Recommendation

The RRC Report recommended the creation of a single Technical Review Committee (TRC) to replace the 12 new drug advisory committees that currently review applications. This committee was to be assisted by subject-specific experts to be selected from a Roster of Experts that would be set up after a nationwide search.

Implementation

Although a single body has not yet replaced the 12 different committees, the latter have instead been constituted into Subject Expert Committees (SECs) [4], with the members for each meeting to be drawn randomly from a pool of experts. CDSCO has also passed an order approving 25 panels of experts in various therapeutic areas [5]. In addition to these expanded SECs, a High-Powered Expert Committee, also known as the Technical Committee, has been set up to meet monthly and review the recommendations of the SECs. These are then approved, rejected or sent back to the SECs with modifications. Together, these committees have ensured that a high degree of scientific rigour is now brought to the review process, and detailed reasons are provided while approving or rejecting applications for clinical trials, in accordance with the directions of the SC.

This reorganisation has also considerably speeded up the approval process. Under the earlier setup, decisions were often stalled because committees had not met in over a year, or even if one or two members of the committee were absent [Reference Shankar6]. However, the new processes put in place by CDSCO have ensured that applications are speedily, yet competently reviewed, bringing the pendency level down to zero [Reference Singh7]. It will be interesting to observe whether the efficiency of the new system can be maintained when the volume of clinical trial applications increases.

Recommendation

The RRC Report recommended the accreditation of the different stakeholders involved in clinical trials, including principal investigators, trial sites and Ethics Committees. The report also stated that a Central Accreditation Council ought to be set up to put in place this accreditation.

Implementation

Even before these recommendations were published, the Drugs and Cosmetics Rules, 1945 (the Rules) had been amended in 2013 requiring Ethics Committees to obtain registration from the Licensing Authority before they could be permitted to review clinical trial protocols [8]. To bring this rule into effect, CDSCO has put in place a system for the pre-screening of applications for registration by Ethics Committees. A checklist of documents required to be submitted by these committees has also been made available.

Commendable, large-scale efforts have been made to ensure rigorous training for the members of Ethics Committees. Over 800 members have undergone training through programmes conducted by two organisations – the Clinical Development Services Agency, a unit of the Department of Biotechnology and CREATE, a consortium of the All India Institute of Medical Sciences, Christian Medical College, Vellore and the Forum for Ethics Review Committees in India.

Simultaneously, steps have been taken to put in place a system for the accreditation of clinical trial centres and principal investigators. The Quality Council of India, an autonomous body that was set up to introduce National Accreditation Programmes, has been entrusted with this responsibility and is currently in the process of reviewing Standard Operating Procedures and developing standards for quality assurance during the accreditation of investigators, trial sites and Ethics Committees. Ethics Committees will be accredited in the first phase, followed by clinical trial centres and Ethics Committees. The newly created Department of Health Research will be a partner in this massive exercise. Accreditation will provide a sense of confidence that the trials will be carried out ethically and that participants will be protected.

However, in order to have teeth, the accreditation process must eventually be accompanied by a legal prohibition on conducting trials at non-accredited centres and through non-accredited investigators.

Recommendation

The legal provisions on compensation have created much uncertainty because of frequent amendments, posing problems for participants and sponsors alike. The RRC Report recommended that compensation be related to causality, that it need not be provided for the therapeutic inefficiency of an investigational product and that strong provisions be made for providing ancillary care for other illnesses during the trial.

Implementation

The CDSCO has clarified that compensation is to be provided to participants or their nominees even in cases of injury or death discerned at a later stage, so long as such injury or death is determined to be trial-related [9]. The amended Rules also state that compensation will be payable for failure of the investigational product to provide the intended therapeutic effect or for the use of placebo in a placebo-controlled trial only where the standard care, although available, was not provided according to the clinical trial protocol. Although the intent of this amendment was to reduce the open-ended financial liability of sponsors under the earlier version of the Rules [10], clarification regarding the definition of ‘standard care’ is still required to ensure complete certainty regarding the obligations of sponsors.

An office order passed in July 2014 also requires sponsors to provide ‘ancillary care’ to trial participants suffering from any other illness during the trial [11]. Again, this phrase must be defined more clearly in order to ensure that sponsors are not required to bear the expenses of entirely unrelated illnesses suffered by participants during the trial.

CDSCO has also set up Expert Committees to frame formulae that will be applied to determine compensation, both for death as well as for different categories of injuries such as permanent disabilities, congenital anomalies and life-threatening illnesses. These formulae have now officially been recommended through a CDSCO order passed in December 2014 [12]. The incorporation of this level of detail in a legally binding instrument is a unique step, given that other jurisdictions usually only lay down a broad obligation to compensate, leaving further guidance about the method of payment and quantum of money to be evolved by industry [13].

Recommendation

The RRC Report observed that ethnic differences can affect the efficacy, safety and dose regimen of a medicine. It recommended that certain factors such as the choice of control group and regional medical practice be taken into consideration while determining whether available data regarding a drug is ethically sensitive or not.

