PIL filed by a NGO against pharma MNSs in India complaining illegal (unregulated) clinical trials being conducted leading to the death of more than 2000 trial participants.
The Supreme Court heard the complaint and reprimanded the government for being negligent in curbing (illegal) trials leading to the death of over 2000 persons who had undergone trials between 2007 and 2012.
“The drug trials are creating havoc to the country” stated the court. It further stated, “You have to protect the health of the citizens of the country. It is your obligation. Deaths must be arrested and illegal trials must be stopped.”
This judgment has hampered the legitimately conducted trials by the multinational pharma companies and other stakeholders involved overall.
(Clinical trials are governed by local laws, established guidelines by various international regulatory agencies like EU regulations and directives, World Medical Association Declaration of Helsinki and ICMR guidelines in India.
Central Drugs Standard Control Organization (CDSCO) under the directive of Director Control General of India(DCGI)is the primary authority and “Drugs and Cosmetics Act, 1940” is the chief regulatory body of clinical trials in India.
Most of the multi -national practice and follow these guidelines and recommendations.)
It is very sad that the entire clinical trials operations are categorized as illegal by pointing finger on multinational pharma companies who have been following all norms and regulations with regard to trials.
We all know the current scenario now. Since the judgment, number of industry personnel, organizations, associations and federations has taken up this matter with deep anguish and concern about the future of clinical trial operations in India. The ultimate result is some pharma companies have closed its trial operations in India; some have shifted the location outside of India. The badly hit are the CROs mostly who were totally dependent on multinational pharma companies. This scenario has already led to some unemployment and loss of foreign investment.
Biocon, Lupin has already shifted locations outside of India. Leading CROs like Veeda, Lambda Therapeutics also moved out to other Asian countries.
ISCR (Indian Society for Clinical Research), ACRO (Association of Clinical Research Organization), FICCI and other bodies have been voicing the concern to the government authorities but nothing has been done and no indications are seen for revival of the trials.
LSW LifeScienceWorld joined others by organizing a conference on May 27, 2014 titled “Clinical Research–Regulatory Norms-Current Challenges and the Future of Pharma Industry in India”.
The objective of this conference was to bring together the regulator and the clinical trial industry to focus on issues related to clinical research/trials area, identify the gap areas, if any in view of the new guidelines released by DCGI office, CDSCO and the Health Ministry and highlight the suggestions / recommendations / solutions consideration of regulatory agencies and wider circulation amongst the clinical trial industry.
The Conference provided an opportunity to clinical trial industry to interact directly with the regulator, policy makers, legal experts, experts in the field associated with the health ministry and the experts from the industry to discuss recent amendments in Schedule Y; challenges to bring new drugs to global market; perspectives on clinical trial sector in India; compensation and related issues; liabilities of stakeholders and mitigation; other related issues.
There was a good response to the conference and representatives from more than fifteen industries directly involved with clinical trials and more than 30 potential beneficiaries participated in the meeting. (For full report read: http://www.lifescienceworld.in/conference-report.html)
The report of this conference was prepared and submitted to the DCGI office and to purview of the Advisor to the current Minister of health and Family Welfare for their information and with expectation of some solution.
As part of an Update, KPMG has prepared two exclusive articles for LSW on the clinical trial scenario below:
Future of clinical trial activity in India
by Dr Waman Parkhi, Partner Indirect tax, KPMG in India
Clinical trials play a very important role in modern healthcare. India has a huge potential for clinical trials. The ‘India Advantage’ includes aspects such as large population with a diverse range of diseases, relatively lower costs of research, availability of trained human power, infrastructure, etc. According to the Indian Society for Clinical Research (‘ISCR’), India has 16 per cent of the world’s population and 20 per cent of the global disease burden. Bulk of the work by this industry is performed for foreign sponsors (pharma companies).
Service tax exemption in 2007
Considering the potential of generating employment, earning foreign exchange for the country and at the same time helping the healthcare industry in India, the Central Government had given a special status to clinical trial industry by providing an exemption from Service tax. In fact underscoring the importance of the industry for India, the Finance Minister during his budget speech in 2007 mentioned that “to make India a preferred destination for drug testing, I propose to exempt clinical trial of new drugs from Service tax”. The exemption continued till 10 July 2014 and was available to services of technical testing or analysis of newly developed drugs, including vaccines and herbal remedies, on human participants by a clinical research organization (CRO) approved to conduct clinical trials by the Drug Controller General of India (DCGI).
Issues with the earlier exemption from Service tax
This exemption had its own set of problems – one, no CRO was generally approved by the DCGI but what was approved was a clinical trial and the approval could be given in the name of the sponsor or a site etc. two,the exemption did not cover existing drugs, three, it did not mention specifically medical devices thus leaving a scope for litigation. Some of the players in the clinical trial chain like sites and principal investigators (PIs) were already being investigated in pockets by Service tax authorities especially after July 2012 when all services, except a few specified services, were covered under the scope of Service tax. While health service in general are exempted under a specific exemption, departmental authorities would contend that clinical trial services are not provided to the patient but to the sponsor and thus not covered under health services.
Due to these limitations in the existing exemption from Service tax, the industry was considering approaching the government to expand the scope of exemption mainly to cover other players in the clinical trial process besides the CRO and expand the scope of products covered under exemption. A few representation were actually made before the previous Government as well as the new Government.
Rude shock by Budget 2014
Not only that the request of the industry was not considered by the Finance ministry, surprisingly even the existing exemption was withdrawn. Finance Minister specifically mentioned in his budget speech that “In furtherance of the effort to broaden the tax base, certain exemptions are being withdrawn, including those extended to technical testing of newly developed drugs on human participants.” The Finance Minister has overturned the philosophy of his predecessor announced seven years back to promote clinical trial industry. The industry will now be saddled with the Service tax making the services dearer by 12.36 per cent. Even the export benefit to the services could be challenged as services of any kind of testing are generally considered to be provided where tests are conducted. Therefore, the foreign earnings notwithstanding, the industry may be asked to shell out Service tax. In fact withdrawing exemption has sent a wrong signal to the global community on the government’s commitment to promote clinical trial activities in India and destabilized investments already made.
