program case report information. This led to the development of a new web-based database search program called Vigibase which makes use of XML (international computer language understandable in different computer programs). XML makes searching easier and also improves data handling, as data fields and their contents are kept together as part of the structured document.94
Remote access to information in the WHO database takes place through internet-based interfaces, a main advantage of this is that the user does not have to install the application interface software on local computers, but can run the program from an internet browser. As new search modules are added or other improvements made, these become instantly accessible for all users, without the need for reinstallation of software.
Vigibase is updated every night, so all correct reports will be entered within 24 hours of receipt by the UMC. Another feature is that technically incomplete reports will be stored as a searchable subset of the database in the same structure as the correct ones. The report handling system has built-in features to speed up corrections, keeping the same high quality standard. For acceptance into the ADR (adverse drug reaction) database, a report has to pass an extensive, error-checking procedure while in a buffer data folder, involving the following:
  • Syntax check
  • Inter-field coherence check
  • Check for duplication
  • Check of drug names and adverse reaction terms.
Vigibase includes new features of the WHO Drug Dictionary, for entering more detailed information about each drug name. However, since ICH has declared it mandatory to use MedDRA terms, Vigibase is also compatible with the MedDRA software.
The WHO database, Vigibase, has these main tables:
  • Report: Case identification, dates, classification
  • Patient: Identification, age, gender, outcome, causality
  • Background: Patient's previous illnesses/predisposing conditions
  • Death: Cause of death, causality, and postmortem information.
 
Total Safety—A Commercially Available Pharmacovigilance Software System
In order to fulfill the regulatory requirements it is essential for companies to have proactive pharmacovigilance programs that include comprehensive risk management plans and signal detection/analysis throughout a product's life cycle.
To address these needs, Aris Global has developed software known as total safety. Total Safety is an integrated software solution that enables companies to implement effective domestic and global pharmacovigilance, clinical safety and risk management programs.
The Total Safety site comprises of the following industry-leading solutions
  • ARISg™ – The world's leading pharmacovigilance and clinical safety system
  • ARISj™ – Japanese pharmacovigilance system
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  • agXchange ESM™ – Modular gateway for extended electronic exchange
  • agXchange IRT™ – Inbound receipt and triage of adverse event information
  • agConnect™ – Clinical safety reconciliation system
  • agComposer™ – Comprehensive periodic and aggregate reporting system
  • agSignals™ – Advanced signal detection and data mining system.
Of these solutions agComposer is a comprehensive periodic and aggregate reporting system that schedules, creates and tracks a full range of submission-ready, ICH-approved periodic reports, including PSURs, bridging reports and other annual reports such as the ASR.
agComposer automatically sets deadlines and reminders to ensure reporting obligations are met on time. As a periodic or aggregate report is due, it can only be generated in cooperation with other departments. agComposer fully integrates the required departments and processes—clinical trial, regulatory and medical information—to ensure deadlines are met and reports meet the various regulatory agency requirements.
 
REGULATORY APPROVALS FOR REGISTRATION OF DRUGS
 
Drug Regulation Scenario
Drug regulation has developed over the past 50 years in response to crises in relation to pharmaceutical products. The initial regulatory standards were primarily related to ensuring the pharmaceutical quality of medicinal products and subsequent developments in the early 1960s led to the development of standards for testing efficacy and safety of new medicines as well.
Despite the existence of standards for drug regulation since 50 years, there are still many problems with the safety and quality of medicines. The primary aim of drug regulation is protection of public health. Medicines are not normal ‘commodities’; they should meet health needs, and access to essential medicines is a fundamental human right. Thus, medicines have additional social value. Appropriate use of medicines requires a ‘learned intermediary’ to prescribe them and a trained person to dispense them appropriately before the consumer takes them.
The market for pharmaceuticals is therefore not a usual market in economic terms, there are major informational asymmetries and monopoly behaviors by suppliers that include patent rights and ‘data exclusivity’ clauses that further strengthen monopolies. In addition to the quality, safety and efficacy requirements, therefore, these are the arguments for regulating the pharmaceutical industry more generally and controlling what it supplies.
Over the past 10 to 15 years, the balance between controlling pharmaceuticals in the interests of ensuring public health and encouraging the development of the pharmaceutical industry has shifted in favor of the innovative industry. Regulation has been seen as an ‘impediment’ to profits 96and industry development. The resulting pressure on regulators has been to approve new medicines quickly—sometimes on the basis of what can only be described as preliminary data—to remove regulatory ‘bottlenecks’, to carry out reviews and evaluations of data in the shortest possible time. There has also been pressure from patient groups to speed up access to new, ‘breakthrough’ medicines, for example in the field of HIV/AIDS.
 
Challenges Faced by the Pharmaceutical Industry
The drug development process is known to be complex, costly and time-consuming. The process is also risky in that most compounds that undergo clinical testing are abandoned without obtaining marketing approval. The cost of new drug development is also critically dependent on the proportion of drugs that fail in clinical testing. Given the length and cost of the drug development process, careful consideration of all factors that have a significant impact on the process is needed to appropriately allocate research and development resources.
The pharmaceutical industry is faced with the challenge of surviving and succeeding in an environment that has become more complicated and uncertain, and one that is characterized by rapid developments in science and technology, and organizational change. From the standpoint of the pharmaceutical industry, the drive for change is the result of a combination of political, economic, technological and social factors; all of which have helped redefine the dynamics of this particular industry. If product is to be marketed globally, pharmaceutical industry is burdened with different requirements for registration of product.
Issues and challenges faced by pharmaceutical industry are not restricted during drug development process alone but well beyond this which includes registration of their product and placing their product in highly competitive environment. Following topics discusse few of the issues.
 
Barriers during Drug Development Process
Most of the tools used by pharmaceutical company for toxicology and human safety testing may fail to predict the specific safety problem that ultimately halts development or that requires post-authorization withdrawal. More generally, there are too few analytic tools (e.g. analytical devices, assay systems, surrogate markers and cell culture methods) to assist in providing medicine safety and effectiveness studies more quickly, with more certainty, and at lower cost. Key enabling technologies involving the use of animals and the use of human tissue in biomedical research are subject to complex regulations which impede drug development.
Regulatory authorities are becoming more risk-averse. This lack of flexibility only entrenches the existing regulatory requirements and perceptions, and often results in the need for expanded studies to quantify potential adverse events. Industry experts feel that alternative approach to 97traditional randomized controlled trial should be evaluated that does not compromise safety and efficacy. Such alternative approaches have been successfully used for high risk diseases such as cancer or AIDS where accepting results from limited size studies combined with post-authorization monitoring have allowed products to come to market far more quickly than by conventional approaches.
Poor communication between the industry, physicians and regulators during medicines development results in requests for additional data and regulatory questions following submission, and in turn these requests lead to increasing unpredictability of outcomes and delays in the marketing authorization process.
 
