On March 19, the government notified the New Drugs and Clinical Trials Rules, 2019, which makes it very clear that it intends to promote clinical research over ensuring the safety of patients and trial participants. This is a bad move considering that 1,443 clinical trial participants died between 2015 and 2018, of which the government said only 88 deaths were related to the trials.
The new rules replace the old, after having shuffled, merged and elaborated sections of the existing Drugs and Cosmetics Rules, 1945 and in the process several questionable provisions have been included.
1. No appeal for trial participants
The new rules state that if a clinical trial’s ethics committee members or sponsors are aggrieved about any decision of the Drug Controller General of India, they can appeal to have the decision reconsidered. However, no such appeal is available to trial participants in matters of compensation for serious injury or death and trial relatedness, that is to what extent the injury or death can be said to be caused by the drug.
As before, researchers are required to provide free medical management as long as required in case of injury during a trial “till such time it is established that the injury is not related to the clinical trial”. However, a new dubious phrase has been added – “as per the opinion of the investigator”. This means that once the investigator establishes that the injury is not related to the trial, the legal obligation to provide free medical care to the trial participant ceases. Here too, a trial participant has no option of appealing the investigator’s decisions. In framing the new rules, the government has missed the chance to remove the provision “till such time…” altogether.
2. No-fault compensation removed
A related glaring omission in the new rules is that of a clause that was present in the February 2018 Draft Rules. This clause mandated interim compensation of 60% of the total compensation to the legal heir of a trial subject, who died or suffered permanent disability, to be made within 15 days of receipt of the opinion of the ethics committee. The World Health Organisation opposed this clause in the draft with Soumya Swaminathan, who was then deputy director general and is now chief scientist, writing to the Union Health Secretary Preeti Sudan that “if the rules are finalised as they currently stand”, sponsors of clinical trials will go out of India.
Subsequently, the government has removed this provision of an almost no-fault compensation that civil society had been demanding.
3. Efficient but not effective
The second goal of the new rules is “to have predictable, transparent and effective regulations for clinical trials”.
Transparency has certainly not increased for trial participants. There is no mention of trial data or results being made available to them or to the public. Rotavirus clinical trial data, for instance, that formed the basis of the public health policy decision to introduce the rotavirus vaccine in India, is not available in the public domain.
The rules reduce the time for the Drugs Controller General of India to decide on a clinical trial application from 180 days to 90 days for drugs developed outside India and to 30 days for “discovery, research and manufacture” in India. This provides a big boost to the clinical trial industry but raises questions about safety being sacrificed for speed. For drugs discovered in India, the rules state that if within 30 days, no communication is received from the Drug Controller General of India, “the permission to conduct clinical trial shall be deemed to have been granted.” This can engender corruption and is tantamount to the delegated authority washing its hands of the responsibility of approving trials.
4. Questionable waivers
Other goals are to make new drugs more quickly accessible to the Indian population and to prevent duplication of studies and data generated from outside countries. Faster accessibility is to be accomplished by waiving local trials of a new drug if “the new drug is approved and marketed in countries specified by the Central Licensing Authority” and “if no major unexpected serious adverse events have been reported”.
It is unlikely that those seeking approval will report serious adverse events.
Moreover, the new rules allow the government to waive or modify requirements relating to animal toxicology, reproduction studies, teratogenic studies, perinatal studies, mutagenicity and carcinogenicity in case of new drugs approved and marketed for more than two years in other countries, if the Central Licensing Authority is satisfied that there is adequate published evidence regarding the safety of the drug.
The largesse of such waivers in the absence of more certain knowledge of the new drug’s safety is worrying. Local trials are essential to determine the effect of drugs in different populations, especially in a country with as much ethnic diversity as India. The Ranjit Roy Choudhury Committee constituted specifically to look into clinical trials had recommended Phase Three clinical trials – in which drugs are tried in a particular demographic population for safety, efficacy and dosage – and bridging studies to assess the impact of the new drug on diverse ethnic populations of India.
The new rules waive this requirement using the circular logic that if there is no existing evidence of differences of the effects of the drug in Indian populations, local trials can be waived.
The only justifiable waiver under these rules is when the drug is used for treatment of a life threatening or serious disease, for a disease with special relevance to India or for a condition which is unmet need in India – extreme drug-resistant tuberculosis, hepatitis C, H1N1, dengue, malaria and HIV and rare diseases.
Even in the case of orphan drugs developed to treat rare diseases, clinical trials should not be waived. Since these drugs are intended for only a small number of patients and the pharmaceutical industry has little interest in them under normal market conditions, they are likely to be less well researched. Despite what the rules imply, clinical trial waivers will not bring down the high costs of drugs.
No answer on patient safety
These new rules are going to be presented in the Supreme Court in a case regarding clinical trial deaths since 2005 as an answer to the demand by petitioners for enhanced safety of trial participants.
The difference between the old rules and the new rules, however, is that the former gave the impression that India was not promoting clinical research. The shuffling of the old rules in drafting the new rules rectifies this, after a fashion, but does little to improve the safety of the Indian patient and trial participant.
The number of foreign origin trials conducted in India is by no means an indicator of an atmosphere for research. While poor citizens of India are still an easy target for clinical trials, most drugs discovered abroad do not depend on clinical trials conducted here. In fact, clinical trials in India are the tail end of a vast elephant with most of the research done in the United States and the European Union.
Some changes for the better
The rules now will apply to bioavailability and bioequivalence studies of new drugs at par with clinical trials. Bioavailability studies demonstrate how much of the active ingredient of the drug is taken up by the body. Bioequivalence studies compare the bioavailability of the new drug with that of a reference drug.
The new rules also mention free post-trial access to new drugs. But there is a spoiler. The trial subject must certify in writing that the trial sponsor shall have no liability for post-trial use of the drug. A trial participant can also only get the drug post-trial if there is no alternative therapy available. Ideally, giving ill people post-trial access to drugs should be done less grudgingly.
What’s missing
Surprisingly, the new rules also include a section on biomedical and health research even though such research is defined as not being clinical trials. The rules do not envisage any regulatory role for the Drug Controller General of India in biomedical and health research, or in the formation of ethics committees, in management or in compensation. It simply says all this will be done “in accordance with the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants specified by the Indian Council of Medical Research from time to time”. Interestingly, the rules specify that biomedical and health research should follow the National Ethical Guidelines but do not have a similar explicit statement for clinical trials.