Revisiting regulatory framework in India for accelerated vaccine development in pandemics with an evidence-based fast-tracking strategy

The COVID-19 global pandemic has led to an unprecedented collaborative effort amongst industry, academia, regulatory bodies and governments with huge financial investments. The only goal is to accelerate the development and deployment of a safe and effective vaccine to control the pandemic. One can refer to the past experience of accelerated development of vaccines such as H1N1/swine flu in 2009, which took 93 days to start the clinical trial after identification of the vaccine candidate, and the similar interval was 167 days for Ebola vaccine in 20141. The vaccine for H1N1 could be deployed while the epidemic was in progress. The Ebola vaccine clinical testing took five years and was approved in 2019 by the European Medicines Agency (EMA) and the US Food and Drugs Administration (FDA) long after the outbreak got over. The vaccines for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Zika viruses are still under clinical testing1.

For controlling novel pandemics (or for similar epidemics and large outbreaks), it is important to get the approval for vaccine/s while the outbreak is actively spreading in the community. The combined collaborative effort for SARS-CoV-2 has significantly accelerated the vaccine development through discovery phase, lead candidate optimization, preclinical studies and starting of clinical trials within two months of onset of pandemic. More than 25 vaccine candidates are already in different phases of clinical trials in the second half of 20202 (Table).

Multiple new vaccine platforms are under development along with the traditional ones. Due to the need of rapid development, DNA and RNA platforms are most suitable followed by recombinant subunit vaccine. The DNA and RNA vaccines can be quickly developed by synthetic process and do not need culture or fermentation3. The regulators have experience of approval of DNA vaccines for personalized cancer management, which may help them in the current situation in examining such candidate vaccines. The application of reverse genetics and next-generation sequencing can also reduce the development time in comparison to vaccine development by conventional platform3. Application of nanotechnology interventions such as lipid nanoparticle and virus-like particles (VLP) of plant origin as carrier/adjuvant is a unique approach2 (Table). However, these novel platforms need to prove their safety and efficacy in adequate non-clinical and clinical trials.

Internationally, acceleration of COVID-19 vaccine development is being done by different groups following a matrix with overlapping tracks from discovery phase and translation to approved product through policy and practice. Hanney et al4 have conceptualized and proposed four tracks: (i) discovery phase and non-clinical research, (ii) clinical trial, data analysis with review of discovery phase research, (iii) clinical practice and public policy development, and (iv) resource mobilization4. The essential requirements for the translation of vaccine candidate from discovery to product are documentation of quality, safety and efficacy. In the emerging regulatory science paradigm, the implementation of evidence-based regulatory practice is becoming more important which helps to evaluate a novel product according to the innovation pathway with more flexibility5.

According to the draft report published on August 13, 2020 by the WHO, there are 138 vaccine candidates against SARS-CoV-2 developed and 29 are in different phases of clinical trials2. Several new types of vaccines are being developed, such as RNA vaccine, which have not been tested in people earlier or have any precedence for regulatory approval. Such new vaccine candidates may need detailed exploration during discovery and non-clinical phase which can continue during initial phase of clinical trial for new risk identification along with documentation of safety and efficacy. Another challenge is to compare the safety and efficacy among the different vaccines. The WHO has proposed a blue print of Solidarity Trial for vaccines for their prioritization6.

Regulatory science approaches in India in COVID-19 pandemic context

According to the practice of US FDA and Central Drugs Standard Control Organization (CDSCO) in India, a demonstration of vaccine effectiveness is based on a clinical disease end point (e.g. prevention of disease) or, alternatively, an accepted correlate of protection. While the US FDA's regulations provide for expedited pathways and emergency use licensure, CDSCO in India does not currently have an expedited pathway formalized for new products addressing novel pandemics or public health emergencies. The authorizing legislations for responding to public health emergencies vest in the Ministry of Home Affairs through the National Disaster Management Act of 20057 and with the Ministry of Health and Family Welfare through the Epidemic Diseases Act of 18978. Emergency response and expedited pathways for regulatory approval do not find specific mention in the Drugs and Cosmetics Act 1940 and Rules 1945, as amended up to 20169, but do so in the subsequently released New Drugs and Clinical Trials (NDCT) Rules 201910.

It is noted that the US FDA “approval under this pathway is subject to the requirement that the sponsor study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate end point to clinical benefit”11. Specifically, with the recent amendment, the FDA Safety and Innovation Act (FDASIA) of 2012 “expanded the scope of available end points that can be used to demonstrate that a product qualifies for accelerated approval, but do not affect the quantity and quality of evidence needed to demonstrate substantial evidence of effectiveness or safety”11. Furthermore, “in 2002, the FDA amended the biological products regulations to incorporate 21 CFR §601.90, Approval of Biological Products When Human Efficacy Studies Are Not Ethical or Feasible. This rule, referred to as the ‘Animal Rule', allows the use of animal efficacy data in lieu of human efficacy data when human challenge studies cannot be conducted ethically, and field efficacy studies are not feasible because of infectious disease epidemiology (in the case of vaccines)”11. In these situations it has been suggested that, “certain drug and biological products (e.g., vaccines) that are intended to reduce or prevent serious or life-threatening conditions caused by lethal or permanently disabling toxic chemical, biological, radiologic, or nuclear substances may be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals and additional supporting data”11.