The saga of pre-clinical trials
Even in case of pre-clinical trials, till July 2012, such activities were held to be exports if the recipient of the service was outside India and the consideration for the services was received in foreign exchange, which is normally the case. Here again, India has a specific advantage available in terms of its technical manpower. However the law is ambiguous and Service tax authorities are contending that pre-clinical trials are testing and therefore such services are provided in India,( in terms of the Place of Provision of Service Rules, 2012) and would be liable to Service tax despite the receipt in foreign exchange. If such an interpretation is adopted the benefit of zero rating an export service (where output services are free of tax and tax charged by vendors on input services can be claimed back as refund from the Government) would be done away with.
Impact of Budget changes on the industry
Both the above examples show that the Government has not even considered requests of the industry – which has a potential of earning foreign exchange for India leveraging its technical manpower capabilities. It has put the industry at a disadvantaged position vis-a-vis competition from neighboring countries in Asia.
Reports indicate that Research-oriented companies have already started eyeing places abroad to shift their trials. While the industry is reeling under pressure from the regulatory issues the latest withdrawal of Service tax exemption would make perhaps sound the death knell to the industry that is already in the intensive care unit.
What should be done for the revival of trials?
Clinical trials earn vital foreign exchange, make available state-of-the art cure available to the patient and an opportunity to the PI to acquaint with the cutting edge research happening all across the world, thus widening his horizons, so crucial for the country’s medical fraternity. Despite this attractive value proposition, the year marked a slowdown in the clinical trials industry due to delayed approvals. Withdrawing Service tax exemption could further hinder growth of the clinical trials industry which is already under immense pressure.
Given the fact that a sixth of the world’s population lives in India and we have the highest disease burden in the world, we need to foster an environment and ecosystem that encourages clinical research. To accelerate the growth of pharma industry and make it a globally strong industry, the government needs to ensure a robust, unambiguous, time-bound and transparent regulatory mechanism.
Also, what is required is to have a new look at the sector and components that are bearing the brunt of Service tax perhaps unintentionally. The ideal way would be to exempt the whole set of activities in the clinical trial supply chain from the levy of Service tax, including activities under pre- clinical trials. Exempting a supply chain in deserving sectors is what the government has already done in the case of education services where the main services of formal education are put in the negative list while ancillary education services like transportation, catering, cleaning services provided to the education institutes are also exempted. Further, the export benefit to technical testing and analysis services should be clearly provided to remove the ambiguity around the eligibility. If this happens the industry will see better days, if this does not, the doomsday could not be far away.
“The views and opinions herein are those of the authors and do not necessarily represent the views and opinions of KPMG in India. All information provided is of a general nature and is not intended to address the circumstances of any particular individual or entity.”
Clinical Trials in India – Is it the end?
The clinical trials industry in India has been in the news fairly often in recent times. A segment that was touted as India’s most valuable proposition; clinical trials in India, has suffered a major setback. Analysts had predicted that the approximately US$ 500million worth industry (as of 2011) would in all likelihood cross the US$1 billion-mark by the turn of 2016 – a target that now seems rather difficult to achieve. However, despite the current chaos, calling it “the end” would be premature and inaccurate, especially in light of the new regulations issued by the CDSCO in July 2014 which help in clearing the chaos that the industry has witnessed over the last year.
The article that follows aims to capture the evolution of the clinical trials segment in India in a sequential fashion.
The criticality and need for scrutiny in clinical trials is integral to the very nature of the industry. Human rights and safety are paramount considerations in carrying out a successful clinical study and ethical concerns therefore are inevitable.
Carrying out clinical trials in India has been the subject of significant debate for a few years now. Some ethical concerns that have emerged are:
Clash between scientific standards and ethical requirements – e.g. use of placebo controls in some types of research
Uncertainties and disagreements in assessing the risks and benefits of research protocols – e.g. in situations where clinical investigators are interested to conduct and complete the research projects quickly
Relation between the risks of a protocol and the informed consent of research subjects – e.g. Allowing clinical research in patients who are incapable of giving informed consent such as drugs for mentally incapacitated patients
Provision of reasonable compensation- providing adequate monetary compensation and reimbursement to volunteers , especially the uneducated or below poverty line populace
The abovementioned points undoubtedly highlighted the need for ethical review of research projects.
An independent review of clinical research projects by experts is thought to minimize the impact of potentially conflicting interests. Independent reviews are expected to mitigate the possibilities of one section of the society taking advantage over another. However, many factors led to unwillingness by the clinical investigators and companies to undergo ethical review of the research projects.
Moreover, the process of ethics review in India was relatively new and hence the implementation not as effective, mainly due to:
Lack of awareness of various regulatory processes especially those related to the ethical review of human research
Lack of proper ethics committees to review clinical trials
Protocol violations and study subjects not meeting the eligibility criteria
Delayed or lack of adverse event reporting
However, the industry continued to perform, as trials continued to be conducted.
In mid 2013, though, a rapid turn of events altered the course of the industry. Of the 162 approvals granted by the Drug Controller General of India until August 31, 2013, 157 trials were cleared in 2012, after a nod from just the New Drug Advisory Committees (NDACs).The Supreme Court thus suspended those 157 trials. Revoking the Ministry of Health’s right to clear clinical trials in the country drastically reduced the number of trials carried out in the country (From over 500 in 2011 to a mere ~107 in 2013).
The Health Ministry amended the Drugs and Cosmetics Act to include new norms for regulation and ethical supervision of trials. Three committees were instituted – a New Drug Advisory Committee, a technical committee and an apex committee, to clear clinical trials. The tiered process undoubtedly makes approvals more time consuming.
