One of the increasingly contentious public health issues in India is the manner in which clinical trials are conducted for new drugs and the manner in which these new drugs are subsequently approved for use on Indian patients.

The HPV clinical trials on tribal women without their “informed consent” was a major scandal that is currently the subject of litigation before the Supreme Court. Similarly, the process by which the Drug Controller General of India (DCGI) approves new drugs for Indian patients has been the subject of much controversy. For several years now, Indian doctors have been pointing out how the DCGI has been playing loose with the law to grant approval for drugs that lack substantive clinical data and that have not been approved anywhere else in the world.

The 59th report of the Parliamentary Standing Committee on Health, tabled in 2012, has raised several red flags regarding the manner in which the DCGI was approving new drugs without adequate clinical trials. In pertinent part, the Committee stated the following:

“In the case of 4 drugs (10 per cent) (Everolimus of Novartis, Buclizine of UCB, Pemetrexed of Eli Lilly and FDC of Pregabalin with other agents), not only mandatory Phase III clinical trials were not conducted but even the opinion of experts was not sought. The decision to approve these drugs was taken solely by the non-medical staff of CDSCO on their own.”

The Ministry castigated the DCGI for the manner of approving its drugs, stating the following: “The Ministry should ensure that the staff at CDSCO does not indulge in irregularities in the approval process of new drugs that can potentially have an adverse effect on the lives of people. It is difficult to believe that these irregularities on the part of CDSCO were merely due to oversight or unintentional.”

The revelation that drugs are being approved without mandatory Phase III clinical trials is disturbing. To understand the importance of these trials, it is necessary to go back and observe the visuals of the thalidomide tragedy from the 60s. Those were more “care-free” days when it came to approvals of new drugs except in the case of thalidomide it caused terrible birth defects in newborn babies. The scandal completely changed the manner in which new drugs were regulated. The new system put in place consisted of three stages of clinical trials, each more rigorous than the previous, with the aim of establishing both the safety and efficacy of the drug.

Despite the HPV scandal and the irregularities pointed out by the 59th report it appears that little has changed on the ground. I had researched and written a few pieces on the manner in which a new drug called Bedaquiline was approved by the DCGI for the Indian market. To briefly summarise the problem with the approval of Bedaquiline: the drug was approved by the DCGI without the mandatory Phase III clinical trials being completed and the drug is being made available to Indian patients without informing them that the drug is yet to complete testing and that the Phase II trials reported a higher number of deaths in patient groups administered with Bedaquiline.

A bone of contention now is whether those Phase III trials can be waived under Indian law. A reported piece in Caravan Vantage takes issue with an earlier piece of mine in Newslaundry, especially on the contention that global Phase III trials cannot be waived. The piece states that I have argued that the “use of Bedaquiline in India may be illegal”. That is not the case – I only argue that the drug was illegally approved, which does not mean that consuming the drug is illegal. The only drugs whose consumption is prohibited by the law are those that are prohibited by the Narcotic Drugs and Psychotropic Substances Act. The report also quotes Anand Grover, who was the lawyer for a patient seeking expedited access to Bedaquiline.

Mr Grover is quoted saying, “The Drug Controller of India can waive phase 3 trials in public interest under Section 122A of the Drugs and Cosmetics Act”. It must be noted here that the Drugs & Cosmetics Act, 1940 has only 38 Sections. Mr Grover is perhaps referring to Rule 122A of the Drugs & Cosmetics Rules, 1945. This particular rule lays down the criteria to import new drugs into India. The pertinent rule states that any application for importing a new drug into the country has to be accompanied by all of the data as specified in Appendix I of Schedule Y. This Appendix I requires the submission of clinical data from Phase I (Human/Clinical pharmacology), Phase II (Therapeutic exploratory trials) & Phase III trials (Therapeutic confirmatory trials). The requirements and goal of each phase are spelt out in Schedule Y.

Phase I trials are meant to get an estimation of the “safety and tolerability of the drug on healthy volunteers”. Depending on the outcomes at this stage, the drug may proceed to Phase II, whose main objective as per Indian law, “is to evaluate the effectiveness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short-term side-effects and risks associated with the drug”. In other words, the trial subjects are not healthy volunteers but patients suffering from the disease sought to be cured. If the new drug shows promise in phase II, it proceeds to phase III trials, which are the large-scale trials that are usually conducted on hundreds or at times thousands of patients, at multiple sites. This is the most critical and rigorous stage of trials and many new drugs will fail at this stage.

In India, phase III trials are split into two stages as specified by Schedule Y, those carried out in India and outside India. In a pertinent part, Schedule Y states that, “For new drugs approved outside India, Phase III studies need to be carried out primarily to generate evidence of efficacy and safety of the drug in Indian patients when used as recommended in the prescribing information.”

Rule 122A allows waiver of local clinical trials in India by way of the following proviso:

“Provided that the requirement of submitting the results of local clinical trials may not be necessary if the drug is of such a nature that the licensing and authority may, in public interest decide to grant such permission on the basis of data available from other countries”. Emphasis mine.

In other words, the provision allows for waiver of local phase III clinical trials in India on the assumption that other countries have approved the drug based on adequate Phase III data generated in their respective jurisdictions. Nowhere does the provision allow the DCGI to waive both global and local Phase III trials.

Mr Grover’s interpretation of Rule 122A, thus, has no basis in the wording of the provision and would be a body blow to public health in India because it would allow more pharmaceutical companies to get drug approvals in India without completing Phase III trials.

The question that must be asked with regard to Bedaquiline is why did the DCGI grant approval without the phase III trials being completed?

If the objective was to make the drug available to Indian patients who could benefit from the drug even while it was in an experimental phase, the DCGI could have asked either the Ministry of Health or the company that invented the drug to sponsor a clinical trial through which the drug could be prescribed to patients. The advantage of registering a clinical trial is that the sponsor would have to necessarily follow the procedure laid down in Rule 122DA of the Drugs & Cosmetics Rules, 1945 — these rules were inserted into the law to prevent scandals like the HPV one. These rules guarantee informed consent, an independent ethics committee to review the trials minimising conflict of interest and importantly, a right to compensation for patients who are adversely affected by the drug.

These are important issues in the context of Bedaquiline, which in other countries has received only “conditional approvals” (such conditional approvals cannot be granted under Indian law). The “conditions” that are imposed by the American FDA includes a requirement for Janssen to carry the following black box warning: “An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4 per cent) compared to the placebo treatment group (2/81, 2.5 per cent) in one placebo-controlled trial”. Similarly, the Janssen label approved by the USFDA is required to inform patients that the drug has gone through only phase 2 trials and that that “the safety and efficacy of [bedaquiline] for the treatment of […] tuberculosis has not been established”. Only when Phase III trials are completed will the USFDA take a final call on granting unconditional approval.