The US FDA can accelerate the availability of appropriate pharmaceutical products and vaccines by using the mechanism of emergency use authorization (EUA). Under an EUA, it is possible for US FDA to authorize the marketing of an unapproved product or the unapproved use of an approved product when a justifiable health emergency or a potential emergency exists11. In response to the COVID-19 pandemic, there has been a growing consensus among regulatory authorities, including from India, to address the urgent need for a safe and effective vaccine. Consequently, the following positions have been communicated following a virtual meeting held under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA): ‘Some vaccine constructs for which there is adequate support from the knowledge around the immune response elicited, may be allowed to proceed to First in Human (FIH) trials without first completing animal studies to assess the potential for enhanced disease provided adequate risk mitigation strategies are put in place in these FIH trials. For some vaccines, preclinical data (e.g. post-vaccination challenge data from animal models, immunopathology studies in animal models) may be required before advancing to FIH clinical trials. In the event that FIH clinical trials are allowed to proceed in the absence of studies in animals that would address the potential for enhanced disease, such studies are, in general, expected to be conducted in parallel with FIH trials so that these data are available prior to enrolling large numbers of human subjects into Phase 2 and 3 clinical trials'12.

Provision for regulatory flexibility in accommodating novel medical countermeasures and interventions in disease management and pandemic control is of utmost importance. India's NDCT Rules, 2019 accommodates “special situations for a new drug where relaxation, abbreviations, omission or deferment of data may be considered”10, but this does not explicitly include public health emergencies such as novel epidemics and pandemics, nor does it have the provision for granting EUA. However, given the scale of the COVID-19 pandemic and absence of specific medical countermeasures, the regulators in India appropriately responded to the unmet need and allowed ‘restricted emergency use’ permission for a few drugs, and also put out a formal notification allowing for manufacture of novel vaccines for COVID-19 and keeping in abeyance rules 81 and 83 of the NDCT Rules, 201913.

For the current COVID-19 pandemic situation, as well as for any such future public health emergency situations such as pandemics, epidemics or localized outbreaks, where there is no specific vaccine, drug or diagnostic tools available, early-stage investigational efforts should be enhanced through idea sharing meetings between research sponsor teams and the regulator's office, expanding the scope of ‘pre-submission meetings’ provided for in the NDCT 2019. In addressing pandemic situations, such meetings should be prioritized, and guidance may be given at the meetings, with records of meeting minutes being put on file for future reference.

This proactive approach may allow for refinement of approaches at the idea stage and prevent wastage of time and resources on the part of the research team as well as at the regulatory end for establishing validity for the candidate in non-clinical (laboratory/in vitro/animal) studies. For time optimization in public health emergency/pandemic response situations, several or all of the clinical evaluation, production planning, distribution strategy and safety evaluation steps of the vaccine development continuum could be conducted in parallel, rather than in a sequential manner. In addition, non-clinical studies should be continued even after the candidate vaccine has been approved to be taken into clinical trial phases.

As of the writing of this article (August 18, 2020), India had three candidate vaccines in varying phases of their clinical development. One of those is a collaboration between a university-based research group that has licensed its candidate to a lead commercialization partner along with an Indian counterpart (Oxford/AstraZeneca Serum Institute/ChAdOx1), while the other two are being developed by Indian commercial entities (Bharat Biotech/Inactivated Virus and Zydus Cadilla/DNA). It is possible that there may be more candidates that will need to be assessed and approved for development in India, mirroring the global trend.

Ensuring timely vaccine - A possible approach

Vaccines in pandemic settings serve dual functions of providing individual protection and curtailment of disease transmission in the community. Timing of the availability and use of the vaccine is key to reducing the overall number of infections and related morbidity and mortality. An adaptive model for vaccine development in public health emergency contexts, comprising one concurrent phase and three sequential phases as illustrated in the Figure, could fulfil the requirements for demonstration of safety and efficacy and enable shortening of the overall vaccine development timeline.

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Figure

Adaptive model for vaccine development in public health emergency contexts.

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Conclusion

Even with full authorization in place, it would be useful to keep track of the performance of the initial modelling of the epidemic and the expected effects of the introduction of a vaccine in addressing incidence of new infections, morbidity and mortality reductions, both among those given the new vaccine as well as among the non-immunized groups and containment of the pandemic. Regulators may, on the basis of such follow up, incorporate the use of adaptive models to the decision-making toolkit for further modifications to the regulatory pathways in emergency situations where new tools need to be developed in a timely manner.

In the event that there are multiple vaccines emerging with EUAs, the choice of vaccine recommended to be rolled out would rest on the outcomes of an iterative evaluation undertaken by the public health authority, in consultation with the regulator, of relative safety and tolerability of the vaccine, duration of protection, the logistical ease for its administration and finally the costs of the vaccine. Regulatory authorities would need to anticipate a scenario where the possibility of different vaccines administered to the same person might arise due to the deployment of multiple vaccines with multiple dosing schedules across the country.

While the focus has been on the regulatory science innovations in developing new vaccines during pandemic or public health emergencies, it must be noted that existing vaccines authorized for other indications may be used by clinical and academic researchers for their protective non-specific immunity effects on different age groups or patient categories. Such repurposing studies will need to be documented as fresh clinical trials, with design, conduct and outcomes subject to conventional regulatory oversight. Should such research yield correlates of protection specific to the emergent pathogen, an accelerated pathway to emergency authorization of such vaccines should also be offered and subsequent rollout strategy would mirror the India Phases 2-3 as outlined above.