– Suneha Kasal and Swini Khara*
Almost as if it was foreshadowing the COVID-19 pandemic, the New Drugs and Clinical Trial Rules, 2019 (‘NDCTR’/ ‘Rules’) brought about significant developments by consolidating and streamlining the framework for regulating clinical trials and approvals thereof. These Rules were introduced with the aim of promoting clinical research in India, and in pursuance of the same, it brought about major improvements and added details pertaining to Ethics Committees (EC), bioavailability and bioequivalence studies, import and manufacturing processes, waivers and compensation guidelines. However, the circumstances in the recent past have raised questions as to whether these new Rules, in their attempt to promote robust clinical research in India, have compromised on the safety and efficacy of trials, making them more sponsor-friendly. This piece explores such issues in the context of striking the right balance between the two.
Earlier this year, the Central Drugs Standard Control Organisation (‘CDSCO’) gave restricted emergency use approval to two vaccines i.e., Covishield, manufactured by Serum Institute of India (‘SII’), developed from a comparable vaccine of Oxford-AstraZeneca; and indigenously developed Covaxin, manufactured by Bharat BioTech International Ltd. However, Covaxin was to be administered to people in clinical trial mode. There is no clarity or guidance provided by the regulator regarding the meaning of such a mode. These emergency use authorizations and the manner in which the trials were conducted have exposed several pitfalls in the NDCTR which endanger the safeguards for trial participants, as well as the sanctity of the approval process. Examining these pitfalls in detail will form the crux of the analysis in this piece.
Based on this premise, the remainder of this piece is structured as follows. First, it attempts to expose the imbalance in the rights accorded to sponsors and trial participants, focusing on the lack of right to appeal and right to be heard in matters of compensation for undergoing a Serious Adverse Event (‘SAE’) or other injuries. Subsequently, the piece highlights the significant lack of transparency in not only the determination of compensation, but also in the approval process. Finally, it discusses the narrow drafting of the accelerated approval provision, and the need for prioritizing the safety of people.
II. The Imbalance between the Rights of Sponsors and the Rights of Trial Participants
Prior to 2019, the Supreme Court observed the deficiencies in the erstwhile regulations for clinical trials, and laid down that the approval of clinical trials should be based on the parameters of safety and efficacy. It noted three parameters: assessment of risk versus benefit to the participants; innovation versus existing remedies; and, unmet medical needs in the country. However, the substance of this criteria seems to have been forgotten, as the NDCTR has not made any explicit efforts to operationalize the vision of the Supreme Court.
NDCTR defines SAE as an untoward medical occurrence leading to hospitalisation, death, or permanent disability of a participant during clinical trials. In the recent vaccination trials of Covishield and Covaxin, there have been a number of events leading to trial injuries, including SAE. These instances have exposed the manner in which the regulatory mechanisms have allowed the dismissive treatment of such injuries.
A. Right to be Heard
Primarily, the disparity is apparent between the rights accorded to trial sponsors and to the participants under the decision-making process stipulated in the NDCTR. This is specifically with respect to decisions regarding compensation. Consideration for death or injury of the participant is to be paid when it results from any of the events listed in Rule 41 of NDCTR. This rule focuses on the trial-relatedness of the injury.
However, neither the NDCTR nor the Indian Council of Medical Research’s Ethics Guidelines are categorical about closing the loop with the participant. That is, the decisions pertaining to the trial-relatedness of the injury/death need not be formally communicated with reasons to the concerned participant. This, coupled with the fact that neither the participants nor their representatives are provided with presence at any level of decision-making, demonstrates how the NDCTR is devoid of adequate participant rights.
B. Right to Appeal for Participants
Any decision of the Drug Controller General of India (‘DCGI’) and Central Licensing Authority (‘CLA’) can be appealed by the aggrieved members of the Ethics Committee, as well as the sponsors. However, such a right to appeal is not extended to the aggrieved participants in decisions on the trial-relatedness of the injury, or in the decisions on quantum of compensation.
