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.

How did you decide to leave a full-time academic position at The Energy and Resources Institute (TERI)and start your own company, Innotech Interventions?

In the beginning, while I was working on academic projects, guiding PhD students, publishing papers etc. at TERI, I was very fortunate to be associated with three projects that were subsequently commercialised and became a major revenue earning source for TERI. In the process, apart from designing experiments, I learnt facets of tech transfer, technology licensing, forming of joint ventures etc. This made me realise that there are immense opportunities and research leads available in Indian Labs that need to be tapped. With this objective in 2015 I started a joint venture with my co-founder, Hamendra Das, that would facilitate in translating and commercialising laboratory innovations – Innotech Interventions.

What were the initial challenges you faced after you transitioned from academia to industry?

The initial challenge was to convince myself that I don’t belong to pure academia anymore. When we try to commercialise innovations, there are a different set of challenges that needs to be considered. I have also realised that academia is well-funded but the scope of getting funding to set up a company is far less. At TERI, I had the backing of a huge institution, but it is difficult to establish credibility when you are a small 4-5-member organisation. Fortunately, the start-up initiative kicked in and there were some good opportunities that we would avail.

You are involved in the production of a mushroom fortified with vitamin D. How did you arrive at the idea? How does this project aim to improve agricultural economy?

Over 70% of India’s adult population is suffering from Vitamin D deficiency. We have conceptualised and developed a simple yet scalable technology for producing organic mushrooms fortified with Vitamin D. Our intervention for vitamin D supplementation targets a natural property of mushrooms and can enhance vitamin D by over 200%. This agro-venture will not only counter the nutritional deficiency of the masses, but also enhance the profitability of mushroom growers. We will attempt to promote mushroom cultivation in an altogether different platform, wherein it serves as a potential business venture for generation of skill-sets, wealth creation, nutrient supplementation and subsequent application in nutraceutical companies. We have planned a marketing strategy to enhance the product value, ensuring a higher rate of return to the farmers. This model can encourage entrepreneurs to take up this venture for enhancing profitability upon implementing different agri-business strategies.

Can you elaborate on your bioremediation/clean-energy project and share some of its benefits?

Exploration and extraction operations of conventional fossil-based energy resources like petroleum and natural gas, as well as the newer non-conventional resources like coal bed methane, shale gas and gas hydrates, generate significant amount of waste water. This huge volume of water brought from the subsurface along with the fossil resources is also known as produced water (PW). Conventional treatment processes fail not only in handling the volumes of PW, but also in meeting the regulatory standards of the effluents due to its unique composition.

The concept developed by Innotech is focused on the very same properties of PW that renders conventional systems unfit for its treatment. The low organic content and high salinity that makes PW unfit for most conventional systems, turns out to be ideal for the prototype developed by Innotech. Our technology integrates an electrochemical process with controlled microbial conversion of sulphate to sulphides. Apart from generating water that is fit to meet the regulatory standards, caustic soda will be generated as second value-added product during this process.

How did you get your funding at different stages? Did you face any struggles in the process?

Funding was never easy. We initiated the process by bootstrapping and investing some of our own money. The first major break was received from IKP Knowledge Park, Hyderabad. The data generated at IKP helped us pitch the concept and its applicability for a much larger start-up fund from Oil India Limited. Our concept also won the Indo-Israel Innovation Challenge, jointly organised by the Indian and Israeli governments. This gave us necessary credibility. In 2018 we got the Water Digest Award in the Best Research Innovation category in Waste Water Treatment. This generated immense interest among the investors.

The story is similar for our Vitamin D fortification project on Mushrooms. It started with our personal money. There were more rejections for this project. At one point we thought it may not be a feasible idea but we went on with the initial experimentation with help of a friend and a cousin who spared some land and resources to start the production. I had sent in applications and given presentations to over 30 different funds and organisations, but all in vain. Finally, I encouraged my colleague to apply again in Biotechnology Ignition Grant (BIG) for the same project. We cleared the BIG hurdle and received a 50 lakh seed fund from them, a major breakthrough. Later we were winners of the Economic Times Power of Ideas competition, and received another seed grant of 5 Lakhs from the Centre for Innovation, Incubation and Entrepreneurship at Indian Institute of Management, Ahmedabad.

How important is the role of incubators and start-up grants for setting up a company?

Incubators are extremely important to set up the experiments to either establish the proof of your concept or to scale up the concept. It provides not only the lab place but an ecosystem with like-minded people. Start-up grants are equally important in the early stage. They are the best bet after the bootstrapping phase, as they normally do not seek equity. Investors at early stages may take a significant amount of equity in your venture and this may become an issue at later stages of funding.

What would your message be to a young scientist who wants to become an entrepreneur?