The time frame for reporting of clinical trials was also amended (reporting within 24 hours). Further compulsory accreditation of all stakeholders has instituted across the board making it mandatory for research institutions conducting trials to enter into a legal agreement with the sponsor and make full disclosures around the nature of relationship between them, the money involved and the regulator fees.
To protect the rights of the volunteers, the new norms also called for a robust awareness programme that would ensure that the patient was fully aware of the risks and benefits entailed in the study.
These developments have undoubtedly had an impact on the growth of the industry, especially because formation of the adequate number of ethics committee will require significant capacity building as the country does not have enough qualified personnel.
The segment witnessed a fresh surge of respite in July this year, as the CDSCO released a set of new guidelines which comprehensively cover all aspects of conducting trials in India. Highlights of the draft included:
Allocating responsibility to the sponsors and CROs for ensuring the design of placebo controlled studies
Investigators work on a maximum of 3 trials simultaneously
The guidelines also cover details around the compensation for the families of trial patients who are injured or succumb during the trials
The issue of patient ethnicity has also been touched upon in the guidelines
The CDSCO further clarified the importance of specific subject expert committees responsible for assessing specific type of drugs
Provisions under which an institutional ethics committee can approve an academic trial have also been laid out
Another important proposal that featured in the CDSCO guidelines was to create an IT enabled system for online submission of various information on clinical trials to streamline process of approval. On implementation this should considerably expedite the entire process.
The guidelines come as a big relief to the industry which has been clouded by doubt and confusion over the last year. There has been an uptick in the clinical trial activity in the country, with the number of trials approved so far being almost twice the number approved last year (within the same time frame).
The most recent Union Budget attempts to remove an exemption on a 12.3% service tax that previously helped contain trial costs may have prompted debates, but the Parliament has yet to decide whether this will continue. How the situation will eventually pan out , remains to be seen.
Clinical trials are the most critical step in the drug development process; to showcase that, as a country we are not able to deal with this crisis in an efficient manner, does not help in projecting ourselves as serious contenders in the global scheme of things. It is important for all stakeholders to liaise and treat this issue holistically; consider all aspects (ethical concerns, impact on the industry, impact on adjacent industries etc).
(“The views and opinions herein are those of the authors and do not necessarily represent the views and opinions of KPMG in India. All information provided is of a general nature and is not intended to address the circumstances of any particular individual or entity.”)
The pharma industry has been abuzz with the much debated and controversial clinical trials in the last few years. The introduction of FDI in the pharma sector, pharma-doctor nexus, branded drugs vs generics etc have been hugely talked about. But clinical trials seem to be on the top of the list that is hugely under the scanner.
There are many who advocate clinical trials while a handful do not appreciate the same as they feel that the existing drugs pertaining to Cancer, diabetes etc are not utilized to the fullest. Their argument is that when there are already many drugs which are yet to be tested, development of new drugs will be of no use.
India, considered as the most favored destination for conducting clinical trials is almost losing ground.
(i) Complicated regulatory policies,
(ii) Contradictory norms by the government agencies
(iii) Several other factors.
But with the Supreme Court of India’s verdict that the government must video record clinical trials of five new drugs, has made it difficult for multinational companies to dodge accountability if the testing of their patented drug reacts negatively.
Recently, 162 trials approved by DCGI (Drug Controller General of India) were stalled following orders from the Supreme Court which subsequently proved to be a major setback for foreign pharma companies that are into drug development.
Early this year, the government of India set up an Expert Committee with Professor Ranjit Roy Chaudhury, National Professor of Pharmacology and Adviser to Department of Health, as Chairman to formulate policies, guidelines and standard operating procedures for approval of new drugs, clinical trials, ethics committee and for banning of drugs already in the market.
The Committee’s report submitted a couple of months ago recommended major changes in the structure of conducting clinical trials. There is a mixed reaction to this report though it is arguably favorable to the industry.(Report: http://www.cdsco.nic.in/Report_of_Dr_Ranjit_Roy.pdf )
The fact is, clinical trial as a subject lacks public awareness. People in general are not aware of what a clinical trial is all about. The media mentions about clinical trials when some negative aspects pertaining to trials occur. What it mentions or exposes is not always a true picture but a report that is not verified or authenticated. They add their own concoction which when read or heard becomes hot topic of discussion and controversy.
The media comes into the picture following complaints registered by NGOs and Health Activist groups just wait for an opportunity to create unwarranted controversy and problems.
Here’s one simple and a classic example:
Most of us undergo might have undergone clinical trial without realizing the same. Our own family physician might have prescribed a new drug or would have asked us to visit specialists or undergo certain tests.
When companies in order to test the newly developed drug conduct trials on volunteers/patients it is considered unethical. Most of the trials conducted so far were being done according to the regulatory norms, guidelines and set rules by the government authorities/agencies.
When certain mishaps like death of a patient/volunteer undergoing trial happens, clinical trial procedure is held responsible for the loss of life. Death of any living being is a severe loss, but clinical trials in a way are mandatory for human survival. It is important to create awareness about the importance of clinical trials so that misconceptions are eliminated.
Clinical Trial is important as it is conducted for the benefit of human survival. What is required is mass awareness.
How to create the awareness?
This can start with the family physician to his patients on individual level.
Media has to take the lead – for this Media has to take the initiative in spreading the benefits and importance of clinical trials.
Professional bodies, associations like ISCR (Indian Society for Clinical research), ACRO (Association of Contract Research Organizations) can conduct workshops, seminars etc.
Pharma companies can take the lead through media campaigns in the interest of public welfare.
