Why are health reforms difficult in India?

India’s health policy confuses the lay person as much as the investor. What does the government really want to do? Does it want to provide health for all its residents (not citizens) under the Universal Health Coverage (UHC) scheme? Will it distribute medicines free to everyone? Is it seeking Foreign Direct Investment (FDI) actively in the pharma sector? If so, why does it create bureaucracy? Overall, why is there so much uncertainty over policy making in India? If the government indeed wants to reform the health sector, why does it find it so difficult?

I think it is because, political, economic and social forces drive or block policy change in India. Reforms depend on key elements such as the presence of domestic economic difficulties (inflation and rising prices), pressure from international financial institutions (S&P and Moody’s rating), a nod from groups with vested interests and strong political leadership. Since India’s economic reforms in the 1990s, the typical ‘back-scratching/palm-greasing’ environment under the ‘license raj’ has been replaced by stronger dependence between politicians and their constituencies, commonly called ‘vote-banks’. Vote-bank politics and its necessary appeasement divert scarce resources and create inefficiencies.

On the other hand, the concentration of power with State Governments has intensified. Health is a state subject in India. This often means that the problem (broken health care system), its solution (UHC) and the political climate to implement that solution are rarely aligned and precious time for agenda setting and political capital is wasted. Policy paralysis appears to be the outcome of incentives created by dependence on parties with different interests. This implies that the government of the day has little influence and is at a disadvantage. However, one sees more willingness from States ruled by political parties that do not hold power at the Centre such as Chattisgarh (BJP), Tamil Nadu (DMK), and Karnataka (BJP). Rajasthan is the only exception. This leaves the Central Government at the mercy of the States to implement its health policy.

Something interesting to note is that reforms by their very nature intend to introduce radical shifts into the accepted system. This requires those who are comfortable in status quo to adapt to environmental changes that affect society. Only a relatively narrow range of policy changes are considered politically acceptable. This “window”,  known as the “Overton Window“,  of politically acceptable options is primarily defined not by what politicians prefer, but rather by what they believe they can support and still win re-election. Therefore politicians are more likely to consider implementing policy reforms not when ideas change among politicians, but when ideas change in the society that elects them. This concept flies in the face of the general assumption that politicians are fools. On the contrary, politicians accept only those ideas that gain amplification through public discourse. In short, the more you lobby, the more the idea gets closer to implementation. How many public debates on health care can you remember watching?

This explains why politicians prefer incremental change to a paradigm shift, since such ideas are rarely adjacent to existing policy and fall outside the ‘window’ making them a political impossibility. Politicians will therefore, prefer to wait until the problem, its solution and the political climate align favorably. If you have ever wondered why there are hardly any programs that encourage disease prevention, it is because the government will move to change something only when pushed to the wall and left with no alternative. This explains the failure to strengthen institutions and governance structures well in advance since politicians like to cross a bridge only when they come to it.
Over the years, because of an indecisive government and the ensuing policy paralysis,  India’s bureaucracy has become more politicized and powerful, performing both administrative and political functions as politicians rely on a few ‘hand-picked’ technocrats to formulate and implement policy. This has led to a greater blurring of transparency and accountability in policy decisions, and a distancing of policymakers and elected politicians from their constituencies when they bring to bear their personal views and interests to decision-making. They would rather work to assuage public opinion as represented by a publicity-hungry mainstream and more recently, the alternate media, than talk to the man on the street to understand the problems he faces.

Despite the federal system of government, there is a large decentralization of power to state governments. As in organizations, it is easy to see why decisions taken at the Centre are sometimes out rightly opposed by state governments or regional parties (eg: land acquisition and FDI in retail) and sometimes simply not implemented (eg: NRHM in UP). This makes the task of implementing policy reforms extremely difficult in sectors such as health care, which is directly controlled by state governments, despite its glaring need and total absence.

As responsible citizens, it is up to us to ensure that we create the right environment that aligns the problem, its solution and the political environment. It is unlikely that the agenda for the 2014 elections can include health. But, we only have a year to create a difference and get into the politician’s mind-space if we want to see the 2019 elections fought on the plank of quality health care for all Indians.

