Playing by protocol
‘Protocol design’ is a regular phenomenon across different industries. However, as far as the clinical trial industry is concerned, it’s an activity of laying down a procedure/steps that would have an impact on the life and death of the patients/participants. Hence, it is no wonder that clinical trial protocol is one of the most scrutinised aspects of any clinical trial by Ethics Committees (ECs). Developing and maintaining a protocol might be a bitter pill to swallow for the clinical trial operators, but for the patient, it gives an assurance that they are the part of a genuine initiative and every effort is undertaken to safeguard/minimise risk to their lives.
Must haves
Basic requirements for any clinical trial protocol are more or less same and as expected, patient’s safety is the top priority. “The health of my patient will be the first consideration,” states Dr Rahul Pandit, Senior Consultant, Intensive Care, Fortis Hospital, Mumbai. He adds, “The ECs all around the world act as per the ‘World Medical Association Declaration of Helsinki- Ethical Principles of Medical Research involving Human Subjects.’ For a clinical trial protocol, a physician shall act in the patient’s best interest when providing medical care. Design and performance of clinical research must be clearly published in a protocol and submitted for review. A preceding assessment of risk involved to patients must be undertaken. A detailed patient information sheet and right to participate or not to participate.”
 “The ECs in their SOPs have mandated monthly, quarterly and yearly project updates submission from the site team to the ECs. The sites have been following this diligently.”Ayan Neogi Business Development, Karmic Lifesciences |
Ayan Neogi, Business Development, Karmic Lifesciences informs that as per Schedule Y Rules in India for conduct of clinical studies on human population, the amended version of year 2005 in Appendix X clearly states the required contents of any Protocol of a proposed study. He says, “Any EC will thoroughly review these contents and will raise concerns in case discrepancies are noted or if the aspects are not appropriately detailed.”
 “For a clinical trial protocol a physician shall act in the patient’s best interest when providing medical care.”Dr Rahul Pandit Senior Consultant, Intensive Care, Fortis Hospital, Mumbai |
Besides the points highlighted by Pandit and Neogi, according to experts, the ECs should also review some specialised areas of research which require additional safeguards. Dr Arun Bhatt, President Clininvent Research, provides some specific details. He says, “Research involving children, vulnerable subjects and those with diminished autonomy should get additional protection. The EC has to review the trial protocol; suitability of the investigators; as well as facilities, methods and material to be used in obtaining and documenting informed consent of the trial subjects.”
Red flags
 “Research involving children, vulnerable subjects and those with diminished autonomy should get the additional protection.”Dr Arun Bhatt President, Clininvent Research |
There are instances when ECs would take an objection to the amendments made in the protocol. Any misplay with the requirements that are mentioned in the protocol would invite the ire of ECs who regularly keep a vigil on it.
Neogi says that ECs can take an objection to the protocol if the study design is not appropriately mentioned in the protocol, highlighting the number of patient visits, the number of blood draws for safety and efficacy assessment, the amount of blood draw etc. He informs that an objection can also be taken if the management of serious adverse events are not appropriately highlighted and mentioned in the protocol, or if the subject compensation to trial related injury and other reimbursements like travel etc. are not highlighted appropriately.
He adds, “If use and duration of the product under investigation and comparator/placebo is not justified appropriately, if the study rationale and the further need of conduct of the proposed trial/study is not mentioned and explained and also if the previous trial results required as per the Schedule Y requirements are not mentioned or not available, the protocol can be rejected.”
Giving the doctor’s perspective, Pandit says, “Lack of patient safety is the major factor and it is followed by objective/hypothesis based on non-scientific data, clear harm shown in animal experiments/experimental studies, lack of provision / consent to accept or withdraw and adaptive methodology based on the prefixed notion leading to a change in protocol during the study.”
 “Inadequate justification for usage of placebo groups and inadequate rescue criteria can become red flags in getting clinical trial protocol approved.”Arohee Ketkar Sr. Project Manager – Clinical Operations, SIRO Clinpharm |
According to Arohee Ketkar, Senior Project Manager, Clinical Operat-ions, SIRO Clinpharm, “Inadequate justification for usage of placebo groups and inadequate rescue criteria can become red flags in getting clinical trial protocol approved.”
