Basic Principles of Clinical Research and Methodology SK Gupta
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Clinical Research–Past, Present and Future1

Vijai Kumar
View the past, understand the present and predict the future
 
WHY IS CLINICAL RESEARCH IMPORTANT TO THE SOCIETY?
Clinical Research involves methodical and systematic study of drugs, devices, biologicals, vaccines used in the diagnosis, prevention or treatment of disease. During the process of clinical research, the physician is treating an individual with an aim to develop an intervention for the patient of tomorrow.
Therefore, the broad aims of clinical research are:
  1. Improve patient outcomes
  2. Improve quality of care
  3. Enhance efficiency of system
  4. Inform health policy.
Clinical research is central to translating the promise of biomedical research into improved clinical practice–the “neck of scientific bottle” through which all advances in biomedicine must flow before they can benefit the public.
 
THE PAST OF CLINICAL RESEARCH
Clinical research has come a long way from the times of The Old Testament bearing reference to a trial of water and bread versus bread and wine. Clinical trials are also discussed in ancient Greek, Roman and, Arab Woks, but it was not until the 12th and 13th centuries A.D. that any ethical codes regarding human experimentation were written down. Moses Maimonides (1135-1204), the Jewish Philosopher, Physician and Rabbi of Cairo, expounded that physicians should seek to help individual patients, and should not use them to further their own knowledge. Roger Bacon (1214-1294), the English Scientist and philosopher and monk, observed that it was difficult for 2physicians to conduct experiments on living human beings, “because of the nobility of the material in which he works; for that body demands that no error be made upon it.”
The 16th century trial of egg yolk + rose oil + turpentine in wound healing when the conventional boiling oil was not available by a French surgeon is another example of early clinical trial.
Although the efficacy of lemon juice in scurvy was first observed in the 17th century, James Lind in 1753 performed the maritime experiment when seamen fell ill.
In this study, there was a balanced allocation of 12 individuals that received
  • A quart of apple juice once daily
  • Half Pint sea water once daily
  • Nutmeg and garlic (dose uncertain)
  • Vinegar, 2 tea spoons thrice daily
  • Elixir of vitriol, qtr ts
  • Oranges (2) and lemon (1).
Complete recovery was observed ONLY in the group administered oranges and lemon.
This was followed by experiments of Mint Water in rheumatic heart disease in 1865, Sanocrysin in TB in 1931. This was perhaps the first randomized clinical trial where 24 patients were divided into two equal groups. One was treated with Sanocrysin and the other with placebo. The treatment order was decided by the toss of a coin. It was also a blind trial.
The first randomized clinical trial where the sample size was statistically determined, and the protocol contained a section on statistical analysis was initiated by the health authorities in UK when they evaluated Streptomycin in Tuberculosis in 1944. It is important to remember that this randomized trial was done NOT to demonstrate efficacy. It was performed to assess the effectives of Streptomycin on the cost of health care delivery, i.e., the pharmacoeconomic aspect of clinical research was the subject of the first randomized trial.
The first multicenter study was also reported in 1944 publication on the evaluation of Patulin in the treatment of common cold (Patulin Clinical Trials Committee). This trial used a common protocol.
The past of clinical research has to be viewed from the perspective of the various stakeholders:
  • Regulatory agencies
  • Manufacturers
  • Medical profession
  • Patients
  • Ethics bodies.
The level of sophistication–manufacturing technology, medical technology, regulatory science, and patient expectation has been an evolutionary process. 3Consequently, the regulatory controls and various other checks and balances have evolved and tried to keep pace with various other developments.
Drug discovery also followed a tortuous path. Essential oils are considered the oldest therapeutic agents known to man besides being used for their fragrance. The Egyptians were the first to discover the potential of these oils. Records show that when Prince Tutankhamen's tomb was opened in 1922, 350 liters of oil were found in alabaster jars. The ancient Arabian people began to study the chemical properties of essential oils. The Europeans began producing essential oils in around the 12th century. It is surprising that there is no mention of any clinical evaluation of essential oils.
For centuries, the history of clinical testing was ruled more by methodological considerations than personal concerns of the research participants. From 1820 to 1906, the US FDA formed a part of various US Government agencies–from US Customs to the Department of Agriculture. In the 1930's the authorities in Great Britain set up the Therapeutic Trials committee to “consider applications by commercial establishments for the examination of new products, submitted with the available experimental evidence of their value, and appropriate clinical trials will be arranged in suitable cases”.
While the US FDA approved a drug on the basis of safety alone, it was amended in 1962 to include evidence of efficacy. Since 1900's, the Food and Drugs act of the US FDA has been amended at least one hundred times to reflect increase in complexity of drug development.
It is extremely important and relevant to understand the role responsibility of the national regulatory agency in the oversight of clinical trials. A vital responsibility of the national regulatory agency is to protect the health of the nation. This public health responsibility requires it to review and amend existing regulations and requirements to further its duty towards the citizens. Since the US FDA is regarded a model agency, it will be appropriate to learn briefly its evolution from a public health perspective.
 