Image courtesy: http://www.topnews.in

What if clinical trials don’t happen in India?

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.

The Life of “PI” and Clinical Trials

Those of us who have seen the movie, ‘The Life of PI’, would agree that the boy, Piscine Molitor Patel or PI had to go through a lot before emerging a winner. What cannot be cured, must be endured.

When one reads about the current scenario as far as Clinical Trials (CTs) are concerned, the Principal Investigator or PI must be also wondering why he is being made to go through so much. All that he or she has done is evaluate a new drug in the best interest of his/her patient. Why is he/she then, being labeled an interested party?

Yes he is interested in his patient’s welfare and in the true spirit of equipoise conducts the informed consent process, screens, and then determines eligibility of the patient, before randomizing the patient to one or the other arm of the trial, with the full comprehended consent of the patient.

Yet in some cases the PI is being pilloried. Patients are being instigated to say that informed consent was not administered as a process, and that they are being made to sign on a piece of paper without even reading or understanding the same.

What is the PI to do in such cases? Have a witness to this process? The basis of the doctor-patient relationship, be it in clinical practice or in a clinical trial, is trust. Do we want video camera recordings to breach this trust and confidentiality, all because some people don’t believe that informed consent is being administered as a process? Should ethics committee members conduct surprise checks as part of their oversight responsibility?

What is in it for the PI? What does he get after putting in painstaking hours for the trial, over and above his busy practice? Such allegations, which affect his credibility and that of clinical trials in general? Does he get money for doing a trial?

He receives an investigator grant. But that is for the conduct of the trial. To pay for the free treatment of his patients including all tests, procedures, and for managing adverse events. To pay his staff who support him in the conduct of the trial over and above their day job.  To ensure drug supply is carefully stored and accounted for. To ensure that processes are and documentation is perfect for the clinical research associate, quality standards manager, auditor, and inspector. To ensure that patient rights, safety and confidentiality are maintained. To ensure that data on the case report form is accurate and verifiable from source documents.

The PI needs to be trained in good clinical research practice and then train his staff. He can delegate but can never abdicate. The ultimate responsibility is his. Whose trial is it anyway? Whose data is on the case report form? Who conducts the trial and manages patients? Every “participant” in a clinical trial is equally responsible, viz., the patient, the doctor, the ethics committee, the regulator, and the sponsor.

Sometimes the PI may also be part of a protocol development team and needs to be especially well versed with all aspects of the drug and design of the study to ensure it is globally and locally relevant.

The PI is at the center of the patient’s universe. Everything revolves around him. Not everyone can be a PI. One needs to not only be qualified by knowledge, training and experience but one also needs to have trained staff, a CR secretariat so to speak, space, time and the mindset of documentation and process (“if it has not been documented it has not happened” – Sir Antoine el Hage, ex-US FDA Commissioner).

He must be trained in the onerous task of not just being vigilant for unexpected adverse events and managing the same, but also in using his clinical acumen for judging whether an adverse event is causally related to the study or drug. This has important implications as the case may then be compensable per section 2.4.7 of the Indian GCP guidelines.

To be fair to the sponsor, the PI should engage the sponsor in a dialogue before determining causality. The current compensation guideline can be misused and can threaten the future of all CTs in India, even investigator-initiated trials.

Just like in the movie, the life of a PI is now as scary since he is adrift on a boat in an uncharted sea of suspicion, with the tiger of media scrutiny and judicial inquiry, not knowing what can happen next. Testing his resilience like never before. Wondering when will this mental torture end. And what has he done to deserve all this? ‘Why me?’, must be his constant refrain to God. When all he wanted was for his patient to get better.

He has taken this risk for his patient. Because the current standard of care was not good enough for his patient. He has tried to make the patient as safe as  he could. He has followed the principles of GCRP in spirit and to the letter. He has subjected himself to the constant monitoring, data clarification, audits and inspections, all for his patients. And yet he gets this in return? From taking the oath of Hippocrates to being labeled a Hypocrite?

Why should he continue to do this? Better to go back to doing only clinical practice. No point in being a principal and principled investigator. Let trials not happen in India. Let new drugs not come to this country. Let patients in India compromise their health by sticking to status quo. Those who can afford will go abroad. Those who can’t afford will have to die here, denied of their only hope for survival.