As mentioned earlier, the consideration for death or injury of the participant is to be paid when it results from any of the events listed in Rule 41 of NDCTR. The decision on the same is taken by the CLA, or by an independent expert committee constituted by the CLA. The committee reaches its decision on the basis of recommendations by the EC. Hence, the ball largely lies in the EC’s court to piece together a report on the trial-relatedness of the event, and to compute compensation on the basis of the information received from the principal investigator and the factors mentioned in Schedule VII. The lack of any right to seek review of the EC’s opinion exacerbates the possibility of erroneous decisions, and forces the participants to rely solely on litigative processes.
Moreover, in case of an injury during the trial, participants are to be provided with free medical care. The period of free medical management to the trial participants is determined merely on the basis of the ‘opinion’ of the investigator. There are no guidelines for the formation of such an opinion. This is particularly problematic, as it is on the basis of this opinion that the legal obligation to provide free medical care to the trial participant ceases, leaving the participants without any option of appealing the investigator’s decisions.
The complications due to the selective absence of internal appeals, and the lack of participants’ voice in deliberations about compensation, become much clearer in light of the treatment of injuries during the COVID-19 vaccine trial. Particularly, a trial participant was subjected to defamation proceedings by the trial conductor for merely relying on a litigative process for an effective remedy, in the absence of any internal relief.
C. Limited Liability of the Sponsor
In place of limited liability of the sponsor to medical management and subsequent compensation on the basis of the EC’s opinion on trial relatedness, the Draft New Drugs & Clinical Trials Rules, 2018 had a provision for No-Fault Compensation (‘NFC’) which failed to make it to the final enactment of the NDCTR. This provision mandated the sponsor to grant interim compensation amounting to sixty percent of the total amount incurred in the injury within fifteen days of the rendering of an opinion of the EC. NFC may be seen as a pragmatic compromise between the limited liability of the sponsor and limited internal relief to the participant. However, in an attempt to relax the regulatory pathways to conduct clinical trials in India, the same was removed. NFC, if in place, would have partially remedied the situation of faulty decisions with respect to compensation or trial relatedness. Therefore, this step of the government has unfavourably tilted the balance against the participants, especially in light of the lack of right to appeal and right to be heard in matters of compensation identified above.
D. Executive Overreach
Rule 42 encapsulates the system and procedure of compensation. This rule is not merely bereft of substantive rights of the trial participants, but it can also be seen as the executive’s attempt to transcend its mandate. Sections 12 and 33 of the Drugs & Cosmetics Act empower the Central Government to make rules for the purpose of giving effect to the provisions of the Chapters III & IV (related to development, manufacturing, distribution, etc). These sections, under which the NDCTR has been framed by the Central Government, do not empower the government to prescribe a system of compensation, as the concerned chapters of the Act in itself are silent on the aspect of compensation. The purpose of the rules prescribed by the Central Government, instead, is to only give effect to the provisions of the Act, which is not inclusive of adjudication of compensation. Thus, NDCTR Rule 42 may be seen as going beyond the scope of the Act.
III. Transparency of Trials
Transparency is not only important from a participant’s perspective for seeking a reasoning behind rejection of compensation. It is also needed in the approval process of drugs by the regulator for greater accountability. Transparency is necessary in terms of the availability of the trial information, enabling scientists and the general public to make informed choices regarding the administration of vaccines.
Transparency, in particular, is an essential feature for the Food and Drug Administration (‘FDA’) in the USA, which, in its guidelines, mandates that all discussions between the expert committee and the sponsor happen in open sessions. Closed sessions are only permitted for the review of confidential information, or trade secrets which would be exempt from public disclosure. Vaccine approval proceedings by the FDA were broadcast and live streamed across the world.