SOME MILESTONES OF DRUG REGULATION IN THE UNITED STATES
  • 1820–Eleven physicians met in Washington DC to establish the US Pharmacopoeia, the first compendium of standard drugs for the United States
  • 1848–Drug Importation Act passes by the US Congress requires US Customs Service Inspection to stop entry of adulterated drugs from overseas.
  • 1850–US Patent Office Commissioner sets up agricultural division, which would lead to the birth of FDA.
  • 1862–Federal Government establishes the Division of Chemistry within the Department of Agriculture
  • 1883–Dr Harvey Wiley becomes Chief Chemist, expanding the Bureau of Chemistry's food adulteration studies. Campaigning for a federal law, Dr. Wiley is called the “crusading chemist” and “Father of Pure Food and Drugs Act”.4
  • 1902–The Biologics Control Act is passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans.
  • 1905–Samuel Hopkins Adams' ten part expose of the patent medicine industry, ‘The Great American Fraud’ begins in Collier's.
    The American Medical Association, through its council on Pharmacy and Chemistry, initiates a voluntary program of drug approval that would last until 1955. To earn the right to advertise in AMA (American Medical Association) and related journals, companies submitted evidence, for review by the Council and outside experts, to support therapeutic claims for drugs.
  • 1906–The original Food and Drugs Act is passed by the Congress on June 30 and signed by the then President Theodore Roosevelt. It prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs.
  • 1911–US Vs Johnson, the Supreme Court rules that the 1906 US Foods and Drugs Act does not prohibit false therapeutic claims but only false and misleading statements about the ingredients or identity of a drug.
  • 1912–Congress enacts the Sherley Amendment to overcome the ruling in US vs. Johnson. It prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser, a standard difficult to prove.
  • 1914–The Harrison Narcotic Act requires prescriptions for products exceeding the allowable limit of narcotics and mandates increased record keeping for physicians and pharmacists who dispense narcotics.
  • 1930–The name of the Food, Drug and Insecticide Administration is shortened to Food and Drug Administration (FDA) under an agricultural appropriation act
  • 1933–FDA recommends a complete revision of the obsolete 1906 Food and Drugs Act. The first bill is introduced into the Senate launching a five year legislative battle. FDA assembles a graphic display of shortcomings in pharmaceutical and other regulation under the 1906 act. Dubbed by one reporter as the Chamber of Horrors, the display is exhibited nationwide to help draw support for a new law.
  • 1937–Elixir Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law.
  • 1938–The Federal Food, Drug and Cosmetic (FDC) Act of 1938 is passed by the Congress containing new provisions.
    • Extending control to cosmetics and therapeutic devices
    • Requiring new drugs to be shown to be safe before marketing, starting a new system of drug regulation
    • Eliminating the Sherley Amendment required to prove intent to defraud in drug misbranding cases
    • Providing that safe tolerances be set for unavoidable poisonous substances.
    • Authorizing standards of identity, quality, and fill-of-container for foods
    • Authorizing factory inspections5
    • Adding the remedy of court injunctions to the previous penalties of seizures and prosecutions.
      FDA says that sulfanilamide and selected other dangerous drugs must be administered under the direction of a qualified expert, thus launching the requirement for prescription only (non-narcotic) drugs.
      Under the Wheeler-Lea Act, the Federal Trade commission is charged with overseeing advertisements associated with products otherwise regulated by FDA, with the exception of prescription drugs.
  • 1941–Insulin amendment requires FDA to test and certify purity and potency of this life saving drug for diabetes.
    Nearly 300 deaths and injuries result from distribution sulfathiazole tainted with the sedative, Phenobarbital. The incident prompts FDA to revise manufacturing and quality controls drastically, beginning of what would later be called Good Manufacturing Practices (GMPs).
  • 1945–Penicillin Amendment requires FDA testing and certification of safety and effectiveness of all penicillin products. Later amendments would extend this requirement to all antibiotics. In 1983 such controls would be found no longer necessary and abolished.
  • 1948–Supreme court rules in US versus Sullivan that FDA's jurisdiction extends to retail distribution, thereby permitting FDA to interdict in pharmacies illegal sales of drugs- the most problematic being barbiturates and amphetamines.
  • 1955–FDA denies a new drug application for the cancer drug, Hepasyn, on the grounds that it was not proven safe because it was not proven effective, an important consideration for a serious disease in which other useful therapies existed. In 1961 the agency was challenged in a hearing over the same issue involving an anti-infective drug, Altafur, which was decided in FDA's favor.
  • 1962–Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in Western Europe. News reports on the role of Dr. Frances Kelsey, FDA Medical Officer, in keeping the drug off the US market, arouse public support for stronger drug regulation.
    Kefauver-Harris Drug Amendments. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them.
  • 1963–Advisory Committee on Investigational Drugs meets, the first meeting of a committee to advise the FDA on product approval and policy on an ongoing basis.
  • 1965–Drug Abuse Control Amendments are enacted to deal with problems caused by abuse of depressants, stimulants and hallucinogens.
  • 1966–FDA contracts with the National Academy of Sciences/National Research Council to evaluate the effectiveness of 4,000 drugs approved on the basis of safety alone between 1938 and 1962.6
  • 1968–FDA forms the Drug Efficacy Study Implementation (DESI) to implement recommendations of the National Academy of Sciences investigation of effectiveness of drugs first marketed between 1938 and 1962.
