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.

Reasons- (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.

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 and articles by LSW with eminent professionals involved in the field of clinical trials

 

Chairman, Dr. Ranjit Roy Chaudhary Expert Commitee

The Report of the Ranjit 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 –

1) 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.

2) 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.

3) 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.

4) 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.

5) Amendments should be prepared on the lines suggested for testing for Bio-availability and for testing of Bio-similars – as proposed by the Committee.

6) The process of Dialogue could begin immediately.

7) 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.

Suneela Thatte, President, Indian Society for Clinical Research, Mumbai (www.iscr.org )

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.

ISCR’s comments on the Compensation Guidelines may be read at http://iscr.org/View-Single-News.aspx?Id=136.

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.

Interview with Dr. Vijai Kumar, President, Excel Life Science Inc., USA

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 opthers that are engaged in drug dicpovery and development. It is also important to mentioin 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 incforemd 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 and 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 is 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 efficacy 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 efficient. 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 has 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) path for biosimilars is 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 and 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 an 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 and 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 community 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: Any impact on Excel Life Sciences’ activities (being India-focused) due to the current scenario that is prevailing.

VK: as I mentioned three is and impact on Excel Life Sciences, but we are learning to minimize our risk by offering other services 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.

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 area

Community education to create awareness and enlist greater participation

Go up in the value chain and not merely commoditize clinical research by recruiting patien

Encourage disciplines such as pharmacoeconomics and pharmacoepidemiology

Become global service providers to Indian pharmaceutical industry

Continue to assure data quality and data integrity to global pharmaceutical companies

Aditya Vats, Manager, Regulatory Affairs, Excel Life Sciences

 

The clinical research enterprise in India is reeling over a recent push to r to justify the existence of trials for human benefit by the end of 2012 following a petition filed by one of the NGO against the industry. The petition alleges that the clinical research enterprise has unjustly exploited the Indian population for global drug development. As a repercussion of the filed petition, commissions were set up, reports were flashed, and hasty decisions were employed. Suddenly and amazingly, in a country of more than 1 billion people, clinical Research and its ill-effects ONLY has come under significant media attention, seemingly only to showcase the flip side of the coin. As is all too common in the press, we are not hearing positive news highlighting the ways which clinical research can improve the quality of life and increase the overall survival of oncology, cardiology, neurology and other high mortality disease patients. Even worse, this negative coverage has created a wave of ignorant comments coming from all quarters, especially individuals not possessing an iota of knowledge about clinical research.

Indian regulatory reforms occurring during the past 18 months became international news, followed closely by both domestic and global pharmaceutical companies. The inception of new reforms, as many research stakeholders involved in the conduct of global clinical trials are now aware, resulted in the laws governing the conduct of clinical research in India undergoing significant changes. The intentions behind the revisions were positive and resulted in a number of much needed provisions. These provisions work to ensure more transparent, efficient, predictable and ethical processes around the trial application review and approval process, study execution and care of study volunteers. A few of the revisions represented an overreaction to past issues related to the compensation of study volunteers who were injured during a clinical trial. The new provisions introduced a significant amount of legal and financial risk to sponsors, service providers and other stakeholders involved in the conduct of global trials in India. As a result, there has been a dramatic drop-off in the number of global trials taking place as reflected in a recent health ministry report: from 529 permissions granted in 2010 to 283 in 2011 and 253 in 2012. This, in a country which was in recent years, expected to be one of the most promising transitional economies for the conduct of clinical research and the commercialization of new therapies. Below are a number of points highlighting revisions widely viewed as advancements to the law, as well as a list of revisions widely viewed as setbacks.