This is the right time. When we completed our PhD (2004), we use to hear about start-ups and spin-offs only during our visits abroad. However, with the start-up ecosystem growing rapidly in the country, this is just the right time to dive in. Personally, I think most of us are afraid because of the financial insecurity and risks involved. Therefore, I would urge the youth to become financially literate as soon as possible, which is not usually the case in our country. One more point I would like to make is that help and assistance are available, one just has to ask and seek. Most importantly, if you have the passion and a good idea, it will be noticed and appreciated. Passion is the best way to get other people involved in your dream. I believe the rest falls in place automatically.

What is the one lesson you have learnt from your journey so far that you would like to share with everybody?

A good team that can take care of all the aspects of the business and pure passion of the founders would be the key to start as well as sustain a venture.

Science outreach efforts currently reach a very limited section of the public in our country, i.e. there are a large number of citizens whom we are not reaching. Why do you feel this is happening?

The existing public outreach programs of science in India are inherently bound to the availability of science educators, who are usually taken from a pool of science enthusiasts with required communication skills. So what they end up doing in most of these public outreach sessions is reaching out to similar science enthusiasts. Now, there are immense amounts of efforts being put in, but they are directed towards people who are already enthusiastic about science. We are not reaching the right people - people who are hitherto disengaged in science. Unless we engage the disengaged, there is no progress. Here, geographical location plays a big role. We arrange all our public outreach programs in and around cities and towns where the population is already exposed to science. But we are not reaching out to people where they don’t have that kind of exposure. It is not that no one is doing it, but we are not reaching the perimeter that we want to reach.

You have written about how our current methods of outreach encourage appreciation of the human achievements in science, but do not encourage rational thought. Can you elaborate a little on this?

Definitely that is a contentious issue, but here is my personal understanding. As an example, talking about the fact that the Mars rover is roaming around on Mars is nothing but factual scientific knowledge being given. Instead, we should incorporate in our public outreach programs how this can be achieved and what are the parameters that scientists have to keep in mind to make it happen. Unless you talk about that, real appreciation doesn’t come. And while you cannot really explain to a general mass in detail how the Mars rover works, I think you can explain to people how optical magnification works. So, when you try to engage people into basic scientific methods, that’s how you gain real scientific temper and real appreciation about science. But, my understanding is that most public outreach programs don’t incorporate that.

Moving forward from here, how do you propose we change this? For example, you have written about the importance of reaching young minds. How do you think we can achieve this?

What would have been ideal would have been a curricular rejuvenation, wherein schools impart some understanding of scientific methods rather than scientific information. But it is easier said than done. So, that’s why perhaps we should have supplemental centres or resource centres for kids all around the country. In this way, kids can have their regular school and curricular commitments, but whenever they have some questions, they can go to this resource centre and find out what is behind this phenomenon or what is behind those mechanisms. And you don’t really need a lot of things to do that. If a fifth-standard student can be given access to very simple, scientifically motivated instruments or models, he/she can actually understand quite a lot by himself/herself. This idea has been around for so long and a lot of district science centres have cropped up in many parts of the country, but the problem is that in making such a district science centre, you actually take into consideration a lot of things that are not necessary, for example, how it should look. But we can actually serve the same purpose by having a science centre in a mud hut in a rural location. It doesn’t need all those peripheral things that drive the cost high and which are not necessary for rural science outreach. For science outreach, you just need a few models and very simple instruments and simply giving access to these kids and that can be done anywhere.

A large portion of the public – the voting and tax-paying public - are adults who are already set into their own dogmas and biases. So, do you have any ideas on how to reach such people with science outreach efforts?

So, that is the most difficult part - adult, disengaged people. Mainly because the sources of information in their day to day life, for example, newspapers (and these days, internet), are very difficult to change and have no gradation of reliability. I think, if geographical spread is incorporated into public outreach programs, you will start reaching out to these people. Even in a location where 50 families live, out of which one family is scientifically engaged and the rest are disengaged, if you have a program there, some of the members of those disengaged families can come forward, and that’s how you reach them. Even one member per family is a good start. But if you keep on doing science outreach only among science enthusiasts, people who have religiously attended your popular science lectures for the past 10 years, you are not achieving that. You have to put in extra effort to do it in a place where there is no history of past public outreach programs, no history of popular lectures being given, and then you will definitely get some of the people who never got exposed to science gaining that exposure.

In the last few years or decades, have there been any outreach efforts that you admire, which you think can be used as an example for others to emulate, going forward?