  • 1970–In Upjohn vs Finch the Court of Appeals upholds enforcement of the 1962 drug effectiveness amendments by ruling that commercial success alone does not constitute substantial evidence of drug safety and efficacy.
    FDA requires the first patient package insert oral contraceptives must contain information about the specific benefits and risks.
  • 1977–Introduction of the Bioresearch Monitoring Program as an agency wide initiative ensures the quality and integrity of data submitted to FDA and provides for the protection of human subjects in clinical trials by focusing on preclinical studies on animals, clinical investigators, and the work of institutional review boards.
  • 1981–FDA and the Department of Health and Human Services revise regulations for human subject protections, based on the 1979 Belmont Report, which had been issued by the National commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The revised rules provide for wider representation on institutional review boards and they detail elements of what constitutes informed consent, among other provisions.
  • 1983–Orphan Drug Act passed, enabling FDA to promote research and marketing of drugs needed for treating rare diseases.
  • 1987–Investigational drug regulations revised to expand access to experimental drugs for patients with serious diseases with no alternative therapies.
  • 1989–The FDA issues guidelines asking manufacturers to determine whether a drug is likely to have significant use in elderly people and to include elderly patients in clinical trials if applicable.
  • 1991–Regulations published to accelerate the Review of Drugs for life threatening diseases.
  • 1992–The US FDA with Japan and Europe establish the International Conference on Harmonization (ICH). The ICH works to reduce the burden on regulation by harmonizing the regulatory requirements in the three regions.
    Prescription Drug User Fee Act (PDUFA) requires drug and biologic manufacturers to pay fees for product applications and supplements, and other services. The act also requires FDA to sue these funds to hire more reviewers to assess applications.
  • 1993–A consolidation of several adverse reaction reporting systems is launched as Med Watch, designed for voluntary reporting of problems associated with medical products to be filed with FDA by health professionals
    Revising a policy from 1977 that excluded women of child bearing potential from early drug studies, FDA issues guidelines calling for improved assessments of medication responses as a function of gender. Companies are encouraged to include patients of both sexes in their investigations of drugs and to analyze any gender-specific phenomena.7
  • 1995. FDA declares cigarettes to be ‘drug delivery devices”
  • 1998. The Adverse Event Reporting System is a computerized information database designed to support the FDA's post-marketing safety surveillance program to approved drug and therapeutic biologic products. The ultimate goal of AERS is to improve public health by providing the best available tools for storing analyzing safety reports.
    The Pediatric Rule requires manufacturers of selected new and existing drug and biological products to conduct studies to assess their safety and efficacy in children.
    The FDA approves the use of Thalidomide for the treatment of Hansen's disease. In tandem with the approval FDA invokes an oversight program designed to help ensure a zero tolerance policy for Thalidomide exposure during pregnancy.
  • Clinical Trials. Govt is founded to provide the public with updated information on enrollment in federally and privately supported clinical research, thereby expanding patient access to studies of promising therapies.
    FDA publishes guidance for electronic submissions that provide for the receipt and archiving of a new drug application entirely in electronic format without any accompanying paper archival copy.
    These are some of the milestone amendments and announcements that the FDA made over the years relating to clinical research, protection of subjects in clinical research, steps to ensure wider patient participation in clinical research. This reflects the concern of the regulators and the process to involve all stakeholders in decision making to ensure compliance and effective implementation.
    The pharmaceutical industry also made significant progress from early 20th century and contributed to the understanding of disease and making available many drugs to combat many diseases.
    It will be clear from the following points how the drug development and regulatory requirements progressed in tandem:
  • 1921–Insulin was discovered.
  • 1928–Penicillin was discovered
  • 1938–Anti epileptic drugs without sedating effects
  • 1940–Anti coagulant - Warfarin
  • 1943–Streptomycin
  • 1948–Methotrexate approved as the first anti cancer drug
  • 1950–Relationship between Cortisol and inflammation
  • 1951–Mono Amine Oxidase inhibitors for Depression
  • 1952–Chlorpromazine for psychosis
  • 1953–6 Mercapto Purine for leukemia
  • 1954–Polio vaccine
  • 1958–Thiazide diuretics
  • 1960–Benzodiazepines8
  • 1963–Measles vaccine
  • Nalidixic acid – forerunner of quinolones
  • 1966–Allopurinol for Gout
  • 1967–First beta blocker – Propranolol
  • US FDA approves first drug for renal transplant rejection
  • 1972–Second generation inhalation anesthetic – Enflurane
  • 1973–Progesterone only oral contraceptive
  • 1976–First ACE inhibitor captopril
  • 1977–First H2 blocker – Cimetidine for acid peptic disease
  • 1983–Cyclosporin for transplant rejection
  • 1986 Interferon – birth of recombinant technology
  • 1986–Monoclonal anti body for renal transplant
  • 1987–SSRIs for depression
  • 1987–Azidothymidine
  • Ciprofloxacin – first quinolone
  • 1989–Erythropoietin for anemia of renal failure
  • 1990 Atypical anti psychotics for schizophrenia
  • 1993–Tetra hydro amino acridine for alzheimer's disease
  • 1990s–Nanoparticles and Liposomal entrapped drugs for targeted drug delivery.
 
