Procedure for drug approval
Three vaccine developers have now made applications to the Central Drug Standard Control Organisation (CDSCO), India’s drug regulator, seeking emergency use approval for their candidate Covid-19 vaccines which are still under trials.
History of drug approval process in India
Central Drugs Standard Control Organisation (CDSCO)
The Central Drugs Standard Control Organisation (CDSCO)under Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India is the National Regulatory Authority (NRA) of India.
The Drugs & Cosmetics Act,1940 and rules 1945 have entrusted various responsibilities to central & state regulators for regulation of drugs & cosmetics. It envisages uniform implementation of the provisions of the Act & Rules made there under for ensuring the safety, rights and well being of the patients by regulating the drugs and cosmetics.
• The Drug and Cosmetic Act 1940 and Rules 1945 were proclaimed by the India’s parliament to regulate the import, manufacture, distribution and sale of drugs and cosmetics. The Central Drugs Standard Control Organization (CDSCO) and the office of the Drugs Controller General (DCGI) was established.
• In 1988, the Indian government added Schedule Y to the Drug and Cosmetics Rules 1945. Schedule Y provides the guidelines and requirements for clinical trials, which was further revised in 2005 to bring it at par with internationally accepted procedure. When a company in India wants to manufacture/ import a new drug it has to apply to seek permission from the licensing authority (DCGI) by submitting the data as given in Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945.
Bulk drugs or APIs
A bulk drug, also called an active pharmaceutical ingredient (API), is the key ingredient of a drug or medicine, which lends it the desired therapeutic effect or produces the intended pharmacological activity. For example, paracetamol is a bulk drug, which acts against pain. It is mixed with binding agents or solvents to prepare the finished pharmaceutical product, eg a paracetamol tablet, capsule or syrup, which is consumed by the patient.
• In order to prove its efficacy and safety in Indian population it has to conduct clinical trials in accordance with the guidelines specified in Schedule Y and submit the report of such clinical trials in specified format.
Some important rules in the procedure for drug approval in India
As per the Drug and Cosmetics Act, the clinical trials may be waived in the case of new drugs which are approved and being used for several years in other countries.
Section 2.4 (a) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says for those drug substances which are discovered in India all phases of clinical trials are required. Whereas its section 2.4(b) says that for those drug substances which are discovered in countries other than India; the applicant should submit the data available from other countries and the licensing authority may require him to repeat all the studies or permit him to proceed from Phase III clinical trials.
Demonstration of safety and efficacy of the drug product for use in humans is essential before the drug product can be approved for import or manufacturing of new drug by the applicant by Central Drugs Standard Control Organization (CDSCO).
The regulations under Drugs and Cosmetics Act 1940 and its rules describe the information required for approval of an application to import or manufacture of new drug for marketing. For an investigational new drug, the sponsor needs to provide detailed information to the DCGI about:
o Generic name, Patent status, Brief description of physico-chemical/biological, Technical information, Published clinical trial reports, Proposed protocol and pro forma, Trial duration, During master file, Undertaking to Report Serious or Life-threatening Adverse Drug Reactions.
The need for local clinical trials in India depends on the status of drug in other countries. If the drug is already approved in other countries, generally Phase III trials are required. Phase I trials are not allowed in India unless the data is available from other countries. Permission is granted by DCGI to conduct Phase 1 trials in India, if the drug has special relevance to a health problem in India, like malaria or tuberculosis.
Bioavailability and bioequivalence (BABE) studies should be conducted as per BABE guidelines. The comprehensive information on the marketing status of the drug in other countries is also required other than the information on safety and efficacy. The information regarding the prescription, samples and testing protocols, product monographs, labels must also be submitted.
An application to conduct clinical trials in India should be submitted along with the data of chemistry, manufacturing, control and animal studies to DCGI.
Stages of approval
1. Submission of Clinical Trial application for evaluating safety and efficacy.
2. Requirements for permission of new drugs approval
3. Post approval changes in biological products: quality, safety and efficacy documents.
4. Preparation of the quality information for drug submission for new drug approval.
Clinical trials of new drugs and vaccines, and their approvals, are governed by the New Drugs and Clinical Trials Rules, 2019.
The 2019 rules provide for “accelerated approval process” in several situations that would include the one like the current pandemic. In such situations, there is a provision for granting approval to a drug that is still in clinical trials, “provided there is a prima facie case of the product being of meaningful therapeutic benefit”.
“Accelerated approval may also be granted to a new drug if it is intended for the treatment of a serious, or life-threatening condition, or disease of special relevance to the country, and addresses unmet medical needs,” one of the relevant provisions of the Rules says. The definition of new drug in the 2019 Rules includes a vaccine.
Emergency use authorisation (EUA)
What is emergency use authorisation (EUA)?
Vaccines and medicines, and even diagnostic tests and medical devices, require the approval of a regulatory authority before they can be administered. In India, the regulatory authority is the Central Drugs Standard Control Organisation (CDSCO).
For vaccines and medicines, approval is granted after an assessment of their safety and effectiveness, based on data from trials. In fact, approval from the regulator is required at every stage of these trials. This is a long process, designed to ensure that a medicine or vaccine is absolutely safe and effective. The fastest approval for any vaccine until now — the mumps vaccine in the 1960s — took about four-and-a-half years after it was developed.
In emergency situations, like the current one, regulatory authorities around the world have developed mechanisms to grant interim approvals if there is sufficient evidence to suggest a medical product is safe and effective. Final approval is granted only after completion of the trials and analysis of full data; until then, emergency use authorisation (EUA) allows the medicine or the vaccine to be used on the public.
What is the process of getting an emergency use authorisation in India?
Experts suggest that India’s drug regulations do not have provisions for an EUA, and the process for receiving one is not clearly defined or consistent.
However, CDSCO has been granting emergency or restricted emergency approvals to Covid-19 drugs during this pandemic — for remdesivir, favipiravir anditolizumab.
How will a Covid-19 vaccine get an EUA in India, then?
Any company seeking to launch a vaccine approved elsewhere would have to conduct local trials to prove it is safe and effective on the Indian population.
In the case of the AstraZeneca-Oxford candidate (AZD1222), Serum Institute of India is conducting trials of its version, Covishield, on around 1,600 participants in India. Bharat Biotech is currently conducting phase 3 trials of its vaccine, Covaxin, and has said it will not be approaching CDSCO for an EUA.
Serum Institute of India has suggested that the company plans to apply for EUA by approaching CDSCO for such approval only after AZD1222 received EUA in countries like the UK.
How often has EUA been granted?
EUA is a relatively recent phenomenon. The FDA granted its first EUA for the civilian population in 2009. The first EUA allowed the use of Tamiflu drug for infants and young children for the treatment of H1N1 infection.
Since then, EUAs have been granted for several medicines, diagnostics, and equipment like ventilators or even PPEs, but never for a vaccine. An EUA can be granted only in a declared public health emergency; previous EUAs came during the spread of the Ebola virus, Zika virus and MERS coronavirus.
Remdesivir or faviparir, which received EUA for treatment of Covid-19, including in India, are existing drugs approved for other ailments. They could not be administered to Covid-19 patients without extensive trials, but because they showed promise in limited testing, in specified conditions, they were therefore “repurposed” for Covid-19 patients through EUAs.
Is there a risk in using a product that has only been granted an EUA?
According to the US FDA, the public has to be informed that a product has only been granted an EUA and not full approval. In the case of a Covid-19 vaccine, for example, people have to be informed about the known and potential benefits and risks, and the “extent to which such benefits or risks are unknown”, and that they have a right to refuse the vaccine.