The draft guidelines, for COVID – 19 were released by the Central Drugs Standard Control Organization (CDSCO), Government of India. on September 21, 2020., which is reproduced from their web site as follows:

A 40-page document with 73 subsections, it declares that it will provide guidance to the vaccine developers to ensure that-

 –vaccines are well-characterized and manufactured consistently.

–Vaccines remain stable at the recommended storage conditions for the duration of the clinical trial during the clinical development stage and throughout its shelf life post-approval.

–adequate toxicity data, as well as immunogenicity in respect of humoral and/or cell, mediated immune response are generated in nonclinical studies in relevant animal models.

–challenge studies in relevant animal species and non-human primates may be conducted concurrently with the clinical trials.

 –adequate clinical data to establish safety and protective immunity are generated.

 –Post Marketing Surveillance including assessment of Adverse Events Following Immunization (AEFI) and Adverse Events of Special Interest (AESI) is carried out to assess vaccine safety in the post-market scenario.

With the pressure on the human population to evolve new vaccine to withstand the deadly effects of COVID – 19 with daily deaths from around the globe without any restriction or exclusion of boundary, the introduction of a vaccine has become imperative and it is time to hear the new guidelines as part of our economy rather than a medical event.

I may not give the whole guidelines in detail since most of us would understand virtually nothing except that the new vaccine would save mankind from total destruction. Some interesting titbits are as under:

  • Chapter 1 begins with an introduction
  • Chapter 2 relates to the background
  • Chapter 3 indicates Chemistry, manufacturing, and controls
  • Chapter 4 revolves around the non-clinical development program.
  • Chapter 5 continues with the Clinical development program.
  • Chapter 6 ends with references.

Chapters 4 and 5 are the lengthiest and cover the core of the guidelines.

Page number 6 with the exhaustive explanation on the preparation of guidelines on the vaccine and how they are different from those for medicines. Let me reproduce it as an introduction to our whole understanding of these guidelines.

“In general, all vaccines including the vaccines against CORONA virus infection manufactured/imported into the country are required to comply with the requirements and guidelines specified in the Drugs and Cosmetics Rules, 1945 & New Drugs and Clinical Trials Rules, 2019, Guidance for Industry and other applicable guidelines published by CDSCO from time to time.

 For manufacturing, rDNA derived vaccines the requirements and guidelines prescribed by the Department of Biotechnology are also required to be complied with. However, vaccines, unlike chemical drugs, are a complex heterogeneous class of medical products, and hence specific consideration in respect of the development of CMC data, non-clinical data, and clinical data will provide a clear understanding of the regulatory landscape for their development and approval in a scientific manner.

Therefore, these documents have been prepared to provide detailed guidelines and regulatory pathways for CMC, nonclinical and clinical development of vaccines including the COVID-19 vaccine.”

Or as a layman, I understand that CMC data, non-clinical data, and clinical data development of vaccines including COVID – 19 is a must for the introduction of vaccines. Emphasizing that all vaccines are required to be characterized and manufactured in compliance with the Good Manufacturing Practices (GMP) as prescribed in the Rules and that It is important that the manufacturing processes of every vaccine are validated, defined, and controlled adequately to ensure batch to batch consistency.

Don’t you agree with if the vaccines produced in every batch is not consistently of good quality and properly validated, our protection against the disease vanishes in thin air?

I would invite their observations on COVID-19 non-clinical data is the norm, then nonclinical safety studies will be required prior to proceeding to FIH clinical trials. The preclinical program for any investigational product should be individualized with respect to scope, complexity, and overall design. The principles of the “3Rs,” to reduce, refine, and replace animal use in testing when feasible should be followed. In some cases, it may not be necessary to perform nonclinical safety studies prior to FIH clinical trials because adequate information to characterize product safety may be available from other sources.

 When needed to support proceeding to FIH clinical trials, nonclinical safety assessments including toxicity and local tolerance studies must be conducted under conditions of Good Laboratory Practices (GLP). Such studies should be completed and analyzed prior to the initiation of FIH clinical trials.

Now, the time to concentrate on clinical trials to assess the efficacy of the vaccine.

Conducting clinical trials in the setting of a public health emergency like the COVID-19 pandemic presents operational challenges. CDSCO has issued brief guidelines providing general considerations to address challenges in conducting clinical trials in the COVID pandemic situation in protecting the right, safety, and well-being of trial subjects. The same should be followed for conducting the trial in the present situation maintaining compliance with GCP and validity of the data generated.

In most cases, the first clinical trial should be conducted in healthy adults, while, phase II trials should be conducted in subjects who are representative of the intended target population for the vaccine at the time of approval.