Yes, “uncontrolled” CTs can play havoc with patients’ lives. It is perhaps the turn of the PI to counter-litigate in patient/public interest. The question is not whether we can afford to let CTs happen in India. The question is whether we can afford not to have CTs happen in India.

This is a guest column by Dr. Viraj Suvarna. These are Dr. Suvarna’s thoughts in his personal capacity and not as an employee of Boehringer Ingelheim India Private Limited where Dr. Suvarna serves as Medical Director.

What are we compensating for?

On Jan 30, 2013 while the country stood in silence as a mark of respect to the father of the nation on his 65^th death anniversary, a gazette notification was passed which could mean the death of good quality serious clinical research in India. It definitely means the death of reasoning, the death of stakeholder engagement when after a year of deliberations and receiving suggestions from at least 32 organizations, they were summarily dismissed and not incorporated in the notification, which is now law. The ethical clinical research industry is faced with a Hobson’s choice, “the necessity of accepting one of two or more equally objectionable alternatives.”

To continue doing clinical trials in the light of the gazette notification, means being not compliant to the law, because some of the provisions are difficult, well nigh impossible, to implement. To stop doing clinical trials, both ongoing and in the future, would mean being morally unethical as it won’t be in patient and public interest.

So what will they do? The way I see it, good quality clinical research by the serious players will continue as patient and public interest is at the heart of what they do. They will face such water cannons, tear gas, and other unreasonable measures but they will soldier on in the interest of patients and the public. But they will not litigate. After all, public interest litigations (PILs) are filed not necessarily in the interest of the public. This industry believes in being industrious, hard working, and committed to the unmet medical and clinical needs of the people who are eligible to be included in clinical trials so that they can serve an altruistic purpose of doing good for the larger community.

What is so abominable about this notification? In the first place, let us understand that compensation is not applicable as a blanket provision in the world of good quality serious ethical clinical research as participants are fully informed, fully comprehend, and only then make a volitional decision to enter the trial. If they suffer from an adverse event related to this participation they are medically managed free of cost. Patients are insured and investigators are indemnified. Despite this, if there are reasonable and justifiable grounds for compensation, the same is done. Per section 2.4.7 of the Indian Good Clinical (Research) Practice (GCP) guidelines, if the clinical trial related injury is deemed related to the study or drug, and is endorsed by the ethics committee, the event is compensable and sponsors have compensated, although in many cases the patient’s relatives, investigators and ethics committee members have wondered why is the sponsor doing so when the patient was well looked after by the sponsor.

There are other reasons to believe that this notification was hastily passed perhaps as a knee jerk reaction to the Supreme Court diktat that either clinical trials need to be stopped or overseen by the Health Secretary to assure that participant rights, safety and well-being are monitored. The notification seems legally untenable and there seem to be internal and external inconsistencies. Some provisions are not feasible to implement. For example, it is mentioned that from the day of serious adverse event (SAE) occurrence the sponsor and investigator need to report to the DCGI’s office within 24 hours and submit a detailed analysis of the same within 10 days. Often one comes to know of the event 10 days after occurrence. It is reported immediately but by this notification one is already non-compliant. Is the DCGI’s office geared for e reporting of SAEs? It should have been worded as from the day one comes to know of the SAE, not from the day of its occurrence. Changes to informed consent forms, contractual changes, getting fresh approvals both internally and from ethics committees will pose operational challenges which can even take as long as 6 to 12 months.

The notification states that medical management of any injury needs to be paid for, for an indefinite period, even if not related to the trial. For example, a participant while traveling to a clinical trial site, has a road accident, and will now need to be medically managed free of cost for the life of that patient. Such blanket provisions do not exist in any part of the world, both developed and developing, emerging and emerged. So is India somewhere in between? Compensation for lack of efficacy or intended therapeutic benefit of the investigational product goes against the basics of clinical research. Sometimes patients do not respond even to approved and marketed products. Use of placebo is generally done as an add-on to current standard of care. Why should a sponsor have to compensate if there is wilful negligence or protocol violation on the part of the investigator? The sponsor does select the investigator, trains him and his team, monitors and oversees the trial conduct with a clinical research associate, quality standards manager and auditor, plus the US FDA, EMEA and the Japanese MOH inspect some sites. Even if the DCGI’s office is unable to monitor, even if ethics committees don’t have the time to oversee, the industry does a very thorough job of monitoring and its standard operating procedures are stricter than any law of the land.

