It took a controversy, as it usually does, for the Indian public to learn about the adverse side effects associated with ASR (Articular Surface Replacement), a hip replacement implant manufactured by Johnson and Johnson (J&J). The J&J fiasco, among many others, could perhaps be avoided if India had a strong pharmacovigilance system in place. Defined by WHO, pharmacovigilance is “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”.
We spoke to Anant Bhan, Adjunct Professor, Yenepoya (deemed to be University), Mangaluru, about key questions surrounding pharmacovigilance and conduct of clinical trials in India. Bhan is a researcher in the area of bioethics and global health & policy.
According to a report filed by an Indian NGO, 3458 deaths occurred and more than 14300 people reported side effects in clinical trials between 2005 and 2013. Yet in only 89 cases was any compensation given. Why the huge gap and what needs to be done to ensure that patients are duly compensated?
We have had a large number of reported deaths linked with clinical trials — this might be an understatement or less likely, an over-statement. More importantly, we need to have knowledge on and clear processes to establish causation. The process currently can be quite onerous and requires ethics committees to play an active role when it’s unclear if they have the training/resources for judgment in this matter. An ideal mechanism might be to move to a true no-fault compensation model. At the very least, we need strict and prompt mechanisms for deciding on compensation with due process built in so that compensation is paid out on time to those eligible.
Does the issue of clinical trial malpractice differ in rural vs. urban settings?
I won’t say there is a huge difference between the two; it is also incorrect to say cities have no issues of clinical trial related malpractices. Overall though, there is a higher availability of trained staff in urban settings and they typically have larger and more well-resourced centres.
In rural or tier II/III cities, availability of staff and resources such as space or beds is low. Staff training may happen through an initial exposure only rather than for a sustained duration. They may also be more likely to cut corners. Some of the recent clinical trial controversies emerged from such cities (e.g. Indore) where medical practitioners engaged in clinical trials were earning a lot of money, but not conducting the trials properly. Large cities also often have greater and stricter oversight, with state drug controller offices often being located there, and (more) frequent site monitoring.
What is the percentage of blame in these cases on the system, the government, the doctors, or is it still a historical baggage we carry?
It is a mix of everything. There was a huge growth phase a few years back and a large number of stakeholders benefited from the boom. Supportive industries such as clinical research organisations and clinical training courses emerged during the time, but their quality control measures were not in place. There was flow of money, but clear guidelines and regulations to address malpractices were lacking. Ethics committees were not exemplary and many of them didn’t understand their responsibilities. Some of them were functioning as independent committees where ethics review was a business. Institutional oversight was lacking and patient awareness was low. Lately, the situation has improved on all of these counts.
How can we ensure quality control and ethical conduct in clinical research organizations (CRO)?
Most good CROs would have existing internal and external systems to oversee or conduct quality research in their institution. Internal systems would include data audits, regular checks and timely filing of data to regulatory authorities. External oversight would include regular checks by sponsors and ethics committees including conducting surprise monitoring visits. There are other mechanisms, like Data Safety Monitoring Boards (DSMB), that look at data in a non-partisan, collective manner in large clinical trials. There are also dedicated firms who perform independent monitoring and audits.
The idea is not to police clinical research all the time, but to pick up deficiencies in the system while they are happening, rather than on a post-hoc basis when the system has defaulted, and controversy has broken out. For all of this to happen, the leadership should be equally committed to preventing malpractices and should assign resources and build mechanisms for making ethical research a priority.
Despite so many controversies, we still see new drug-related issues cropping up frequently. Does this raise questions about the implementation of pharmacovigilance in our country?
Pharmacovigilance gives a better sense of the long-term benefits and risks of drugs & devices. The clinical trial environment is a strictly controlled one, with a smaller number of participants. When large-scale marketing occurs and the number of people taking a drug/device increases, one starts picking up issues that might not have been registered in the controlled setting.
Usually, mechanisms in (industry) sponsor-driven trials and follow-up for pharmacovigilance purposes are often robust, as they have to submit data to regulatory authorities on a regular basis and face swift penalties in case of data manipulation. At the same time, they also have the interest of making their product look beneficial in clinical studies and in long-term follow-up, having invested heavily in it. Obviously, relying on them alone for submitting information is not prudent, and one must have external oversight.
So how do we tackle malpractices in the pharmaceutical sector, specifically for pharmacovigilance?
The solution requires a larger nationally available pharmacovigilance framework where regulatory bodies acquire clinical data independent of company sources. We now have a national program in place, but it is still a work in progress. Our doctors need to get in the habit of reporting issues on a regular basis and we require larger resources and trained staff for effective investigation of any adverse reactions. They must have an awareness of what needs to be reported, having established causality of adverse reaction due to a given drug or device. It is also important that while a company might get to protect its Intellectual Property (IP), data should be available for public scrutiny to the extent possible for ensuring transparency.
Why do we not see more whistleblowers coming out?
In case of whistleblowers, the whole system often turns on you with zero protections, possibility of threats, with those brave enough to come forward being sidelined, victimized and thrown out of their jobs. Many of the cases where a whistleblower did come out have not seen the expose come to fruition. Unlike Ranbaxy where Dinesh Thakur could bring about a certain level of change, partly due to existing mechanisms within the US regulatory system, India lacks a system with in-built protective mechanisms for people to share information without facing major repercussions. Some of these issues would also be picked up and addressed anyway if we have more transparency available through independent watchdogs.
What international efforts are being put in place to regulate clinical research, especially in low- and middle-income countries, and how do we improve India’s status as a hub of global clinical trials?
Reforms in international guidelines (Helsinki 2013, CIOMS 2016) have tried to address some vexing issues. Today, there is a realization that collaboration is the way to go in a globalized world. Funding agencies are moving towards ensuring accountability and zero tolerance to research malpractice. There is an increasing concerted global focus to ensure that lax regulations in low- and middle-income countries are not taken advantage of and that there is oversight both from the sponsor country and local country where research is happening to prevent any kind of exploitative research.
India is a large market; it’s also an important R&D hub for a variety of reasons. So while there was a dip in clinical trials post-2013, there should be recovery happening now. The key question is - are we rebuilding an ecosystem which is now ethical, resilient & top quality in nature? This is necessary to avoid further pitfalls, and to make sure we engage our patient participants in a respectful manner. We need to move towards a model where India takes its rightful share as a major R&D producer and destination not because how cheap costs are, but because of the quality, reliability, and ethical conduct of science.