India, on the other hand, in its Rules, does not make it obligatory for sponsors to bring details of primary and secondary outcomes of the clinical trials, or the anonymized data, into the public domain within a stipulated period of time. Identifying this, public health activist groups like Progressive Medicos and Scientists Forum and All India Drugs Action Network have petitioned for clinical trial data to be made public. While the Clinical Trials Registry of India lists ongoing and completed trials on its website, it does not disclose detailed results. In the current scenario, there is a big blind spot in the bridging of data from foreign trials of Covishield with the ethnicity data of the Indian population, and the bridging of efficacy with the immunogenicity data of Covaxin. This vacuum could be resolved to a limited extent by making the data pertaining to COVID-19 vaccine trials public, thus allowing the clinical trials to be peer-reviewed. It would also help the general public make an informed choice. India could thus follow a similar approach as the FDA, which has codified the regulatory requirements, procedures, and timelines for submitting information on results to the concerned public platform.
IV. Measuring Safety and Efficacy in Accelerated Approvals
NDCTR has brought about a fast-track procedure for approval of drugs, along the lines of the emergency use authorization (EUA) procedure by the FDA in the US, and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. NDCTR has termed this EUA procedure as the accelerated approval process in the Second Schedule. This route is also meant to serve serious unmet medical needs in the country. However, there are issues in the NDCTR for accelerated approvals which risk the safety of the people administered with such a drug.
To begin with, the accelerated approval under Schedule 2(2)(ii)(A) self-imposes a low standard for securing an approval from the CLA. This is evident from the manner in which the Rules allow the seeking of approval for any drug after completing merely Phase II trials, with the condition of proving remarkable efficacy in the trials. The standard of remarkable efficacy must be appreciated due to its direct link to safety of the drug. The correlation between safety and efficacy is as simple as the collection of data on safety parameters like hospitalization, side effects, complications, and SAE, which would allow one to observe and monitor the extent of suboptimal efficacy in a larger population. However, the rules do not elaborate on what constitutes remarkable efficacy, or how it can be established.
Even more interestingly, Phase II trials mainly confirm only immunogenicity data. Thus, the requirement of mere Phase II qualification significantly compromises the safety of the drug before administering it to a larger population. It is only in the Phase III trials that the testing on a larger population develops the efficacy and safety data for the drug. Hence, demanding remarkable efficacy at only Phase II trials is absurd. This laxity becomes glaringly evident in the premature approval of Covaxin, which was accepted without any efficacy data.
The emergency use authorization process in the USA leaves scope for the regulator to issue guidelines and criteria for authorization depending on the emergency so declared. Accordingly, the FDA has issued guidelines requiring data to be submitted from at least one well-designed Phase III trial providing safety and efficacy information in a clear and compelling manner. Even the amended UK regulations for approval of COVID-19 vaccines leave sufficient space for prescribing requirements and conditions to be followed while granting temporary approval. Acknowledging the highest priority accorded to public safety, nine pharmaceutical companies voluntarily pledged to produce efficacy data from Phase III trials (even if not completed) before applying for an EUA. Similarly, the NDCTR could also have had sufficient flexibility in issuing specific standards of approval to adapt to different emergency situations such as COVID-19, H1N1, or Ebola virus without compromising on quality.
India already waives local clinical trial requirements for drugs which have been approved in other listed countries discretionally. This further lowers the bar for getting an approval based on foreign clinical data without any relevant data available for ethnic factors in the Indian context. If not for accounting for ethnic data, it would be in public interest to raise the bar even slightly from only Phase II trials for securing an accelerated approval with remarkable efficacy.
In fact, the need for such an amendment is further justified by the loose enforcement of rules by the CDSCO in the approval of Covaxin. Herein, the sponsor failed to produce any efficacy data for Covaxin, prior to the approval, which was given merely on the basis of immunogenicity data generated in the Phase II trials, whereas the accelerated approval process specifically requires remarkable efficacy to be proven.
Now, it must be noted that immunogenicity does not guarantee efficacy. Yet, CDSCO released regulatory guidelines for the development of COVID-19 vaccines and circumvented this requirement of remarkable efficacy by bridging immunogenicity with efficacy through estimates. These estimates would be made on how effective the vaccine would be based on other similar prior clinical trials or established/ expected immune responses which may be effective. The act of determining efficacy on the basis of estimates can be attributed to NDCTR’s silence in providing any threshold for proving remarkable efficacy. Hence, ultimately, safety of the drug cannot be guaranteed by immunogenicity without proving remarkable efficacy.
