While finding a solution for COVID-19, Indian drug laws must balance safety and speed

On 20 March, the department of biotechnology, under the union ministry of science and technology, in consultation with the Drugs Controller General of India, or DCGI—the authority responsible for approval of licenses of drugs and vaccines—issued an office memorandum, setting out timelines for faster approvals of applications for COVID-19 related vaccines and treatments. In the meantime, several companies have already joined the race to be the first to develop a COVID-19 drug and vaccine. For instance, the Indian pharmaceutical firm Cipla has tied up with the Hyderabad-based Indian Institute of Chemical Technology, to work on an antiviral drug for COVID-19. Meanwhile, many countries such as the United States have already begun clinical trials for potential drugs and vaccines.

At this stage, it is up to the governments to assist and regulate the companies to ensure that a drug or vaccine is developed as quickly as possible, and also ensure safety and effectiveness. The Indian drug law, however, does not provide clear guidance on how to move quickly to ensure the availability of a safe and effective treatment.

Any drug or vaccine to combat COVID-19 among Indians would have to be invented in India or imported once it has been developed abroad. In both scenarios, the testing pathway for the Indian authorities to approve a drug for sale in India is very similar. Notably, this pathway treats an existing drug that has already been approved for the treatment of other diseases as a “new drug.” This new drug therefore needs to be tested again to see if it can be repurposed for COVID-19, since no scientific data exists demonstrating the drug’s effectiveness on the new disease.

The regime for testing and approval of drugs and vaccines is governed by the Drugs and Cosmetics Act, 1940 or Drugs Act; the Drugs and Cosmetics Rules, 1945 or Drugs Rules; and the New Drugs and Clinical Trials Rules, 2019—all administered by the Drugs Controller, India or DCI. The DCI is a body of officers that the 2019 rules establish, which is headed by the DCGI. The Drugs Act, Drugs Rules and Clinical Trial Rules make up a comprehensive regime for the regulation of the manufacturing, testing, approval, sale, stocking and marketing of pharmaceutical drugs, homeopathic, ayurvedic and unani medicines, and cosmetic products in India. 

Governed by the Second Schedule of the Clinical Trial Rules, tests for new drugs are conducted in three major stages. “Product Characterisation,” the first stage, is aimed at clarifying the nature of the drug, which involves determining the chemical composition of the active ingredient, its molecular weight, physical properties, solubility, acidity, basicity, dosage form, method and so on. The next stage—“Pre-Clinical Trials”—involves testing the drug on animal subjects, including rodents such rats and non-rodents such as rabbits and monkeys, depending on the nature of the test, the nature of the drug, and the nature of the disease that the drug is intended for. 

The pre-clinical trials are done in two parts. The first, pharmacology, deals with the working and affectability of the drug. These tests attempt to understand the drug’s movements through the subject’s body and how it is metabolised, absorbed, excreted and so on. The second part, toxicology, is the safety leg of animal testing and provides a glimpse of whether the drug is safe to use; whether it has any allergenic, carcinogenic or mutagenic properties; and its side effects.

If the animal-testing stage is successful, and there is sufficient confidence regarding the safety and efficacy of the drug, the DCI gives the go-ahead for the third stage of “Clinical Trials,” or human trials. While animal testing provides necessary information regarding the safety and efficacy of a drug, such data is not sufficient. A drug intended for use in humans must be tested on human subjects before it can be launched in the market. Clinical trials are conducted in three phases, prior to the launch of a drug, and a fourth phase is conducted after the drug is available in the market.

The first phase involves pharmacology studies similar to those conducted on animal subjects. The second phase of clinical trials is exploratory studies intended to evaluate the effectiveness of the drug and determine its risks and side effects—for instance, the dosage of drug that is to be administered to the patient is also determined in this phase. The third phase involves confirmatory studies, and is aimed at verifying the data gathered by all the studies so far. The fourth phase, post-marketing studies, is conducted after launch, with access to a much larger sample size, in order to optimise the drug’s use. These include drug-drug interaction studies—to understand how the drug reacts when taken in combination with other treatments—dose-response studies, and epidemiological studies and so on. 

If all the phases of human trials are conducted successfully or even during, the drug is often placed for approval before several government committees, such as the Technical Committee, the Apex Committee and the Subject Expert Committee or multiple independent ethics committees, under the DCGI or the Central Drugs Standard Control Organisation, or CDSCO—the national regulatory body for Indian pharmaceuticals and medical devices under the ministry of health and family welfare. These committees oversee the clinical trial mechanism and protocols. Once the results of the first three phases are approved, the drug becomes available for manufacture, marketing and sale.

This entire process is time consuming and can take anywhere from a few months to a few years, since the regulator’s permission is required at multiple stages, and results of most such stages are placed before the CDSCO for review and approval. The government has correctly identified this as one of the issues to address, in the office memorandum, in order to reduce development time for COVID-19 vaccines and medicines.

The memorandum issued by the department of biotechnology, or DoBT, has now reduced the timelines for various stages of review and approval to seven to ten days. In March, the DCGI also sent a communication to the major pharmaceutical companies announcing fast track approval for COVID-19 drugs.