Introduction of Clinical Trial and Research at academic level
LSW LifeScienceWorld brings out a special feature on the current scenario in India pertaining to Clinical Research and Trials. The highlight of this feature are exclusive interviews conducted by LSW with Suneela Thatte, President, Indian Society for Clinical Research and Dr. Vijai Kumar, President & Chief Medical Officer, Excel Life Science Inc..
Clinical Trials in India – Are we losing out to other Asian Countries
Clinical Trials as defined by the Bill and Belinda Gates Foundation is “ a prospective biomedical or behavioural study of human subjects that is designed to answer specific questions about biomedical or behavioural interventions. (vaccines, drugs, treatments, devices or new ways of using known drugs, treatments or devices)”
In other words “Clinical Trials are sets of tests in medical research and drug development that generate safety and efficacy data.”
History of Clinical Trials
The first clinical trial is supposed to have been conducted in 1747, when James Lind discovered “Citrus fruit as a cure for Scurvy”
Clinical trials and Drug discovery in India can be traced back to two ancient scripts – the Charaka Samhita ( a text book of Medicine) and Susrata Samhita ( a text book of Surgery) as early as 200 BC and 200AD respectively.
Modern Clinical Trials are conducted in 4 different phases to prove the safety and efficacy of the new drug.
In Phases I to III, the new drug or treatment is tested on a small group of people and then in larger groups of people to evaluate the safety, efficacy to determine safe dosage range, side effects and compared to commonly used treatments. In phase IV, studies are done after the drug/treatment has been marketed to gather information on the drug’s effects on various populations and any side effects associated with long term use.
The major reasons for failure of Clinical Trials are insufficient efficacy, safety concerns, and sometimes lack of funding.
Market size of Clinical Research
The World market for Clinical research is estimated roughly at USD 60 to 65 billion. 70% of this is in U.S. followed by U.K. Asia is now a preferred destination for the conduct of Global Clinical Trials.
India a major preferred Clinical Trial destination
India is a major preferred destination due to the availability of large ethnic patient population, highly educated work force, a wide spectrum of diseases, lower operational costs, English speaking population and favourable Economic and Intellectual Property environment and regulations.
Controversy in India’s Clinical Trial Industry
Clinical Trials in India was at its peak in 2010 with about 500 approved clinical trials. The number dropped to 325 in 2011 and 262 last year.
The plunge in approved trials came after the Government of India responded to an outcry over the number of deaths recorded in the trials and adopted new rules to force trial sponsors to pay more compensation and required independent Ethics Committees to monitor the trials. ‘Safety of Indian subjects comes first’ was the essence of the new rules.
To compound the problem, The Supreme Court of India, on a PIL filed by the NGO – Swasthya Adhikar Manch, opined that no clinical trial should be allowed for new drugs till a mechanism is put in place to monitor and protect the lives of trial subjects on whom the drugs are tested.
Further the Supreme Court has asked the Centre not to allow Clinical Trials for untested medicines. Meanwhile, the Prof. Ranjit Roy Choudhury Expert Committee constituted by the Union Health Ministry to formulate policy and Guidelines for approval of new drugs, clinical trials and banning of drugs has submitted its recommendations in July 2013, which says :-
Clinical trials can only be carried out at centers which have been accredited for such purpose.
Ethics committee of the Institute must also be accredited.
For any adverse effect (AE) or serious adverse effect (SAE) , the Sponsor Investigator is responsible.
No compensation needs to be paid for therapeutic inefficiency, since the very purpose of clinical trials is to determine safety and efficacy of given drug, vaccine, or device.
Whereas, the Industry is happy about the recommendation about the compensation, the NGO’s and others are up in arms about it. The Industry is unhappy about the recommendation regarding the accreditation of Centers for clinical trials and the Ethics committee.
While the Clinical Trials scenario in India is getting murkier by the day, due to no clear guidelines, laxity in implementation of regulations and inordinate delay in according approvals, the Sponsors of clinical Trials are looking for new destinations for their trials in countries like Malaysia, Taiwan, Singapore and other Asian countries where there is a favourable and speedy Regulatory climate.
If the Government of India, the Ministry of Health, the DCGI and other agencies like the DBT, ICMR, CDSCO etc do not take serious note, India will soon lose its place as the preferred destination for Global Clinical Trials.
LSWis of the opinion that safety of trial subjects is of paramount importance. Implementation of Prof. Ranjit Roy Committee recommendations may not be the ultimate solution to the problems plaguing the Clinical Trial Industry, but it would be a beginning for cleansing the Industry of unethical practices which puts the lives of our patient population at risk.
S G B Rao, Publisher, LSW LifeScienceWorld
The Report of the Roy Chaudhury Expert Committee to formulate policy and guidelines for approval of New Drugs, Clinical Trials and Banning of Drugs was submitted to the Government at the beginning of August 2013. During the last three months the Report has been placed on the CDSCO website of the Ministry of Health and Family Welfare, reviewed in detail by the Government, discussed at various meetings by the different stakeholders, suggestions have been forthcoming and the Government has, with a few changes, accepted the Report. This intense activity augurs well for speedy implementation of the recommendations contained in the Report. It is important to convince the Supreme Court that many of the recommendations have actually been implemented so that the new phase of ethical and transparent clinical trials in India could begin on 15th December 2013, the next day of hearing of the Public Interest Litigation at the Supreme Court.
Several of the recommendations have been welcomed by all players. Implementation of these recommendations could begin immediately by means of a gazette notification. Some of these areas are the process of Accreditation of centres for carrying out clinical trials, Institute Ethics Committees and the Principal Investigators. This whole process could be outsourced to an independent organization such as the Quality Control Association of India.
The plans for ensuring transparency at every step are already available and the Committee are aware that steps were taken by the CDSCO in this direction before the work of the Committee. This process needs to be accredited.
Training of Institute Ethics Committees should also be considered as a recommendation which could be outsourced. Several organizations are considering setting up training programmes. It is recommended that the Government and the different organizations set up a Centre for Training which would provide a Certificate to those who have undergone training.
