Being clinical with rhetoric

In Munnabhai MBBS Boman Irani, as Dean of a Medical College, tells medical students on their first day, that doctors need to be clinical. He meant that as a doctor one cannot be too close to a patient as this can reduce objectivity and come in the way of sound clinical decision-making. So what does clinical mean? The concise Oxford dictionary puts it as being coldly detached, dispassionate, and objective. Etymologically, it is derived from the Greek word, ‘klinikos’, meaning bed or the bedside of the patient.

Against this backdrop, one can’t help but reflect on the current media rhetoric surrounding the way clinical trials are being conducted in the country. I am not for a moment discounting all that is being showcased but I would like to see this balanced with data. In any field, there will always be good and bad apples. One swallow does not a summer make. Similarly, a few bad apples should not spoil the entire basket. Before tainting and distorting reality let’s put the facts on the table and then decide.

The word, ‘trial’ itself means an experiment. A participant (not a subject as no one is being subjected to the experiment) is one who is informed of everything that participation in the clinical trial entails, and only after s/he has fully comprehended, and checked with his/her family doctor and relatives, is s/he expected to consent. Of his/her own volition, understanding that participation involves possible risk and possible benefit, so as long as one believes that the benefit is worth the risk, one willingly participates. It is this altruistic motive which makes a participant a hero. Not a guinea pig.

A “guinea pig” is a misnomer as the animal is neither a pig (it is a rodent), nor from Guinea (from the Andes mountains). Even if one wishes to do a trial on animals, one needs to have permission from an ethics committee which oversees research on animals. Those who feel that clinical trial participants are simply made to sign an informed consent document need to witness the process. A patient or participant information leaflet, written in a language that the participant can understand, is first explained to the participant in his/her own language. All queries that the participant may have are addressed by the principal and principled investigator/delegate. The informed consent form is also explained similarly. Innovative methods could include use of a speaking book which talks to the participant, the way books for children are designed, of what s/he is getting into when being part of a clinical trial.

One could also think of using an iPad and make the participant see for himself/herself exactly what the participant will need to go through from beginning to end of the clinical trial. This way the participant sees himself/herself going through all steps of the trial, and only after the process has been explained does the participant make his/her decision. No force, no incentive. Vulnerable populations are not selected. Those who cannot make their own decisions are provided with assistance. Functionally literate participants may also be recruited with due legal precautions (impartial witness) being adhered to. Ethics committee members can and do oversee the process, and can do random spot checks. Video-recording of the process, with protection of the participant’s confidentiality, is another suggestion.

As a sponsor of the trial, investigator selection is paramount. Training is meticulously done. Regular oversight by a clinical research associate, quality standards person, and auditor follows. Inspection by a regulatory authority is also done, even by the US FDA and/or the EMEA as data from global trials, involving patients in India, is a part of global regulatory dossiers.

The Drugs Controller General of India (DCGI)’s office now refers global clinical trial applications to the New Drugs Approval Committee (NDAC), comprising academic experts from the respective therapeutic area and pharmacology. Going forward, the DCGI will ensure that contract research organizations, ethics committees, and sites are accreditated. The serious players in clinical research will survive while the fly by night operators will be weeded out.

In short, there are enough checks and balances from all “participants” in clinical trials, each of whom has an equal responsibility towards the ultimate participant, the patient.

Since 1994-95, global clinical trials have been placed in India by multinational ethical research-based corporations and the quality and ethical standard, viz., ‘Good Clinical Research Practice’, is rigorously followed across the globe. Even if locally applicable regulatory requirements are relatively lax in some countries, the MNC’s Standard Operating Procedures, which are stricter than any regulatory standard, are adhered to.

It is a myth to think that trials in India are cheaper. In fact because this is an out of pocket market where most have to pay for their healthcare-related expenses, and very few are reimbursed, sponsors have to spend much more per patient, having to pay for all laboratory tests and diagnostic procedures.

It is incorrect that India is being used as the destination for global clinical trials. The number of trials being placed in India and the number of participants from India in global trials is decreasing, and more trials are being placed in China, Korea, other Asian countries, Central and Eastern Europe, and Latin America among the merging markets.

At any point in time, the participant can withdraw from the trial without any problem or reason given. If an adverse event is experienced, the care of the participant is borne by the sponsor at no cost to the participant or institute.  If the event is serious or results in death as an outcome, and is judged, to be related to the trial or drug tested in the trial, by the investigator and confirmed by the ethics committee, the same is compensable, though ideally the relatedness should be in agreement with the sponsor. This does not happen in many developed markets where one has to claim for compensation. In India, the clause for compensation is included in the informed consent document. A formula for the same has also been proposed recently. It is only to be fervently hoped that this process is not misused.

In what are called, “outcome trials”, death or a serious adverse event is an endpoint, i.e., a point at which the trial for that patient has ended. Naturally in such trials many such events are anticipated. However, such trials are also important as approving a new drug, only based on softer endpoints, e.g., blood pressure or HbA1c reductions, are not enough in the long run, as has been repeatedly seen with some drugs, which had to be withdrawn from the market later.

Rarely is a new drug compared to a placebo. The placebo is almost always used as an add on to standard therapy in both arms, which makes it that much more difficult for a new drug to demonstrate efficacy, but in the interest of patient safety this is the preferred way of evaluating a new drug, even if this means many promising molecules may fall by the way side.

When so much is happening in the right direction, why are we not looking at the full picture before passing judgment on the way clinical trials are being conducted in India? Why are we not considering the tremendous benefits that accrue to clinical trial participants, doctors, institutes and society at large, besides of course the foreign direct investment inflow into the country? Why are we not thinking of the development of clinical research (CR) in the country that this will stimulate? When doctors are investigators in good clinical research practice it also helps them be better doctors in clinical practice.

Sponsors may draft protocols but it is doctors who ultimately review, make changes, and finally approve the document after the protocol development meeting. It is the doctor’s patients whose data enters case report forms from source documents. It is this data that gets into the database, gets analyzed, and then included in the final study report. Only when all investigators are in agreement with the statistical analysis plan, analysis and report, does the report get signed after the end of study meeting. From the report is written the manuscript and again only after all the doctors, who participated in the trial, review and approve the content, does it get submitted to a peer-reviewed journal and finally published.

Even negative trial results are published. Data Safety Monitoring Boards and Data Steering Committees, independent of the sponsor, can do interim analyses and decide on premature stopping of a trial based on futility, overwhelming efficacy or unacceptable safety in one arm.

It begs the question, “whose trial is it anyway?” It is really a sponsor’s trial? Or is it an experiment in which all stakeholders own and share equal responsibility? Let us all exhort ourselves to remember this and do our duty diligently. We owe it to all our participants whose altruistic motive has helped advance medical science and enabled many more patients and their loved ones benefit from their participation.

CRedibility begins with CR (Clinical Research).

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“My Pharma Reviews”is happy to introduce a guest post by Dr. Viraj Suvarna. These are his thoughts in his personal capacity, and not as an employee of Boehringer Ingelheim India Private Limited where Dr. Suvarna is Medical Director.

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