'Malaysia, Korea are preferred to India as global clinical trial sites'

The New Drugs and Clinical Trial (NDCT) Rules, 2019 have brought changes in the Indian clinical trial regulations. However, the regulatory environment on the ground needs to adapt further to ensure India gets a higher share of global clinical trials. In an e-mailed interview with Sohini Das, Indian Society for Clinical Research (ISCR) President Sanish Davis outlines the problems and the possible solutions. Edited excerpts:

India now has a 3-4 per cent share of global clinical trials. The US has 23-24 per cent. What are the reasons for India’s low share? 

Global clinical trials are run in 25-30 core countries. There is intense competition to have these studies on advanced or complex unmet medical needs in a country. Countries like the United States, China, Japan, Australia, and some advanced European Union economies are typically chosen as study locations due to their mature regulatory and ethical review processes. 

Over the past several decades, some smaller countries (South Korea, Poland, Singapore etc.) have made concerted efforts to showcase their stable and predictable regulatory systems and research ecosystem. 

India went through a challenging past decade, when there was regulatory streamlining and a lot of changes were made in the way trials are conducted.

Although the implementation of the NDCT Rules 2019 has brought a sense of predictability on paper, it will likely take several years before innovation-focused pharmaceutical companies become fully accustomed to the changes and the impact is felt on the ground.

There are several reasons as to why trials are still just trickling in and India is not back to doing 500 or more trials in a year:

i) The predictability or the regulatory timelines, while clearly stated in the rules, are not translating (to as much) on the ground. We are only able to start our sites after 5-6 months, and this significantly diminishes India’s attractiveness as a country to conduct global clinical trials (GCTs). Some of our government sites do not initiate the review of proposals in the ethics committee until the Central Drugs Standard Control Organisation (CDSCO) grants approval for the trial. This leads to a situation where even if the CDSCO approval comes in the 90-working day timeframe (4.5 calendar months), the sites would still not be able to contribute to the study as the trial would be over globally.

In comparison, countries in our neighbourhood (e.g. Malaysia and Korea) are able to start their sites in 2-3 months and are increasingly being preferred for GCTs across sponsors.

ii) Clinical trial review and approval process: Analysis of the minutes from Subject Expert Committee (SEC) meetings reveals a significant occurrence of protocols in which SECs (and/or CDSCO) make unreasonable requests for including elements that do not directly impact the safety or efficacy in the Indian population. This results in additional delays in the timeline, as sponsors must seek internal approvals for these single-country modifications and subsequently rejoin the queue for SEC meetings, causing India to experience delays in commencing trials on schedule.

iii) Site readiness and clinical trials as a care option: Sites in India are slow to start and unable to recruit patients in the short window that is available to them to enrol in a global trial. The delay in enrolling patients also makes the investigator lose out on the opportunity to learn how the new drug behaves in patients. Clinical trials are not offered as a treatment (care) option even in diseases with high unmet medical need like oncology, inflammatory bowel disease or rare diseases. Sites in India are more or less defined by their own patient database and walk-in patients, and this severely restricts patient numbers in our trials (the exceptions being clinical trials, or CTs, in conditions like cardiovascular disease, diabetes or other infections like malaria/tuberculosis where India can contribute significant number of patients from each centre).

There is hesitation in referring patients from hospitals to clinical trial sites, thereby losing the opportunity to have clinical trials as a care option.   

Has the regulatory environment eased in terms of approvals for clinical trials? 

The NDCT Rules of 2019 have brought in “predictability” of the review and approval system. Prior to this, the standard timelines for review and approval was between six and nine months.

The areas where the regulations have brought in significant predictability include post-trial access, medical reimbursement and compensation in case of serious adverse events related to the study drug (becoming the only country that has this provision that ensures patient safety) and further clarity on the safety reporting process. These new rules are well-balanced. They protect the rights, safety and well-being of the clinical trials participants, and at the same time, make it convenient for researchers to conduct good quality, ethical clinical trials.

What is the importance of having local trial arms for chronic diseases or cancer therapies etc? 

In the past, there was always a challenge that the clinical practice/guidelines followed for the treatment of a disease (e.g. chronic diseases/oncology) were different from those of developed countries. So, it was considered that for the study to be relevant for Indian patients, there has to be a local trial arm. Today, in a vast majority of diseases, clinicians in India use the same guidelines/standards of care as in the West for patient treatment. Hence, the need for local trial arms is becoming irrelevant.

This shift in practice is also because patients are now more aware and even go to the internet to check for the best treatment for their condition. They also get a second opinion, sometimes from the West, especially in oncology and rare diseases.

What is the representation of the Indian genome in global drug development processes? Do you think this needs to increase?

