CDSCO Draft Guidelines: Industry gives its verdict

My first reaction to the draft of the said guidelines is that of welcome. The effort is timely. Also, it has taken important variables into consideration. It can be super fined to adjust for, say, phase of trial or else alternate use of pre-marketed drug. But then, the guidance is meant for use of Ethics Committees. Any complex mathematical model will be intimidating to the members of Institutional Ethics Committee (IEC). For IECs it has given direction, clarity and simplicity. While the proposed compensation rules have sound moral basis, the draft leaves certain areas nebulous. Definitions of injury, eligibility to seek compensation, authority to decide its quantum and confounding factors (like adverse events with placebo or an approved drug) have not been considered in totality. With such vagaries in rules, insurance premier cost will be heavy, and that may impact the business. I have worked out five scenarios (see table below) and that did not take me more than 40 minutes – that too trying to understand the formula.

Suneela Thatte Executive Director – Customer Operations, Quintiles India

The multiplier B in the formula is a reproduction of ANNEXURE 6 SCHEDULE IV to Workmen’s Compensation Act, 1923. It is therefore not arbitrary. These are not “Rules” to lay down the tortuous liability in a Civil Court. The intent is to provide a benevolent gesture to anyone participating in clinical trials. Granted that there is implicit “No-fault-liability”. I do not think the industry should be touchy about it, essentially because the maximum amount of compensation can be covered by incredibly small premium. Limitation of the formula is that the compensation cannot be worked out if the subject is below 16 years age. Also, if a ceiling on the amount of compensation is not kept, then the hunt will be for poorer subjects. This is not desirable. A large number of volunteers in BA/BE studies are college students. To decide the multiplicand (A in the formula) there needs to be further guidance for such eventualities. I am sure, there will be more gaps to be filled in. The right course for industry now is to provide practical suggestions, before guidance is released. It will be a great step forward if the DCGI convenes a meeting with representation from industry and Insurance Regulatory and Development Authority (IRDA) to consider compulsory insurance for every subject in every clinical trial. My uneducated guess is that the premium will drop drastically. Also, if we hold that a volunteer obliges mankind by participating in a clinical trial, this compulsion ought to be acceptable. I feel, it is now a question of “How to do it”? rather than “Whether to do it? or Why it is wrong!”

Apurva Shah Chairman, ACRO

Overall, in spirit and intent, we believe that the guidelines are an extremely important step forward in addressing some of the key concerns and challenges in doing clinical trials in India. There is clear intent to provide clarity, introduce governance and provide transparency which is indicative of Central Drugs Standard Control Organization (CDSCO’s) seriousness in moving the industry forward. What is also important is that what has evolved is as a result of collaborative discussions between the government, regulators, the industry, not for profit organisations and other key stakeholders while ensuring that the interests and safety of patients are kept foremost.

Specifically on each of the guidelines

Dr Arun Bhatt President, Clininvent Research

The registration of Ethics Committees is a welcome step given the critical role they play in the oversight of a trial. There are, however, a few areas within the guidelines that need to be addressed, most importantly what one does in the interim period between when a registration is submitted and registration is granted. We also need to understand what happens if registration is declined so that a patient’s safety is not compromised. More clarity as to what constitutes a quorum as also the definition of a lay person and medical scientist is also required. We need more clarity on which guidelines need to be followed as there are references to compliance with both ICMR and Indian GCP guidelines which are not really consistent with each other. While we have never disputed the need to pay compensation, there was a need to develop clear guidelines in determining the quantum of compensation in respect to study-related injuries to ensure fairness to the subject (or their heirs) and consistency for the sponsors/administers of clinical trials. While the CDSCO Guidelines have recommended a system for computing compensation, such a system needs to be robust and must leave no room for ambiguity. For instance, in recommending a scale of zero to 100 to be used in determining the seriousness and severity of the disease, the guidelines leave a lot of room for subjective opinion which could cause confusion and debate, thereby delaying the process of awarding compensation.

