India’s share of global clinical trials, minuscule to start with, has seen a steady decline from 1.5 per cent a few yearsback to the current 1.2 per cent. This is indeed inadequate for a country with the second highest population and the highest disease burden in the world. However, the recently released rules bring some much needed clarity. Adherence to regulations and ethical processes will build confidence amongst stakeholders, including patients
On March 19, the Ministry of Health and Family Welfare (MoH&FW) announced the new set of rules for drugs and clinical trials. These rules bring some clarity on many aspects and could change the entire scenario of clinical trials and research in India. For instance, according to new regulations, the time for approving applications has been reduced to 30 days for drugs manufactured in India and 90 days for those developed outside the country. The same was mentioned by Drug Controller General of India (DCG(I)) S Eswara Reddy at the 12th Annual ISCR Conference, Delhi held in February.
He had also said that “in case of an application for conducting clinical trial of a new drug or investigational new drug as part of discovery, research and manufacture in India, the application is to be disposed of within 30 days. And, in case there was no communication from DCG(I), the application will be deemed to have been approved.”
The rules will be applied to clinical trials, bio-availability or bio-equivalence studies, new drugs and regulation of ethics committees relating to clinical trials and biomedical health research. According to the Indian Society for Clinical Research (ISCR), the number of clinical trials being conducted in India, as a percentage of global trials, currently stands at 1.2 per cent, which was 1.5 per cent a couple of years ago. It is indeed inadequate for a country which has the second highest population and one of the highest disease burdens in the world.
The case of ‘Ankit Sharma’
For about past one year, 59-year-old Ankit Sharma (name changed to protect the identity of the patient as per clinical trial guidelines) from Haryana has been undergoing a clinical trial in Delhi for high cholesterol. A type-2 diabetes patient, he had suffered heart attack in 2002 and had undergone a Coronary Artery Bypass Grafting (CABG).
Over the next 16 years, he made the rounds of 10 different hospitals and underwent 13 angiographies. The patient’s next stop was All India Institute of Medical Sciences (AIIMS), where he underwent an electrocardiography (ECG) and then echocardiography (ECHO) came into the line. When quizzed by a doctor at AIIMS on number of angiographies, he said, “Doctors kehte rahe, main karwata raha. (Doctors told me to do them, I kept doing them).”
Distressed with continuous tests, he finally landed up at Medanta – The Medcity, where Dr Sanjay Mittal, Senior Director – Clinical Cardiology and Head of Research, Medanta – The Medicity advised him to join a clinical trial.
A stranger to this medical term, Sharma was a bit hesitant to pursue it. Nevertheless, once he was given a brief about the whole process, he filled the ‘Informed Consent Form’ and joined the trial last year. After the required lab tests were done, he was put on a course of medication, which ultimately helped improve his condition. He remains part of the ongoing trial, and most of his reports are fine with a team of doctors monitoring his health. The trial is currently in phase three and the final result is expected to be out in about five years, inform his doctors.
Clinical trials: The key for drug development
Clinical trials is key for any drug development. It has been going on since decades and the pattern of diseases has been changing, informs Chirag Trivedi, President, ISCR. He quoted a speaker from the ISCR Conference panel discussion who had said that the burden of non-communicable diseases is such that some years down the line, the impact on the GDP of the nation, if you build roads or if you don’t build roads, will be lesser, as compared to the entire negative impact on the GDP of the nation if you do not control diabetes and hypertension. “Thus, there is a need to come up with newer medication, as we are not yet able to find the cure for these diseases, we are just able to control them,” Dr Trivedi had said.
Today, understanding of diseases is expanding which helps pharma companies to find out new molecules that patients need — that’s where the essence of clinical trials lies.
Shedding light on the rules and regulations, Dr Trivedi informs, “Some years ago, due to certain new rules introduced then which were against the basic tenets of clinical trials, there was a significant drop in the number of global clinical trials conducted in India. Worldwide, clinical trials kept on taking place, but we were not a part of those trials, and hence those drugs would not be introduced in India because the law says that trial data is required to get a drug registered, so that it can be then available to treat patients.”
What numbers speak
“We are 16 per cent of the world’s population and have got 20 per cent of the global disease burden in India. It is such a large burden that we need to tackle it differently. As per the data available from www.clinicaltrials.gov, the US currently has close to 40 per cent of the clinical studies, the European Union has close to 30 per cent, while China has almost ten times the number of studies that India has today,” informs Dr Trivedi.
In addition, he says that companies are supposed to register their studies into the public registry before they even enroll their first patient. It is a mandate since last 10 years.
Globally, it would cost $1.2 billion to $1.5 billion to get one drug from research to market, with the cost of many failures already built into this figure. The general probability of success is that in phase one, there is just 10 per cent chance that the molecule will see the light of the day. At phase two, the odds improve to 20 per cent and at phase three, it’s 60 per cent.
Dr Trivedi also informs that in 2010, we had 500 clinical trials in India, which dropped to 17 global clinical trials in 2013. Later, in 2014, these were approximately 70, which then increased to 97 in 2017, and similar numbers were witnessed in 2018 too.
The significant dip in the number of global clinical trials in 2013 caused some clinical research organisations (CROs) to shut shop post 2013. A further set back was the withdrawal of trials being run by leading academic centres like the US National Institute of Health (NIH) due to the stringent rules.