Challenges Related to Cost Factor
Over the past few years, the growth of the worldwide pharmaceutical industry has been slower than the increases in research and development (R & D) costs, and this has led to a cost-earnings differential that cannot be sustained indefinitely. Firms have found it increasingly difficult to sustain historical levels of growth principally because of two converging factors. First, the earnings of the pharmaceutical industry are being increasingly squeezed between pricing constraints due to government policies and generic competition; and second, through the rising costs of R & D due to increasing legislative requirements and growing technological sophistication.
As a consequence of these pressures on pharmaceutical earnings, combined with that of rising R & D costs, pharmaceutical firms have been forced to adopt a number of cost containment measures in addition to those pertaining to the safety and efficacy of drugs. The need to demonstrate ‘value’ to the consumer has now become imperative.
Traditionally, the pricing methods adopted in the former producer-driven environment for pharmaceuticals was essentially based on what was considered to be ‘fair returns’ for the high costs and risks associated with innovation. Today, however, much of that has changed. The deregulation of generic products has helped to bring about a much greater acceptance of product substitution, which in turn has led to changes in consumer choice— an event that has acted as a catalyst for change within the marketplace. Therefore, rather than being producer-driven, the market for pharmaceuticals today is essentially customer-led.
Price has become the key indicator of how the marketplace truly values the products that are discovered, marketed and sold. Consequently, the price that a company charges for a product is the culmination of every decision made along the chain of discovery to marketing. Therefore, in order to be able to survive this challenging environment, pharmaceutical companies can no longer permit their internal processes to determine price levels, as this has now become the privilege of the customer.98
The demand for innovation in an increasingly complex, global business environment has necessitated new approaches to organization because the requirements for success in the marketplace have changed in a number of profound ways. In addition to demands for efficiency, quality and flexibility, pharmaceutical companies are also required to simultaneously cut costs, improve standards of quality, shorten product development times, and introduce innovative products that customers value. As a result, companies have been forced to re-examine every aspect of how their businesses are implemented and conducted, and this has given rise to a number of important issues that question the long-held and accepted ways of managing pharmaceuticals.
The discovery, development and marketing of new pharmaceutical products are the essence of the research-based pharmaceutical industry. As a result of the transformation toward a customer-led marketplace, important issues have been raised which present a number of challenges to many pharmaceutical companies. Of greater significance is the issue of cost.
The total cost of bringing a new product to market from discovery through to launch, including the cost of capital with a risk premium and the cost associated with failures, is estimated to be approximately $800 million, over a 10 to 12 years period. Of this total, around 30 percent of the costs are concentrated in exploratory research while the remaining 70 percent are invested in subsequent development phases. At the same time, the percentage of money spent on innovation has been increasing steadily from around 6 percent in the 1960s to approximately 20 percent by the late 1990s.
Both the increased cost together with the growing quantity of resources being invested in pharmaceutical innovation are due to a combination of factors other than inflation. Traditionally, the rate of growth of the firm has been linked to new product introductions, as it was believed that increased investment in innovation generally guaranteed more novel products. Furthermore, the shift from acute to chronic therapy has increased the complexity of research as well as the regulatory approval process. Demands for regulatory data have almost doubled since the mid-1980s thus increasing the time it takes to get a product to market. In addition, companies with low levels of new product innovation have spent vast amounts of capital in an effort to secure future sources of revenue.
Owing to the culmination of these factors pharmaceutical companies face the immediate prospect of lower margins and almost no price flexibility for existing products in the world's largest markets. Therefore, the fundamental question that arises is whether pharmaceutical companies can afford to keep spending on innovation at current industry levels?
 
Challenges to Improve Input/output Ratio
Regarding the level of research productivity within pharmaceutical firms, two important features have emerged. First, companies have discovered that 99as research moves up the technology curve it not only becomes more complex and costly, but that the level of output begins to decline as well. Second, as size and complexity increase, so do organizational inefficiencies. This combination of technological complexity, increase in cost, the effect of diminishing returns, as well as greater bureaucracy have consequently led to growing levels of inefficiency within the innovation process. The implication of this long-term decline in innovative productivity within the pharmaceutical industry suggests that companies are not as successful as they used to be at innovation.
It is universally acknowledged that in customer-led markets the customer's perception of value is paramount. It is for this reason that the products that do not meet the requirements and satisfaction of the customer base will not be able to recoup the investments made. Therefore, this is another challenge faced by pharmaceutical companies to improve the input/output ratio by customizing innovative output to match more closely the needs of sophisticated, cost-conscious and value-driven customer base.
 
Challenges in Producing Unique Product Rapidly
Historically, the largest pharmaceutical companies have achieved the majority of their sales by developing so-called annuity drugs that treat long-term chronic diseases within the largest number of patients. Because of this, the real strength of all of the pharmaceutical majors is contained in the various therapeutic classes they serve. However, most of these categories are now mature and already have relatively well satisfied patients. With mature products going off patent and with no new major therapies on the immediate horizon, there is the potential for a price ceiling to be placed for large-volume categories experiencing the move to generic status for many of the leading products. Consequently, the move toward organized generic, class and therapeutic substitution is a signal that imitative R & D will be less rewarding in the future. Economic venture into large number of ‘me-too’ drugs might be a futile.
One of the most important issues facing most pharmaceutical companies at present is the question of whether they have the capacity to convince their customers to pay premium prices to cover production costs, as well as to provide satisfactory returns for the future development of additional undifferentiated drugs. Many of the currently untreatable diseases such as AIDS, cancer, migraine and multiple sclerosis are those that provide the most lucrative business opportunities. At the same time, healthcare providers and insurers within the industrialized nations continue to debate the sensitive issue of whether society can afford the costs of maintaining and extending the quality of life. As a result, an inherent paradox exists.
The challenges pharmaceutical companies are facing is to rapidly produce unique products that are truly successful in treating unconquered diseases, while at the same time obtaining high prices that are required to pay for cutting-edge research.100
 
Challenges in Establishing “Value-for-Money”
One of the most significant developments in the move toward customer-led change is the accelerated search for mechanisms to establish a sense of ‘value-for-money’. This has led to the creation of pharmacoeconomics, which encompasses a set of potentially useful approaches for making more rational decisions for selecting drugs. Such approaches include analysis of cost versus benefit ratio, cost effectiveness, cost minimization, cost utility, the quality of adjusted life years and eventual outcomes. Pharmacoeconomics will enable the pharmaceutical companies to demonstrate value in order to support the marketing of products. It could also be used when selecting projects for R & D purposes.
In most instances, however, there are conflicting forces at work. On one hand, healthcare payers as well as providers demand the lowest-cost solution to their healthcare problems while remaining partial to acquisition costs. Conversely, pharmaceutical companies wish to avoid the downward pressure on prices by focusing on product value rather than on the cost of acquisition. Further escalating the value-cost conflict is the fact that there are no global standards for pharamacoeconomic techniques, coupled with a severe lack of conformity on how customers interpret output. When these factors are combined, the use of a particular set of approaches that are based on single cost structures becomes problematic.
 
Challenges in Convincing Customers to Accept the Product
In order for pharmaceutical companies to be able to reverse the decline of their profit margins, it is important that an atmosphere of acceptance be created among customers concerning the value of drugs rather than of their costs. If customers are not convinced that healthcare costs can only be reduced through integrated approaches and not by ingredient cost management, then this effort will surely fail. Conversely, unless research-based firms can discover a mechanism through which future returns for a successful product can be secured, thereby justifying the significant investment required for high risk, cutting-edge research, there will be a general decline in the number of products offering genuine solutions to healthcare problems.
Another challenge faced by research-based pharmaceutical companies is the need to convince their increasingly cost-conscious customers to look beyond the management of acquisition costs, and to appreciate instead the overall value of a drug in terms of its total savings in overall healthcare costs.
Furthermore, many of the development pipelines are currently saturated with chemical class variations, which will only serve to provide low-grade improvements in efficacy or safety. Such substances only have a limited potential to create meaningful differentiation over existing brands, or cheaper generic or therapeutic substitutes. In addition, the degree of patent protection available no longer provides a safety net over gross profit margins. Thus, the 101key issue centers on the extent to which a customer perceives how much a product is worth.
Inevitably, many pharmaceutical companies will have to implement an in-depth review regarding the potential marketability of their product pipelines. Therefore, pharmaceutical companies, need to decide whether they should continue to develop products for which customers are unlikely to pay enough in order that firms may recoup their development costs, or should such projects be abandoned in the first instance?
 
Challenges due to Changing Market Environment
In the past, it was widely accepted that the more money and effort were put into innovation the greater was the chance of discovering new products. Corresponding to this stream of thought, it was also believed that the greater the number of new products introduced to the market, the greater the prospect of achieving considerable market success and hence competitive advantage. Although somewhat correct, this is no longer the case due to the changes that have occurred in the marketplace. Since much of today's management practice and operating culture in large industrial research laboratories was established prior to 1970, many of the institutions and instincts developed in this early period are now at odds with current realities. A new set of rules has emerged which now governs the market for pharmaceuticals, and as a result, requires re-examination of the assumptions upon which traditional pharmaceutical management is based.
In today's customer-driven market the degree of innovation success is a function of how well a product is perceived to offer new or better solutions to a customer's clinical problems. Companies are forced to make decisions based on resource allocation. They must favor new and better products, select from those considered marginal that will establish clinical and cost value from the customer's perspective, and abandon all products deemed mediocre. Success in the pharmaceutical industry is no longer determined by product innovation alone, but through a combination of value generating factors.
For many years the role of the physician was deemed crucial to ensuring product success. This was most common in instances where physicians had complete freedom of choice with regard to prescribing, or where there was relatively little concern for cost containment measures. However, since the end of the 1980s a rapid change has occurred as both public and private payers have come to realize that a policy of cost containment could only become truly effective if industry-focused supply side controls are effectively linked with physician and patient focused demand side controls. This has resulted in the development of a wide array of containment measures ranging from formularies to prescribing guidelines, mandatory substitution of cheaper products, as well as practice protocols. Therefore, while the physician remains an important constituent in the marketplace, the upstream consolidation of 102buyers together with tighter cost control measures has irreversibly changed the balance of power.
In summary, pharmaceutical manufactures should meet the needs of a modern and aggressive market and satisfy the healthcare need of cost-conscious customers rather than just sell pharmaceuticals. Companies need to look beyond “me-too” products and move towards developing innovative targeted therapies that address the underlying molecular mechanisms of disease. Ultimately, keeping both biology and clinical practice in mind throughout the entire drug discovery and development continuum can increase the likelihood that compounds reaching the development-candidate stage will have the safety and tolerability profiles and pharmaceutical characteristics necessary for successful clinical development.
 