In addition to these three long term measures several short term steps need to be taken immediately. These are –
Reviewing the 162 clinical trials with the Technical Committee on the criteria recommended by the Roy Chaudhury Committee. These trials which do not meet those standards need to be rejected and a list of selected proposals should be presented to the Supreme Court.
Steps should be taken to set up one Technical Review Committee instead of 12 New Drugs Advisory Committee. Lists could be prepared after a nationwide search and the Committee selected from the names approved.
Those recommendations regarding Ancillary Care, No Compensation for Therapeutic Ineffectiveness, compensation for clinical trials in Academic Research and the mechanism for identifying the cause of a Serious Adverse Event or Death should be notified and this would be a salutary step in the process that would begin again.
The Committee for weeding out unnecessary drugs and combinations, as suggested by the Committee should be formed immediately and begin its work, with an expected timeline for the Report. The work needs to be begun before the next Supreme Court hearing.
Amendments should be prepared on the lines suggested for testing for Bio-availability and for testing of Bio-similars – as proposed by the Committee.
The process of Dialogue could begin immediately.
Academic clinical research protocols could, from the next course for MD and DNB need to be approved only by the Institute Ethics Committees along the lines suggested by the Committee.
Finally it would enhance the process if, before restructuring of the CDSCO a well motivated, young, qualified scientist with aptitude for research is selected and appointed for helping CDSCO to implement the Recommendations assisted by an Advisory Committee selected for this purpose.
I believe that if these steps are taken then a new era of ethical clinical trials could begin.
Ranjit Roy Chaudhury
Chairman – Ranjit Roy Chaudhury Expert Committee
“There are a lot of misconceptions and erroneous allegations made about clinical research”
LSW: Your views on the recent report on Clinical trials by Dr. Ranjit Roy Choudhury.
ST: We are in the process of reviewing and consolidating our feedback on the Professor Ranjit Roy Chaudhury Expert Committee To Formulate Policy And Guidelines For Approval Of New Drugs, Clinical Trials And Banning Of Drugs and so would not like to comment, as yet, on the specifics of the report.
ISCR is fully supportive of the need to create a more robust and regulated environment in India for the conduct of clinical research which ensures the practice of the highest standards of ethics and quality and where patient rights and safety are protected. To that extent, the report overall is a step in the right direction although we believe there are a few areas that need more clarity and addressal. We were part of the consultative process that the Expert Committee organised as a precursor to writing the Report and had submitted our views as a professional body representing the interests of stakeholders across the clinical research spectrum.
What is required now is clarity on the direction and shape that the recommendations in the Report will take.
LSW: The DCGI’s new policy on compensation has resulted in the abrupt withdrawal of trial activities being conducted by number of US companies. Your comment.
ST: The Gazette notification on Compensation (Rule 122 DAB) in January, 2013, outlined specific procedures to be followed in reporting serious adverse events, including deaths, occurring during clinical trials and procedures for payment of compensation. While much of the content of the new rules was consistent with discussions that the regulators had with various stakeholders in the industry, there were some clauses that were irrational and against the basic principles and conduct of clinical research. These clauses raised a lot of concern amongst sponsors of research. It is a misnomer that it is only US companies that have been impacted by the compensation guidelines announced in January, 2013. There are several Indian biopharma companies, domestic teaching and medical institutions and not for profit organisations who do clinical research in India and they are equally impacted by these guidelines.
Our concern is that with these recent developments, local innovation and academic research (of which there is a lot taking place in some of our most prestigious and well known hospitals) would be severely impacted. More importantly, patients would be most impacted. For many of them, participation in a clinical trial can provide early access to new therapies including for debilitating and life-threatening conditions. For patients who have run out of other options, clinical trials are often the last option. Without clinical trials there can be no new therapies.
LSW:The very factor of compensation is confusing. It is difficult to assess the nature of injury/death during the trial period. (An injury/death outside of the trial period/area (road accident/cardiac arrest etc) if occurs, and the victim’s relatives claim that the incident occurred due to effect of drugs/trials (like dizziness) and seek compensation – which is not reasonable. How to overcome a situation like this?
ST: On the specific issue of causality, it is very difficult to precisely determine causality of an adverse event in a clinical trial as there are several factors at play including the patient’s underlying disease and other pre-existing conditions, age, genetic and environmental factors. The responsibility for establishing causality is one of the key areas that have been closely reviewed and recommendations made in recent guidelines and reports. These are a step forward in ensuring a more robust and objective process is in place to determine causality.
Sponsors of clinical research are not against compensation. A standardized compensation formula that is transparent, objective and all encompassing is what all stakeholders of the clinical research process have been waiting for for several months now. However, a compensation formula on its own will be ineffective until such time as we have more clarity on the compensation guidelines that were introduced on January 30, 2013. Stakeholders across the spectrum have raised concerns with some of the rules within the guidelines and while there are indications from the regulatory authorities that these concerns will be addressed and Minutes of the DTAB Meeting addressing them have been made public, we are still awaiting the changes to be effected. Only once these changes are in place will we have more clarity on the real impact of the compensation-related developments because in isolation the compensation formula will have little relevance and impact at this point in time.
With regard to the compensation formula, there is a need to ensure that participants in a clinical trial are not being coerced or induced into participating in a trial with the promise of large compensation. This is a responsibility that both Ethics Committees and Investigators in particular must take on and ensure. Indian GCP Guidelines are clear in stating that “Subjects should be reimbursed for expenses incurred, in connection with their participation in research. They may also receive free medical services. However, payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in research against their better judgment. All payments, reimbursement and medical services to be provided to research subjects should be approved by the IEC.”
LSW:The Supreme court’s stay on DCGI’s approved clinical trial projects is a major setback for the Indian industry. India, considered as a prime destination for conducting clinical trials globally has lost its standing. Your view.