CLINICAL RESEARCH IN INDIA — 1950-1987
 
Regulatory Agency
India has been a branded generic pharmaceutical market. The Patent Act was amended in 1970 to withdraw product patent. Clinical trials were not mandatory to obtain new drug approval. The first amendment to the Drugs and Cosmetics Act relating to new drug approval was made in 1987 by Schedule ‘Y’, when the first applicant had to conduct clinical trials in 100 patients and, subsequent applicants were required to establish bioequivalence with the first product.
Progress of clinical research is directly proportional to the regulatory requirements laid down by the national agency that in turn reviews and modifies regulations as the drug discovery programs of the pharmaceutical industry become progressively complex.
 
Institutional Review Boards
There have been islands of excellence and contribution to global knowledge base through clinical trials in India. Examples are, Prostaglandins in Fertility Control and Maternal health, injectable and implantable contraceptives.
Consequently, composition of Institutional Review Boards (IRBs), their perception of responsibilities towards clinical research was not in consonance with international standards. The IRBs were mainly responsible for approving government funded research projects and academic research.9
 
Medical Professionals
Most of the members of the medical community were not engaged in clinical research, especially at an international level. They were involved in a few studies for local regulatory approval. Hence, their exposure and experience with various global guidelines, regulatory requirements, etc. was minimal. Since the average faculty member of any institution in India is inundated with patients, the voluminous source documentation required or global studies were not practical in India. Most of the clinicians were involved in research funded by various government agencies and, a few international agencies like the WHO, World Bank, UNICEF, etc. Medical education in India does not include details of drug development and research methodology as part of curriculum.
The country's medical professionals could not contribute to various globally important clinical trials that significantly changed the concepts of medical practice in the fields of cardiology, metabolic disorders, hypertension, etc. Practice of medicine was based more on individual opinion than evidence-based medicine.
 
Pharmaceutical Industry
The Indian segment of the pharmaceutical industry was concentrating on process research for Active Pharmaceutical Ingredient, product and formulation development between from 1950 till few years ago. Since there was no requirement and incentive for clinical research and, product registration was not dependent on evidence showing efficacy and safety, there was no impetus for the industry to conduct clinical research.
The indigenous pharmaceutical industry depended extensively on published literature in international journals for product promotion. The multinational segment of the industry hardly carried out any clinical trials of their innovative products because of lack of patent protection and data exclusivity. Marketing of pharmaceutical products in a generic market was mainly driven by pricing and not much attention was paid by either the pharmaceutical industry or the users about the need to generate local data.
The absence of locally relevant clinical data also put the national regulatory agency in difficult situations during the same period. For example, the Drugs Controller General (India) did not have sufficient data to decide on the continuation of quinolines in the management of diarrhea. Similarly, there was no local data when the controversy about the use of Ketorolac in elderly patients arose in mid 90s. More recently, the national regulatory agency had to depend on data from outside India on the banning of prokinetic agents. Evidence based decisions could have been taken if there was sufficient local clinical data to help the national regulatory agency take decisions on matters relating to public health. Although this prompted the Drugs Controller's office to issue instructions to conduct post-marketing trials to document safety, this is followed more in breach than practice.10
This led to a chronic neglect of building a cadre of professionals to manage various aspects of industry-sponsored research. There was minimal awareness of clinical research as a career option for both medically qualified persons and professionals of other disciplines.
 
Media and Society
The Media was not covering the clinical research area since its attention was more on drug pricing, availability of drugs and, quality control standards of drugs. Medical research connected with family planning methods, control of national programs like TB and Malaria received more attention.
There were no attempts to educate the society at large about the complexities involved in drug research and development. The lay public was not aware of the cost and time taken to discover, develop and introduce a new drug. It was not found necessary to educate the public on various aspects of human research. No attempt was made to communicate constantly the need of the medical community to undertake research to make therapeutic interventions available to the society. It was also not found necessary to involve the society to enhance the public trust and confidence in medical research.
 
