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Patient recruitment: A paralysed process?

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India has the dubious advantage of having a varied patient pool, ranging from different types and severity of diseases like diabetes, hypertension and cancer caused a result of lifestyle choices, to tropical like malaria, kala-azar and H1N1 influenza virus as well as diseases of viral origin like HIV, hepatitis etc. This has long served the cause of clinical trials in the country since pharmaceutical companies get the requisite volunteer mix for testing their drugs. Dr (Prof) YK Gupta, Head, Department of Pharmacology and spokesperson of AIIMS informs, “One can get subjects in adequate numbers to evaluate new molecules sensitive as well as resistance to conventional medications needed for chloroquine resistant malaria, MDR and XDR tuberculosis and resistant staphylococcus. Treatment naive patients are also relatively more as compared to developed world.” Yet, the recruitment process for the trials has become a bone of contention in the progress of clinical trials sector. According to Centerwatch survey, 70 per cent of all trials are delayed by one to six months owing to patient recruitment issues. 80 per cent of clinical trials conducted globally are delayed due to slow patient recruitment process. India too is facing this problem and the industry feels that patient recruitment, which accounts for almost one third of the time and drug development budget, has gradually become a critical bottleneck in the Indian clinical research arena.

Recruitment process in clinical trials

“Growth of clinical trials sector can happen only by following strict ethical guidelines, strong regulatory oversight and action on those who violate it. India needs to make her own guidelines, regulations which addresses the ethical milieu sociocultural and economic conditions on our own country.”
Dr (Prof) YK Gupta
Head, Dept. of Pharmacology and Spokesperson, AIIMS

Laws have been formed to ensure that patients volunteering for clinical trials are protected. It is mandated that the recruitment of subjects in any trial has to be as per the guidelines of Indian good clinical practice (GCP) and informed consent of the volunteers. In the true sense, ‘informed consent’ has to be ‘understood consent’ of the patient. It has to be in the language that is easily understood by the patient so that he can take a decision after being fully aware of the benefits and risks involved in the trial.

“The recruitment process in clinical trials is quite straightforward. Patients who volunteer to participate are taken through a robust informed consent process. This is done in local language as appropriate. Once this is complete, patients sign an informed consent document to indicate they have fully understood the requirements of the study. It is imperative that patients are only enrolled in a study if they meet the criteria and they understand the potential risks and benefits. For certain patients groups, such as children, consent is provided by a designated parent or guardian,” informs Dr Shoibal Mukherjee, Chief Medical Officer, Quintiles India and Head, Asia Medical Sciences Group.

Gupta reiterates Mukherjee’s views and further elaborates, “Special precaution needs to be taken if the patient is not competent to take a decision, say due to psychiatric illness, in the case of children, unconscious patients etc. Assent or consent in the presence of competent witness is required in such instances. In case of specific diseases, the patient is screened on the basis of specific needs to meet the inclusion and exclusion criteria. The placebo must not be used in place of standard care treatment however adding it to standard treatment and care can be permitted.”

Loopholes and challenges

“Those who do not wish to be filmed should be able to waive this right and still be allowed to participate in the trial as long as the informed consent process is well managed and documented in other way.”
Dr Shoibal Mukherjee
Chief Medical Officer, Quintiles India and Head, Asia Medical Sciences Group

While the guidelines are in place they have not been effectively implemented. Therefore, India’s rise as a clinical trial hub as been severely curtailed and aspersions have been cast on the safety and ethicality of the trials being conducted in the country. The laws and regulations enforced have also not proven fool-proof and given rise to further complications, making the patient recruitment even more complex. As a result, over a period of time the total number of clinical trials being conducted in India dropped significantly and pharma firms started looking at other South East Asian countries for their requirements.

“Indian hospitals have to invest in training of the investigators/ staff in science, ethics and regulation governing clinical research, create computerised patient databases, and develop research infrastructure to improve overall conduct of clinical trials including recruitment of patients.”
Dr Arun Bhatt
President, Clininvent Research

According to the Tufts Center for the Study of Drug Development has reported that about 30 per cent of Principal Investigators (PIs) under-enrol in a given trial, and about 20 per cent fail to enrol a single patient. Patient recruitment process for clinical trials in India is also mired in controversies and challenges. Dr Arun Bhatt, President Clininvent Research talks about the traditional recruitment pattern followed in the industry, “Most trials in India are conducted at public hospitals; these are attractive to sponsors because they have a large number of treatment-naïve subjects. There is a lack of focus on important research priorities, such as the creation of databases on subjects. As most Indian sites lack patient databases, it becomes difficult for them to identify suitable subjects rapidly. However, the large patient loads at these hospitals make big demands on the physicians’ time, which becomes a recruitment barrier in conducting clinical trials.”