CLINICAL DATA MANAGEMENT
 
Introduction
All clinical trials are performed to answer certain questions about the efficacy and safety of a drug or device. The answers solely depend upon the quality of data, which are collected during the trial and submitted after the trial. The study data are the immense asset for the pharmaceutical and biotech companies. Probability of getting a marketing approval for a drug or device increases if the study data are accurate. Hence, data management plays a crucial role in ensuring the success of a trial. Adopting proper methods to manage the trial data helps in increasing the quality of data. Learning, practicing and improving upon these methods has led to the creation of clinical data management as a specialty.
Drug development encompasses stages such as formulation, toxicology and clinical trials. Clinical trial or a study in turn has various stages as depicted in Figure 1.23. However these may overlap. A study starts with an objective, which gets translated to a protocol, proceeds with identification of sites and management of the trial.
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Fig. 1.23: Overview of clinical trial processes
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Actual process of data management is initiated with the collection of data.
 
History of Clinical Data Management
Clinical data management (CDM) has evolved from a data entry process into a diverse process to “provide clean data in a useable format in a timely manner”, “provide a database fit for use” or “ensure data are clean and database is ready to lock”.
Though clinical data management had to be done with whatever data was collected for clinical trials from its earliest days, the processes were given a major focus in the early 1970s, when the Public Health Service recognized the need for good practices in clinical data management. With the advent of electronically transmitted clinical trial data, standardized practices and procedures developed further. Regulatory requirements have advanced the necessity of clinical data management as a science.
Quality of the trial data is much more critical as pharmaceutical companies invest vast amounts of money in drug research. It is also vital for regulatory submission and approval. Hence, CDM has grown from a mere data entry process to a technology based science.
 
Oracle Clinical (OC)
It is a vendor developed data management system and also known as a Relational Database Management System. It is used for managing database design and data acquisition for clinical study.
The global library contained in OC is a central repository for the objects that compose data collection definitions for clinical studies. This allows for objects to be re-used for multiple studies, saves time in study set-up and ensures that there is standardization and consistency of data collection and reporting. OC can be customized to contain “Views” that allow the data to be browsed. System generated error messages are programmed to conduct Data validation. They are called—
Validations: Programmatic procedure which checks for illogical or incorrect data, e.g. check AE Start Date is after the Stop Date.
Derivations: Programmatic procedure which calculate data based on data that are stored in the database, e.g. Derive Age from Birth date.
The Oracle clinical applications allow electronic data to be created, modified, maintained and transmitted. Therefore, in accordance with 21 CFR Part 11, procedures and controls are established to ensure the authenticity, integrity and when appropriate the confidentiality of electronic records. Such procedures and controls include:
  • Audit trials: The use of secure, computer-generated, time-stamped audit trials to independently record the date and time of entries and actions that create, modify or delete electronic records
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  • Electronic signature certification: Individuals must be trained to use applicable systems/programs and that training must be documented
  • Electronic signature controls: Ensure uniqueness
    Two distinct ID components (non-biometric).
    All individuals receive a unique sign-on and password that is considered the electronic signature. Every sign-on ID has assigned security to allow or prevent software access as well as software functionality
    The user sign-on is the legally binding equivalent of the individual's handwritten signature
  • System and data security: Limits system access to authorized individuals.
 
Overview of Clinical Data Management
Clinical data management refers to the management of data capture and data flow processes in conduct of a clinical research. It begins with design of data capture instrument and data collection, continues with data quality control procedures and ends with database finalization. The locked database undergoes a statistical analysis after which it is ready to be submitted to the regulatory authority for approval. Processes used to support the clinical data must be clearly defined and documented. Documents supporting CDM activities include protocol and standard operating procedures (SOPs).
 
Data Management Plan
Before starting with the data management processes, a data management plan (DMP) must be put in place. DMP helps to proactively assess and plan for the study-specific data management processes. The DMP serves as the backbone of overall quality system of data management (DM) and outlines:
  • How and when each step of the CDM process must be carried out
  • What documents are to be created and finalized
  • Defines the data management tasks, responsibilities, deliverables and timelines
  • Which SOPs or guidelines will apply to the various processes
  • What document or output to collect or produce
  • What level of quality must be achieved.
Preparation, review and finalization of the DMP involves participation from sponsor, lead data managers, project managers, biostatisticians, database programmers, lead clinical research associates (CRAs), project directors, medical monitors and clinical scientists.
Some of the key elements included in a typical DMP include (Fig. 1.24):
  • Trial work flow
  • Study set-up/design
  • Computing environment
  • Database development and testing
  • CRF management, including CRF flow and tracking105
    zoom view
    Fig. 1.24: An outline of the development and review process of a DMP
  • Data capture, data entry and study specific guidelines
  • Serious adverse event reconciliation
  • Data validation procedures
  • Coding procedures
  • Lab data management
  • Data transfer procedures
  • Discrepancy management
  • Reporting processes
  • Study lock
  • Quality audit.
 
Data Capture and Collection
Data capture is a key concept in data management. This refers to procedures for gathering and recording data from or related to subjects in the study. It could either be paper-based or through electronic data capture (EDC). Promise of enhanced efficiency has led to increasing movement towards implementation of the electronic medical record and to computerized automation in general.
 
Paper CRF Based Study
Trial data are written on paper CRF(s) at the investigator sites. The study coordinator refers to “the source” (patient, patient's chart or other medical records, source document, etc.) and transcribes the data onto the paper CRF. This is just the first of many ‘transcription’ processes in clinical data management. These CRF(s) are periodically reviewed by CRAs to ensure that the data is valid and complete. A copy of the CRF is retained at the site and additional copies are sent to the sponsor and the data management team where the data is entered into a database. Data can be transferred from the paper CRF to the customized database in different ways.
  • One way is to scan the CRF. The scanned images of the CRF(s) are electronically transferred to the database. Data entry is then performed as per the scanned images of CRF(s) into the database
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  • Image recognition technology includes optical character recognition (OCR) and optical mark recognition (OMR). Here the data is captured from handwritten printed copies. Then the handwritten information is translated into electronic text documents. The image recognition software converts the scanned image to machine-readable and editable text.
Data editors then review the data in the database and identify any discrepancies in the data. These are resolved using a Data clarification form (DCF), which is sent to the investigator at the site. After all the discrepancies are resolved, the data in the database is declared as “clean”, at which point the database is locked. These paper CRF(s) have to be retained for up to 15 years at the sponsor and investigator sites.
Paper based trials have their own disadvantages. The cost of printing and distributing CRF(s) is high. Enormous amount of time is spent in resolving simple data entry errors. Study performance information is not available to project managers in time for smooth conduct of trials. Repetition of tasks by different departments in regard to serious adverse event recording and reporting is common.
 
EDC Based Study
EDC is the capability to collect data electronically, without using paper CRF(s). It could consist of both online and off-line technologies. EDC is defined by the Clinical Data Interchange Standards Consortium (CDISC) as follows:
Collecting or acquiring data as a permanent electronic record with or without a human interface (e.g., using data collection systems or applications that are modem-based, web-based, optical mark/character recognition, or involve audio text, interactive voice response, graphical interfaces, clinical laboratory interfaces, or touch screens). Note: ‘Permanent’ in the context of these definitions implies that any changes made to the electronic data are recorded via an audit trial.”
Interactive voice response system (IVRS) consists of interactive speech or touch-pad menu-driven systems that take the caller through a series of prompts. Responses are entered through a telephonic keypad. This technology is typically used in areas such as patient randomization, adverse event reporting, trial supply management, patient visit tracking, assisting with study startup or collecting subject diary information.
The database designed electronic CRF, (eCRF) is a true replica of the paper CRF in order to store the subject data when viewed on-screen. These eCRF (s) will have built-in real-time data validation checks. The data is entered directly into the interface of the central/global clinical database and immediately available for review to authorized study staff. This technology is also referred to as remote data entry (RDE) or remote data capture (RDC). eCRF(s) have certain advantages over paper CRF(s). They are:
  • Facilitates faster and more active management of the data gathering and processing workflow, thereby accelerating the transmission time of data to the sponsor
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  • Automated data edit checks alert the site to possible errors in data entry
  • Ensures faster correction of issues and immediate site education, hence is cost saving
  • Ensures immediate viewing and review of the data by the sponsor and data management, hence online feedback is provided to the site immediately.
EDC has its own demerits. Primarily the reluctance of the investigators to use technology is a concern. As use of technology not only involves newer processes but also integration of other systems and groups, it requires higher planning and investment.
 