Five scenarios
Monthly Income Rs = A	Age	Multiplier = B	Before trial	Trial	Administered	Outcome = D	Risk factor = F	Disability
20000	18	226.38	Healthy	BA/ BE	Trial Drug	Death	0
20000	18	226.38	Healthy	RCT	Placebo	Death	0
20000	18	226.38	Diseased	RCT	NCE	Death	25
20000	18	226.38	Healthy	RCT	Comparator	Injury	10	40%
20000	60	117.41	Diseased	RCT	NCE	Death	50

Similarly, there are no details about who determines the percentage of disability and how this percentage is to be determined or how one determines the risk factor. There is no information either on who determines whether an injury/death is study related and what formula is to be calculated for those under 16 years or above 65 years. Unless we have fool proof and objective criteria to determine compensation, we will be in a situation where objections and counter objections will set the process back rather than take it forward. So, while we welcome the move to create a formula for determining compensation, it needs to be reviewed and made fool proof. Overall, as we have stated in the beginning, these are initiatives in line with what we at Quintiles are firmly committed to—patient safety, ethics and quality—and we look forward to a more regulated industry that will have patient interests at its core.

Last year in October ACRO welcomed the move making registration mandatory for Ethics Committee.

1. Registration of Ethics Committees:

This is a necessity and we welcome this. As a matter of fact we helped them collect the names of the IEC names our members work with and have requested all of them to get registered.

2. Composition of Ethics Committee

By having a more clear guideline on the following issues a lot of issues can be avoided later

1. Essential to describe quorum requirements as (½ x total number of members) + 1
2. Definition of lay person
3. Certificate of training in areas mentioned in the clause
4. Essential to give definition of basic medical scientist

3. Compensation

This is an another welcome step from the regulators. By attempting to clearly direct how the adverse effects from clinical trials are compensated we will be able to respect the life of our people who offer themselves for the betterment of the lives of millions who will benefit from the drugs.

This will also clear off the ambiguity and will make everyone accountable for the responsibility they should carry when doing clinical trials.

We believe it’s a good draft but there are the following areas which need clarity:

1. Suspected unexpected serious adverse reaction (SUSAR) vs current Schedule Y requirement of reporting all unexpected SAEs
2. General consideration. Injuries can be physical or psychological/emotional.
   Psychological/emotional injuries are difficult to define and are likely lead to unnecessary debates / claims.
   A scale of 0 to 100 shall be used for determining the seriousness and severity of the disease
   Such a scale is arbitrary and likely to lead to different assumptions by different stakeholders leading to unnecessary debates and delays.
3. To determine the compensation in case of trial related injury
4. It is percentage disability caused to the subject due to clinical trial.

Who will / how to decide percentage?

Vijay Moza Chairman, Clinical Research Education &  Management Academy (CREMA)

There are several issues with these guidelines. Today, there are several concerns about ethics committee functioning. How competent such ethics committee are in deciding compensation?

The preamble to the guideline describes injuries as physical or psychological/ emotional psychological/emotional injuries are difficult to define and are likely lead to unnecessary debates/claims.

In step 4, there is a scale to determine the seriousness and severity of the disease.

The compensation is for serious adverse event—permanent injury OR death. Why should severity be judged to determine compensation? Such a scale is arbitrary and likely to lead to different assumptions by different stakeholders leading to unnecessary debates and delays. To determine the compensation in case of trial related injury, percentage disability is to be determined. Who will/how to decide percentage? This also seems to be arbitrary and will lead to controversies and debates.

It seems that proposed quantum compensation guidelines will serve the need but still there are a lot many if and buts prevalence into it. It is now on the Ethics Committee to present fine tuned guidelines.

A compensation has to be on the same pattern as is prevalent internationally. Present compensation is inadequate irrespective of whether patient is terminally ill. Lack of proper compensation will always be discouraging patients to go for trials. Ethics committees should play a constructive role in determining the quantum of compensation which should be binding on sponsor.

u.sharma@expressindia.com