“Patient selection for different therapeutic areas depends upon the study complexity and the core study objectives.”
Nimita Limaye
Vice President, CDM, Medical Writing and Risk Based Monitoring, Tata Consultancy Services

The unwillingness and ignorance of the patients also hinder the recruitment process. Nimita Limaye, Vice President, CDM, Medical Writing and Risk Based Monitoring, Tata Consultancy Services (in her individual capacity) explains, “It has been reported that upto 70 per cent of eligible patients choose not to participate. Reasons in India are multi-fold – negative publicity, the fear of side-effects, too much travel time, lack of awareness of the ongoing trials and their significance, or the patients are already enrolled on other trials, limited access of the clinical site to the target patient population also the scarcity of time of qualified and motivated investigators support patient recruitment. Inclusion, exclusion criteria are also often very stringent, thus impacting recruitment.” She says, “Ongoing regulatory changes resulting in delays in regulatory approvals are also significantly impacting the interest in conducting clinical trials in India. While a vast treatment naïve, therapeutically diverse patient pool still exists, even Indian companies such as Biocon, Piramal and Lupin are conducting some of their trials overseas resulting in a direct increase in drug costs.”

Gupta feels that the biggest challenge for all stakeholders of clinical research is creating confidence in the patients, public, and even the parliamentarians. Mukherjee also feels, “Patients in India have a very low level of awareness of research practices and clinical trials, and do not specifically seek out clinical trials unlike in more developed countries.” He adds, “For many disease categories, patients travel long distances to receive care at a reputed institution and it may not be possible for the patient to visit the site repeatedly to meet requirements of the study protocol. Such patients should not be recruited for a trial. Each of these factors leads to challenges in patient recruitment.”

Limaye also highlights that the complexity of the diseases and its procedures can also give rise to challenges while selecting the patient profile for the study, “Patient selection for different therapeutic areas depends upon the study complexity and the core study objectives. Oncology for example, is a relatively more complex therapeutic area in terms of endpoints, role of comparator drugs and adverse events reporting. Thus patient recruitment is not easy in the case of oncology trials. Targeted approaches help maintain demographic homogeneity. Recruitment is not a challenge only in the case of critical diseases such as AIDS, but also for more routine ones like diabetes and heart ailments. While India has a large patient pool, there is shortage of centralised databases of patient profiles, and high recruiting sites, add to the challenges.”

“About 80 per cent of the clinical trials do not complete on time. Though recruitment is not a problem in India, patient retention is.”
Apurva Shah
Co-founder and Group Managing Director, Veeda Clinical Research

Apurva Shah, Co-founder and Group Managing Director, Veeda Clinical Research opines, “Slow recruitment or inadequate retention of trial subjects continues to be the leading cause of study delays. A vast majority of eligible candidates are either unaware of available trials or have a poor perception of clinical research.”

Shah reveals, “About 80 per cent of the clinical trials do not complete on time. Though recruitment is not a problem in India, patient retention is.”

AV consent: Problem or panacea?

“There are no real challenges to patient recruitment. However the introduction of the audio-visually record system in the informed consent process, has posed some challenge wherein some patients have started showing lack of willingness to participate in CTs as they feel it is an invasion of their privacy.”
Dr Viraj Suvarna
Medical Director, Boehringer Ingelheim India

The Supreme Court’s recent mandate is that an audio visual (AV) recordingshould be made of the informed consent from patients for participation in clinical trials. The order aims to ensure that the subject volunteering for a clinical trial is made aware of all the pros and cons of the study. However, this move has spurred several debates and arguments. Many believe that it would cause further problems in patient recruitment and deter those who want to conduct clinical trials in India.

Dr Viraj Suvarna, Medical Director, Boehringer Ingelheim India feels, “There are no real challenges to patient recruitment. However, the introduction of the audio-visual record system in the informed consent process has posed some challenges wherein some patients have started showing lack of willingness to participate in clinical trials as they feel it is an invasion of their privacy.”

“Motive of the regulators behind having AV recording of IC process was right. However, regulators should have studied the implications of recommended changes and practical feasibility in much detail before implementing it. Again the guidelines are not exhaustive and clear on how to meet the regulators expectations.”
Dr Anil Pareek
President – Medical Affairs & Clinical Research,
Ipca Laboratories

Dr Anil Pareek, President – Medical Affairs & Clinical Research, Ipca Laboratories emphasises, “Motive of the regulators behind having AV recording of IC process was right. However, regulators should have studied the implications of recommended changes and practical feasibility in much detail before implementing it. Again the guidelines are not exhaustive and clear on how to meet the regulators expectations.” He analyses, “With this guideline, it is becoming difficult for the sponsors to convince investigators because some have started exploiting the sponsors by asking more money despite receiving the necessary infrastructure for AV recording. Moreover, investigators are also facing a challenge in convincing the patients to agree for AV recording, which may further affect patient participation in clinical trials. Ultimately, because of this poor participation, patients may be deprived of benefits of new drugs. Regulators should check/study the best practices adopted by more developed regulators world over to ensure authenticity of informed consent process.”