After several consultations between Central Drugs Control and Standards Organization (CDSCO) and industry representatives, the rules were amended in 2014 to make the process for clinical trials more balanced. Today, India is the only country where we have audio-visual recording of informed consents. The country also has a formula to determine compensation to be awarded for any trial-related injury, Dr Trivedi highlights.
“Earlier, the timelines were not defined for the approvals that the regulators will give for a clinical trial. Initially, it used to take approximately six to 18 months and thus many of the applications kept lying in the DGC(I)’s office. Global trials on the other hand get fast approval and this is where we fall behind while participating. In 2015, DCG(I) had said that the approvals will come in six months and the industry witnessed approvals being given around that time frame,” says Dr Trivedi.
He further says, “Now, as per the current set of draft rules, they want to give incentives to the Indian companies to innovate. If an Indian company is doing the trial, they will deem the approval in 30 days if the company doesn’t hear from the regulators, similar to the United States Food and Drug Administration (US FDA). For global clinical trials, where multiple countries are involved, the timeline is 90 days. Apart from it, the introduction of the pre-submission meeting or the post-submission meeting is a welcome step — today, according to the current rules, we don’t have a consultation meeting. For instance, if I have a query, there is no written recommendation for it.”
ISCR had given a lot of recommendations on various aspects of these draft rules — comments on the timeline and on issues regarding discrepancies in the ethics committee, among others.
Attempts and efforts
For years, a lot of effort went in to educate people on various levels to make them understand the benefits of clinical research. The rules then got amended to become more balanced which protected the rights, safety and well-being of the patients and at the same time, facilitated the conduct of ethical clinical trials in India, emphasises Dr Trivedi.
He adds, “Currently, as per www.clincialtrials.gov, there are still close to 300,000 studies running worldwide, whereas India is involved in only about 1.2 per cent of those studies. With India being the second most populous country in the world and having approximately 1/5th of the global disease burden, we require more clinical research to develop drugs for our patients.” Also, according to him, there are Indian as well as international guidelines that pharma companies and CROs have to follow in addition to taking approvals from the health authorities and institutional ethics committees.
The new regulation
notifies that patients who are injured during a clinical trial conducted in India will be entitled to medical management for as long as required in the opinion of the trial’s investigator, or until it is established that the injury is not related to the trial.
“Clinical trials in India went through a very challenging few years and we are still in the process of rebuilding the trust and confidence of sponsors in placing trials in India. It is incumbent on all those involved in clinical research to publicise the new rules so that we can have more clinical trials in India. Our patients are waiting,” Dr Trivedi says.
Research means understanding your population
Patients undergoing clinical trials are an important part of the process. As Dr Mittal of Medanta – The Medicity puts it, every human being is a potential patient. He says, “90 per cent of diseases today are still not treatable. Patients need a treatment that can make them feel better, and there lies the value of research. We can just help the patient to have less symptoms and control the progress of the disease to some extent, but we don’t have the best possible cure,” he emphasises. He opines that research doesn’t mean just clinical trials, it means understanding your population.
Sharing the example of a trial for a group of drugs targeting heart failure that took place some years ago, Dr Mittal says, “The global trial was completed and results were published in 2014. It was such a huge trial that there was remarkable difference between the old gold standard and the new drug. However, it was pre-maturely stopped in India because the interim analysis found that there was already drastic difference, but then it was approved only in 2018. It took so many years for the drug to come to the Indian market since the approval process took too long,” he mentions.
He notifies that after 2012, there were certain knee-jerk reactions for which certain clauses were included into the regulations, which made it impossible to conduct most trials in India. That’s the reason for the reduction in the number of trials post 2012.
In his view, as a clinical trial takes place, doctors look out for better treatments to make patients survive. “So, this population (pointing to the patient currently undergoing clinical trial for high cholesterol) has to be taken into consideration. If I don’t treat with the new drug, 50 per cent of patients are still going to die when compared to the new drug where the 100 per cent survival is not possible. This thing was not taken into consideration and the report went out that there were huge number of deaths in the clinical trials,” he informs.
How will the taboo break?
India saw a decline in the number of clinical trials between 2013-2015 due to an uncertain regulatory environment, says Suneela Thatte, Head, R&D Solutions, IQVIA. “However, on account of multi-stakeholder advocacy, the Indian regulators have taken several steps to restore balance and bring about transparency in regulations governing clinical research in the country,” she adds.
Apart from it, she says, “Public awareness and education is an important requirement in clinical research. The public at large needs to understand the role that clinical trials play in the drug development process and the ethical and legal framework under which these are planned, conducted and reported. Also, it is equally important to spread awareness about clinical research within the medical community as many medical practitioners are not fully aware of the clinical research process and the rules and regulations governing it.”
She also feels that the government should invest in good governance so that adherence to regulations and ethical processes can be monitored and non-compliance, if any, can be addressed appropriately, thereby building confidence across all stakeholders, including patients.
Thatte is appreciative of the efforts of the CDSCO and MoH&FW in bringing out the new clinical trial rules which not only promote innovation and scientific advancement, but also patient well-being. She says, “We hope that these balanced rules will bring about further clarity in regulations governing clinical research in India, promote ease of doing business and will in turn help the country to be a significant participant in global clinical research and drug development.”