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 into 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. 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.
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 from a disease called 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 hard 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 its 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 at that time 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).
Before any potential new medicine can be 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 will take 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. 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 5–10 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:
- Proteins and enzymes
- 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.
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 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 either 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.
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.
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.
- (Random) collections of discreetly synthesized compounds.
- 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%. 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 serial 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.
- X-ray crystallography: 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: Efficacy, potency and selectivity in vitro and in vivo;
- Physicochemical properties: For example, Lipinski's “rule of five”
- Pharmacokinetic properties: For example, permeability in the Caco-2 assays
- Chemical optimization potential
Lead optimization is the complex, nonlinear 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 “drug-likeness.” 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 feed back 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. 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.
This data is 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.
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.
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
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: It is responsible for finding new compounds and assuring that they are safe enough to test in humans.
- Medicinal chemists: Whose 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/molecularbiology/screening: Examines each New Chemical Entity (NCE) in a set of high throughput screens.
- Safety evaluation: Demonstrates that the NCE and its metabolites do not accumulate and do not cause harm during short-term administration.
- Formulations research: Develop 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 in animals, to establish the doses for human studies.
- Process research: Manufacture the NCE in sufficient quantity for advanced testing, dosage form development.
- Legal affairs: Writes and files the patents necessary to protect a company's inventions.
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:
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 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 positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), 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 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 such 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 (POC) studies 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 suggest 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 phase. The trend toward 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.
The need to speedup 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 becomes 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.
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 added 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
Preclinical drug development is a stage that begins before clinical trials (testing in humans) during which important safety and pharmacology data is 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 non rodent (e.g. dog). The choice of animal species is made 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. This data allows 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.
- 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:
Langendorff's heart preparation: The objective is to study the effect of drugs—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—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 d-tubocurarine by using rectus abdominis muscle of frog.
In Vivo Studies
It 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.
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, gastrointestinal system, and other systems can be studied
- Results easier to interpret and extrapolate
Some of the examples of in vivo studies are:
- Non-invasive 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.
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 are:
- 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.
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,
- 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 endpoints 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 (Figs 1.3A and B).
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. Other objectives of toxicokinetic studies include:
- To relate the toxicological findings to clinical safety.
- To support in selecting species, treatment regimen and designing subsequent non-clinical toxicity studies.
Several toxicity studies need to done before a drug goes into the clinical phase. They are:
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. 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. These studies need to be carried out for all drugs proposed to be studied or used in women of child-bearing age (Figs 1.4A and B).
The drug should be administered throughout the period of organogenesis in animals if the test drug is intended for women of child-bearing age and if women of child-bearing age are to be included as subjects in the clinical trial stage.
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 fetal development.
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, Photo-Allergy, Rectal Tolerance Test, Ocular Toxicity Studies, Inhalational Toxicity Studies, Hypersensitivity (Fig. 1.5).
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:
- Point mutations
- Chromosomal mutations
- Genomic mutations
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.
Studies should be performed for all drugs that are expected to be clinically used for six months or more than six month 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.
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:
- 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 developed 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 New Chemical Entity. 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 microdialysis 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
- 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 or
- 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 Practice (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
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 non clinical 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.
Drug discovery and drug development is being revolutionized due to changes in technology. Technologies like genomics, proteomics, high throughput screening 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 (Fig. 1.9).
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.
Before the sponsor proceeds to study a new drug in human, approval has to be obtained by through Investigational New Drug Application.
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:
- Research (noncommercial)There are three IND application types:
- An investigator IND application: It 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.
- Emergency use IND application: It 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: It 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.
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: (1) if the participants will be protected from unnecessary risks; and (2) 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 1980's, 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 toxicology 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 does not have the data to make such a determination) (Flow chart 1.1).
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 (Center for Drug Evaluation and Research), 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.
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 days initial review period.
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.
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.
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 INVESTIGATIONAL NEW DRUG 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.
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