Clinical trials: Safety of research participant is the ethical mandate!

Dr SV Joga Rao

The Supreme Court of India in its recent order directed the Government of India to furnish details as to regulatory controls governing clinical trials in India. This is in response to a writ petition filed by a group of public spirited citizens seeking judicial intervention pertaining to certain clinical trials conducted on women undergoing psychiatric treatment in one of the cities in India.

Initial media reports claimed that these trials were conducted over a period of two years flagrantly violating the applicable regulatory guidelines and mostly without getting mandated approvals from institutional ethics committees (IEC). This particular incident is not an isolated one. Of late, there were reports indicating such conduct of trials involving women and children in other states as well.

Speaking for Indian context, the clinical trial industry which is barely a decade old has recently been projected by an influential industry association to grab business value to the tune of $1 billion by 2012-13. Naturally this kind of projections made the sub-continent as one of the world’s most preferred destinations for clinical trials. According to some quarters by this year-end, India will be conducting more than 15 per cent of total global clinical trials.

The conducive environment has succeeded in drawing drug companies to India to undertake diverse clinical trials for multiple reasons like, technically competent workforce, low cost, adequate infrastructure, and friendly drug control system and more importantly availability of patients and healthy volunteers.

Booming clinical trial industry has raised very serious issues pertaining to conduct of trials and human safety. The regulatory framework governing clinical trials in India takes within its fold, The Drugs and Cosmetics Act and allied rules, Schedule Y and most significantly Ethical Guidelines for Bio-Medical Research on Human Participants generated by Indian Council of Medical Research. Apparently, owing to the pressure mounted by Supreme Court, recently two Gazette Notifications have been issued dealing with Registration of IEC and related formalities and compensation in case of injury or death during clinical trial.

In the entire ambit of regulatory control governing clinical trials, ethical review by IEC plays a crucial and pivotal role. In fact the role of IEC informs us that the gamut of clinical trial is not merely a matter of business proposition but an area of humanitarian concern.

As a teacher of healthcare ethics and law for more than two decades and as a chairperson of select institutional ethics committees for almost a decade, I write to share my experiences about the role, responsibility, accountability and functioning of IEC in the context of regulatory framework and particularly the landscape of challenges that are encountered.

As a chairperson, by and large I was a mute spectator during first few meetings. Literally, I could not decipher anything that was deliberated. Presentations by PIs and ensued interactions were too technical, fully loaded with medical jargon. Apart, I could not comprehend what has been stated in protocols and large volumes of related documents. I used to wonder, why participation of a person from legal background was mandated by the guidelines.

At that time, fortunately, I came across Dr Vasantha Muthuswamy and Dr Nandini Kumar (then with ICMR, New Delhi) in a National Conference held in New Delhi. From then onwards, on several occasions, I used to interact with them about IECs and its role in clinical trials. Till their superannuation and even thereafter they have played a singular role in generating public awareness and facilitating evolution of pertinent guidelines.

I have had the opportunity of receiving tremendous insight about clinical trials and the need for sensitive policy and law sensitive to human concerns.

These experiences enabled me to realise the role of a legal professional (either as a chairperson or member of IEC). While taking other members into confidence, I took several initiatives of bringing awareness among IEC members about the legal and regulatory framework governing clinical trials, and more particularly, the role and responsibility of IEC in the backdrop of ICMR and related international guidelines. Similarly, members have been consistently informed about legally binding contractual relationships between and among key stakeholders like sponsor, CRO, SMO, hospital and principal investigators.

By and large, none of the PIs were aware about any of the clauses envisaged in Clinical Trial Agreement (CTA) and significantly clauses like Indemnification and Limitation or Exclusion of Liability were absolutely incomprehensible. I used to discuss threadbare about the meaning and implications of this type of clauses in the Scheduled IEC meetings. In addition, the role and responsibility of IEC in according approvals to trials and particularly the basis on which the approval requires to be premised was repeatedly and consistently emphasized.

During that period ICMR had invited me to participate in several workshops organised exclusively for IEC members (nationwide) focusing on capacity building pertaining to legal and regulatory framework governing clinical trials. Singularly, I would want to mention about our struggle relating to incorporation of certain clauses in Informed Consent Form (ICF) and Patient Information Sheet.

