The Indian Clinical trial regulations have undergone major changes in the past few months. After receiving inputs from various stakeholders these will be modified, but some additional changes will also be enforced. The ultimate goal is to streamline the process of new drug and clinical trial approvals. The Ethics Committees (ECs) seem to be at the receiving end in the initial orders & notifications
Gazette Notification 72E is about registration of ECs. The salient points therein are:
Under explanation of the term EC it states “………………it shall be responsible for reviewing and approving the protocol, the suitability of investigators, facilities, methods and adequacy of information to be used for obtaining and documenting informed consent of study subjects and adequacy of confidentiality safeguards “
Gazette Notification 53E, is regarding compensation to the subjects in case of trial related injury. The responsibilities of the EC mentioned here are
As per the gazette notification, compensation is due to a subject under the following conditions, some of which will soon be modified
(a) adverse effect of investigational product(s);
(b) violation of the approved protocol, scientific misconduct or negligence by the Sponsor or his representative or the investigator;
(c) failure of investigational product to provide intended therapeutic effect;
(d) use of placebo in a placebo-controlled trial;
(e) adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;
(f) for injury to a child in-utero because of the participation of parent in clinical trial;
(g) any clinical trial procedures involved in the study.
Review and approval of a proposal
The problems start with corum for the meeting. Guidelines are specific about the minimum number and the type of members that constitute a corum. Often due to last minute apologies the pivotal group may not be present and the meeting has to be postponed. Alternate would be to have 2-3 members of each variety so that the quorum is always complete. But given that these members are attending voluntarily, is it not a waste of their time?
The EC is supposed to assess the suitability of the site and investigator. Is only a CV of the investigator sufficient? Should the EC not get an opportunity to talk to him/her to see if he has experience and has an inclination for research? Should the members not visit the site to check for readiness? How will this visit differ from the Clinical Research Organizations (CROs) site qualification visit? Duplication of work!
The EC has to evaluate the proposal from the point of view of its risks to the subject versus the benefits to the subject as well as society. Who out of the team can carry out a risk benefit analysis? It is generally the medically qualified persons, but not all of them have they been trained for the task? It is said that for an active EC member with access to internet, it takes 2 full days to read documents related to a proposal and to form a rational opinion. How many practicing doctors can spare this much time? When there is more than one proposal to be discussed, a true assessment seems difficult.
While evaluating the scientific aspects of a study, one often comes across situations where the proposed sample size is huge in order to prove equivalence or on inferiority. The sponsor may have already mentioned the statisticians note in the proposal but is it not true that anything can be proved of disproved by having an adequate sample size? If there is no statistician on board analyzing the ethically correct sample size would be difficult. Again the rule of thumb is that true differences do not need huge samples to show statistical significance. How often do ECs question the need of putting so many subjects at risk?
Monitoring the study
The gazette notification recommends that the ECs should maintain constant vigil on trials approved by them by having planned as well as surprise monitoring visits, identifying deviations from protocol and taking immediate action. But there is no guidance about what is to be monitored and at what frequency. Should they concentrate only on the consent process or check trial documents, or check method of drug administration? How will this visit be different from the CRO’s monitoring visit? Since the EC is short on manpower can this activity be outsourced, and if yes, who will pay? Again in case of Independent Ethics Committees will they be allowed to visit institutions freely? Is there not a possibility that “surprise” visits are unsuccessful since no responsible person is available at the site?
EC is supposed to act on protocol deviations. In the practical world, the EC learns of a deviation in a scheduled report, or at the end of the study. In both instances, the damage is already done. Can EC take strict action like stopping the trial? Since most ECs are supporting research at an institution, how many are willing to go that far?
Review of SAEs and compensation
An EC is supposed to review all SAEs reported to it and carry out a safety review. It will also decide on the compensation, if any, to be paid and reassess the risk benefit on an ongoing basis. The safety review has to be sent to DCGI in 21 days after occurrence. The investigator has to report it to EC within 10 days of occurrence. Assuming that he barely meets the deadline, in effect the EC gets 11 to 14 days to act. This means more meetings more often. Will all members be ready to devote so much time? If a subcommittee is formed, it must necessarily have the medical person. Will he have so much time to spare?
Guidelines for compensation are difficult to follow. Who has the responsibility of gathering income data of the subject and how to validate it? If the income is less than minimum prescribed, the minimum wages act has to be followed. But that is different in different states and levels of skill. As I write this, I understand these guidelines will undergo some change.
ECs will require voluminous record keeping and archiving. A secretary’s job in an EC will have to be done by a professional and possibly be fulltime. To be ever ready for surprise inspections, should the EC have regular mock audits? Who will pay for these?
Today we have more than 500 ECs registered, but do we have sufficient trainers who can give more than basic training?
The new regulations will certainly make the life of ECs difficult. It may no longer remain a voluntary activity given the time and effort needed to successfully run an EC. It will also mean that the sponsors will have to bare additional cost burden in their projects for the ECs. This is the only way the clauses of continuous training, monitoring and review will be fulfilled.
EC seems to be the port of call for all major issues in the trial. The work load of ECs is going to increase and it will not be fair to expect members to devote so much time without expecting any returns. As a first step EC members should be paid for review, site visits and for the time they devote. Audits should be held to prepare for inspections. Archival services could be used for record keeping. Since ECs will have a say in deciding relatedness, severity of injury and compensation to be paid, it is possible that some of them could be dragged to court. Hence one should also insure the committees themselves. These acts can ensure competent individuals continue to work for ECs. Even if all this cost is apportioned per study to the sponsors, it will be a miniscule portion of the total trial expense, hence affordable and a necessary expense to improve the quality of research in India.
|Consultant Pharmawisdom (August 2013)|