Representative image. Photo: Retha Ferguson/Pexels.
On June 29, the Hyderabad-based company Bharat Biotech announced it had received permission from the Drugs Controller General of India (DCGI) to conduct human trials for its new COVID-19 vaccine, named COVAXIN. The company worked with the Indian Council of Medical Research (ICMR) and the National Institute, Pune, to develop the vaccine.
The announcement made headlines as the indigenous indigenous vaccine – the company’s claim – to receive a green signal to conduct human clinical trials. On July 2, it grabbed the country’s attention anew when ICMR director-general Balram Bhargava sent a letter to 12 hospitals and research centres around India instructing them to participate in the clinical trials and conclude them by August 15 – a punishingly short deadline by any standards. He had effectively reduced the participant enrolment date by a week.
The ethics committees
Under rule 80(2) of the New Drugs and Clinical Trials Rules 2019 (a.k.a. Rules) clinical trials have to be undertaken before manufacturing any investigational new drug, including vaccines.
According to Rules 19 and 25, and its first and third schedules, every clinical trial must:
1. Have permission from the DCGI and strictly follow the approved protocols;
2. Have the relevant ethics committee’s approval (these committees must already be registered with the DCGI);
3. Be registered with the Clinical Trial Registry of India (CRTI); and
4. Adhere to ‘good clinical practices’ as defined in the Central Drugs Standard Control Organisation (CDSCO) guidelines.
Per Rule 2(o), there are two types of ethics committees: those for clinical trials and those for biomedical and health research. Only the former can approve or reject clinical trials.
The Rules’ second schedule lists this committee’s duties and responsibilities. For example, the committee must ensure the safety and well-being of all trial participants and periodically review the trial.
We have tabulated the 12 institutes tasked with conducting the trials based on data from the CDSCO website and the trial’s registration. We found that as of July 4, half of the respective institutes’ investigators still hadn’t received their respective ethics committees’ approvals. Also note that the ethics committees of four of the 12 sites have only just been registered and two of them are less than a year old.
This is a problem because it suggests the corresponding sites are not well-versed with clinical trials as well as that the respective committees could have been constituted just to facilitate the COVAXIN trial.
A primary ethical principle laid down among the good clinical practices is that researchers must ‘do no harm’ (2.4.1). According to the Rules, the DCGI can grant accelerated approvals only in extenuating circumstances, such as natural disasters. It’s also empowered to approve the drug’s manufacturing before the phase III trial results are available if the drug showed “remarkable efficacy with a definite dose” in phase II trials. However, additional post-licensure studies may be required to verify clinical benefits.
So it’s quite clear that while the approval of the drug or the vaccine can be expedited, the ethical principles themselves can’t be bypassed.
Powers and jurisdiction
ICMR chief Bhargava had also said in his letter, “Non-compliance [of the dates] will be viewed very seriously”. This is odd because the power of ICMR to act against doctors and research centres is questionable on four grounds.
First, ICMR is neither a statutory body nor a regulatory body. It is only the apex body in India for formulating, coordinating and promoting biomedical research. It doesn’t have the power to directly initiate punitive action.
Second, ICMR doesn’t find any mention in COVAXIN’s trial registration. It is also neither the sponsor nor the principal investigator.
Third, according to the Clinical Trial Rules, only the DCGI can initiate action when investigators fail to comply with the Drugs and Cosmetics Act or the Rules. And in such cases, the DCGI may – after giving a show-cause notice – issue a warning, reject the trial’s results, suspend or permanently cancel the permission granted and/or debar the investigator or sponsor from conducting any trials in future.
Fourth, if the doctors at the trial sites don’t adhere to ICMR’s research guidelines, they will be guilty of professional misconduct under the Section 7.22 of the Indian Medical Council Regulations 2002. In such cases, the power to punish lies with the State Medical Council.
All together, ICMR’s act of interference with the trial – by directly communicating with the investigators at trial sites – may have been beyond its purview.
Trials sites’ readiness
According to the ‘good clinical practices’ guideline 3.1.1, the clinical trial’s sponsor is responsible for selecting the investigator(s) and institutions, taking into account their appropriateness and availability of facilities.
However, four of the six sites that have received approval from their respective ethics committees – Gillurkar Hospital, Jeevan Rekha Hospital, Prakhar Hospital and Rana Hospital – are small private hospitals that are neither research centres nor attached with any medical college. The table below shows the number of vaccine trials undertaken at these sites. Given this is the case, it’s not clear how these sites were chosen and if they are qualified to participate in human clinical trials for a vaccine for a new virus even as a pandemic is underway.
In a press release on July 4, ICMR had said that it had said its unreasonable deadlines not to compromise patient safety but to cut ‘red tape’. While trying to ensure a clinical trial as important as the present one isn’t slowed by bureaucratic lethargy, the speed advantage shouldn’t come at the cost of ethical and procedural requirements originally designed to ensure trials are fair, safe and useful.
So the vaccine’s approval, production and mass administration should proceed with great care. Any misstep with regard to safety protocols at this stage will have a major impact on the faith of India’s citizens on the public healthcare system.
Note: At 8:22 pm on July 9, 2020, the line about the ages of the ethics committees was edited to note that two of the four young committees are less than a year old, not two others as was originally stated.
Aakash Sethi and Gayatri Laha are third-year medical students at the Government Medical College, Baroda, Gujarat.