Wouldn’t such blanket compensation clauses promote research misconduct? Won’t patients be induced to participate in clinical trials? Additional committees of experts from academia, who have probably never done a global clinical trial in their life, have been appointed to oversee the conduct of clinical trials, adding to the layers of delay. There is no clarity on how would one determine causality, and accordingly determine the amount of compensation, and the sponsor may not have the opportunity of representing to an independent arbitration committee.

While the ethical research minded industry does support the mandate for compensation for clinical trial related injuries/death in the new compensation rules, and this step will further strengthen human subject/participation protection systems in clinical trials, the gazette notification if not suitably amended will be difficult to implement. Access to new medical innovations for unmet medical needs will become an issue as no new drugs may reach the Indian market. The research/innovation culture recently propagated by the government may take a back seat for academic (including investigator initiated) research and we would miss this golden R & D opportunity to build research capacity and capability.

Knowing the genuine clinical research industry, united in adversity, clinical trials will go on and Indian patients will continue to benefit even if it means the industry is being unfairly ‘PIL’loried. This is because it is genuinely interested in patient welfare. It’s not that one does not want to compensate. Obviously where indicated one must, has and will compensate. But let’s not be unfair to an industry which has helped many patients live better lives. Clinical trials don’t kill patients. Rather, if not for the clinical trial especially in oncology, many a patient would have died a premature death. Let’s not kill reason, let’s not kill clinical trials, let’s not kill ourselves. Let’s be balanced and understand the benefit to risk ratio, maximizing benefit, minimizing risk and optimizing the therapeutic experience for the patient. Primum non nocere – at least do no harm.

These are Dr. Viraj Suvarna’s thoughts in his personal capacity, and not as an employee of Boehringer Ingelheim India Private Limited where Dr. Suvarna is Medical Director.

India’s Decision to Invoke Compulsory Licensing

A variety of factors such as growing population and economy, increasing life expectancy, expanding middle class, higher income levels, rise in incidence of diseases, increased government outlays and better awareness about health are expected to make India’s health care a US$ 280 billion industry by 2020[1].

Despite this growth, health care delivery and services in India continue to be lacking. India houses 16% of the world population, 21% of the global diseases and the largest burden of communicable diseases in the world[2], yet its health care infrastructure is one of the weakest and not comparable with other developing nations. The government spends just 0.9% of GDP on health care.

Health care costs in India have risen in the last few years.  As new technology and better products are introduced, and medical negligence cases are brought under the purview of consumer courts, health care costs have increased. To make matters worse, health insurance covers only 14% of the population[3]. A WHO study has reported that 40 per cent of Indian families end up in debt due to high medical expenditure.

On one hand, it is in this context that the decision by the Indian Patent Office to issue a compulsory license (CL) to Natco for Bayer’s anti-cancer drug Sorafenib must be viewed. The CL means the drug will now be available at Rs 8,800 per month, a 97% reduction from Bayer’s Rs 2.8 lakh. Globally, people working on public health and access to medicines have welcomed the decision.

On the other hand, the first CL issued in India, has set a precedent. This is a rare instance globally where a general CL has been issued, not bound by ‘government use’ provisions or those allowed only in cases of ‘extreme urgency ‘ or ‘national emergency’. A CL that can be utilized by a generic company unconditionally means CLs could possibly be used to promote competition. In certain quarters, the CL on sorafenib is viewed as a step towards building domestic manufacturing capacity and know-how in a new range of drugs. Recently, the government decided to issue CLs on three more cancer products, two from Roche – including Herceptin, the popular drug to treat breast cancer – and one from BMS.