A common misconception is that India serves as the global hub for clinical research. India has less than 1.2 per cent of the total studies registered on a major global repository of clinical studies (www.clinicaltrials.gov). The representation of the Indian genome definitely needs to increase considering that the country is the second most populous nation in the world and has almost one-fifth of the global disease burden. 

A recent study revealed that of 424 multinational clinical trials sponsored by foreign organisations to evaluate potential drugs for conditions like asthma, bacterial infections, and cancer, 26 had recruited or planned to recruit over 60 per cent of their volunteers from India. Gayatri Saberwal, a policy research professor at the Institute of Bioinformatics and Applied Biotechnology in Bengaluru had expressed concern over this. What is the environment when it comes to trial ethics? 

The secondary research done by Saberwal et al, which was published by PLOSone, used the data in India’s clinical trial registry (ctri.nic.in). It analysed a total of 473 studies over a eight-year period that were deemed sponsored by MNCs (including pharmaceutical companies, National Institute of Health, US). The analysis showed that 62/473 trials were completed, with completion dates available in the registry.

Five trials (8 per cent) had 60 per cent or more planned recruitment from India (which was arbitrarily chosen as overrecruitment from the author’s standpoint). Four of the five (7 per cent of 62) had a foreign sponsor, and therefore, there was an unfair burden-benefit ratio on the Indian population. Here are a few observations on this data:

The clinical trials registry of India is the repository of all clinical trials being conducted in the country. It collects data when the trial is registered on it, before the first patient is enrolled. So this database cannot be assumed to be accurate with regards to how many patients were enrolled in a trial. This is also not the stated purpose of the clinical trial registry. It is meant to provide the public information and the assurance of the clinical trials that are being conducted in India by sponsors, whether government or private. 

• The total number of trials conducted in India by MNC sponsors is 473 over an eight-year period. This itself shows the very low number of studies done by foreign sponsors in India (about 60 a year).
   
• 6/7 cases of “over enrollment” had foreign sponsors, but the diseases for which the trials were being done are very common for India (HIV, Covid-19, breast cancer, schizophrenia, haemorrhoids and eye disorder). None of these diseases are rare in India.
   
• Globally, trial sample sizes are shrinking as the years go by. A typical global Phase III trial for a compound now does not have more than 500 patients at most and there are about 30 countries where the sponsors do the study. The major countries like the US, Japan, China and developed EU nations get higher patient numbers in a traditional setting as there are clearly articulated patient numbers in these countries' regulations. Hence, it is quite likely that India may not get more than 10-25 patients as a country commitment for a global trial.
   
• Usually sponsors (both Indian and MNCs) give a higher projection when they apply for approval for clinical trials with the CDSCO. That is because in case India can start the study earlier, then the sponsor does not have to go back to the CDSCO for approval for additional patients since that can typically take about 5 months. So, the projected numbers in the Clinical Trials Registry- India (CTRI) is a reflection of this reason and not a definite commitment of the sponsor to over-enrol.

What needs to be done to increase Indian participation in global clinical trials. What steps are the government and industry bodies like the ISCR taking in this regard? 

India needs to do as many clinical trials as required by the Indian patients. As mentioned earlier, we have a huge disease burden in India and a large unmet medical need exists for our patients. Thus, we certainly need to find newer treatment options for our patients. 

In the backdrop of the stable, balanced regulatory environment, India now needs to strengthen its entire clinical research ecosystem so that it can effectively scale-up to meet the needs of the Indian patients. All the stakeholders will have to come together to build this ecosystem: the government, regulators, policy-makers, hospitals, doctors, paramedical staff, ethics committees, industry including biopharma companies, CROs (contract research organisations), service providers, and more importantly, the patients. 

Our hospitals will have to make sure that they have the requisite infrastructure to plan and manage the clinical trials. They will need to strengthen the expertise across the spectrum of people involved. Investigators (doctors conducting clinical research) play a pivotal role in this. They are the ones who treat the patients, understand their diseases and are the ones who see the effect of newer treatments on their patients. They play an important role in engaging their patients who participate in clinical trials.

The ethics committees play an important role in overseeing the rights, safety and well-being of the clinical trial participants. The New Clinical Trial Rules, 2019 have entrusted them with more responsibilities and the ethics committees across the country will need to have the requisite knowledge and infrastructure to perform their role. 

Various efforts are being undertaken to strengthen the ethics committees, and these need to continue. Due to the downturn experienced in 2013-14, the industry witnessed a talent erosion since many companies significantly decreased their number of trials in India. This led to people changing their fields or taking up other roles and responsibilities. 

A large-scale capacity building is the order of the day for the industry, across all levels, since the war for talent is heating up now, as we see the number of trials increasing in India. ISCR is partnering with all stakeholders to ensure that the growth and success of clinical research is boosted by capacity building.