ST: Please see ISCR note on the SC Hearing of 30 September, which also carries a link to the SC order published on the SC website http://courtnic.nic.in/supremecourt/temp/wc%203312p.txt.
There is no mention of a stay on clinical trials.
We appreciate that the Court Order took note of the observation of the Ministry that “clinical trials are necessary for the development of new drugs in the country. India has the capacity and knowhow for drug discovery research. However, there should be a robust system for conducting clinical trials in the country to ensure that trials are conducted in a scientific and ethical manner and in compliance to the regulatory provisions.”
The value and role of clinical research in ensuring better and more effective treatment for several thousands of patients in India is often overlooked. It is only through clinical research that we have found and will be able to find newer and better medicines to treat our population and reduce mortality rates for various diseases, including those unique to our part of the world. The Government of India sponsored Working Group on Disease Burden for the 12th Five Year Plan refers to the “triple burden of disease” that developing countries like ours are facing arising from Communicable Diseases, Emerging Non-Communicable Diseases related to Lifestyles and Emerging Infectious Diseases. In the larger context of India’s unique healthcare requirements and the growing incidence of endemic diseases and emerging lifestyle diseases, we need clinical research to develop new and effective medicines and vaccines to tackle our mammoth disease burden and unmet medical needs. India has 16% of the world’s population and 20% of the global disease burden and yet, less than 2% of global trials take place in India. If we have to find better and more cost effective cures for these diseases in a population that is multi-racial and heterogeneous, it is necessary to conduct clinical research in India
LSW:Some of the health activist groups and the NGOs do not have even the basic knowledge of the subject they are fighting against. The recent court order is due to petition filed by some of them. As President of ISCR, what are your views on such activities conducted by these groups and any plans to counter such activities by ISCR.
ST: Any industry or sector needs to be challenged by individuals or groups who will question its rationale and relevance and ensure that there are enough checks and balances to safeguard public interest. So too clinical research. But this should not be through a misinformation campaign that comes at a cost to a larger national need and concern, in this case the health needs of our population and the access of patients to better and more effective medicines. There are a lot of misconceptions and erroneous allegations made about clinical research. In all of this, the value and role that clinical research has played in new medical discoveries and better treatment has been lost. This does not mean we do accept wrong doing. As in any industry , there will always be players who operate at both ends of the spectrum. While we do not condone any irregularities, we must acknowledge there are several hundreds of clinical trials taking place in the country in compliance with international and local guidelines. Activism must be directed at finding solutions, not at creating a deterrent or causing unnecessary fear and disincentive for stakeholders who include patients and investigators. It must also be remembered that all of us and our families are beneficiaries of clinical research as all the medicines that we benefit from have resulted from clinical trials
LSW:Public awareness on clinical trials is almost nil. Does ISCR have any plan to create a massive public awareness to educate on clinical trial as this is a vital subject every common man should know about.
ST: ISCR is an association of clinical research professionals whose aim is to build awareness of clinical research as a specialty in India and to facilitate its growth in the country, while helping to evolve the highest standards of quality and ethics. Therefore awareness and education are a key focus and objective for us. Since ours is a not for profit organisation, we do not have big budgets to spend on a massive advertising campaign. However, given the important role and reach that the media has, we have been actively involved in running awareness workshops and attending editorial meetings to create greater awareness about the role and relevance of clinical research in the hope they will cascade this to the public at large. We believe that the media can play an important role in educating the larger public about clinical research, while also highlighting the rights and responsibilities of patients. It is only through clinical research that better and more effective treatments can be discovered for lifestyle illnesses and illnesses that are endemic to our country.
LSW:As of now, the CROs and CMOs are not in a happy state of mind due to the factors known. Your forecast about the industry.
ST: While there has been a lot of uncertainty and unpredictability in the regulatory environment over the last couple of years in particular, there has also been a lot of progress made by regulators in ensuring a tighter regulatory framework. To that extent, we must acknowledge that we have moved forward in ensuring a safer and more secure environment for the conduct of clinical research in India. The regulators now need to ensure that industry concerns on some of the pending issues like compensation guidelines are addressed on priority, the backlog of clinical trial applications are addressed and that there is sufficient machinery and resources to manage the roll out and implementation of the recent guidelines and notifications. Currently there is a lack of confidence of stakeholders in doing or participating in research in India. If we do not address this on priority, India will lose out in the quest to discover and develop new medicines and in ensuring that patients have access to these medicines. It is a battle of confidence that regulators need to win in ensuring the progress of the industry.
LSW:Any other views/comments.
ST: In the larger context of India’s requirements and the growing incidence of endemic diseases and emerging lifestyle diseases, clinical research is needed to develop new and effective medicines and vaccines to tackle our mammoth disease burden. India has 16% of the world’s population and 20% of the global disease burden and yet, less than 1.5% of global trials take place in India. It is only through clinical research that we will be able to find newer and better medicines to treat our population and reduce mortality rates for various diseases, including those unique to our part of the world.
There have been over 40 US FDA clinical trial audits done in India with no critical findings reported. There have also been several European regulatory audits of Indian clinical trial sites, again with no critical findings. Global studies have also shown that there is no difference in quality of data across regions, including India, ( http://www.drugs.com/clinical_trials/no-differences-quality-clinical-trial-data-across-regions-reports-journal-14004.html and http://www.acrohealth.org/assets/files/Desai%20Drug%20Information%20Journal%20Article%20July%202012.pdf) and so we must recognize the clinical research being done in India is already of a very high standard. Unfortunately the good that has come of clinical research for several thousands of patients in India is often overlooked.
The Indian Society for Clinical Research (ISCR) is an association of clinical research professionals which aims to build awareness of clinical research as a specialty in India and to facilitate its growth in the country while helping to evolve the highest standards of quality and ethics.