Advancements:

1. Constitution of 12 therapeutic New Drugs Advisory Committee’s (NDAC) for evaluating clinical trial study applications 2. Formation of Medical Device Advisory Committee for medical device trial approval 3. Institution of face-to-face study defense meeting with the DCGI and NDAC panel 4. Guidelines for industry for submission of clinical trial application 5. Introduction of various application and amendment submission checklists to make regulatory requirements clearer: E.g. Global Clinical Trial; Addition of sites; Import license; etc. 6. Registration of all Ethics Committees nationwide under Ministry of Health per rule 122 DD to ensure credibility and oversight 7. Revised guidelines to streamline reporting for serious adverse Clear guidelines, under 122 DAB, addressing the compensation issue under Appendix XII of Schedule Y - Compensation in case of injury or death during clinical trial 8. More comprehensive Informed consent form capturing additional information with respect to socio-economic status of the subject 9. Sponsor premises including their employee, subsidiaries and their branches will be open for inspection by the officers authorized by CDSCO (licensing authority) 10. Establishment of apex safety committee for determining serious adverse event causality based on sponsor and investigation reports 11. Licensing authority will have the vested power to: a. Issue warning letters b. Recommend that study may be rejected or discontinued c. Suspend or cancel clinical trial application d. Debar Investigator and Sponsor to conduct any future trial

Setbacks:

1. Certain clauses in Appendix XII (Compensation in case of injury or death during clinical trial) listed below were interpreted by the global pharmaceutical companies as major hindrances: a. Failure of Investigational product to provide intended therapeutic effect b. Use of placebo in placebo controlled trials

The introduction of advancements were welcomed by the stakeholders, but at the same time compensation for anything and everything under the sky did not recognize the very purpose of research.

The above situation has since expanded multifold, withthe recent rulingto suspend more than 150 clinical trials thus leaving the clinical research enterprise in penitent state of affairs. The decision from the Supreme Court has literally resulted in research coming toa standstill and slow processing of new and old proposals at the licensing authority office. Moreover, the facts from the market analysis firms already confirm a loss of $200 billion due to ongoing pandemonium.

Most importantly, the vital flow of innovative new and potentially life improving treatments has come to a complete stop.

The recently concluded hearing provided fresh lease of life by granting conduct of clinical studies approved by the three tier system – New Drugs Advisory Committee, Technical Review Committee and Apex Committee. In addition, a call was made to implement the use of audio and video aids when consenting clinical trial subjects.. This will be like swimming in an uncharted sea with an eternal hope of survival,as nowhere else in the world is this approach being practiced as part of Good Clinical Practice. The execution of process will require cost, time, space for recording and logistics of training site staff about storage and archival of transcripts and - more importantly -awareness amongst subjects about the process.

The development of a robust review system and framework for conducting research in the country is widely appreciated. Conscious efforts should be made to upgrade the already existing regulatory policies in a phased mannerism, whilenot hampering the research needs of the country. All the stakeholders (research enterprise, academia, ethics committee, sponsors etc.) whole heartedly admire the new reforms, but anticipatesound rationale during implementation of these laws, thereby not halting the current progress of clinical research. Research is a necessity for making new drugs available to patients which are safer, more effective and at a lower cost than those already existing in the market. That process will always involve risk for every stakeholder, including patients. Mankind has never advanced without taking risks. How can we expect to now if we don’t?

Human impact of holding off approval of clinical trials: Dr Ashish Rastogi, Asst. Director-Clinical Operations, Excel Life Sciences

 

Clinical trials in India have been on hold since allegations of irregularities in the conduct of clinical trials surfaced in 2011. Subsequently a Public Interest Litigation (PIL) was filed in the Supreme Court of India. The matter is still under deliberation.

During this entire period till Sep 2013, despite reorganization of the entire review and approval mechanism, very few clinical trials have been approved. The number of studies approved in 2010 was 529 as per the MOH report on Clinical Trials in India (30.8.2013), but has fallen precipitously to approximately 6 new approvals in all of 2013. . The reorganized process worked to ensure proper checks and balances of applications, through the addition of several new layers of review. Whereas prior to 2011, most new applications for clinical trials only needed to be reviewed and approved by the office of the Drugs Controller General of India (DCGI), the new process included review by a panel of 10 physicians with expertise in the particular therapeutic are of focus for the drug under consideration. Further changes and safeguards included review by yet another committee, the Apex committee, a group of three members charged with review and approval before sending the application back to the DCGI for final approval. Since then, there have been numerous applications which have completed this rigorous review process and have received NDAC and Apex Committee approvals; however for various reasons the clinical trials have yet to see the light of day.