Phase III clinical trials may be designed to provide an estimate of vaccine efficacy or to provide an indication of the ability of the vaccine to prevent clinical disease on the basis of immunogenicity data.

On occasion, an assessment of a specific safety aspect may be the primary (or a coprimary) objective in a phase III trial.

 In case, a vaccine has been developed and has undergone clinical trial development outside India and marketing authorization application for the same has been submitted to CDSCO, the clinical data generated will be considered for evaluation of the overall safety and effectiveness of the vaccine.

 However, additional clinical trials may be required in the local population to confirm the safety and effectiveness of the Indian population.

Special consideration for COVID-19 Vaccine

Considering the urgent need for a safe and effective vaccine for the prevention of COVID19, clinical development programs of the COVID-19 vaccine may proceed through an adaptive and seamless approach.

However, as applicable for any vaccine, regardless of whether clinical development programs proceed in discrete phases with separate studies or via a more seamless approach, an adequate data, including data to inform the potential risk of vaccine-associated Enhanced Respiratory Disease (ERD) will be needed.

The above paras of instructions specifically enshrined in the guidelines throw much light on clinical trial instructions. It is of indicative nature and anyone to learn the total nuances of the process can read the whole 40-page guidelines. Pages 21-39 deals with Chapter 5 deal with various aspects of the clinical trial, the core of the guidelines.

Special consideration for Efficacy of COVID -19 Vaccine

It is important to know the predominant features related to COVID – 19 vaccine.

 We have been informed that either laboratory-confirmed COVID-19 or laboratory-confirmed SARS-CoV-2 infection is an acceptable primary endpoint for a COVID-19 vaccine efficacy trial and that acute cases of COVID-19 should be virologically confirmed.

SARS-CoV-2 infection, including asymptomatic infection, can be monitored for and confirmed either by virologic methods or by serologic methods evaluating antibodies to SARS-CoV-2 antigens not included in the vaccine.

Now is the time to know the statistical considerations for the vaccine.

To ensure that a widely deployed COVID-19 vaccine is effective, the primary efficacy endpoint point estimate for a placebo-controlled efficacy trial should be at least 50%, and the statistical success criterion should be that the lower bound of the appropriately alpha-adjusted confidence interval around the primary efficacy endpoint point estimate is >30%.

 The same statistical success criterion should be used for any interim analysis designed for early detection of efficacy. A lower bound ≤30% but >0% may be acceptable as a statistical success criterion for a secondary efficacy endpoint, provided that secondary endpoint hypothesis testing is dependent on success on the primary endpoint.

How do we monitor the vaccine utility?

It is anticipated that adequately powered efficacy trials for COVID-19 vaccines will be of sufficient size to provide an acceptable safety database for each of the younger adult and elderly populations, provided that no significant safety concerns arise during clinical development that would warrant further prelicensure evaluation.

COVID-19 vaccine trials should periodically monitor for unfavorable imbalances between vaccine and control groups in COVID-19 disease outcomes, in particular for cases of moderate to severe COVID-19 that may be a signal for vaccine-associated ERD.

It has also been suggested that as post-marketing clinical evaluation, assessment of vaccines for safety and effectiveness must be conducted on case to case basis

As a post-marketing clinical evaluation, post-marketing assessment of vaccines for safety and /or effectiveness of vaccines should be considered on a case by case basis depending on the category, nature of the vaccine, and the quantum of data generated through the non-clinical and clinical development program in terms of Clinical rules issued in 2019.


The purpose of this article is to introduce ourselves with the expansive but critical guidelines issued by Central Drugs Standard Control Organization Directorate General of Health Services Ministry of Health and Family Welfare Government of India on COVID – 19 vaccines that may be developed internally or from abroad but to be manufactured in India, which is the way for the poor of the world to get vaccines at the cheapest cost and the best quality. During the discussion, quality has been repeatedly stressed by the authorities so that the first batch of vaccine remains in the same quality scale as the last one but both save mankind from the pandemic.

With the excellence achieved in the medicinal world with the cooperation of the industry, the Government of India or other stakeholders, namely, the Indian public, vaccine for COVID – 19 would arrive soon, produced in billions of dozes and mankind would be saved.


Disclaimer : My intention was to inform everyone of the excellent guidelines of the Government of India on the COVID – 19 vaccines which may arise in near future. I am not a doctor or an expert in the medical field.  These views are purely my personal ones. Neither nor the other government authorities are responsible for my views. Please consult relevant documents for guidance.

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May 2021