So, I definitely admire Arvind Gupta. He has a very different take on public outreach, doing it in a very different way. He’s not someone standing on a podium and talking about achievements, but instead he is someone who has people making models themselves, finding out how scientific principles and natural laws work. I think that is definitely difficult - you will have thousands of popular lecturers, but it’s very difficult to get a thousand Arvind Guptas. So, when you get at least one Arvind Gupta, you should capitalize on that and make him mentor similar people. Secondly, I am actually very fond of the amateur astronomy programs, which are present all over the country now. You are given a telescope, you are taught how to use that telescope, you are given some idea about what to look at, and then you go out on your own and try to record. I think that’s the best example of placing the scientific method in the hands of people who are not scientists - citizen science programs. In fact, there are many avenues where you can actually engage citizens, for example, conservation biology. People have been doing it all over the world. We should come up with these kinds of ideas. When you give a ninth-standard student the job of counting sparrows in his locality, and he finds after one year that indeed the number of sparrows is going down, he will try to find out why. This kind of awareness is different.

So, you are hopeful for the future?

Yes, definitely. We should have a positive outlook on this.

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You've spent a long time studying brain development. What new things have you learnt? What would be your most important finding?

My group of talented students and postdocs have discovered several cool things about how the brain is constructed. One team identified an “organiser” in the embryonic brain that acts as a “lighthouse” instructing nearby cells to take on the properties of the hippocampus - the learning and memory centre of the brain. Another team identified a molecular “switch” that instructs stem cells in the embryonic hippocampus whether they should produce neurons or glia (support cells). Yet another team identified how DNA is modified in the stem cells of the brain so that they produce one specialised type of neuron versus another. We also obtained an insight into a developmental connection between evolutionarily ancient “emotion centre” of the brain, the amygdala, and the more recently evolved neocortex, where our language, cognitive functions, and perceptions are processed. All in all, it’s been quite a ride and we are fuelled by the excitement of what unusual discoveries lie ahead!

A lot of your papers on PubMed talk about genes involved in the development of a part of the human brain. What percentage of brain development do we truly understand as of now? How much more do we need to know to understand brain development fully? Are any of these genes more important than others?

We don’t work on the human brain, we study the embryonic mouse brain as a model. The genetic mechanisms that shape the mouse brain are similar to those in the human, so our insights would hold for understanding human brain development as well. We know of several genes that are important in controlling various aspects of brain development, now we and other labs across the world are studying how these genes interact with each other - in different combinations in different brain structures, and at different stages in development.

You study the development of brain cortex and amygdala. One is the seat of reasoning and the other the seat of emotion? Are these two parts of the brain really very different from each other? Does the common perception that reasoning and emotionality are mutually exclusive, also visible in the brain's anatomy/development?

The amygdala and the cortex connect to each other. Yes, one processes emotion and the frontal cortex processes reasoning, but to actually ACT on anything one needs the motor cortex, the spinal cord, the nervous system works together. The amygdala is an evolutionarily older structure, even reptiles and amphibians have it. The neocortex is unique to mammals. It’s as if additional processing, integration, reasoning i.e. “higher cognitive functions” have been added on to the existing brain structure, during evolution. One of our studies identified that the genetic mechanisms used to produce one component of the amygdala are very similar to those used to produce the neocortex. The provocative hypothesis we put forth is that the neocortex may have arisen in evolution by expanding and modifying one part of the amygdala. This study created quite a buzz, and was the MSc thesis work of a young student in my lab, Ryan Remedios (Remedios et al., Nature Neuroscience, 2007).

Why did you choose to study brain development? Was it a gradual process or were you driven by a particular question or a personal life experience?

I have been fascinated with the brain since Std XI. What drove my imagination was visual perception. How does the brain create such rich representations of the outside world within itself? I just *had* to study the brain - no other organ or other scientific discipline gripped my interest more.

You've been a vocal scientist and involved in science outreach. You've spoken on TED Talk India and are now set to talk at TEDxGateway Mumbai. Do you think talking about your work to non-specialists has helped you or your work in any way?

Speaking to non-specialists, teaching students, doing workshops with school kids - all are invaluable for a scientist to clarify what they really, truly know, and what they are fuzzy about. It’s a lot of fun preparing for such a talk because you get triggered by your own quest to understand the topic properly - you read more widely than you otherwise might have, you “chew” on the questions you ask yourself, and the audience may ask you, in every spare moment. In one such session, when I was preparing to make the periodic table of elements more comprehensible to my son’s standard 8 friends, I found myself reading and discussing with colleagues in the Chemistry Department at TIFR, and it took some 20 glorious hours of preparation for me to understand the topic well enough to be satisfied I could introduce it creatively to 14-year olds. As I happily told my students afterwards, that we have the *best* jobs! We are paid to read, think, explore - whatever grips our curiosity is fair game. And reading widely, outside our areas of expertise, stimulates our minds to work better when we are reading within our specialisations.

What would you like to say to a young neuroscientist in India?

The sky’s the limit. The study of the brain is a journey of unparalleled excitement, twists and turns. Neuroscience is a fledgling field in India, so there’s freedom to find your niche and explore! There is so much enthusiasm and interest in learning about the brain, and it is rewarding to see young students who want to enter this field.