Implementation

CDSCO passed an order requiring the ethnicity of the local population to be factored in while granting approvals for new drugs. Thus, SECs must take into account certain properties of compounds that are likely to make them more sensitive to ethnic factors [14].

Recommendation

The RRC Report recommended that only drugs that fulfil a real medical need ought to be made available. In October 2013, the SC also attached conditions to approvals of clinical trials by requiring the following three factors to be determined in relation to new drugs – risk/benefit assessment, the innovativeness of the new drug v. the existing therapeutic option, and unmet medical need in the country.

Implementation

The three factors in the SC order have now been incorporated in a draft amendment to the Rules published in the Official Gazette in February 2015 [15]. This amendment makes an addition to Form 44 as well as Appendix I of Schedule Y, requiring the entity seeking permission to conduct clinical trials to submit data regarding these three factors. Decisions of the TRC granting approvals for clinical trials now also justify the manner in which these three criteria are met, and are publicly accessible on the CDSCO website.

Another measure that has been taken to protect the rights of participants is an order stating that placebo-controlled trials (which have also been under the scanner) will be permitted only when the trial is designed in an ‘appropriate, efficient and ethical’ way [16]. However, official guidance on how these parameters are supposed to be met remains to be worked out.

Thus, measures for the protection of participants have been implemented without imposing onerous obligations on sponsors and investigators. The actions taken by CDSCO to encourage the conduct of clinical research in India are discussed in the next section.

Recommendation

The RRC Report stated that the hallmark of a good regulatory agency is a ‘transparent, time-bound decision-making process with clear-cut timelines.’ It recommended that deadlines be set for different activities and a transparent website be maintained with up-to-date information.

Implementation

First, CDSCO has set itself targeted timelines within which to process applications, with 6 months being the outer limit for the review of applications for the approval of new drugs and clinical trials. As already mentioned earlier, CDSCO has cleared its entire backlog, and in a bid to become more accessible to applicants, it arranges for daily public grievance meetings at the office of the Drugs Controller General of India (DCGI). Additionally, it proposes to introduce a system of formal Pre-Submission meetings that will be arranged between applicants, CDSCO officers as well as subject experts. These meetings will allow regulatory pathways to be tailored for particular applicants depending upon the information submitted by them. The idea behind this system is to introduce ‘transparency, accountability, predictability and speedy disposal’ [17]. Steps are also being taken to ensure the use of information technology at every stage of the clinical trial process and in September 2015, the CDSCO launched a new online submission system for clinical trials applications.

Recommendation

The RRC Report recommends that compensation need not be paid for death or injury due to ‘totally unproven unrelated causes.’ However, if an Adverse Event or Serious Adverse Event occurs during a clinical trial, the sponsor is to be responsible for providing medical care and treatment to the patient at his cost till the resolution of the event.

Implementation

Sub-rule (1) of Rule 122DAB of the previous version of the Rules required the trial participant to be provided with ‘free medical management as long as required’. An amendment to the rules in December 2014 restricts the scope of this obligation to provide that the liability of the sponsor ends once it is established that the injury is not related to the clinical trial. However, Expert Committees setup to determine this causality must also function quickly and efficiently in order to ensure that sponsors are not required to bear the expenses of medical treatment for injuries that may prove to be unrelated to the trial.

Recommendation

The RRC Report recommended that the audiovisual recording of the informed consent process be undertaken in the case of research on vulnerable populations that have a diminished capacity to protect their own interests. Audiovisual recording was also recommended for those participants that were willing to participate, but did not wish to provide written consent.

Implementation

CDSCO went a step further than the recommendation in the RRC Report and required audiovisual recording of the informed consent process to be made mandatory for all participants in clinical trials, vulnerable or otherwise [18]. This order was met with protest from the clinical trial industry and has now been modified through an amendment to the Rules in July 2015 [19]. The amendment restricts the audiovisual recording of the informed consent process to vulnerable subjects in clinical trials involving ‘new chemical entities’ or ‘new molecular entities’. It also states that only audio recording will be needed in clinical trials involving anti-HIV and anti-leprosy drugs.

Thus, the amendment is now in conformity with the original recommendations made by the RRC Committee. This readiness on the part of the regulator to modify its decisions speaks well of its flexibility and willingness to change.

This flexibility is also exhibited in the decisions taken by the CDSCO to reverse the original restrictions that it had placed on the number of trials that one investigator could undertake at a time, as well as the minimum number of beds that were required for a hospital to be eligible as a clinical trial centre. These restrictions have now been lifted, and it is the Ethics Committees that have been entrusted with determining the suitability of clinical trial sites as well as the capacity of the investigator to undertake more than three trials at a time [20].

This willingness of the regulator to engage with civil society and industry is an encouraging start towards the creation of a conducive climate for clinical research in the country.