Attempts to review and further strengthen the systems are most welcome in the industry. However merely adding layers of extra requirements without giving a careful thought to the implementation or implications are not justified. We have road safety laws. Everyone knows how important it is to use helmets while riding two wheelers. We have red lights, pedestrian crossings, subways, over bridges and fines for over speeding. Yet everyday there are reports of road traffic accidents or pedestrians being overrun. One might argue that these are a result of lack of application of laws, corruption or lenient fines. These are the same arguments that are being used to tighten controls in clinical trials.

Will modifying cars that do not allow speed over 10km per hour or disallowing people from walking reduce accidents. In other words you cannot have regulations that strike at the very basis of processes. To travel you need vehicles that can drive at different speeds, people will need to walk to different points. Over regulation or interference in the scientific base of clinical research will not help anyone- least of all the persons whom these laws are meant to protect. Everyone recognizes the need and importance of clinical trials in furthering medical science to provide new and better treatment options to the vast majority of suffering patients. From conception to market availability, any new drug takes between 5 to 10 years of meticulous hard work by various stake holders to determine the safety and efficacy of the drug. The most important partner in this development process are the patients who volunteer to participate in these clinical trials – after being explained the risks associated with participation. Whatever their reasons for participating, each volunteer contributes to the pool of knowledge that furthers medicine and science. Medical management is constantly evolving. There are safety issues with even the simplest of drugs like paracetamol – a common drug used for the treatment of mild aches and pains. In many diseases even the best doctors and the best management do not reduce the suffering of patients. It is this suffering or unmet need that clinical research hopes to fill one day - the need for better and safer medicines.

What is the human impact of the delay or hold off in clinical trial approvals?

Recent events in the USA, where a government shutdown happened due to budgetary cuts, provide a hint to how much of an effect withholding access to clinical trials can have. The effect of the shutdown in the US on NIH trials is just a small example of what a few days of delay can cause to clinical trial volunteers. There are estimates in the US press that 200 people per week could lose out on getting lifesaving therapy (Washington Post date ). If we think about it - clinical trial approvals in India have been on hold now for 8-10 months. One can’t even begin counting the number of patients who would have lost out on getting critical therapy that might have saved or at least prolonged their life.

Death and disability would be greatly reduced if appropriate therapy is made available in time. Any family that has seen their loved one pass through the various phases of cancer can tell the immense mental torture of seeing their loved one die, or be unable to experience a better quality of life due to lack of an appropriate treatment.

In order to estimate the human impact, a review of enrollment projection data from Clinical Trial Registry of India (CTRI) was undertaken. The web based registry is maintained & hosted at the ICMR's National Institute of Medical Statistics (NIMS). It is a free and online (www.ctri.nic.in) public record system for registration of clinical trials being conducted in India. It was started on 20th July 2007. Initially it was a voluntary measure, however since 15th June 2009, trial registration on the CTRI in India has been mandatory.

We evaluated the clinical trials done in India for Lung cancer between Jan 2010 and Dec 2012. Lung cancer was chosen, as it is one of the leading causes of cancer sickness and death affecting Indian population. A recent article in the NEJM reported 7 deaths in S Asia per lakh population in a year due to lung cancer (2010)1, up nearly 20% from 2005. Some estimates, such as the GLOBOCAN 2008 data (International Agency for Research on Cancer) put the lung cancer mortality for India at nearly 10 deaths per lakh population in a year(estimated number of deaths 41865).3 It is clear from these statistics that lung cancer places a significant mortality risk for Indians.