Data Privacy
The ICH Guideline for Good Clinical Practice (GCP) states, “The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with applicable regulatory requirement(s).”
Adherence to sponsor's privacy policies is essential for maintenance of subject confidentiality. Security of all paper and electronic data has to be maintained. Paper CRF(s) are preferably stored in fireproof vaults with restricted access and all electronic data are protected with a password and firewall. Regulatory issues associated with patient data collection include finalization of error correction rules for CRF(s) using GCP, ensuring computer systems are 21 CFR Part 11 compliant and ensuring that all SOPs related to data management are in place and adhered to.
Investigator's training helps to generate better quality data thereby avoiding the generation of frequent queries. Detection of training issues by study monitors for common problems associated with CRF(s) and looking for recurring types of queries adds to improve the quality of the data.
 
CRF Design
CRF(s) are instruments used to collect data from the clinical trials. They are designed to collect all data points specified in the protocol. CRF(s) standardize the collection of study data and also help in meeting the needs of medical, statistical, regulatory and data management personnel. The CRF(s) are filled in by the investigator and then forwarded to the data management unit for entry and review.
In terms of design a well-designed CRF(s) should have the following features:
  • Consistency across patients and sites
  • Clear, concise and easy to fill questions
  • Support data management activities
  • Well-designed headers
  • Aid computerization of data
  • Reliable and clean data for analysis
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  • Grouping of similar type of data together
  • Collect raw data rather than calculated data
  • Avoidance of long fields of free text
  • Easy access of header information
  • Legible font style and size
  • Sufficient margins for binding and punching purposes.
Some of the CRF essentials include study name/identifier, unique subject identifier, form name, page number, signature of person completing the form, date of form completion, instructions (when to complete, where to send) and numbering of items for easy reference.
While designing a CRF, there are typically three types of question responses that can be incorporated:
  • Open response: This typically involves free text, for example, adverse event (AE) text, medication text, medical history details, date/time, numeric lab values
  • Closed response: This typically consists of check boxes, multiple choice, etc
  • Combination response: This consists of a combination of both open and closed type responses. For example, on the medical history record, a question asking for specifying if any abnormality present, requires an answer yes or no (closed). If the answer is yes, then one is asked to specify details of the abnormality (open).
Before design finalization, a pilot is carried out with few ‘dummy’ CRF(s) to identify potential troublesome fields; accordingly training sessions are conducted for investigators and CRAs during study initiation. The CRF design review and finalization involves participation from the project data managers, statisticians, regulatory managers, medical monitors, lead CRAs and clinical scientists.
A set of CRF completion guidelines are finalized and documented in the DMP. This serves as a guideline to the investigators while filling in the CRF(s) and would typically consist of the following instructions:
  • Read and follow all instructions carefully
  • Write legibly on the form
  • Use permanent ink on the forms
  • Ensure all questions are answered and complete
  • Write answers inside the space provided
  • Submit original forms when necessary
  • Use appropriate mechanisms for making corrections on the CRF(s)
  • Check the forms before submission to the data management unit
  • Ensure that patient ID information is correct
  • Follow correct schedule/visits for forms submission
  • Follow procedures for visits/examinations/tests that are not done and for unscheduled visits
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  • List abbreviations, if applicable
  • Instructions for early terminators/study discontinuation
  • Instructions for SAE reporting.
 
Clinical Database/Data Management Technology
A comprehensive system is required to manage clinical trial data including database creation and automated data entry screen design, efficient support for double data entry, terminology encoding, data validation, query management, data review and reporting, flexible database import and export.
Such systems are evolved out of the deep rooted knowledge and experience of professionals, the system can then represent an unparalleled level of maturity and a rich understanding of the day-to-day requirements for efficient and effective clinical data management workflow processes — from database set-up, to data quality controls and final export. The system has to be complete, intelligent, easy to learn and use and powerful.
A clinical data management system (CDMS) enhances the efficiency of the clinical trial process. Implementation of the CDMS involves planning and interaction of various teams. Design of CRF data flow into the system either manually or electronically is the first step. Subsequent steps are creating the global database, validation/derivation procedures, data extraction programs and reporting. One can also integrate dictionaries, AE (Adverse Event) reporting systems, EDC/RDC (Electronic Data Capture/Remote Data Capture) and CTMS (Clinical Trial Management System) with CDMS. It is essential to ensure that data is automatically transformed from a collection format to the reporting formats as needed by the sponsor and the regulatory authorities.
The main objective of database design is to capture and store clinical data accurately. The essential features of good design are ease of data capture, efficient creation of analysis data sets and accommodation of source data transfer formats.
 
CRF Login and Inventory
The paper CRF(s) from site must be efficiently transmitted to the data management unit for entry and processing. Typical methods include faxing, mailing, scanning and in some cases hand delivered by the site monitor. Once the CRF(s) are received at the data management unit, each CRF page must be logged into the CDMS and each page gets inventoried into the CDMS. Tracking inventories are set-up to detect missing pages and duplicate pages. When the CRF(s) are received as faxes or scanned images, some of the CDMS(s) can automatically store the images in a CRF image database. When paper CRF(s) are manually received, one can scan the CRF pages and store the images in CDMS. Subsequent processing steps may utilize images rather than paper.110
 
Audit Trial
21 CFR Part 11 compliance requires that all persons accessing the clinical data management system must have electronic signatures of their own. All CDM personnel who access the database must have their unique electronic signature/user IDs. Any modification, change, updation or deletion made in the database will be captured in the ‘audit trial’. A well-designed audit trial captures details of the date and time of change, user ID of person making the change, original entry on database, final entry on database (changed value) and the reason for change.
 
Data Entry
Data entry refers to the process of transferring data from the paper CRF to the database. This is also referred to as transcribing the data. Data entry results in creation of electronic data, which corresponds to the CRF data. Once data is entered into the database, it is reviewed and validated by the data editor. Emphasis for data entry is on typing speed and typing skills, since this activity requires large amounts of data to be keyed into the database. Data entry consists of both double entry and single entry.
 
Double Entry
This involves entry of the same CRF page by two independent data entry personnel. The first data entry personnel keys in the data into the database. Later, a second independent data entry personnel keys in the same data. In case of a difference or discrepancy between the first and second entry, a ‘pop up’ box throws up, alerting the second data entry personnel to either key in what they see or to accept what the first data entry personnel has entered. Another option is to have a ‘third’ personnel review the differences/ discrepancies and resolve them. Thus double data entry serves as a quality check on the data that is entered into the database.
 
Single Entry
This involves entry by single data entry personnel. This process is used when there are sufficient and extensive checks built into the database that would detect certain errors that might be missed out by the data entry personnel. Single data entry is extensively used in EDC and RDC systems, where the investigator and site personnel directly key in the data. This eliminates having data entry personnel within the data management unit. Once the data is keyed in directly at site, it is ready to be reviewed, edited and validated by the data editors.
Data entry could be of two types:
  • Data entry is done locally at the site database and then transmitted periodically to the central database via internet or using a dialup line.111
    zoom view
    Fig. 1.25: Types of data inconsistencies
    Sometimes the data is also sent using other electronic media such as a CD, floppy or as a mail attachment
  • Data entry is done online directly into the central database via internet. Usually these systems are web-based and the data are available in real time for review.
 
Data Review and Validation
Once data entry is complete, the data is ready to be reviewed by the data editor. The data editor ensures that all discrepancies are addressed and resolved and that the database is finally clean and ready to be locked. Discrepancies are any inconsistencies found in the clinical trial data that need to be addressed. Discrepancies include incomplete data, illogical data, incorrect data and illegible data (Fig. 1.25).
Discrepancies could be checked either manually or through computer-generated checks (validations and edit checks) that are programmed into the database. System-programmed validations are designed before start of the data management activities and these serve as checks or alerts to the data editor. The data editor ensures that all discrepancies and validations are addressed and resolved before locking the study.
Data cleaning or validation refers to a collection of activities by data management, used to assure validity and accuracy of the clinical data. It comprises of both logical and statistical checks to detect impossible values due to data entry errors, coding and inconsistent data. The DMP and SOPs clearly defines the tasks, roles and responsibilities involved in cleaning a database.
There are various types of checks that must be performed and various types of data points and discrepancies that must be addressed during the process of review and cleaning (accordingly validations could be programmed for these discrepancies).112
 
Point-by-Point Checks
This refers to cross checking between the CRF and the database for every data point. If the data editor performs this check, it serves as a second quality check apart from double data entry. Incorrect entries or entries missed out by data entry are corrected during this check. Special emphasis is given to dates, numerical values and header information, where there are likely to be more data entry misses.
 
