What if clinical trials don’t happen in India? Indian patients will continue to be treated with existing standard of stagnating care. The world would have moved on to better medicines buoyed by innovation. But Indian patients will need to be excluded from this wave of change for the better.
The Drugs Controller General of India (DCGI)’s office will be less busy and can then focus on other activities. The New Drug Approval/Advisory Committee (NDAC) may need to be disbanded. No new drugs will come to market.
Even if drugs are discovered or invented in India they need to be evaluated in clinical trials involving Indian patients if they have to be approved for use in India. In fact in such cases phase I or first in man trials will need to be conducted in India.
If the golden goose is killed it won’t lay the golden egg. If innovation is killed, no new drug will need to be evaluated in trials, and no copy or generic will be manufactured using another process. There will be no need for patents for innovation or incremental innovation. No need for data exclusivity.
But why are we thinking of such a scenario? What has the Supreme Court said? Only that if trials are uncontrolled they can play havoc with patients’ lives. Yes. True. So are trials not controlled?
The gold standard pivotal clinical trial is a prospective, double blind, randomized, active and/or placebo controlled trial. But obviously what Justice Lodha meant was unregulated trials. So are trials in India not regulated?
What does Schedule Y of the Drugs and Cosmetics Act have to say? What are the Indian GCP guidelines for? Perhaps he meant to say that these guidelines are not being followed? And who oversees the same? Are institutional or non-institutional ethics committees doing their job of visiting sites and overseeing the informed consent process?
All valid questions. Let me attempt to answer them.
The first global trials were placed in India way back in 1994-1995. By multinational research-based companies who stand by ethical, quality and compliant principles in the way they conduct trials. Whose SOPs are even stricter than the law of the land. Who regulate themselves even more stringently than the applicable local regulatory requirements.
Why? Because they have the most to lose.
Millions of dollars are spent in doing a trial appropriately. Naturally it is in their interest to do the trial correctly so that the data is credible and patient safety is not compromised. They stand to lose the most if incredible data is the basis for approval. Later if the drug has to be recalled from the market it is the company who faces the worst backlash, not only in terms of financial loss, which one can recover from, but in terms of integrity, trust, and corporate image, which once sullied can never come back.
The sponsor will want to know at the earliest if the drug is not effective or is not safe so that the same can be discontinued as soon as possible. Kill a drug early before it kills you. Rather than make a drug more safe for a patient, make the patient more safe for the drug.
So what do such companies do to ensure that the trial is conducted appropriately, compliant with their SOPs, the protocol, applicable local regulatory requirements and the Declaration of Helsinki principles?
It begins with identifying unmet medical need. Then finding the druggable disease target. From combinatorial chemistry libraries of potential hits, leads, and candidates, robotised high throughput screening methods try to match the best candidate to the target, with optimal pharmacokinetic (what the body does to the drug in terms of absorption, distribution, metabolism, and excretion) and pharmacodynamic (what the drug does to the target in the body) properties.
The best candidate is then taken through pre-clinical, in vitro, in silico, and finally clinical testing where the rubber literally hits the road. Safety first is the motto. Phase O or microdosing is also used to allometrically scale and better predict the dose that needs to be first tested generally in healthy volunteers (phase I).
Phase II involves patients where again safety is paramount followed by proof of concept from an efficacy point of view. Phase III then validates the phase II results in a larger patient population across different sites and countries. If positive this pivotal data is then submitted to regulators for seeking marketing authorisation approval.
Even after approval, testing may continue in the post-marketing environment (phase IV) within the approved label indications. If the drug needs to be tested in a new indication one goes back to doing a phase III trial.
In India, if such innovator drugs have to be marketed they need to have safety and efficacy data in a minimum number of Indian patients. If Indian patients are included during the global clinical development program for the drug it helps in two ways. Eligible Indian patients stand to benefit from the drug at the same time as patients from the rest of the world. This data can then be used to seek expedited approval from the DCGI so that other eligible Indian patients also benefit.
Of course Indian patients are also at risk, as are patients from other parts of the world, which is why such trials are carefully monitored. Selection of the investigator and site, based on specific criteria, is paramount. Training of the investigator and site staff is important. And the close and continuing oversight in the form of monitoring visits, quality checks, and audits. Ethics committees also do their bit of reviewing and approving protocols as well as visiting the sites to ensure there is no oversight. Regulators refer protocols to academic experts before approving the same.
Informed consent is administered as a process. Comprehension is ascertained. It is not a mere signature on a document. The patient can read the information, discuss with the family physician and only then decide on whether to participate. Functionally literate patients can be taken through a Speaking Book so that they understand in their language what it means to participate in a clinical trial.
No payment is made to the patient. The patient is insured. Treatment for any adverse outcome is borne by the sponsor so it’s free of cost for the patient. All investigations and procedures are also done free of cost for the patient.
Compensation is also done in cases where the investigator and ethics committee decide that the serious adverse event is related to the study or drug. Serious adverse events are reported to the regulator, ethics committee and other investigators in a timely manner.
Study-related high end equipment is often donated to the site so that other patients can benefit. In some trials, e.g., in cancer the patient may receive drug free of cost for life. So often the patient may have died if he had not been a part of this trial. He would not have been able to see his grand children graduate or get married if he was not part of the trial. The extra lease of life means a lot to the patient and relatives.
So what if trials don’t happen in India? We won’t get new drugs. Our health statistics won’t improve. The world would have moved on. India will lag behind. Our doctors may continue to go abroad in greater numbers and the brain drain may cripple us. Indian patients too would go abroad in search of cure or alleviation, reversing the current medical tourism. Indigenous innovation may dry up. Is this progress or “congress” or regress?
There is no question. If clinical trials don’t happen in India, disease will advance. And will adversely impact the health of the economy. Old is gold but in such cases a few new advances will always add to the glitter. Your only hope to get better may be stuck in the queue. This is just my view.
This is a guest post by Dr. Viraj Suvarna. It is a part of a series of posts on the state of clinical trials in India. Dr. Suvarna writes here in his personal capacity and not as an employee of Boehringer Ingelheim India Private Limited where he serves as Medical Director.