Analyzing Data from CTRI

The CTRI database was searched for ‘Lung Cancer’ trials taking place between January 2010 and September 2013, resulting in a total of 30 trials. Domestic, Investigator initiated, Ayurvedic therapy and trials not involving chemotherapy were then removed. The final analysis set comprised 16 trials. The number of trials registered in each year is shown in table 1.

Table 1: Year wise distribution of registered clinical trials in Lung cancer patients Year Number of trials 2010 12 2011 4 2012 5 2013 1 Sub-Total 22 Minus Domestic Trials 4 Total 16 Global Trials Avg 4 studies per year

- The 16 global studies were supposed to enroll 8,654 patients, of which India contributed 1,144 lung cancer patients, or 13.2% of the global sample size.

- Average contribution per study from India comes out to be ~ 71 (1144 patients/16 total trials ).

- From the table above, on an average 4 trials were expected to enroll in a year. Therefore, if a we assumed the average, we could expect 4 studies to be approved and enroll trial volunteers in 2013.

- If 4 trials would enroll in 2013, 284 Indian patients (71 patients X 4 trials) would have participated in the trials. All the studies were for second or third line interventions in patients with late stage cancer (3b and 4). This provides an indirect estimate that most of these patients if not all had very few alternative therapies available to them.

Therefore, one could reasonably conclude that the stopping of clinical trials for a year would in effect prevent 284 Indian patients from participating in clinical trials. In other words it would deny them a chance to have access to therapies that may have benefited them and prolonged their life.

What would have been the magnitude of benefit? No direct estimates are available. A study reported an average survival for ‘untreated NSCL (Non small cell lung cancer) to be 7.15 months. 4 The increase in Survival rates reported in lung cancer studies for different therapies range between 2 to 4 months.5 Taking an average of 3 months, it could be expected that for 284 lung cancer patients, access to clinical trials would have brought 852 (284 X 3) months of increased survival. (i.e. a total of 71 man years-852/12 months).

Discussion:

There are limitations of such an analysis. These are based on CTRI data which is an online registry. There is no way to confirm if the data on the registry is factual, or it is only based on projections.

None the less it is clear even if only one tenth of these figures (i.e. 7 man years out 71 man years increased survival) are correct then the delay in approval of clinical trials would have denied a fairly good number of Indian lung cancer patients a chance or hope not to mention the impact on benefit to society from such research. That is in effect the real impact of holding clinical trials.

References:

1. Noncommunicable Diseases; David J. Hunter, M.B., B.S., M.P.H., Sc.D., and K. Srinath Reddy, M.D., D.M.; N Engl J Med 2013; 369:1336-1343October 3, 2013

2. Lancet. 2012 May 12;379(9828):1807-16. doi: 10.1016/S0140-6736(12)60358-4. Epub 2012 Mar 28.

Cancer mortality in India: a nationally representative survey.

Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, Badwe R, Kumar R, Roy S, Suraweera W, Bray F, Mallath M, Singh PK, Sinha DN, Shet AS, Gelband H, Jha P; Million Death Study Collaborators.Tata Memorial Hospital, Mumbai, India.

3. http://globocan.iarc.fr/factsheets/cancers/lung.asp#MORTALITY1

4. Syst Rev. 2013 Feb 4;2:10. doi: 10.1186/2046-4053-2-10.

Survival of patients with non-small cell lung cancer without treatment: a systematic review and meta-analysis.

Wao H, Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B.Center for Evidence Based Medicine and Outcomes Research, Department of Internal Medicine, Morsani College of Medicine, University of South Florida Clinical and Translational Science Institute, 3515 East Fletcher Avenue, MDT 1202, Tampa, FL, 33612, USA.

5. A rapid and systematic review of clinical effectiveness and cost effectiveness of paclitaxel, docitaxel, gemcitabine and vinorelbine in NSCLC, A Cleg et al, Health Technology Assessment, NHS R&D HTA Program.

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