Missing Data or Blank Field Checks
Missing data and blank fields must be queried for, unless indicated by the investigator as ‘not done’, ‘not applicable’ or ‘not available’. It is better to program validations for missing data fields rather than review them manually. Examples of missing data include missing AE/medication term, missing start/stop dates, completely blank CRF(s) where none of the question responses are provided.
 
Data Consistency Checks
Checks are designed to identify potential data errors by checking corresponding events, sequence of dates, missing data (indicated as existing elsewhere) etc. Checks include cross checking between data points both across different CRF(s) and also within the same CRF.
Consider an example of inconsistent data across different CRF records: On the AE record, an AE is reported with action ‘concomitant medication’; however on the Concomitant Medication record, there is no appropriate medication administered within the timeframe.
Consider the AE record where fever is reported with action ‘concomitant medication’:
Event
Start Date
Stop Date
Action
Outcome
Fever
13-Jun-2005
20-Jun-2005
Concomitant Medication
Resolved
Now consider the concomitant medication record where paracetamol is reported as follows:
Medication
Start Date
Stop date
Outcome
Paracetamol
21-Jun-2005
21-Jun-2005
Stopped
Here, paracetamol has not been given in the appropriate timeframe and hence this data is considered inconsistent.
Examples of inconsistent data across different fields, but within the same CRF include (a) an AE reported with a ‘start date’ but the outcome is reported as ‘continuing/persisting’ (b) stop date of a medication is greater than the visit date.113
Consider another example of an antibiotics record versus a trial medication record. Data consistency checks are to be reviewed both within a particular CRF and across different CRFs. Note the two sections/modules in the antibiotics record. The first section is designed to “report doses of antibiotics taken before intake of first dose of trial drug”. The second section is designed to “report doses of antibiotics taken after intake of first dose of trial drug”.
The first section of the antibiotics record is reported with the following details:
Antibiotic
Dose
Route
Start date
Stop date
Amoxicillin
6 mg
Oral
11-May-2001
14-May-2001
The second section of the antibiotics record is reported with the following details:
Antibiotic
Dose
Route
Start date
Stop date
Streptomycin
7 mg
IV
16-May-2001
17-May-2001
The trial medication record where the first dose of trial drug is reported with the following details:
Trial medication
Dosage
Route
Dosing dates
XX
50 mg
IV
15-May-2001
In this example, a crosscheck of data between the two sections of the same antibiotic record and also between the antibiotic record and trial medication record shows that the data reported is logical and consistent.
 
Laboratory Data and Range Checks
Laboratory data has to be treated in a special manner, as they are different from all other CRF data. The data have to be interpreted with the help of reference ranges and must be expressed in the specified units for proper interpretation. This is much more important when data are combined from multiple studies. If the units are different they have to be converted to one common unit before interpretation. Hence, the data have to be stored along with the original units in which they were captured. Linking the data with proper normal ranges is critical. Reference ranges may have to be taken from the study specific ranges or standard books when ranges are not available with the data.
Range validations are designed to identify statistical outliners, values that are outside normal variation of population under study and values that are physiologically impossible. An example of an ‘out-of range’ discrepancy 114is the reporting of hemoglobin value as 90 g/L, where the normal specified range as per the protocol is 110 to 160 g/L. While carrying out range checks, data editors need to ensure that appropriate range values and range units are applied for the particular test performed. For example, ranges for WBC types could be applied in units of either ‘percentage’ or ‘absolute’. A granulocyte value could be reported in the unit of percentage, whereas the corresponding range could be applied in the absolute unit, hence the granulocyte value would most definitely be out of range.
Consider the following cross-check between the hematology record and AE record:
Hematology record:
Hematology test
Date
Result
Normal range
WBC
05-Jan-2006
13,710 cells/cu mm
4,300–10,800 cells/cu mm
AE record:
Event
Start date
Stop date
Outcome
Streptococcal infection
04-Jan-2006
07-Jan-2006
Resolved
In this case, a validation should ideally be programmed to flag a WBC ‘out of range’ discrepancy. The study guidelines may instruct the data editor to either query the site to confirm the correct value or to accept the discrepancy since an increase in WBC count is justified by streptococcal infection in the same time frame.
 
Discrete Value Group (DVG) Discrepancy Checks
DVG is a question where there is a fixed or expected set of responses. DVG(s) are built into the database in the form of drop-down options. An example of a DVG is the set of responses for the severity of an AE – ‘mild’, ‘moderate’, ‘severe’ and ‘life-threatening’. However, if the severity is reported as ‘not known’, which is not part of this DVG, it constitutes a DVG discrepancy.
Another type of DVG discrepancy is a ‘length’ discrepancy. When the database is designed, each free text field is assigned a maximum number of characters that it will be allowed to accept when the data is keyed in. If the text reported exceeds the maximum number of characters, a length discrepancy is created, which needs to be addressed by the data editor.
 
Header Inconsistency Checks
Examples of discrepancies with the header information include (a) an incorrect visit date like 30-Feb-2005 (b) an incomplete visit date like 12-Jan, whereas the date is expected to be reported in the DD-MM-YYYY format (c) incomplete patient initials.115
 
Missing Pages Checks and CRF Tracking
Details of transmittals and receipt processes of CRF(s) and DCF(s) are documented and maintained during all stages of the data management process. Missing and expected pages tracking systems are also planned and setup in the DMP. Tracking reports of missing pages have to be maintained to identify CRF(s) misrouted in-house as well as CRF(s) not sent from the site.
 
Protocol Violation Checks
Protocol adherence ought to be reviewed at all stages of data management. Violations found have to be queried. Special emphasis is given for reviewing primary safety and efficacy endpoints, adherence to inclusion and exclusion criteria, adherence to trial drug dosing regimen, study or drug termination specifications, etc.
 
Dates Out of Sequence Checks
Dates out of sequence, refers to dates either in the header or the body of the CRF being inconsistent and out of sequence. Sequence of visits are reviewed and if found to be out of sequence, will be either queried or corrected. Examples include (a) a record belonging to visit 4 has a visit date belonging to that of visit 2 (b) one of the records within a particular visit has a visit date that is out of sequence with the visit date of the other records of the same visit (c) the trial medication is to be taken on a ‘daily’ basis as per the protocol, however, the dosing details on one of the dates has not been reported in the trial medication record.
Example where one of the screening records is reported with an incorrect ‘year’, hence there is a screening visit date out of sequence:
Record name
Visit date
Demography
20-Feb-2006
Med. history
20-Feb-2005
Inclusion criteria
20-Feb-2006
AE
20-Feb-2006
 
Continuity of Data Checks
These are checks performed for ensuring continuity of events (AE(s), medications, treatments/procedures etc.) across the study and across visits. Overlapping start/stop dates are checked across visits.
For example, consider a scenario where the protocol states that AE(s) are to be reported in visits 1, 2 and 3. “Headache” is reported as follows:116
Start date
Stop date
Outcome
1
01-Jan-2004
12-Jan-2004
Continues
2
01-Jan-2004
12-Jan-2004
Resolved
3
20-Jan-2004
20-Jan-2004
Resolved
There is an issue in visit 1 reporting, where the ‘stop date’ has been reported and the outcome is reported as ‘continues’. There is also the issue of overlapping start/stop dates in visits 1 and 2. All such issues are queried and clarified with the investigators.
 