When it comes to participation in a clinical trial (either as a patient or healthy volunteer) informed consent plays a crucial role. From ethics point of view, this is a very significant non-negotiable compliance factor. Rigorous and close scrutiny of all the clauses envisaged in ICF is very crucial for IEC for the purposes of deciding whether a particular proposal deserves to be approved or not.

Quite often, we used to encounter serious dilemmas relating to envisaged risks and complications. Either the words used to convey risks or complications are very vague or contradictory in nature at times.

Particularly, with regard to ‘medical care’ to be provided to a research subject in the event of any kind of adverse event, we used to get a stock response from almost all trial sponsors i.e., clinical trial insurance takes care about the same.

On the basis of detailed perusal of relevant terms and conditions of clinical trial insurance, I used to vehemently contest this claim on the ground that the insurance policy provides compensation (provided if such adverse event encountered by the research subject doesn’t fall under the ambit of exclusion clauses stated in the policy) only but not medical care. Even assuming for the sake, when will such compensation be paid to the research participant and till that point of time who will be responsible for the care and well being of the research participant? Literally, these concerns were never given credence, during the initial years.

On several occasions, approvals have been withheld seeking amendments and incorporation of specific clauses to this effect. Very rarely, we used to get positive response from sponsors, in this specific regard.

On a couple of occasions, our decisions were contested by arguing that IECs at other centres have already approved and more particularly, the trial being a multi-site centric, amendments cannot be accepted heeding a site specific decision. In addition, they used to justify their claim on the ground that there is not statutory mandate towards this end.

In majority cases, our concern about ‘medical care’ to be rendered to a research participant in the event of any injury or adverse consequence has not been positively addressed.

From then onwards, we have collectively taken a decision to insist on such a clause as a matter of institutional policy. To that effect, we have substantially succeeded in seeking compliance from several sponsors. Recently issued gazette notification quite explicitly puts at rest the so called ‘contest’ as projected by select sponsors. Now it is amply clear that warranted ‘medical care’ must be rendered to needy research participants as a matter of statutory mandate. Hereinafter, sponsors can not take the shelter under convenient contractual terms and conditions to support their claim in not rendering medical care.

In a way recently issued gazette notification mandating registration of IEC is the warranted step in the right direction. This is something that is long overdue at a fundamental level.

However, the responsibilities of IEC envisaged under the notification relating to compensation to injury or death warrant a thorough re-examination. For instance, as per the notification, IEC is expected to file a report before Drugs Controller General of India (DCGI) as and when asked detailing with clear reasoning as to whether the adverse consequence (injury or death) experienced by the research participant is attributable to clinical trial or not. And if so, what is the recommended amount payable by sponsor as compensation. The ultimate decision will be made by the licensing authority.

The crucial issue in this regard is, on what basis IEC can come to appropriate conclusions. No doubt, the input rendered by PI is a matter of great relevance. Particularly, in cases where, the research participant is a patient, it would almost be impossible for IEC to reach an objectively verifiable finding. On many occasions, the cause of adverse consequence may not be ascertainable without postmortem. Speaking for our context, getting nod of postmortem is a very difficult task. Unless such death is construed as medico-legal case, postmortem as such cannot be mandated. Even assuming that, there is a consensus as to postmortem, nevertheless, facility to conduct or organise postmortem as such may not be feasible.

In the absence of convincing and reliable input and information, IEC may find it very difficult to either decide about the cause of adverse consequence or recommend quantification of compensation. No doubt, there are guidelines pertaining to quantification are made available. However, there is mounting criticism against these guidelines questioning the rationale and basis. Similarly, some of the clauses require substantial changes. In this regard, the clause dealing with deemed clinical trial injury or death warrant need a re-look.

While positively appreciating the evolving and emerging nature of regulatory framework governing clinical trials in India, the need for a more meaningful consultation particularly with IEC members cannot be undermined. Undoubtedly, issuance of recent Notifications indicates a knee-jerk reaction and apparent response to Supreme Court’s ongoing interventionist role.

While considering safety of research participants as the most fundamental ethical mandate, it is our bounden duty to ensure that the applicable policy, law and regulatory framework are sensitive to this concern. Towards this end, purposeful contribution from everyone concerned is the need of the hour.