“The US FDA is one of the most transparent organizations that has a well laid out and consistent policy “
LSW: : As you are aware, the current hot topic in India pertaining to the scientific fraternity, researchers, pharma and biotech industry is ‘Clinical Trial’. The Supreme Court’s earlier order of halting 162 trials that were already approved by DCGI, and now, ordering video recording of clinical trials to be conducted are a setback for multinational companies, and for the country’s (India’s) development on the research front. Your comment.
VK:We are certainly passing thru a difficult phase which if not preventable, was certainly worthy of attempts to reduce the fall out. Constant attempts by all stakeholders to engage the community on the benefits of research in general and clinical research in particular would have also influenced the court to help understand the complexities of drug development. It is not that only multinational companies are affected. The situation is also affecting Indian companies like Lupin, Zydus, Torrent, Dr. Reddy’s Labs and others that are engaged in drug discovery and development. It is also important to mention that National Institutes of Health, USA has terminated more than 35 trials being conducted in collaboration with various institutions.
Regarding video recording of the informed consent process, I am sure the members of the committee recommending this procedure are aware of the patent load of our institutions. If that is the case, I wonder how they feel this is practical. The learned members of the committee must be aware that the duration of the informed consent process varies from a few minutes in a study involving superficial trauma, conjunctivitis, vitiligo, etc., while the process in conditions like Dementia, stroke, acute myocardial infarction, traumatic brain injury, etc., may take up to 2-3 hours. There are several practical and logistic issues- who will store the video camera, what happens if the person storing the equipment is on vacation, or busy elsewhere. There are several socio-cultural and religious concerns. Who will monitor if the equipment is used solely for the purpose of the informed consent. It appears that the committee did not seek the opinion of the people conducting the trial. Finally, the DCGI during its site inspection visits should review the frequency of the EC members’ presence during the informed consent process. It is also necessary to foster interaction between various ethics committees in a city to share best practices.
LSW: Any impact on Excel Life Sciences’ activities (being India-focused) due to the current scenario that is prevailing, and if so, steps being taken.
Yes, certainly there is impact on Excel Life Sciences, However, we grabbed this opportunity to engage our clients in the US and other places to explore other opportunities in India such as assistance in identifying pre-clinical facilities, API manufacture and formulation development. We are also undertaking series of training programs for the clinicians and ethics committee members across the country. We are fortunate to have a wide skill set within the organization with extensive experience of drug development, and not merely clinical development of drugs.
LSW:You must have gone through the recently submitted Report of Prof. Ranjit Roy Chaudhary Expert Committee on the recommendations to the government on New Drugs and Clinical Trials. Your views on the same.
VK:It covers a wide range of issues, and given the time at their disposal, I commend the output. Although I have a number of comments, I would like to highlight the ones that have a significant impact on the contribution of clinical research in clinical medicine. Clinical research is not an end in itself, but a means to improve patient care. This was a watershed moment and I expected a seminal report, not only to guide the regulatory agency to ensure that more clinicians participate in clinical research, but also provide directions and recommendations to promote pharmacoeconomics, pharmacoepidemiology and other disciplines to improve health care delivery in the country. The committee seems to have mistaken the forest for trees. I am sure many others share my opinion. The report reflects the crisis of confidence, mistrust and suspicion between the industry and government. It seems to elevate clinical research to and esoteric exercise that only elite institutions can perform. It is common knowledge that clinical trials of ambulatory patients with hypertension or diabetes can be done more efficiently in second or third tier cities which see a large number of such patients than super specialty tertiary care hospitals in metro cities. This is one example.
Surprisingly, there is no clinician with hands on experience as a member of the committee
There is no mention of meeting with ethics committee members
The committee assumes that the new drugs Approval Committee (NDAC) is either dysfunctional or broke. Although, it has admitted in the report that members of the NDAC are not so keen to attend the meetings due to delayed payment of fees, I am surprised that by recommending constitution of the Technical Review Committee , the experts feel this will lead to prompt payment of fees and the system will be fully functional and efficient. The expert committee should have provided guidelines on ways to expedite payment to retain members’ interest. After all, the NDAC is in existence for over 2 years, and instead of identifying the deficiencies (if any) and fixing them, the committee feels a new committee will cure all ills. We have to humbly accept the fact the paucity of experts in all fields of drug development ( perhaps with the exception of API manufacture and formulation development to some extent) in the country and it would be a game of musical chairs as most of the members of the current NDAC would occupy their seats in the renamed committee.
The learned members missed a golden opportunity to transform good clinicians to credible investigators. They have recommended Post Marketing Surveillance (PMS) as a “Mantra” to monitor ongoing drug safety. PMS has been in place for more than five years, and the committee missed an opportunity to review its function/role. It is generally believed that the office of the DCGI does not pay attention to the reports the pharmaceutical companies submit. Instead, the committee could have recommended mandatory “post approval studies” following approval of a new drug. Whether a branded generic or and NCE, the number of patients in such approval trials are very limited to provide meaningful information about efficacy and safety. In case of branded generic, multiple applicants (which are usually the case) should be directed to evaluate different aspects of the drug. For example, if it is and antihypertensive drug, different applicants should be asked to evaluate it in different populations, namely, in hypertension + Diabetes, or concomitant Ischemic Heart Disease, Renal disease and efficacy e, etc. This will provide information on safety and efficacies on a large number of patients for the DCGI to take decisions on issues related to continued availability of drugs, and not depend on information available globally. Mandatory post approval studies will also help the country increase its investigator data base, spread clinical research to tier II and tier III cities, help develop ethics committees, engage the community and disseminate information about benefits of clinical research and encourage greater number of patients to participate in research. This will also reduce load on some centers in metropolitan towns where it is not uncommon to find a single clinician doing more than 15 trials at a time.