The Present Global Scenario of Clinical Research
The present scenario has evolved over the last thirty years because of:
  1. Tremendous progress of understanding the pathophysiology of diseases
  2. Opening of new frontiers in medicine – Immunology, Cellular basis of Malignancy, Cardiovascular diseases, Metabolism, Psychiatry and Neurology
  3. Discovery and development of drugs with precise and complex mechanism of actions and use of rDNA technology in treatment of a multitude of conditions
  4. Development of surrogate markers
  5. Advances in regulatory science
  6. Change in societal expectations
  7. Change in IRB norms
  8. Media explosion
  9. Incidents of fraud, misrepresentation of results in clinical research
  10. Increasing costs of drug development
  11. Shrinking patient base in traditional areas of research – US, Western Europe, Japan, Canada
  12. Need to reduce the cost and time of drug development
There are currently 23,168 drugs in various phases of development–Cancer 24.95, CVS 7.95, Infectious Diseases 10.95, CNS 10.5 percent, Immune System 5.1 percent, Hormonal 5.3 percent, Miscellaneous 6.1 percent and others 29.2 percent.
Out of the more than 90,000 trials performed globally, more than 60 percent are performed in the US. While the US FDA accepts foreign data to approve US FDA NDA's, it is interesting to recount that, while the number of foreign clinical trials 11submitted to US FDA as part of NDAs has increased from 43 clinical trials in 1980 to 5777 in 1990s, this number is still less than 10 percent of all global trials. It is very clear that the majority of clinical trials are still performed in the US, because the country accounts for approximately US $ 350 billion out of a global pharmaceutical market of US $ 500 billion.
The FDA recently reported (2003) that 25 percent of investigational new drug applications include critical data from studies conducted outside US. In 2001, the Department of Health and Human Services (US Government) office of the Inspector General reported that the number of foreign investigators conducting research under US FDA IND rose from 41 in 1980 to 271 in 1990 and 4,458 in 1999 (Fig. 1.1).
zoom view
Fig. 1.1: Objectives of progress in medicine
However, if the twin objectives of progress in medicine as depicted above are to be met, it is interesting to consider the following facts to determine if these could be met with efforts to expedite drug development are confined to the US and a few other countries.
The number of patients required per NDA has gone up from approximately 2800 patients in the 1970s to over 6300 in the late 1990s. While the US FDA review time for NDA is reducing (depending on the therapeutic category of drugs), the clinical development time is increasing from about 4 years in the 70s to over 6 years currently.
Some other facts also indicate that clinical development has to be globalized in order to meet the objective of getting the drugs to the patients in a timely manner at manageable costs.
While the USA remains an important geography for conduct of clinical trials of new drugs, the enrollment pattern and time taken to complete the same are not satisfactory.
  • 35 percent of delays due to patient recruitment
  • 15-20 percent of investigators DO NOT enroll ANY patients
  • 30 percent enroll 5 percent of evaluable patients12
  • 20 percent of the investigators are average performers
  • 30 percent are top performers – consistently enroll up to 70 percent patients in phase II and III trials
  • Patient retention rate in phase II and III trials – 70 percent (Ken Getz at the 2006 ACRP Annual meeting in Phoenix, AZ)
It is also important to remember that every patient not completing the study and lost to follow-up costs the pharmaceutical company approximately US $ 44,000 A DAY.
If one considers the pipeline of biotechnology and device industry, it is easy to recognize that clinical research confined to the US and Europe will not serve the interest of all the stakeholders. According to CenterWatch, 82 percent in Europe and 94 percent in the US miss the enrollment deadlines.
In a survey by Harris poll in 2004, it was noted that in the US, one in eight (13%) physicians is an investigator, 87 percent are not involved in clinical trials, about 34 percent participated in the past but not currently involved. With the continuous increase in the number of clinical trials being conducted and the number of subjects required for each trial, the demand for clinical investigators is increasing.
The clinical research environment in the US and Europe has had its fair share of problems.
One of the most worrisome features in the US is related to Phantom Investigators. Center Watch as early as in November 2001, reported the presence of Phantom Investigators. In 2000, the US FDA reported that the warning letters to investigators contain more citations of failure to personally conduct and supervise the clinical trials. In 2000, approximately 19 percent of investigators receiving warnings or the more serious Notice of Initiation of Disqualification and Opportunity to Explain (NIDPOE) were cited for failing to supervise their trials. Figures for 2001 indicate a three-fold increase in the number of investigators cited for improper/ insufficient supervision of clinical trials.
According to Center Watch (November 2001), an anecdotal analysis of 20 cases where principal investigators received warning letters from the FDA, the PI rarely accepted responsibility for failure to supervise the study. In 39 and 17 percent of the cases, study coordinators and nurses, respectively, received the blame.
