The Covid-19 pandemic has wreaked havoc on mankind, infecting well over 13 million, and claiming over half a million lives. It has also severely impacted economies across the world. Our healthcare infrastructure has been pushed to its limits and our frontline healthcare professionals are working to the brink of exhaustion, risking their own lives to save others. We bow to them.
In the midst of all this, scientists across the world are working feverishly to find a vaccine for this disease. The hopes of billions rest on this. The World Health Organization (“WHO”) has (as of July 15, 2020) declared that there are about 23 potential vaccine candidates that are currently in various stages of clinical trials. Out of these 23 vaccines, vaccines being developed by: (a) Sinovac (inactivated +alum); and (b) University of Oxford / AstraZeneca has entered into the Phase-III of its clinical trials. In addition, as of July 15, 2020, there are around 140 vaccine candidates in preclinical evaluation (trials not commenced).
In India the following eight domestic pharmaceutical players are working on the development of vaccine for coronavirus: (a) Bharat Biotech International Limited (developing vaccine in collaboration with Indian council of Medical Research and National Institute of Virology); (b) Zydus Cadila; (c) Biocon Limited; (d) Serum Institute of India Private Limited (working with AstraZeneca Oxford Vaccine, which is in the Phase -III clinical trial. The Company is also developing live attenuated vaccine with US based biotech firm Codagenix); (e) Panacea Biotec Limited; (f) Indian Immunologicals Limited (developing vaccine in collaboration with Australia’s Griffith University); (g) Mynvax Private Limited; and (h) Biological E. Limited.
Out of the aforementioned domestic players, the Drug Controller General of India till date, has accorded its approval to conduct Phase I/II human trials to: (a) Bharat Biotech International Limited’s Covaxin; (b) Zydus Cadila’s ZyCoV-D; and (c) Biocon Limited’s Itolizumab.
Regulatory Regime for Approval in India
Vaccines are classified as ‘New Drugs’ under the New Drugs and Clinical Trial Rules, 2019 (“NDCT Rules”)
As discussed in our previous blog-post titled “NCOVID-19: From detection to a cure. A regulatory overview” [can be accessed here], these newly developed vaccines shall be classified as a ‘new drug’, which is defined under Rule 2(w) of the NDCT Rules to include, inter alia, ‘a drug, including active pharmaceutical ingredients or phytopharmaceutical drug, which has not been used in the country to any significant extent’, ‘a drug approved by the Central Licensing Authority (“CLA”) for certain claims and proposed to be marketed with modified or new claims’, ‘a fixed dose combination of two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio’, ‘a modified or sustained release form of a drug or novel drug delivery system of any drug approved by the CLA’, or ‘a vaccine, recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal anti-body, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug’.
It is interesting and important to note that ‘a vaccine’ is dealt separately than that of a ‘new drug’ under the NDCT Rules. A drug unlike a vaccine would be a new drug only for 4 (four) years from the date of its approval. However, a vaccine shall always be deemed to be a new drug under the NDCT Rules. This would mean that even after the vaccine is approved by the concerned authority, the manufacture and import process would still require approval from the CLA under the NDCT Rules. This is a deviation from the procedure prescribed under the Drugs and Cosmetics Act, 1940, and the Drugs and Cosmetics Rules, 1945, wherein once the drug is approved, licence for import and registration is granted by the CLA and approval to manufacture a drug product is provided by the State Licensing Authority.
WHO’s Access to Covid-19 Tools (“ACT”) Accelerator
WHO towards the end of April, 2020, launched the ACT Accelerator to bring together governments, scientists, businesses, civil society, and philanthropists and global health organisations to speed up an end to the pandemic by supporting the development and equitable distribution of tests, treatments and vaccines, the world needs to reduce mortality and severe diseases, restoring full societal and economic activity globally in the near term, and facilitating high-level control of Covid-19 disease in the medium term.
This being a global guidance document also has reference under Indian legislature as an accelerated approval mechanism as listed below.
Expected Timeline under Normal Circumstances
The NDCT Rules provide for a timeline that is followed in relation to approvals for new drugs.
Step 1 – Ethics Committee Approval:
Any person / entity desirous of undertaking a clinical trial, under the NDCT Rules, is required to setup an ethics committee and obtain prior approval of this committee, whose registration with the CLA will be valid for 5 years. In our experience, we have usually seen that the healthcare institutions get their ethics committee registered with the regulatory authority.
Basis the information made available on the Clinical Trial Registry of India’s website, we understand that out of the total of 12 Indian entities, which are in the race to develop the vaccine, the ethics committee of only five such entity is approved and rest other are under review.
Step 2 – Submission of Application to Conduct Clinical Trial:
Application for permission to conduct clinical trials, along with information and documents as specified in the Second Schedule and fee as specified in the Sixth Schedule is required to be submitted to the CLA in Form CT-04.