In the past, its decision to invoke CL added to the embarrassment of the Indian government during the 2012 visit of US Secretary of State, Ms. Hillary Clinton. As such the relationship between India and the US has seen a downward spiral, with widening differences on trade and diplomatic issues. During Ms. Clinton’s visit to India, she also raised the case of a first time grant of the compulsory licence[4]. While Trade Minister Anand Sharma has strongly objected to the US move of tightening the screws on India at the WTO, could the Indian government have better balanced the need to create access to life-saving medicine to its citizens and the WTO regulations?

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[1] Source: http://www.indianhealthcare.in; Wikipedia article on Healthcare in India

[2] Source: WHO Health Statistics 2011

[3] Source: Rashtriya Swasthya Bima Yojna website [http://www.rsby.gov.in/about_rsby.html]

[4] http://www.livemint.com/2012/05/13234416/India-US-see-differences-wide.html?d=2

India’s Health Policy: Flip Flops or Opaque Policy Shifts?

The directive from the Drug Controller General of India’s (DCGI) office to all State Drug Controllers to issue trademarks for generic names instead of brands – even if it was just to resolve trademark issues – is yet another display of confounding decision making by the Union Government that has been plaguing the country in general and the health care sector in particular.

Over the years despite knowing of its multiplier effect on GDP, India never attached great importance to the improved health of its population. Policy lapses witnessed the private sector stepping in to address a fast rising demand for health care creating one of the most privatized medical systems in the world. As a consequence, India is confronted with the problem of meeting growing expenditure on health care which is heavily skewed towards out-of-pocket expenses for its citizens, driving large sections into poverty.

India’s future lies in its demographic dividend – the advantage of having a young, healthy and productive work force. And to reap the benefits of this work force we have to achieve decent health and education outcomes for the majority. India averaged 8% p.a. GDP growth rates over the 11^th Plan period. And yet, its public spending on health has hovered around an abysmal 1-1.2% of GDP, one of the lowest in the world. The Approach Paper to the 12th Plan declared an increase to only 1.58% by 2017. And how is this possible, given the government’s recently vocalized desire to move towards universal health care (UHC) for not just its citizens but its residents that include millions of illegal immigrants as well?

India chose to begin its journey towards UHC with one step – to provide free medicines through its public health system. The Centre released approximately Rs. 30,000 crores to the States to fund the procurement of medicines, over the next 5 years (2012-17) under the ongoing NRHM. After the Supreme Court’s intervention and with the five public-sector pharmaceutical companies lying in shambles, the government quickly approved the new drug pricing policy that led to the inclusion of 348 medicines (approximately 30% of medicines and 60% of the market) into the National List of Essential Medicines (NLEM) and effectively under a price controlled not by the market, customers and competition but by the government.

Simultaneously, in an ostensible effort to make medicines affordable to its residents (not citizens), the government did two other things: 1) allow foreign direct investment into brown field projects in the sector with caveats such that foreign companies who invest in India will produce stipulated quantities of essential medicines and invest in local manufacturing and R&D 2) demonstrate that it will use compulsory licensing more as a weapon of choice than as one of need.

Both these steps make sense in the short term thus providing political capital to the government for the upcoming general elections in 2014, but harm the future of India as a preferred destination in the long term, thus depriving the opportunity to create economic capital. What vindicates this point is that to this date, there has been no effort from the government to invest in creating the infrastructure required to deliver superior health outcomes to the population despite it being the root cause for the inflow into the private sector despite all its societal evils.

However, all this pales in comparison to the DCGI directive to state drug controllers to not issue marketing licenses for trademarks or branded drugs but in their generic names alone. While the technicality of this decision alone warrants a separate column, it suffices to say that this makes no sense whatsoever. Authorities are expected to regulate or legislate to help either the industry, traders or end consumers. This decision helps none of these groups or anyone else. All it does is commoditize the industry thus threatening to wipe out small and medium players who lack the financial strength to compete with MNCs who despite severe pressure on profit margins will survive. The consumer has little or no knowledge of the brands of medicines and therefore is unlikely to benefit from the decision. The only group that will benefit are the middlemen – the traders – who will control the supply of medicines and make unholy profits in the bargain. Under harsh criticism, the DCGI recently clarified informally that this directive was more to resolve trademark issues. Apparently, too many similar sounding trademarks confuse doctors and retailers. If it really is the reason, the decision is laughable. Isn’t it easier for similar sounding trademarks to be denied by the regulators, thus pushing the onus back on the industry to decide on clearly differentiated trademarks?