Phantom Investigators are people who are delegating work to clinical staff. This is allowed, and individual staff responsibilities may be reflected appropriately in regulatory documents and site signature responsibility logs. However, the ability to delegate many aspects of clinical trial execution does not relieve the PI from fulfilling the principal responsibility of overseeing the conduct of the trial.
The same Center Watch article goes on to add that several major sponsors have also noted investigator absence. The FDA has observed that a number of investigators do not comprehend their extent of commitment while signing the 1572. It appears that many investigators do understand their responsibilities, but are too busy and must therefore delegate extensively. According to Center Watch, “there are a lot of 13overworked and undereducated people in the clinical research enterprise”. Gary Chadwick of University of Rochester IRB has the impression that the problem occurs in large research mills or dedicated clinical trial centers. Stan Woollen, former Acting Head of the US FDA's BioResearch Monitoring Information Service says that the FDA gets concerned when there is a long list of sub investigators in the 1572.
Before 2000, ORPP (office of Research Participant Protection) only supervised NIH funded studies in the USA. However, when OHRP (office of Human Research Protection) was formed in 2001, its charter included oversight of NIH funded and FDA regulated studies. This has led to a perceptible fall in the number of investigators cited for improper/insufficient personal supervision of clinical trials.
It must also be pointed out that the proportion of Academic Medical Centers involved in pharmaceutical industry sponsored clinical research fell from 63% in 1994 to 265 in 2004. One of the important reasons is the complex bureaucracy and delays in initiating clinical trials in academic trial centers. In a personal conversation with the author, a medium sized biopharmaceutical company mentioned that the average time for a local IRB was 280 days.
The UK does not seem to free of problems either. The cost of doing trials in the UK is among the highest in Europe and around ten times higher than in emerging areas in Eastern Europe, India and China (New Scientist, March 2006). Nevertheless, big pharmaceutical companies have preferred UK because of the heritage. According to a report by management consultancy firm McKinsey cited in New Scientist, the UK is squandering its best selling point. The massive patient base that the National Health Service (NHS) offers is a powerful research resource, but red tape and bureaucracy during trial approval are causing disruption and longer start-up times compared with many other countries.
The evidence is easy to find. If a company wants to set up a large trial across 30 different NHS sites, it needs to agree honorary contracts with each primary car trust. This means that a researcher working on the trial needs to have 30 different police checks, health checks, etc. Patient recruitment delays are also a problem. This is the result of a stretched NHS, where there are too few specialized clinical trial nurses, where clinicians fear they will slip in their career paths if they take time out for clinical research, and where foundation hospitals and GPs have no easy way of finding trials that are recruiting patients.
It must be conceded that the UK government has responded to calls for action with unusual vigor. In 2004, it created the UK Clinical Research Collaboration (UKCRC) to make the necessary changes, bringing together the NHS, funding and regulatory bodies, academic or voluntary sector organizations, academia and industry.
One of the UKCRC's first jobs was to find a better way to coordinate trials nationwide, so it set up the Clinical Research Network (UKCRN). The research network controls a number of smaller networks specializing in specific disease areas. The first of these, set up before UKCRC, focuses on cancer research. It has doubled patient recruitment in just three years. This was followed by mental health network 14focusing on dementia and neurodegenerative disease, diabetes, strokes and medicines for children.
Another idea under consideration is the introduction of research “passport”. It means that researchers need complete honorary contracts with one primary care trust for it to be recognized by all the others.
Meanwhile, academic clinicians are being encouraged to get involved with clinical research with a new career track, which has been developed in under a year. This means doctors wishing to pursue clinical research will not be penalized on their route to achieving consultant status. It should also speed up patient recruitment by meeting the shortage of skilled researchers.
There is also a plan for new R and D strategy for the NHS that proposes to tackle red tape and access to funds for the researchers. The potential is enormous – 52 million patient records will allow for phenomenal research that could benefit society, for example enabling active surveillance of drug safety.
However, this strategy and action plan does have its critics who label it as “incoherent” and biased towards the industry.
The present is merging imperceptibly with the future. There is no time for any one to wait to prepare for the future. The future is now and, many stakeholders at many places are gearing to meet the challenges of increasing complexity of drug development in the future.
Some important developments have already begun in clinical development. These include.
 