There is a system of inspection of clinical trial sites in place for over one year. The DCGI has actively collaborated with US FDA in training its staff. Over 550 sites have been inspected until now. Instead of reviewing the progress of the current system and make it and effective tool to rate institutions and investigators, the committee has embarked on a recommendation to for and accreditation council. Once again, before finding out if the system is working or what needs to be done to achieve the objective, the committee in its wisdom decided the need for an accreditation council. I also suggest the DCGI start to develop a list of clinical investigators who do not comply with the protocol, and whose data quality and data integrity is questionable as a result of inspection of the site. This will certainly act as a deterrent to errant investigators and alert the sponsors to avoid these investigators. The US FDA has a list of Clinical investigators Inspection List that is always current. This will also fulfill a recommendation of the committee to use information technology more efficiently.
While the committee has recommended the DCGI approver certain drugs evaluated overseas with a safety record of 4 years, they insist the DCGI evaluate reports of trials done only at approved sites. How are they confident that the sites in High Point, North Carolina or Falls River, Massachusetts are better than Kokila Ben Ambani Hospital, Mumbai or Metro Hospital, NOIDA which have a record of numerous clinical trials.
LSW:Some of the US companies has already stalled/withdrawn its trials being conducted in India which is a setback. Your views.
VK: we cannot find fault with their decision. The goal posts are moved at the end of every Supreme Court hearing. However, we all hope that the Supreme Court will continue to stand by its opinion to continue research and development activities of the pharmaceutical industry. All developments point to a resumption of activities, because I believe the regulatory agency will put into place pragmatic and realistic checks and balances as a result of the present case in the Supreme Court. Incidentally, even Indian companies have expressed their disappointment and anguish at the decision paralysis.
LSW:A few words on the Regulatory front in US pertaining to clinical research and trials and any challenges.
VK: The US FDA is one of the most transparent organizations that have a well laid out and consistent policy. The other feature is the facility to telephonically resolve issues. It is not uncommon to have a conference call with multiple FDA participants. However, while there is a well laid out path for generic variations of chemical entities, the path for biological equivalents is still not clear, in spite of moving the group under the purview of Center for Drug Evaluation and Research ( CDER) from the Center for Biological Evaluation and Research ( CBER). The jury is still out on biosimilars. The FDA circulated draft guidelines to the industry in March 2013. The primary concern is safety of the biological product produced by a route different from the innovator. Long term safety is a concern of the US FDA and US Congress, and it appears that, unlike Europe, the US is likely to take some time before allowing biosimilars on a large scale. The 351 (K) paths for biosimilars are still not clear. We need not reinvent the wheel and implement certain US FDA practices to make our system responsive. For example, public confidence in DCGI functioning will get a tremendous boost if it publishes the findings of its clinical site inspections and mechanism to ensure that investigators follow the protocol and not com [promise safety and interests of trial participants. After all, this will only help the DCGI discharge one its functions, i.e., to safeguard public health.
LSW:The credibility of the Ethics Committee in India is often questioned pertaining to their lack of knowledge on the subject. What is your opinion on this?
VK: it is not surprising. Some small institutions and independent Review Boards (Independent ethics committees) have definitely cut corners and may have compromised on certain aspects. The DCGI has taken a commendable initiative to register the ethics committee after ensuring their constitution per ICMR guidelines. We cannot hold the ethics committees alone responsible for the level of knowledge / information on the science and art of clinical research. It is an evolving process, and every effort must be made by all stakeholders – regulators, biopharmaceutical industry/ contract research organizations, investigators and trial participants to share information on an ongoing basis. I believe we learn a lot for the participants, but unfortunately, only lip service is provided to their courage, conviction and sacrifice when they sign up for clinical trials. Their role needs to be recognized, and I suggest we observe a “Patients day” to do so.
LSW:In India, unfortunately, common man is not aware of what clinical trial is all about. Many of the CROs, clinicians, investigators opining the lack of awareness of this subject. How to create awareness about clinical trial in general?
VK: very pertinent question. I have the following suggestions:
Demystify clinical research. Indians are not guinea pigs. People raising the guinea pig bogey conveniently ignore that for over 50 years, all the drugs administered to Indian patients have been the result of populations in the USA, Europe and other parts of the developed world volunteering to participate in clinical trials.
Deglamorize clinical research. It is not an elitist activity that can be carried out in tertiary care super specialty hospitals in metro cities. It helps the average physician gain more knowledge about the action of drugs and choices for optimal patient care. It is a scientific activity carried out under stringent ethical conditions with economic gain to all stake holders. Economic activity resulting in profit making is necessary, but profiteering from any activity, including clinical research is evil.
All stake holders to collaborate and strengthen the hands of the national regulators to ensure safety and interest of participants.
Popularize clinical research. Take it to tier II and tier III towns, particularly, the post approval studies to substantially increase the number of clinicians undertaking clinical research. This will help us gain valuable information about prevalence of various diseases under real life conditions.
We need to ask patients who participated in clinical trials to share their experience with a wider audience thru appropriate media. It is only and aware and educated communities that can appreciate the complexity of drug development process and actively participate in clinical research.
Considering that less than 20,000 people currently participate in clinical research, all the stake holders need to work towards educating the community so that we have at least 1% of the population ready to participate in clinical research to advance medical science and treatment.
LSW: Future of trial activities in India.
VK: I sincerely hope we can learn from the ongoing litigation. I believe we have to potential and capabilities to take the science of clinical research to the next level. As the new drug discovery and development activity increases in India and overseas, we can transform clinical research to play a more meaningful role in health care. I suggest we prioritize our activities in to the following areas:
Community education to create awareness and enlist greater participation.
Go up in the value chain and not merely commoditize clinical research by recruiting patients.
Encourage disciplines such as pharmacoeconomics and pharmacoepidemiology.
Become global service providers to Indian pharmaceutical industry.