However, the Drugs Act, Drugs Rules and Clinical Trial Rules do not provide a sufficiently detailed fast-track process for the scientific development of an entirely new drug in India. Under Rules 75 and 80 of the Clinical Trial Rules, a relaxation of certain tests is available, in public interest, for drugs that have been approved for use abroad and are intended to be imported into India. It is done by allowing firms to present the entirety of the data collected from the human-trial stage and some of the toxicology data from the animal trial stage from abroad. This means that product characterisation and animal pharmacology studies of any imported COVID-19 drug will still need to be conducted in India, and which toxicology studies may be modified or relaxed will be determined by the DCI.

Rule 1(2) of the Second Schedule of the Clinical Trial Rules governs an accelerated approval process in the case of diseases of special relevance to the Indian scenario, where there is an unmet medical need. The rules say, for instance, that in such a scenario, the clinical trial may use “non-standard end-points,” which ought to be “reasonably likely” to predict clinical benefit. End points are pre-determined outcomes for a trial and are often defined according to standard protocols, and the rules suggest that these could be modified to accelerate the trial. Further, the rules state, if Phase II of the human trial shows “remarkable efficacy”—in scientific parlance, this would mean if the drug achieves an effect relatively close to what is desired—Phase III may be waived and confirmed later in post-marketing studies. It outlines other suggestions, stating that the potential of the drug to address the “unmet medical need” should be assessed based on the stage of development it is in. The rules also state that in exceptional situations such as war time or in the case of rare diseases, the licensing authority may approve a drug if its safety has been established, even if all phases of clinical trials have not been completed. In the case of drugs that are already approved, where a new claim—a new dosage, a new targeted disease, or so on—is being made, the law essentially states that the data required may be decided on a “case by case” basis.

Though the skeleton of the law seems broad, it is lacking in details for measures to ensure safety and transparency in these processes. For instance, no detailed standards of appropriateness have been set out in the Drugs Rules or in the Clinical Trial Rules, and there is no guidance for the DCI to determine “remarkable efficacy” or the appropriate new endpoints. The rules do not specify how these decisions will be taken, who ought to staff the committees that take these calls, nor a direction on ensuring transparency on the committee’s decisions. The need to ensure that a drug marketed as a cure or vaccine for COVID-19 is safe to use is paramount. However, ensuring that a COVID-19 drug is available to Indian hospitals as soon as possible is also the need of the hour. How does the Indian legal regime balance these two needs? Unfortunately, it does not. 

The responsibility to ensure speed, therefore, falls upon the DCI’s executive shoulders, due to lack of an adequate legal and regulatory framework. This could take the form of putting all applications marked “COVID-19” to the top of the pile—that the DCGI will ensure that no file sits on a desk for longer than is necessary. These are all absolutely necessary measures, and it appears, from the office memorandum and a note circulated by the DCGI to pharmaceutical companies, that the DCGI and DoBT are prepared to take such measures. 

However, since neither the rules nor the memorandum clearly outline which clinical or animal trials for a drug can be abbreviated and by how much, which can be deferred and until when, and which can be omitted altogether, it is unclear what more the DCI can do. It may be assumed that in treatments relating to life-threatening diseases, safety cannot be compromised, and so no test ought to be unnecessarily deferred or omitted. But which trials can be abbreviated and by how much is a question that the DCI needs to address. Considering there are many committees to get approvals from, it is possible that emergency meetings of such committees will be held if a COVID-19 drug needs to be discussed. The memorandum notes that the CDSCO will form a “CORONA unit to address queries on development of diagnostics, prophylactics and therapeutics for COVID-19.” It further states that a link “in this regard” will be made available on the CDSCO website. However, information on the constitution of the committee is not available on the website, nor are records of its meetings, if any.

In fact, the DCGI has said that for COVID-19 drugs developed and approved outside India, human trials and animal toxicology studies may be waived, if appropriate. It is less clear, however, what the DCGI’s plan is for medicines developed in India, beyond directing their officers to avoid procrastinating on COVID-19 files. 

The purpose of the Drugs Act and the Drugs Rules is to balance the need for a quick response time with the need for safety. There are few legal provisions in the books to ensure that no company and no government authority cuts corners finer than necessary. There are very few protocols envisaged to ensure that unnecessary delays are eliminated without compromising necessary patience. In the corporate race to be the first past the post to develop a COVID-19 drug or vaccine, the law must ensure that no company misuses the ensuing panic to have an ineffective, or worse, an unsafe drug approved. Similarly, the law must also make sure that no government authority neglects its duty and approves a drug which does not meet testing benchmarks.

The pandemic has made visible the glaring holes in the Indian drug regime, and it is necessary to plug these holes as soon as possible. People need a cure soon, but not at the cost of safety, and the law needs to provide an effective mechanism to balance all the needs arising from a global pandemic such as the coronavirus.

Corrections:

1.     An earlier version of this article did not address the fast-track processes laid out in the Clinical Trial Rules of 2019, and instead used the Drugs Act and the Drugs Rules to assess India’s drug regime. Parts of the article’s analysis have been updated to reflect the fast-track approvals and the regulations for expediting a clinical trial detailed in the 2019 rules.

2.     The paragraph beginning “If all the phases of human trials …” has been corrected to reflect the fact that a drug may be available in the market before the fourth phase of clinical trials is complete.  

The Caravan regrets the errors.