Coding Checks
All the data such as concomitant medications, adverse events, medical history and diseases have to be substituted with a standard reference terminology. This is known as ‘coding’. The reference terminology may come from sponsor specific dictionaries or other published dictionaries. The coding of data helps in grouping them under specific systems. Such groupings are required for summary analysis of these data. Coding is done before the database lock.
As an example, consider medications ‘paracetamol’ (generic name) and ‘Crocin’ (trade name) reported on the CRF. Both medications have the same active ingredient ‘paracetamol’ and hence must be considered as the ‘same entity’ for analysis purpose. Hence, both terms must be coded to ‘paracetamol’, so that the safety and efficacy analysis during statistical analysis is not affected.
There are certain terms that cannot be directly coded without further clarification from site. For example, the adverse event “ulcers” requires a ‘location’ (gastric, duodenal, mouth, foot, etc.) in order to be coded. Hence, this must be queried to the site in order to obtain the location of the ulcer.
Standard global dictionaries having their unique coding structures are used for coding terms collected in clinical trials. Different dictionaries follow different structures and different hierarchies based on the classification levels. However, there are many similarities among the dictionaries. There is a term or text (AE, medication, disease) that is often referred to as the “preferred term” and the related “code”. In addition to terms and codes, dictionaries generally have auxiliary tables. For example, AE dictionaries have information on effected body systems and drug dictionaries may have additional information on the key ingredients.
Some of the common standard dictionaries used are:
  • MedDRA—Medical Dictionary for Regulatory Activities
  • COSTART—Coding Symbols for a Thesaurus of Adverse Reaction Terms
  • WHO-DRL—World Health Organization Drug Reference List
  • WHO-ART—World Health Organization Adverse Reactions Terminology
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  • ICD-9-CM—International Classification of Diseases, Ninth Revision, Clinical Modification.
Auto-encoding: Most modern and advanced coding dictionaries heavily depend on auto-encoders rather than manual coding. Once data from the case report form has been entered and verified, the process of auto-encoding begins, where the text of the investigator term in the clinical trial database is compared to the text strings stored in the dictionary database. When an exact match occurs, the code from the term in the dictionary database is automatically entered into the clinical trial database and the term is considered auto-encoded.
Auto-encoders help in handling synonyms, misspellings, word variations, etc. Auto-encoders may be built-in with CDMS or as stand-alone systems. Auto-encoders have numerous advantages over manual coding such as the ability to handle large numbers of terms and the ability to facilitate consistent coding, without having to rely on the manual re-evaluation of previously coded terms.
 
External Data Checks
During the conduct of a clinical trial, some data external to the CRF(s), such as laboratory data, PK/PD data and device data (ECG, images, flowmetry, vital signs) are also collected.
Central labs are used to maintain ‘uniformity’ across the study and across the sites. External data from all the study sites is directly sent to a central lab, from where the vendors provide electronic transfer of computerized data into the sponsor's database. Electronic transfer of data helps in avoiding the transcription errors. At the time of data transfer one has to take care that all the variables are included and are loaded onto the proper study/visit without affecting the blinding.
Data management tracks loading of incorrect subject number, incorrect visit number, incorrect study number, incorrect date/time of sample collection, incorrect date/time of examination, etc. Missing data such as missing collection date/time of blood sample, missing date/time of ECG, missing location of chest radiograph, missing systolic/diastolic blood pressure, missing microbiological culture transmittal ID, etc. are also tracked by data management. Incorrect and incomplete loading details are communicated to the centralized vendors so that the appropriate data can be subsequently ‘reloaded’.
 
Duplicate Data Checks
This refers to duplicate data entries of a particular data value within a single CRF or across similar CRF(s). Duplicate entries and duplicate records are generally deleted as per guideline specifications. Examples of duplicate data include:
  • Treatment ‘physiotherapy’ on ‘30-Aug-2001’ reported twice on either the same treatment record or across two different treatment records
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  • Both visit 4 and visit 10-blood chemistry CRF(s) (with different collection dates) are updated with same values for all tests performed. In this case, either the collection date on one of the CRF(s) is incorrect or the reported blood chemistry values in one of the CRF(s) are incorrect
  • Both ‘primary’ and ‘additional’ medical history CRF(s) at screening are reported with same details of abnormalities.
 
Textual Data Checks
All textual data are to be proof read and checked for spelling errors. Common examples of textual data include pre-existing conditions in medical history record, adverse events, medications/antibiotics, physical examination findings, etc.
 
SAE Reconciliation Checks
An adverse event is any undesirable experience associated with the use of a medicinal product in a patient. The event is considered as a serious adverse event (SAE) if it results in any of the following outcomes:
  • Death
  • Life-threatening illness
  • Inpatient hospitalization or prolongation of existing hospitalization
  • Persistent or significant disability/incapacity
  • Congenital anomaly/birth defect.
Expedited reports are required by the regulatory agencies for certain SAE(s). Accordingly the investigator submits the SAE report to the sponsor and the SAE details are subsequently maintained in the SAE database. The SAE details from the clinical trials are also reported on the CRF(s) which are sent to data management. Before close of study, the data management staff must compare and reconcile the SAE data in the SAE database with that in the clinical trial database, to ensure that all SAE(s) were collected and reported properly (Fig. 1.26).
zoom view
Fig. 1.26: Diagrammatic representation of SAE reconciliation
119
 
Discrepancy Management
A discrepancy is initially in an open or un-reviewed status. The data editor addresses the discrepancy and resolves it, based on the project-specific guidelines or standard guidelines. There are various actions that can be taken to address a discrepancy:
Closing discrepancy per internal correction: The data editor can ‘internally’ resolve and close out the issue without sending a query to the site. This action is applicable when the resolution is fairly ‘obvious’. For example,
  • A lab value 0.6 is out of range and an ‘out of range’ validation is generated. The data editor refers to the CRF and notices that the value is actually 6.6 and not 0.6 and that the value was incorrectly entered by data entry. In this case, the data editor could change the value in the database to 6.6
  • A medication is reported as ‘paracetamol’. This will not code and hence would throw up a coding validation. Since this seems to be very obviously a misspelling, the guidelines may allow the data editor to correct the spelling to ‘paracetamol’.
Closing discrepancy per clinical team: A discrepancy can sometimes be closed out directly based on instructions from the clinical scientist. Based on an ongoing review, the clinical scientist can instruct the data editor to either create a query to the investigator or provide a resolution for a discrepancy.
Generating a query to the investigator: The study guidelines can include instructions to the data editor to query a discrepancy in case it cannot be resolved by internal correction. Queries are generated on data clarification forms [DCF(s)], which are in turn sent to the respective sites. DCF(s) are also referred to as query forms, correction forms or discrepancy forms. DCF drafts can be auto-generated from a discrepancy management system and contain the query text templates.
The process of query management can be broadly classified into five steps.
  • Creating queries: Queries for discrepancies are entered onto the DCF manually based on reports from the discrepancy management system or the system may create them automatically. A DCF should ideally contain queries belonging to the same patient and to the same site.
A DCF would typically consist of the following entities:
  • Study number/ID
  • Site number
  • Patient number
  • Investigator name
  • Date of generation
  • Unique DCF ID
  • Query text
  • Space for the query resolution (to be filled by investigator)
  • Date and signature of investigator
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Fig. 1.27: Process of discrepancy management
In the case of Remote Data Capture (RDC) systems, queries are entered directly into the database. The investigator answers the queries online and the responses are then available to the data editor
  • Sending queries: DCF(s) are delivered to site via fax, paper mail, in person or by e-mail. In the case of RDC systems, the queries are immediately accessible to the investigator who can view the queries and provide resolutions online
  • Tracking queries: The data editor tracks the flow of queries between self and the site. Following up on delayed responses and misrouted DCF(s) is important
  • Resolving queries: Once the DCF is received from a site, the responses are integrated into the database. Common types of resolutions include retaining the queried value as the correct value, replacing the incorrect value with the correct one provided by the investigator, updating a missing response provided by the investigator
  • Re-querying: Re-queries are needed when the investigators do not provide a response or provide an incorrect/inconsistent/incomplete response or provide the same response to a query (Fig. 1.27).
 
Query Writing
Good query writing is extremely important so that the investigator can fully understand the query and hence would in turn provide the correct response. This helps in avoiding re-queries and reduces the turn-around time for query integration into the database.
General tips for query writing include having a thorough understanding of the guidelines and protocol, stating the problem in a simple way, being precise and to the point while wording the query text, using proper punctuation and grammatically correct sentences and avoiding repetition of words in the query text.121
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Fig. 1.28: Diagrammatic representation of database lock
 
Database Closure
Database closure is done to prevent unauthorized or inadvertent changes to the database once the final analysis of the data has begun. This process is referred to as ‘soft-locking’ the database. This is done after completion of last patient last visit (LPLV).
Database lock is critical in randomized trials to ensure the integrity of the randomization process (as the blind has been broken). Database closure is done when all the discrepancies and validations are resolved, all edit checks are completed, all missing data/external data are in-house, all terms are coded, all lab ranges are applied and SAE(s) reconciled. In other words it is done once the database is cleaned completely (Fig. 1.28).
In order to safeguard the integrity of the data well-defined procedures for the database closure have to be documented and followed. A database can be unlocked with special user access in case there is a necessity of making further updates or modifications to the database. In such cases, the change control procedures must be clearly defined and documented. Change control procedures include notifying the study team, clearly defining the changes being made, specifying the reasons for the changes and documenting the dates when the changes are made. Database closure is followed by final analyses, which lead to conclusions on the trial and for the regulatory submissions.
 