On one hand, India signals that it will welcome much needed FDI into the sector. But on the other it threatens to disregard product patents, invoke compulsory licensing, discontinue issuance of marketing licenses to trademarks while controlling prices on essential drugs and also considers controlling prices for patent-protected innovative drugs as well. Such indecisiveness about policy bodes ill for a country that faces the daunting challenge of enrolling, financing and providing acceptable health outcomes for 1.2 billion citizens and millions of other residents, illegal or otherwise. For such largesse, it could actually do well with help it can garner from all quarters.

Why then is the government alienating itself both from the domestic industry as well the international society? These policy flip-flops are confounding! Why would the Indian government risk global criticism by openly demonstrating clear indecisiveness? Is this driven by an argument about poor public sector performance in delivering health care? Undeniably, it has been lacking, which reflects in the dismal health outcomes in the country. Or as noted academic scholar, Kaveri Gill wonders in a blog post, is this seemingly open decision-making process merely a dangerous opaque shift in policy, which has very little to do with evidence and even less to do with broad-based consensus? 

Being clinical with rhetoric

In Munnabhai MBBS Boman Irani, as Dean of a Medical College, tells medical students on their first day, that doctors need to be clinical. He meant that as a doctor one cannot be too close to a patient as this can reduce objectivity and come in the way of sound clinical decision-making. So what does clinical mean? The concise Oxford dictionary puts it as being coldly detached, dispassionate, and objective. Etymologically, it is derived from the Greek word, ‘klinikos’, meaning bed or the bedside of the patient.

Against this backdrop, one can’t help but reflect on the current media rhetoric surrounding the way clinical trials are being conducted in the country. I am not for a moment discounting all that is being showcased but I would like to see this balanced with data. In any field, there will always be good and bad apples. One swallow does not a summer make. Similarly, a few bad apples should not spoil the entire basket. Before tainting and distorting reality let’s put the facts on the table and then decide.

The word, ‘trial’ itself means an experiment. A participant (not a subject as no one is being subjected to the experiment) is one who is informed of everything that participation in the clinical trial entails, and only after s/he has fully comprehended, and checked with his/her family doctor and relatives, is s/he expected to consent. Of his/her own volition, understanding that participation involves possible risk and possible benefit, so as long as one believes that the benefit is worth the risk, one willingly participates. It is this altruistic motive which makes a participant a hero. Not a guinea pig.

A “guinea pig” is a misnomer as the animal is neither a pig (it is a rodent), nor from Guinea (from the Andes mountains). Even if one wishes to do a trial on animals, one needs to have permission from an ethics committee which oversees research on animals. Those who feel that clinical trial participants are simply made to sign an informed consent document need to witness the process. A patient or participant information leaflet, written in a language that the participant can understand, is first explained to the participant in his/her own language. All queries that the participant may have are addressed by the principal and principled investigator/delegate. The informed consent form is also explained similarly. Innovative methods could include use of a speaking book which talks to the participant, the way books for children are designed, of what s/he is getting into when being part of a clinical trial.

One could also think of using an iPad and make the participant see for himself/herself exactly what the participant will need to go through from beginning to end of the clinical trial. This way the participant sees himself/herself going through all steps of the trial, and only after the process has been explained does the participant make his/her decision. No force, no incentive. Vulnerable populations are not selected. Those who cannot make their own decisions are provided with assistance. Functionally literate participants may also be recruited with due legal precautions (impartial witness) being adhered to. Ethics committee members can and do oversee the process, and can do random spot checks. Video-recording of the process, with protection of the participant’s confidentiality, is another suggestion.

As a sponsor of the trial, investigator selection is paramount. Training is meticulously done. Regular oversight by a clinical research associate, quality standards person, and auditor follows. Inspection by a regulatory authority is also done, even by the US FDA and/or the EMEA as data from global trials, involving patients in India, is a part of global regulatory dossiers.

