Understanding The Regulatory Regime For Clinical Trials In India

History of the Legal Framework Concerning Clinical Trials in India

The pharmaceutical industry is largely governed by the Drugs and Cosmetics Act, 1940 as the umbrella legislation along with the associated Drugs and Cosmetics Rules, 1945. Part XA and Schedule Y of these rules was the first systematic regulatory framework for clinical trials in independent India.

However the report of the Ranjit Roy Choudhary Committee in the year 2013 highlighted several shortcomings in the incumbent framework, which was buttressed by the opinion of the Supreme Court in the case of Swasthya Adhikar Manch, Indore v. Ministry of Health and Family Welfare. Therefore significant amendments were introduced by the way of the Drugs and Cosmetics (Third Amendment) Rules, 2013.

It was only in Kalpana Mehta v. Union of India, that the Supreme Court came to note that the blatant violation of human rights that occurs when minor girls and other members from vulnerable communities are forced to become subjects for clinical trials without even apprising them of the adverse effects it may have on their health. Therefore, the Apex Court directed the Central Government to bring about an overhaul in the regulatory regime with roper checks and balances in place to ensure fair conduct of clinical trials. When the government failed to respond within the given time, it gave an ultimatum of two weeks' time for formulation of the new rules, following which draft rules for a new framework were submitted for public consultation. Finally, in March 2019, the incumbent New Drugs and Clinical Trial Rules, 2019 (the Rules) were adopted.

Clinical Trials: The Application

Before initiating clinical trial, an applicant is first required to submit an application to the Central Licensing Authority (CLA) of the Central Drugs Standards Control Organisation (CDSCO). The Drugs Controller General of India (DCGI) usually acts as the CLA. However, before such application can be preferred, it is important that the applicant collect data of pre-clinical studies. These are studies conducted on animals resembling immune systems similar to humans. These studies provide the preliminary data regarding the prospects of a vaccine.

Alternatively, the applicant can also choose to have pre-submission meetings and discussion with the CLA to gauge the prospects of approval. The subject-expert committees scrutinize the application in this regard.

The application when submitted along with results of pre-clinical studies, must be either accepted or rejected within 30 days, if the drug is sought to be manufactured in India and within 90 days, if the drug is sought to be manufactured outside India. In case, the CLA gives no response within the prescribed time limits, it is deemed that the approval has been granted.

There are only two circumstances under which there is no requirement of submitting an application. These are:

• When the drug is sought to be manufactured solely for academic purposes, and
• When the drug has already received approval for marketing in any of the countries listed in the Schedule.

Parallelly, the applicant is also required to secure approval of the Ethics Committee (EC). This is a committee constituted by the applicant himself however, there are statutory guidelines for its constitution, for example, it must consist a minimum of 7 members, half of them must be independent members having no relation to the applicant, it must adequate representation from medical experts, pharmacologists, general laymen of society etc.

A clinical trial consists of three primary constituents, the sponsor, the investigator and the subjects. . The sponsor is vested with funding the trial and arranging for logistical requirements, such as a safe venue for the trial, equipment, laboratories, tools etc. A sponsor may be a natural person or a medical institution. The investigator is a qualified pharmacologist who carries out the trial and the subjects are the humans on whom the trial is conducted.

Clinical Trials: The Procedure

After getting the approval, the applicant may begin the clinical trial, which consist of four phases. The first phase consist of clinical pharmacological study in which the drug is tested for any adverse effects on human. For this, not more than 2-3 healthy humans are selected and they are administered the drug to ensure that the drug does not cause any severe adverse effect on humans.

Post this, phase two of the trial, also known as the exploratory phase commences. Under this phase, a homogenous group of 10-12 people, that is, people of the same age group, having similar medical histories etc. are selected and the therapeutic effects of the drug on this group are recorded. If positive results are obtained during the second phase, the researcher may proceed with the third and the most important phase.