This act of CDSCO finding ways around this provision can be attributed to lack of clarification on what constitutes ‘remarkable efficacy’ in the Rules, which warrants the need for revisiting the criteria for remarkable efficacy. Hence, it is important to improve on the accelerated approval process to ensure that a mere requirement of clearing Phase II trials is not enough to authorize a drug, but that the need for proving remarkable efficacy is strictly enforced. This could be achieved by providing a threshold or clear demarcation on what constitutes ‘remarkable’. This also brings us back to our emphasis on the need for transparency, as there is no sufficient information in the public domain on how the regulator bridged the efficacy and immunogenicity data. Lack of public information raises doubts on whether the NDCTR requirements were even satisfied to meet the ‘remarkable’ criteria.
The accelerated approval clause empowers the CLA to set protocols for post-licensure studies. These studies are used to generate the data on a larger population for verifying the clinical benefits. However, the CLA has not issued sufficient post-licensure protocols for COVID-19 vaccine trials, unlike in the USA and the UK. This NDCTR provision is actually a well-deliberated provision as it ensures that there are conditions attached to the continued approval of a vaccine. However, this clause should not have limited the protocols to be issued only for post-licensure studies or clinical trials, but should have been expansive enough to include other conditional requirements for emergency - authorized drugs. These conditional requirements are necessary to accommodate any changes in circumstances post-approval. Such conditions have also been cautiously issued by the UK while issuing emergency approval to COVID-19 vaccines to regulate the process effectively. These conditions can range from changes to the validity period of the approval and specific conditions for revocation and quality maintenance, to conditions on storage, use, supply, distribution, and other necessary guidelines.
While the NDCTR has brought about much-needed changes to monitoring clinical trials and drug development, this piece has argued the need to find more space for participants’ safety and rights in the current framework. As argued, the trial Rules particularly favour the sponsors through selective appeal mechanisms. Hence, the very first step in empowering the participants is to provide them with the basic right to appeal and the right to be heard in decisions affecting their well-being and safety. The missed opportunity of gaining some relief from arbitrary decisions on trial-relatedness in the form of ‘No-Fault Compensation’, has also been explored. Further, as demonstrated, the clinical trial mechanism is not only devoid of participant rights, but also of transparency. The piece emphasizes the need for and the manner of bringing about transparency through publicizing the primary and secondary trial data, and involving participants in the decision-making process.
The accelerated approval process needs further refurbishing to prioritize safety, as well as greater clarity as to the threshold for “remarkable efficacy”, instead of merely listing the stage of a trial when the drug can be given a green light. The absence of these allows the regulator to work around the rules and succumb to external pressure in approving the drug without adequate data on efficacy, as we can see from the recent approvals of Covishield and Covaxin. In these unprecedented times, it is hoped that further experience and developments in the field will pave the way for improving the legislation to make it more conducive for both patients and sponsors.
* Suneha Kasal and Swini Khara are V Year students of B.A., LL.B. (Hons.) course at the National Academy of Legal Studies and Research (NALSAR) University of Law.
 NDCTR, Ch. III, IV, V, VI, VII, VIII, IX, X.
 NDCTR, rr. 2, 30, 8, 14, 47, 53, 58, 60, 68, 72, 76, 78, 81, 87 81.
 NDCTR, r. 42.
 NDCTR, r. 40.
 Immunogenicity is the ability of the vaccine to provoke an immune response in the body, but not whether the immune response is successful in preventing disease. Efficacy is the effectiveness of the immune response so invoked in preventing the disease.
 NDCTR, Sch. 2(2)(ii)(A).
 NDCTR, Sch. 2(2)(ii)(A)(d).
 NDCTR, Sch. 2(2)(ii)(A)(d).