The Phases as mentioned in Paragraph 3(2) of First Schedule of NDCT Rules are as follows:
30 days from the date of receipt of such application.
Post which, it shall be considered as a deemed approval.
Phase I / Clinical Pharmacology Trials / “First in Man” Study:
The objective of studies in this phase is the estimation of safety and tolerability, with the initial administration of an investigational new drug into humans. Phase I trial should preferably be carried out by investigators trained in clinical pharmacology, with access to necessary facilities to closely observe and monitor the subjects.
|1 – 6 months
Phase II / Exploratory Trials:
Primary objective – evaluate the effectiveness of a drug for a particular indication(s) in patients (group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population), with the condition under study and to determine the common short-term side-effects and risks associated with the drug.
Additional objective– evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further studies in Phase II or III.
|6 months to 2 years
Phase III / Confirmatory Trials:
Purpose is to obtain sufficient evidence about the efficacy and safety of the drug in a larger number of patients, generally in comparison with a standard drug and/or a placebo as appropriate. In this phase, the group is between 1000-3000 subjects. If the results are favorable, the data is presented to the licencing authorities for a commercial licence to market the drug for use by the patient population for the specified and approved indication.
|1 – 3 years
Phase IV / post-marketing trials:
This phase takes place post obtaining the approval from the licencing authority. Such trial might not have been considered essential at the time of new drug approval due to various reasons, such as limitation in terms of patient exposure, duration of treatment during clinical development of the drug, need for early introduction of the new drug in the interest of patients, etc. Phase IV trials include additional drug-drug interaction, dose response or safety studies and trials’ design to support use under the approved indication e.g. mortality or morbidity studies, epidemiological studies, etc.
|Patients are monitored for long-term side effects of the treatment that go beyond the time frame of the other phases.
Manufacture of New Drugs for Clinical Trial:
A licence from the CLA must be obtained to import a new drug for conducting a clinical trial. The licence, if granted, is valid for a period of three years.
Accelerated approval mechanism
The NDCT Rules provides for an accelerated approval mechanism for drugs, intended to be used in life threatening or serious disease conditions or rare diseases or for diseases of special relevance to the Indian scenario or unmet medical need in India, disaster or special defence.
This fast track process provides for an approval, based on data generated in clinical trials where surrogate endpoints are considered rather than using standard outcome measures such as survival or disease progression, which are reasonably likely to predict clinical benefit, or a clinical endpoint. Further, in situations where clinical safety evidence and efficacy have been established even if the drug has not completed the normal clinical trial phase, an application can be made to the licencing authority for expedited review process, wherein the licencing authority will examine and satisfy certain conditions. Waiver of local trials may also be considered, and approval may be granted if foreign approval data sets are accepted. Approvals can be granted, subject to detailed post approval surveillance reporting of adverse events.
Fast track approval for a COVID-19 vaccine.
In relation to Covid-19, the regulator had on May 25, 2020, announced a ‘Rapid Response Regulatory Framework’ to provide a fast track approval mechanism in relation to approvals for a potential vaccine.
- Preclinical studies done outside India may be considered and the application would be examined based on quality of such data that is generated.
- An applicant may, in parallel, submit an application for conducting appropriate phase of clinical trial to CDSCO for consideration at the time of conduct of the pre-clinical studies, based on proof of concept. This would be subject to approval after examination of the pre-clinical trial data sets.
- Data generated outside India will be considered and examined and an abbreviated pathway may be considered for Covid-19 vaccine, based on scientific rational and level of completeness of data in human trials in addition to satisfactory preclinical data. Phase I/II or phase III multicentric study on statistically significant sample size may be considered based on initial safety studies, proof of concept and dose finding.
Desperate times call for desperate measures. Given that time is of essence, shortening of the time period for release of Covid-19 vaccine is of utmost importance. That said, while there is a need to fast track approvals, one cannot ignore the fact that lives of the global population are at stake. Clinical trials need to be performed with scientific rigour and there has to be absolute demonstration of safety and efficacy parameters in whichever candidate that emerges as a successful winner in this race to save mankind.
 Draft landscape of COVID-19 candidate vaccines
See also: http://www.isrctn.com/ISRCTN89951424
 Explanation to definition of ‘New Drug’ Rule 2(w) of the NDCT Rules.
 Second Schedule of the NDCT Rules.
 A surrogate endpoint is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship.
 The conditions for expedited review process are: (a) it is for a drug that is intended to treat a serious or life threatening or rare disease or condition; (b) if approved, the drug would provide a significant advantage in terms of safety or efficacy; (c) there is substantial reduction of a treatment-limiting adverse reaction and enhancement of patient compliance that is expected to lead to an improvement in serious outcomes.