Though the purpose of the trial is to discover a remedy to any disease, sometimes the trial itself is so risky to a patient’s life that EC would not allow it to take place. Moreover, the clinical trial’s future also depends on the eligibility of the investigator. “If an EC feels that the investigator is not competent to conduct the trial, it can reject protocol,” informs Bhatt.
Latest trends
Over the last few years, the use adaptive design methods for clinical research and development based on periodically accumulated data have found many takers in the industry. It allows great level of flexibility and efficiency. Adaptive designs vary based on the adaptations applied. An adaptive design is crucial for a clinical trial as it allows for modifications as and when needed.
Pandit provides details about the latest trends in adaptive clinical trials. He says, “By definition it means changing the key parameters during the trial based on the data from current or external studies. The commonest trend is to change the sample size at interim analysis. The second most common adaptation is to change the hypothesis or objective, for e.g., switching between a non-inferiority trial to superiority trial. The other adaptations are to change the end point or drop or add new arms in the study. All of these lead to an increase in the Type I error which is rejecting a ‘null hypothesis’ when it is in fact true.”
 “Various adaptive designs are under discussion, but their feasibility, statistical and clinical validity, and acceptability to regulatory agencies are not yet fully resolved.”Arun Nanivadekar Independent medical research consultant |
According to Arun Nanivadekar, an independent medical research consultant, various adaptive designs are under discussion, but their feasibility, statistical and clinical validity, as well as acceptability to regulatory agencies are not yet fully resolved. However, on a positive note he says, “Progress is likely to take place case by case to begin with, and then pick up speed as all parties develop confidence about them. Novel statistical methods for using historical data on placebo so as to avoid the use of placebo control again are also under discussion. Proposals for embedding phase 3 trials in routine practice have also been made.”
Loopholes in the protocols
In India, clinical trials are always associated with controversies. The Indian Supreme Court’s recent outburst over the alleged deaths during clinical trials in the country has added strength to the voices of opponents of clinical trials. Can these deaths be attributed to the protocols that clinical trial operators might not have followed properly? Or do these deaths indicate that ECs have not been able to plug the loopholes in such protocols?
Amid the controversy, Neogi puts his weight behind ECs. He asserts, “ECs consist of people from different backgrounds. As per the Schedule Y requirements in India, for review of each protocol, the quorum of an EC should be at least five members with the following representations: basic medical scientists (preferably one pharmacologist), clinicians, legal expert, social scientist/representative of non-governmental voluntary agency/philosopher/ethicist/theologian or a similar person and a lay person from the community.”
Neogi adds, “The idea behind having all these roles in place is to validate the protocol from all angles so that no loopholes are left. Cases are evident where ECs and scientific review committees at the sites have time and again asked for clarification or have rejected protocols wherein they thought that there is no scientific rationale to conduct and support the study or wherein they thought that the subject’s safety and wellbeing is at risk. The ECs in their Standard Operating Procedures (SOPs) have mandated monthly, quarterly and yearly project updates submission from the site team to the ECs. The sites have been following this diligently.”
However, contrary to Neogi’s views, Pandit opines, “The new trial protocols, adaptive methodology and innovative trial designs have increased the loopholes and it is a constant challenge to plug them. The whole concept of independent ECs needs to be reviewed.”
Bhatt is in favour of ECs. While justifying his stand, he opines, “In India, the clinical trial protocol is reviewed by the Drug Controller General of India’s (DCGI) office, New Drug Advisory Committee and other bodies like Indian Council of Medical Research (ICMR). If these bodies do not see any loopholes in clinical trial protocols and approve them, one can not hold an EC alone responsible for any issues in them.”
India is already a favourite destination to perform clinical trials. However, certain practices during these trials have also raised a question mark over their credibility. Though there is a lot of hype around deaths during these trials, the fact is that India’s share in the global clinical trial market is hardly around two per cent. In future, the clinical trial market in India would continue to grow and in order to avoid further catastrophes, clinical trial protocols that are already in place would have to be more stringent and more vigilantly monitored by ECs.
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