The third and the most important phase called the confirmatory phase involves testing the drug on thousands of people, heterogeneous in their age groups, genders, medical histories and physiological factors.

Once the CLA is satisfied of the success of phase three, the approval for large scale manufacturing and market distribution of the drug is given.

There also exists a fourth phase, called the 'Post-Approval Studies'. It involves further research on more intricate aspects of the drug, after the approval for its development on a large scale has been given.

Principles Governing Clinical Trials

The subjects which are chosen for the trial must be duly informed of the entire treatment that is to be meted out to them along with the possible side effects if any. This is to guarantee informed consent of those on whom the new drug shall be tried. The consent has to be voluntary and in writing. The subject must be informed that he or she has the right to withdraw from the procedure at any time. Relatives of the subject also possess the Right to Information and ask the investigator about any doubts that they might have. If the subject is a minor, due consent must be obtained from the legal guardian.

Along with this, the investigator must commit to keep medical records and other information pertaining to the subjects completely confidential.

Prior to the commencement of the trial, the sponsor and the investigator are required to enter into a Pre-Trial Agreement, which has clauses providing for the responsibilities of each of them, fees to be paid by the sponsor, the standard of care to be ensure by the investigator etc. It also consists of a detailed Standard Operating Procedure (SoP) which lays down the step-by-step procedure to be followed by the investigator. The investigator is obligated with providing detailed records of results and progress made. Each subject must have a separate Case Report Form (CRF). The same have to be submitted by the investigator to the authorities. The sponsor may appoint a monitor in his discretion, who shall oversee that the investigator is carrying out the trial as per the agreement and the SoP.

Throughout the process of the trial, the investigators are required to adhere to three cardinal principles of clinical trials, as provided by the Helsinki Declaration, 1964. They are:

• Justice
• Respect for Persons
• Beneficence

International Standards for Clinical Trials

When it comes to international legal standards for clinical trials, the WHO Guidelines on Good Clinical Practices for Trials on Pharmaceutical Products, 1995 form the model law. Regulatory frameworks of most prominent jurisdictions are based on the WHO guidelines. However, some of the salutary provisions in these frameworks which may also be adopted by India have been discussed below.

1. Clinical Trial Networks: The U.S. framework has provisions for collaboration with other countries in case there exists a scenario where more than one countries are simultaneously working on developing a drug. It allows investigators of U.S.A to join other clusters across the globe conducting similar trials.

The Indian framework lacks such a provisions. However, such a provision is of extreme importance, especially in current times when the entire world is trying to develop a vaccine for a single virus.

2. Tiered structure: The EU divides its clinical trials into three categories- (1) Clinical Trials, (2) Low-Interventional Studies and (3) Non-interventional studies. While the EU Regulation No. 536/2014 is not applicable to non-interventional studies, it applies to low-interventional studies only in a limited sense. Low-interventional studies involve use of non-authorized is their use is evidence-based and supported by the published scientific evidence. These trials should not pose more than a minimal additional safety risk or burden to participants compared to normal clinical practice.

While the Indian framework for clinical trials is appreciable on many counts, there is still some scope of improvements is some aspects. For example, India is yet to be member of the Pharmaceutical Inspection Co-operation Scheme despite repeated requests from industry stakeholders to the Centre in this regard. Similarly, there is a need for explanatory notes by DCGI, training institutes for ECs and investigators etc. The requirements for additional approval by the Genetic Engineering Approval Committee (GEAC) in certain cases also makes the process more time-consuming and increases the regulatory hassles.

Despite these, the silver lining is that ICMR is constantly working to better the Indian framework. For instance, talks are under way to develop specialized clinical trial centers affiliated with ICMR, which will overhaul the current lengthy procedure. Similarly, a relaxation in some norms has been given in light of efforts to develop a vaccine for COVID-19. With this, one can only hope that the otherwise stringent regulatory framework for clinical trials in India does not pose as a hindrance for development of a COVID-19 vaccine.