ADAPTIVE TRIAL DESIGN
 
Adaptive Sampling Designs
Adaptive sampling designs, also called response adaptive designs, for statistical experiments are ones where the accruing data from trials (i.e., the observations) are used to adjust the experiment as it is being run. Typically, decisions as how to sample during an experiment are made and fixed in advance. For example, in a classical clinical trial, patients are allocated to one of two different treatment options with half being assigned to each therapy. At the end of the experiment a decision is made as to which treatment is more effective. In contrast, in an adaptive clinical trial, patient outcomes can be used as they become available to adjust the allocation of future patients. This allows one to improve expected patient outcomes during the experiment, while still being able to reach good statistical decisions in a timely fashion. Thus adaptive procedures can offer significant ethical and cost advantages over fixed standard procedures. A situation in which adaptive procedures have become particularly relevant are AIDS clinical trials, since many new drugs come to market, yet classical randomized studies may pose ethical dilemmas and time delays.15
Unfortunately, adaptive procedures are more complicated to design and to analyze, and in some settings more difficult to implement. Notwithstanding this and other issues, the US FDA has given is considering adaptive clinical trial designs for AIDS. The objective is to strengthen ethics while expediting drug development (Janis Hardwick and Quentin F. Stout – Computer Science, University of Michigan, Ann Arbor).
 
Translational Research
Translational Research is already happening in oncology. Attempts are made to discover sensitive and predictive biomarkers for various cancers. Predictive biomarkers are supposed to identify patients that will improve with continued therapy.
Translational research is really about trying to bring together the progress we are making in the laboratory with the progress we are making in the clinic – Robert C. Bast Jr. Vice President of the office of Translational Research – University of Texas M.D. Anderson Cancer Center in OncoLog, March 2004.
Translational research focuses on identifying new drugs, antibodies or genes that would either neutralize the oncogenes, the ‘accelerators” that turn tumor growth, or would replace the “brakes” on cell growth, the dysfunctional tumor suppressor genes. Targeted therapy can also intervene in the signaling pathways of cancer cells so that cancer cells would be stimulated to self-destruct, whereas normal tissues would be spared.
 
GLOBALIZATION OF CLINICAL RESEARCH
In the existing scenario, globalization is inevitable. Drugs will be made for patients all over the world and, while clinical trial subjects will continue to come form traditional areas of the US and Europe, many emerging countries like India, South Africa, Latin America, Thailand, etc. will contribute patients for a large number of clinical trials.
With globalization we need to consider some important factors, especially those relating to patient demographics. For example, in a study among participants in AIDS clinical trials in Canada revealed that the number of women was gradually increasing.
One of the best illustrations of the lack of inclusion and representation of target populations in drug trials is the common practice of excluding elderly subjects. This group, the most rapidly growing segment of the population, is often underrepresented in clinical research. For example, NSAIDs are commonly used in elderly because of the high prevalence of musculoskeletal disorders, especially in women. However, in the major drug trials evaluating NSAIDs, only 2.1 percent of patients were 65 years of age or over and less than 0.1 percent were over 75. In practice, elderly people are among the largest users of drugs and have the highest incidence of drug related side effects.
Elderly people who are included in clinical trials are generally younger and predominantly male. The inclusion of older, frailer individuals in drug trials presents 16investigators with challenges, including the increased likelihood that these patients may be unable to complete the trial for a variety of reasons. At the same time it must be borne in mind that it is these patients who are commonly prescribed drugs for hypertension, heart failure, arthritis, etc.
 
FUTURE TRENDS
India can exploit the following attributes to play a meaningful role in global clinical development programs:
  • Legal system
  • Regulatory mechanism
  • Exposure to basic and industrial research
  • Growing pharmaceutical sector
However, it is extremely important to pay attention to the expectations and needs of all the stakeholders.
 
REGULATORY AGENCY
The office of the Drugs Controller General (India) recognized in time the growing importance of clinical research and took appropriate steps to ensure synchronization of the regulatory systems with ICH requirements. The regulatory agency needs to implement its plans to conduct regulatory inspections of clinical trial sites. It may be appropriate to initiate this program by identifying studies conducted by Indian companies. The global pharmaceutical companies have tried and tested quality assurance, audit and inspection mechanisms. The Indian sector has embarked on a serious clinical trial program and, regulatory inspection of these trials will certainly go a long way to enhance the credibility of such studies.
 
Pharmaceutical Industry and Service Providers
The pharmaceutical industry has enthusiastically welcomed the government's announcements about intellectual property and permission to conduct simultaneous phase global clinical trials. In a country like India that is democratic, it is essential for the sponsor to:
  • Exhibit consistency and uniformity of practices globally
  • Train the physicians and IRB members in all aspects of drug development and, not only clinical research and GCP
  • Eliminate conflict of interest by people involved in conducting clinical research. Maintain respectable investigator-sponsors relations
  • Do not use clinical research as a weapon in the public relations armamentarium. Use it to promote credible evidence
  • Let patient well being be the prime objective and responsibility of the physician
  • Make informed consent “truly informed”.17
 
Institutional Review Boards
Perhaps the toughest function among all stakeholders is that of the IRBs. The ethical issues surrounding:
  • Personalized medicine
  • Gene therapy
  • Early stage Translational clinical trials in cancer and HIV infections pose ethical, legal, intellectual, scientific and administrative issues. It is extremely important for the IRBs to engage in constant dialogue with the other stakeholders to enable them to protect participants while promoting science.
  • It might be useful if the IRBs review ongoing translational studies in oncology and HIV infections to appreciate the complexities relating to informed consent, patient well being, etc.
  • Accreditation of IRBs to national and international bodies must be actively encouraged.
 
