Regulatory Requirements for Clinical Trials

I. Introduction:

India is one of the major destination for conducting clinical trials. The Drug Controller General of India (DCGI) is the governing body responsible for all pharmaceutical-research and regulatory issues in India. While conducting clinical trials in India, regulations have come to ensure safety and wellbeing of the study subjects in the trial.

In 2005, India became fully compliant to TRIPS. Since then the policymakers have been trying to make changes in the policy framework and regulatory environment in order to promote clinical trials in India. These changes are known to have encouraged the international Clinical Research Organisations (CROs) to expand their clinical research. Recently, pharmaceutical companies that are involved in clinical trials are being trailed by a growing concern over the clinical research ethics followed in India. Global pharmaceutical companies are outsourcing their projects to India for several reasons: enhancing profit, cutting the cost of drug development and speeding regulatory approval and fostering a less hostile environment among the worldʹs impoverished ill. Clinical trials are more than 50 per cent cheaper in India compared to developed countries (Jayaraman, 2004; Singh. 2008; Bigoniya et al., 2010; Bajpai, 2013). The reasons for low cost of drug development are cheap human resource, low recruitment cost and lower rate of compensation for any injury sustained or death during the research process. In fact, CROs even recruit patients without any formal assurance of compensation because a large proportion of participants in India are illiterate and lured into trials by offers of free healthcare and financial inducements. However, they are often unaware of the benefits and risks of taking part in a trial, and many may not even be able to distinguish between treatment and research. Also, the concept of informed consent before enrolling in a trial is not very clear.

II.Human Clinical Trial Phases:

The process of human testing of experimental drugs and devices is conducted in four phases as described below.

CDSCO regulates the clinical trials for drugs and medical devices in India. Demonstration of safety and efficacy of the drug product for use in humans is essential before the drug product can be approved for import or manufacturing and marketing in the country. The Rules 122A, 122B and 122D, 122 DA, 122DAA, 122E of Drugs and Cosmetics Rules and Annexure A, B, C and D of Schedule Y, describe the information/data required for approval of clinical trials and/or to import or manufacture of new drug for marketing in the country.

Document Requirements for Approval of Clinical Trials (Phase-I/II/III/IV):

For new drug substances discovered in India, clinical trials are required to be carried out in India right from Phase I. For new drug substances discovered in countries other than India, already conducted Phase I data is required along with the application. After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat Phase I trials and/or to conduct Phase II trials and subsequently conduct Phase III trials.

For permission of such clinical trials the documents required to be submitted are as follows:

1. Form 44.
2. Treasury Challan of INR 50,000 (for Phase- I) / 25,000/- (for Phase-II/III clinical trials).
3. Source of bulk drugs /raw materials.
4. Chemical and pharmaceutical information including: a) Information on active ingredients, b) Data on Formulation.
5. Animal Pharmacology.
6. Animal Toxicology.
7. Human / Clinical pharmacology (Phase I).
8. Therapeutic exploratory trials (Phase II).
9. Therapeutic confirmatory trials (Phase III).
10. Special studies – Bio-availability / Bio-equivalence.
11. Regulatory status in other countries.
12. Prescribing information.
13. Application in Form -12 alongwith T-Challan of requisite fees (in case of import of investigational products).

III. Different Phases:

Below are each of the phases described in detail. The number of study subjects and sites to be involved in the conduct of clinical trial will depend upon the nature and objective of the study.

a. Phase I Clinical Trials:

• Phase I clinical trials should usually be carried out by investigators trained in clinical pharmacology and having the necessary facilities to closely observe and monitor the subjects.
• These may be carried out at one or two centers.
• At least 2 subjects should be used on each dose.
• The documents required for Phase I Clinical Trials are:
  1. Systemic Toxicity studies
     1. Single dose toxicity studies
     2. Dose Ranging Studies
     3. Repeat-dose systemic toxicity studies
  2. Male fertility study
  3. In-vitro genotoxicity tests
  4. Relevant local toxicity studies with proposed route of clinical application (duration depending on proposed length of clinical exposure)
  5. Allergenicity / Hypersensitivity tests (when there is a cause for concern or for parenteral drugs, including dermal application)
  6. Photo-allergy or dermal photo-toxicity test (if the drug or a metabolite is related to an agent causing photosensitivity or the nature of action suggests such a potential)

b. Phase II Clinical Trials:

• Phase II clinical trials should normally be carried out on 10-12 patients at each dose level.
• These studies should usually be carried out at 3-4 centers by clinicians specialized on the concerned therapeutic areas and having adequate facilities to perform the necessary investigations for efficacy and safety.
• The documents required for Phase II Clinical Trials are:
  1. Summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I trial.
  2. In case of an application for directly starting a Phase II trial – complete details of the nonclinical safety data needed for obtaining the permission for Phase I trial, as per the list provided above must be submitted.
  3. Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure.
  4. In-vivo genotoxicity tests.
  5. Segment II reproductive/developmental toxicity study (if female patients of child bearing age are going to be involved).

c. Phase III Clinical Trials:

• If the drug is already approved/marketed in other countries, phase III data should generally be obtained on at least 100 patients distributed over 3-4 centres
• If the drug is a new drug substance discovered in India and not marketed in any other country, phase III data should generally be obtained on at least 500 patients distributed over 10-15 centres.
• The documents required for Phase II Clinical Trials are:
  1. For Phase III Clinical Trials Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I and II trials, with appropriate references.
  2. In case of an application for directly initiating a Phase III trial – complete details of the non-clinical safety data needed for obtaining the permissions for Phase I and II trials, as per the list provided above must be provided.
  3. Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure
  4. Reproductive/developmental toxicity studies:
     1. Segment I (if female patients of child bearing age are going to be involved), and
     2. Segment III (for drugs to be given to pregnant or nursing mothers or where there are indications of possible adverse effects on foetal development)

d. Phase IV Clinical Trial:

Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I, II and III trials, with appropriate references. In case an application is made for initiating the Phase IV trial, complete details of the non-clinical safety data needed for obtaining the permissions for Phase I, II and III trials, as per the list provided above must be submitted.

Permission to carry out these trials shall generally be given in stages, considering the data emerging from earlier Phase(s). CDSCO will initially examine such applications, if any particular data is lacking, the applicant will be informed  or else the applications will be forwarded to the members of IND committee in case of Investigational New Drugs (INDs) or to the members of New Drug Advisory Committee (NDAC) in case of new chemical entities other than IND.

IV. Conclusion:

Clinical trials are absolutely necessary for medical research. Human subjects are required to ensure safe and effective drugs and medical devices. The goal of these trials is to provide the public with innovative and safe products whose benefits outweigh the risks. Informed consent is the most important and potentially the easiest way to minimize exposure to liability for all parties involved in clinical trials. All participants in clinical trials will benefit from full, freely given and informed consent. Researchers must strive to adhere to established standards of conduct and approved protocols for their particular trial. Clearly, as in all medicine, all results, actions and patient interaction must be clearly documented. Although litigation can be anticipated, clinical trials ultimately serve to advance medicine and develop newer and better medical products and treatments and are invaluable medical research tools. The increased of clinical drug trials by pharmaceutical companies striving to bring more drugs to market is leading to a growing volume of lawsuits being filed by trial participants. The participants who file the suits frequently charge that they were inadequately warned of potential risks of the trials. But despite measures taken, some observers say there has been an increase in the number of cases filed by unhappy participants, or their survivors. Clinical trials are likely to remain a potential hot, bed of litigation if those trails are not managed appropriately and appropriate attention is not given to fulfilling the ongoing duty to provide informed consent information to patients. The developments in this sector individually and collectively may have significant implications for the future of human subject’s research. Expanded tort liability and increased government regulation will have a chilling effect on medical research, slowing down or even completely discouraging promising clinical trials. If researchers, hospitals and medical schools take appropriate steps to protect the dignity and rights of those willing to participate in the important cause of advancing medical research, they will increase the pool of volunteers, facilitate the conduct of clinical trials and restore some of the confidence lost in the wake of recent abuses. The research community should take this early experience as a warning and should reflect carefully on practices where research involving human subjects is concerned. As a result of the many claim promoting conditions that have been outlined, researchers are likely to be visited by tort litigation to an extent heretofore unknown. The sunny view of this trend is that the best aspects of the current regulatory regime that is, self-regulation driven by professional integrity will be preserved, but litigation will promote more attention to detail and increased public accountability. More likely, as litigation increases, the future of human subjects’ research will feature a more grinding regulatory approach.