Quality Assurance and Quality Control (QA/QC)
QA/QC audits are done periodically—on an ongoing basis as well as at or after the end of the study. QA audits are systematic and independent examinations of trial-related activities and documents to ensure that the CDM related activities and processes were conducted and completed and that the data were accurately recorded, analyzed, documented and reported according to the protocol, SOPs, GCP and applicable regulatory requirements.
Errors or findings are mismatches found between the CRF and the database during a review. They could be due to incorrect transcriptions, incorrect data processing (at the level of data entry or data validation) and incorrect query 122integration. The error rate or quality index (QI) is calculated as number of findings against the number of fields in the database. The acceptable error rate is pre-determined by the sponsor and is documented early on in the DMP. For example, a sponsor may require a quality index of 99.9 percent, whereas another sponsor may require a quality index of 99.5 percent.
The sample size for audit should be statistically appropriate and could vary from sponsor to sponsor. For example, some audits could use a 10 percent random sample where the system can randomly auto generate 10 percent of the total enrollment for analysis. Some other audits could involve a 100 percent sampling of all safety and efficacy end points.
Interim analysis may be done at regular time intervals for an ongoing study, if specified in the protocol. The analysis may be done monthly, quarterly, biannually, annually, etc. depending on the study duration. The analysis could also be done either on specified modules in the study like safety modules or efficacy modules, or on all modules. Findings from the analysis give a clear picture if the study is on track. Decisions are taken on the proceedings of the trial and if needed, amendments to the protocol are made in order to ensure successful completion of the trial. If major deviations are found against the protocol or the expected results, the data is assessed as a whole to evaluate the quality of the study and decide if the study should proceed as planned. Analyzing findings on a periodic basis helps in making appropriate rectifications to the database early on in the study. Accordingly training is provided to the data management staff so that the findings and errors are not repeated for the rest of the incoming data.
Final analysis is done after completion of LPLV. This analysis collates the data from all the interim analyses as well as the data analyzed after the last interim and gives a combined result of all the data modules. The final analysis gives a collective conclusion about the safety and efficacy of the trial drug, which would be part of regulatory submissions (Fig. 1.29).
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Fig. 1.29: Overview of processes in clinical data management
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Data Storage and Archival
All trial related paper documents including CRF(s) and/or electronic files must be stored in a secure and controlled place. It is good to scan all paper documents so that they can be archived in an electronic form. Open formats such as Operational Data Model (ODM) offered by CDISC or PDF are recommended for storage.
Information regarding all clinical data, database design specifications, external data, structural metadata, coding dictionaries, lab ranges, audit trial, listings for edit checks and derived data, discrepancy management logs, queries, program codes, PDF formats of CRF(s), data management plan, validation documentation, regulatory documentation, documentation/memos of deviations from SOPs and other working procedures, are stored in a central document library and should be included in a clinical data archive.
 
Clinical Data Management Softwares
Listed below are different software systems categorized as clinical data management systems (designed to capture clinical trial data), drug safety system (designed to capture adverse events), remote data systems (RDC-designed to capture clinical trial data directly into the interface/software application) and data exchange solutions (applications which connect/integrate two different kinds of software applications being used to capture clinical trial data) (Fig. 1.30).
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Fig. 1.30: Summarized process flow of clinical data management
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Recent Advances in CDM
Clinical trial systems to conduct clinical trials electronically have become a necessity today to increase the time to market as well as decrease the cost of trials. The various technologies utilized include EDC systems, adverse event reporting systems (AERS), OCR, OMR, IVRS, etc. These and many other technologies are providing number of benefits in the conduct of the clinical trial. Technology enables advances in trial design, faster data entry, more efficient communications between participants, and improved process management, collection of clinical endpoint data directly from the patients. Technology can also help in the design of a clinical trial especially in the randomization process. It is possible to design a trial that is automatically 126modified as it progresses through an adaptive trial design. Continuous monitoring of a critical variable from EDC data can automatically adjust the sample size of a trial for the power that is desired.
EDC decreases paper handling, improves data clarification process, provides validations at the time of data entry, provides realtime access to data, allows for remote monitoring, speeds up regulatory agency submissions and lessens the number of CDM resources required to process the data. EDC data can be integrated by loading of SAS datasets or transport files into a data repository that becomes the source for study analysis and reporting. EDC systems can also be integrated with IVR systems, electronic patient diaries, labs, EKGs and AERS. With lab integration investigators can also look at lab data on-line.
Smart pens are available which enable patients fill out a form, and then use the pen itself to transmit the recorded data via a cradle to the database. Discrepancies in the data are shown to the site, which can correct them against the paper copy. The pen also creates an exact copy of the CRF to be saved online.
Electronic devices such as personal digital assistants [PDA(s)], palm pilots are very efficient in capturing data from subjects. These typically work in an offline mode and are slowly replacing paper-based subject diaries. These devices can also display metrics or tracking status to monitor patient schedules and compliance with alerts to record the data as per the protocol. Some can even help collection of various parameters such as measurement of pain, etc.
Biometric devices provide another way of data collection. Electronic spirometers can record the time, date and measurements of home-administered pulmonary function tests. Some devices can simultaneously record numerous physiological variables.
Data are stored in the memory of the clinical data systems or on paper, microfiche, computer tape, computer disk, optical laser disk or smart cards. Data may be transmitted through hard-wired direct connections, disks, audiotape or videotape broadcast, microwave fiberoptic links. Retrieval of data can be done by automated prompts, query, and search programs. The output may be in a typed format, an audio format or a visual format (e.g. pictures, graphs and tables).
A number of technologies are available to help better communication between sites and sponsors who can help achieve higher quality data in a shorter period of time. Trial portals are available where start-up and other documents can be downloaded, completed and can be shared with the sponsor. In addition, these portals can be used for live investigator training, site personnel training and for investigator meetings. Monitors can send edit checks and protocol changes to the trial sites via the portal. Monitors can conduct protocol-compliance checks by examining the data being collected and fully manage trial processes from their home or office via these web 127portals. They can also query sites and generate data-correction forms in realtime. Sites can be graphically shown their recruitment, time from query to response, queries per page, and many other metrics. These reports will allow the site to understand areas that need improvement, or areas in which they excel. Over all, much less efforts are spent reviewing and managing queries which helps to increase study capacities and smooth conduct of multicenter studies.
Desktop productivity tools have been integrated with ERP systems to enable process functions and data to be available through familiar desktop applications. They provide access to tasks such as time management, budget monitoring and organization management from a desktop. Globalization management systems are available to accelerate capturing, authoring, managing and distributing content across multiple formats and languages. To avoid the problem of clinical trials generating mountains of paperwork, FDA is promoting eSourcing. This involves capturing clinical data electronically at the source meaning in the patient diaries and eCRFs. FDA is also encouraging completely paperless submissions of clinical trial results. As a method of eSourcing investigators can record all trial data in their laptops and the same can be synchronized daily with central servers.
Integrated data capture and management systems with lab data integration, integrated dictionary coding and translation tools provide for better reporting. Some systems can help generate the extracts for analysis in analytical tools and also help in generating submission files exactly as requested by FDA. Web-based tools for safety research with search engine, querying, access to information sources—including FDA and WHO datasets, help manage and analyze data efficiently. FDA has collaborated with private vendors for electronic review tools, which provide quicker access to key information.
 
Data Standards
Data standards are being developed to overcome the problems of data integration from different systems. Data structure (variable names, variable types and labels), screen layout/paper CRF module, completion instructions, monitoring guidelines, standard reports, tables, listings, laboratory data, global libraries are all being standardized. Clinical data interchange standards consortium (CDISC) is at present leading the way. There are currently over 60 companies that are members of CDISC, and many companies are starting to adopt the CDISC models, even down to the variable name.
Apart from data management personnel, the senior management, clinicians, statisticians, medical writers, auditors, regulatory affairs, IT support and central labs contribute to these data standards development. Standards have become the necessity of the day because of the rapidly increasing number of drugs in development and global submissions.128
 
CRF Imaging System
Document imaging and workflow systems streamline document handling by eliminating duplication services, reducing hand-offs, simplifying storage, automating process tracking, and speeding distribution. Character recognition software automates data processing so that the staff can focus on data quality instead of data entry.
Case report form (CRF) imaging and workflow application are also sold by Integic by the name “CRF WorkManager” and by ISI as ‘CRFTrack”.
 