Medical Profession
Currently, there is a dearth of physicians capable of conducting clinical trials. In such situations, the clinicians need to guard their professional integrity to maintain the confidence of the public in medical research in general and, clinical research in particular. The road of clinical research is strewn with examples of scientific misconduct and fraud. It will be useful for the investigators to remember.
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when evaluating a clinical trial protocol. This will help them to provide valuable inputs to the sponsors to develop appropriate protocols.
It will also benefit if the medical curriculum includes research methodology and statistical basis of clinical research in undergraduate courses. Medical students can inturn with pharmaceutical companies and CROs to gain practical insight into various aspects of drug development and clinical research and consider clinical research as a career option.
 
Media
Media does play a significant role in all walks of life. However, we cannot expect media to play the role of “patient educator”. It will continue to look for slips and falls. Will continue to ignore and downplay success stories and the positive contribution. All the stakeholders will have to continue to work at achieving success and progress despite the media and, not because of their help. Efforts should continue 18to educate the media. We should encourage participants of clinical trials to recount their experiences. The patients should be mobilized and invited to speak at clinical trial meetings.
 
Society
Progress is possible when there is active participation of the community. Currently, the efforts are scattered and not visible. In a highly literate country like the US less than 5 percent of the population participates in clinical research. If 5 percent of the Indian population participates in clinical research, we shall have 50 million patients. If we have modest targets, we can work towards achieving it. Even if we target 2 percent of the population in the next five years, it will take considerable planning and efforts to accomplish this. Progress without societal involvement is unthinkable. It is time for appropriate persons among various stakeholders to get together to involve the society on a proactive basis. A well-informed society is the best spokesperson for this endeavor to succeed.
 
Training
Training is the most crucial and rate limiting step in the process of clinical research. India can outperform China if we have a sound training program in place. Various estimates by investment bankers, analysts and others put the figure of patients participating in clinical trials in India by 2010 at 2 million. To achieve this, we need at least 40,000 clinicians (each investigator enrolling 50 patients. This is a far cry from the current rate of about 15 all over the world and, at the most 30 in India) and 200,000 clinical research professionals to manage this enterprise. This appears almost impossible. Even if one targets at 10 percent of this number, India can provide up to 200,000 patients by 2010. This would need about 4,000 physicians and 20,000 clinical research professionals such as CRAs, CRCs, Project Managers, Biostatisticians, Medical Writers, etc.
It is imperative for a collective effort to achieve this in a credible manner. All the stakeholders should supplement the very laudable efforts of Institute of clinical Research, India, Academy of Clinical Excellence and others.
 
SUMMARY
Indian clinical research enterprise can play a significant role in expediting global drug development if we identify the mistakes of the past committed around the world. We need to pay attention to:
  • Training
  • Prevention of fraud
  • Involve the society on a proactive basis
  • Pay attention to good science and sound ethics and commerce will follow.19
We need to view the past, understand the present to be able to predict the future.
Success in clinical research is a challenge to the professionalism, integrity and trust of all the stakeholders.
SUGGESTED READING
  1. Center Watch – Chasing Away Phantom Investigators, November 2001
  1. Ethical and Policy Issues in Research involving Human Participants. National Bioethics Advisory commission.   Bethesda,  Maryland USA., August 2001
  1. FDA Centennial. Exclusive Executive Report by FDA News. 2006
  1. James Love. The Scientist. Vol. 17, issue 7. p 46. April 11, 2005
  1. Janis Hardwick and Quentin Stout. Computer Science, University of Michigan,   Ann Arbor,  MI, ISA emails: jphard@umich.edu and qstout@umich.edu
  1. Kenneth A. Getz. In Center Watch, Applied Clinical Trials, etc.
  1. New Scientist, March 2006
  1. OncoLog. M. D. Anderson's report to physicians about advances in cancer research
  1. Richard A. Rettig Industrialization of clinical Research. Health Affairs, March/April 2000
  1. Richard Horton. Controlled Clinical Trials. 2001;22:593-604
  1. Scott Gottlieb, MD. Deputy Commissioner US FDA. Speech before 2006 Conference on Adaptive Trial Design,   Washington  DC., July 2006
  1. The Globalization of Clinical Trials. A Growing Challenge in Protecting Human Subjects. Janet Rehnquist, Inspector General, Department of Health and Human Services, September 2001.