The Drugs Controller General of India (DCGI)’s office now refers global clinical trial applications to the New Drugs Approval Committee (NDAC), comprising academic experts from the respective therapeutic area and pharmacology. Going forward, the DCGI will ensure that contract research organizations, ethics committees, and sites are accreditated. The serious players in clinical research will survive while the fly by night operators will be weeded out.

In short, there are enough checks and balances from all “participants” in clinical trials, each of whom has an equal responsibility towards the ultimate participant, the patient.

Since 1994-95, global clinical trials have been placed in India by multinational ethical research-based corporations and the quality and ethical standard, viz., ‘Good Clinical Research Practice’, is rigorously followed across the globe. Even if locally applicable regulatory requirements are relatively lax in some countries, the MNC’s Standard Operating Procedures, which are stricter than any regulatory standard, are adhered to.

It is a myth to think that trials in India are cheaper. In fact because this is an out of pocket market where most have to pay for their healthcare-related expenses, and very few are reimbursed, sponsors have to spend much more per patient, having to pay for all laboratory tests and diagnostic procedures.

It is incorrect that India is being used as the destination for global clinical trials. The number of trials being placed in India and the number of participants from India in global trials is decreasing, and more trials are being placed in China, Korea, other Asian countries, Central and Eastern Europe, and Latin America among the merging markets.

At any point in time, the participant can withdraw from the trial without any problem or reason given. If an adverse event is experienced, the care of the participant is borne by the sponsor at no cost to the participant or institute.  If the event is serious or results in death as an outcome, and is judged, to be related to the trial or drug tested in the trial, by the investigator and confirmed by the ethics committee, the same is compensable, though ideally the relatedness should be in agreement with the sponsor. This does not happen in many developed markets where one has to claim for compensation. In India, the clause for compensation is included in the informed consent document. A formula for the same has also been proposed recently. It is only to be fervently hoped that this process is not misused.

In what are called, “outcome trials”, death or a serious adverse event is an endpoint, i.e., a point at which the trial for that patient has ended. Naturally in such trials many such events are anticipated. However, such trials are also important as approving a new drug, only based on softer endpoints, e.g., blood pressure or HbA1c reductions, are not enough in the long run, as has been repeatedly seen with some drugs, which had to be withdrawn from the market later.

Rarely is a new drug compared to a placebo. The placebo is almost always used as an add on to standard therapy in both arms, which makes it that much more difficult for a new drug to demonstrate efficacy, but in the interest of patient safety this is the preferred way of evaluating a new drug, even if this means many promising molecules may fall by the way side.

When so much is happening in the right direction, why are we not looking at the full picture before passing judgment on the way clinical trials are being conducted in India? Why are we not considering the tremendous benefits that accrue to clinical trial participants, doctors, institutes and society at large, besides of course the foreign direct investment inflow into the country? Why are we not thinking of the development of clinical research (CR) in the country that this will stimulate? When doctors are investigators in good clinical research practice it also helps them be better doctors in clinical practice.

Sponsors may draft protocols but it is doctors who ultimately review, make changes, and finally approve the document after the protocol development meeting. It is the doctor’s patients whose data enters case report forms from source documents. It is this data that gets into the database, gets analyzed, and then included in the final study report. Only when all investigators are in agreement with the statistical analysis plan, analysis and report, does the report get signed after the end of study meeting. From the report is written the manuscript and again only after all the doctors, who participated in the trial, review and approve the content, does it get submitted to a peer-reviewed journal and finally published.

Even negative trial results are published. Data Safety Monitoring Boards and Data Steering Committees, independent of the sponsor, can do interim analyses and decide on premature stopping of a trial based on futility, overwhelming efficacy or unacceptable safety in one arm.

It begs the question, “whose trial is it anyway?” It is really a sponsor’s trial? Or is it an experiment in which all stakeholders own and share equal responsibility? Let us all exhort ourselves to remember this and do our duty diligently. We owe it to all our participants whose altruistic motive has helped advance medical science and enabled many more patients and their loved ones benefit from their participation.

CRedibility begins with CR (Clinical Research).

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“My Pharma Reviews”is happy to introduce a guest post by Dr. Viraj Suvarna. These are his thoughts in his personal capacity, and not as an employee of Boehringer Ingelheim India Private Limited where Dr. Suvarna is Medical Director.