Scan, Fax or Import CRFs
Software applications are available to scan locally or remotely and import CRFs quickly and easily. Powerful imaging tools and the ability to fax-in CRFs also help improve the quality and accessibility of documents (Fig. 1.31).
Quick and easy scanning: CRFs can be organized into a batch that share common attributes, and assigned keywords to clinical and process information for convenient access. In addition, users can scan documents remotely into a centralized database through remote scan.
Fax-in capabilities: Users in remote locations can now be connected in more ways than ever. Regardless of where the user is, CRFs can be faxed into the same database. The process is fast and secure, allowing the user to focus on gathering CRFs for submission.
Import files: CRFs in TIFF format can be imported into the application used and included in an existing or new batch. Files can also be replaced or revised, allowing for easy movement and management of pages and versions as they change.
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Fig. 1.31: CRF import and export system
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Powerful imaging tools: A palette of imaging tools helps the readability and presentation of scanned CRFs with options to detect and set page orientation automatically, set rotation of pages by reformatting pages or changing the display, and clean pages by removing unwanted holes and scanner marks. In addition, user can set filters to de-skew text, ignore holes, clean edges, remove horizontal and vertical lines and more.
 
Index by OCR or Barcode
Assign attributes and numbering information to CRFs through a number of different methods: by page template, OCR, barcode or manually. Also, create virtual CRFs for specialized separation.
Index manually, by OCR or barcode: There are several options for indexing scanned pages into proper CRFs. If manual indexing is required, helpful page templates can be created to define a page structure for a CRF, so that certain pages that share a common format can be easily identified and indexed (Fig. 1.32).
OCR indexing is a convenient and automatic way of indexing page numbers through specified keywords and “zones” on CRFs. OCR Indexing can also be run in batch mode, allowing multiple batches of scanned files to be indexed at once.
Barcode indexing allows user to gather attribute information automatically and accurately through barcode recognition of protocol, investigator and patient information.
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Fig. 1.32: OCR indexed scan page
Create virtual CRFs for specialized separation: Create a virtual CRF that condenses pages from multiple patients into a single document based on specified criteria. For example, with Virtual CRFs the user can copy Adverse Event pages from patients in a protocol for review, and then convert the Virtual CRF to PDF. The PDF can then be distributed to internal reviewers (Fig. 1.33).130
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Fig. 1.33: Virtual CRF
 
Add Navigation, Ensure Quality and More
Bookmarks, hyperlinks, annotations and comments can all be added to images and eventual PDFs effortlessly. In addition, QA tools ensure the quality and integrity of pages with a number of options – through searching file size, setting statuses and checking page settings. And with the ability to route pages to be reworked, managing the workflow is easier than ever.
Create bookmarks and hyperlinks: Bookmarks and hyperlinks are created easily to ensure submission compliance. In addition, create TOCs that add a structural hierarchy to PDFs that enhance document navigation, and export them as a CSV file for later reference.
Annotate and comment: Through a variety of annotations, user can add notes and highlights to CRFs, most of which can also be preserved in PDF. Whether it is notes for clarification or notification, hyperlinks that navigate to predetermined pages, or highlights within CRFs, there are multiple options to choose from. Additional options to lock show and search annotations make it easy to manage comments for team-wide collaboration.
Perform QA: Through specialized workflows and QA tools; the application helps ensure the validity and integrity of documents. Search for specified protocols and investigators by file size, as well as for blank pages or specific types of pages, such as DCFs and cover pages. In addition, define the status of a page as “Passed”, “Rejected”, or “None” during a workflow and then route pages to the appropriate destination. User will be able to ensure quality as the workflow is happening (Fig. 1.34).
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Fig. 1.34: QA tools
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Review and Manage Globally
Everything the user needs to manage CRFs better – with an easy-to-view workspace, remote global access, collaborative capabilities and convenient EDMS integration – are conveniently at your fingertips today with the existing software applications.
Automatic PDF conversion: With speeds up to 72,000 pages per hour, converting paper CRFs to electronic format has never been quicker and easier. CRFs converted to PDF are ready for submission and can contain bookmarks grouped by Domain and Visit with the proper hyperlinks between DCF and CRF pages. Additional features that prepare CRFs for PDF conversion allow users to create and manage annotations (Fig. 1.35).
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Fig. 1.35: Automatic PDF conversion
Create workflows and route jobs: Administrators can also create workflows and route jobs to appropriate departments and keep track of the workflow as it happens. It is easy for administrators to view remaining pages for each job, as well as assign, reject or confirm completion of jobs.
Remote global access: CRA's, clinical trial monitors, investigators, and other key team members can fax and view CRFs from remote investigator sites and access the information they need through the CRF web portal.
A collaborative environment is created among clinical trial team members through a secure web interface. Members can download patient PDFs for offline review, assign and restrict access to CRFs for secure document access and ensure the integrity of CRF documents.
Convenient integration: Integration with oracle clinical and clintrial allows for faster workflow task processing. To streamline clinical operations as much as possible, split-screen data entry integration allows for greater speed and quality during first and second pass data entry.
 
Track and Report
Accurate CRF tracking and reporting: In dealing with an overwhelming amount of information, software applications simplify the tedious process of reviewing and verifying CRF collection (Fig. 1.36).
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Fig. 1.36: Accurate CRF tracking and reporting
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A simpler, more accurate way to track CRFs: Maintaining complicated spreadsheets that track CRF information is no more required since a simpler and powerful method is available in the software applications. Users can perform vital QA functions through a host of automated search methods. Users can perform searches to determine missing and contained pages, advanced searches by keyword, drug, investigator, patient and workplace.
Detailed reporting: In addition to searching across patients and by keyword, user can also view more detailed tracking, such as page history, user history and audit trail mapping. Print reports for streamlined QC on CRF documents and submission requirements.
 
Direct Access Solutions
The means by which a direct connection into sponsors’ clinical data management systems can be made. This access ensures that processes and standards are followed, while the sponsor maintains control over data. This is a permission provided to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities and sponsor's proprietary information.
 
eDiaries
A patient diary is a tool used during a clinical trial or a disease treatment to measure treatment compliance. An electronic patient diary registers the diary in a storage device and allows for monitoring the time the medication was taken, and symptoms or quality of life data were recorded.
Patient diaries are way to find out if a patient takes the medication according to the treatment schedule, which is an important problem during clinical trials and the treatment of degenerative diseases with relatively few symptoms.
 
Clinical Trial Portals
Clinical trial portal has been designed as a single entry or a ‘one-stop-shop’ allowing you to search for comprehensive information on the on-going clinical trials (registry) or results of completed trials (database) conducted by the innovative pharmaceutical industry worldwide.
WHO International Clinical Trials Registry Platform is one of the most valuable sources of evidence about safety and efficacy of health interventions. Extensive media coverage is also done on several cases selective reporting of results. Such trial registration and full reporting of trial results would help ensure a full and unbiased public record on safety and effectiveness public record on safety and effectiveness.133
Many journals in addition to International Committee of Medical Journal Editors (ICMJE) now accept only registered trials for potential publication. It is a global, neutral, independent body with convening capacity (i.e. World Health Assembly resolutions). It is authoritative and has an important role in setting norms and standards in research, policy and practice {Good Clinical Practice, Ethics guidelines, Classification standards (e.g., ICD)}. WHO contributes to capacity building (i.e. in developing countries) and has a political legitimacy, accountable to 192 member States. WHO shows commitment to achieving equity in health and has been defined a coordinated global “platform” for trial registration.
The goal is to strengthen public trust in clinical research by promoting transparency and accountability. The objectives are to ensure that all trials worldwide are registered and thus publicly declared and identifiable and ensuring that a minimum set of results are publicly reported for all registered trials and support use of trial registration information for recruitment, research planning, etc.
Some important portals complying with requirements set out by the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the International Committee of Medical Journal Editors (ICMJE) guidelines, and the WHO 20-item Trial Registration Data Set are—
  1. International Clinical Trials Registry Platform (ICTRP).
  2. Australian New Zealand Clinical Trials Registry (ANZCTR)
  3. International Standard Randomized Controlled Trial Number Register (ISRCTN).
  4. University hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR).
  5. Netherland's Trial Register (NTR).
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