Limaye raises her concern and insists, “AV consenting, while a good measure, may not be very practical, especially in the Indian scenario, there may also be patient data privacy issues and cultural sensitivities that need to be addressed. In addition, to the best of my knowledge, while this has been recommended by the FDA, this is not mandated anywhere else in the world. Many steps are being taken in the right direction for curbing unethical practices and ensuring patient safety and these should contribute to restoring patient confidence.”

“I suggest there should be a provision for taking a waiver from the DCGI. At the same time the AV recording should be only mentioning the drug name, subject’s name and his willingness to participate. otherwise it takes away about an hour of recording.”
Kiran Marthak
Member of Board of Director and Global Head of Clinical Development, Lambda Therapeutic Research

Mukherjee opines, “Patients should be informed of their right to have the consent process video-recorded. However, those who do not wish to be filmed should be able to waive this right and still be allowed to participate in the trial as long as the informed consent process is well managed and documented in other ways.”

Kiran Marthak, Member of Board of Director and Global Head of Clinical Development, Lambda Therapeutic Research feels, “There are many females who have enrolled themselves for the HIV and TB trials and do not wish to be filmed. It has reduced the enrollment by 50 per cent. I suggest there should be a provision for taking a waiver from the DCGI. At the same time, the AV recording should be only mentioning the drug name, subject’s name and his willingness to participate, otherwise it takes away about an hour of recording. It is difficult for the investigator to spend so much time and he starts immediately feeling that there should be an option of removal of the rule about AV recording.”

Gupta too opines, “The amendments in rules to address these issues and some clarifications about the procedures need to be clarified. The ethics committees should be empowered to relax AV rule after due consideration in such specific situations. As the basic philosophy of the Government order is to ensure that the enough effort has gone to make the trial subject fully understood the risks and the benefits involved in the trial, AV recording is the ideal thing. However, there are certain situations where this will be logistically difficult for e.g. women following purdah/ burkha system, trials of HIV, sexually transmitted diseases, certain contraceptive trials, conditions of acute emergency etc.”

The final verdict on whether SC’s new dictate would aid or cause further detriment to the clinical trials industry in India is yet to come.

Need for change in regulations

So, what needs to be done to mitigate the challenges in patient recruitment and revive the growth of the clinical trials sector of India? Industry experts believe that reforms in the regulatory scenario is essential to bring in a positive change. Limaye feels that there needs to be a focused effort towards nurturing a healthy relationship between the stakeholders and ensuring that the investigators have access to the right patient pool, do not have conflicting trials, are well trained and are motivated.

Gupta opines that the growth of clinical trials sector can happen only by following strict ethical guidelines, strong regulatory oversight and action on those who violate it. He says, “India needs to make her own guidelines, regulations which addresses the ethical milieu sociocultural and economic conditions on our own country. For ensuring the adherence and enforcement of the guidelines, strong oversight mechanism is must.”

Mukherjee also presents his views, “At present the threats to the viability of clinical research in India are from ill conceived, difficult to implement regulations and the slow pace of regulatory decision-making that has led to international sponsors curtailing research initiatives in the country. At the same time local sponsors are having to undertake clinical development activities outside the country at great additional expense.” He points out, “India has the highest disease burden in the world and many patients do not have access to standard care. Clinical trials provide the opportunity for patients to benefit from a high standard of patient care mandated by the study protocol. Unfortunately, current policy initiatives are driving sponsors away from India. With studies not being initiated, patients are being denied the opportunity to participate and benefit from clinical trials.”

The way forward

While it is essential to bring in regulatory changes, experts believe that several other steps also need to be taken to bring back growth to the clinical research arena. Some of them are:

  • Better accessibility to resources: In other countries, government agencies make information about clinical trials freely available to patients through websites and other information channels. In the US, the Food and Drugs Administration’s websites are a good example of this, but there are many other public sources of information such as the US National Institutes of Health, the US National Cancer Institute, and many university and research institution websites. However, that’s not the scene in India. Mukherjee discloses, “Regrettably, such information is not made easily available by the Indian regulatory agencies or research institutions, although the Department of Health Research, Ministry of Health and Family Welfare has taken some initiatives in this direction. And I feel the media can also help patients in this regard.”

    In an attempt to bring better transparency, the details of ongoing trials in India are now listed on the clinical trial registry of India (www.ctri.nic.in) which has resulted in increasing visibility. Though there is no facility for volunteers to register on this site. Commenting on timely corrections and updation for a better accessibility in the clinical trial process, Limaye mentions, “The importance of clinical trials is to be made apparent to patients, and along with this many things need course correction, the right checks and balances are being laid out and patients, especially those who have no means of availing of existing therapies, should be made aware of the positive benefits of clinical trials.”

  • Encouraging innovation: Pareek says, “No doubt regulatory changes are made to strengthen the systems and regulations and to bring transparency in conducting clinical studies. Such changes will definitely discourage malpractices. But the bigger picture lies ahead when Indian pharma companies will conduct clinical trials not just as a regulatory ritual but to develop their indigenous innovations/ideas. If majority of Indian companies start doing this then India will be exploring its potential talent in the true sense.”
  • Strategising for progress: The right approach and strategy are essential in clinical trials. Suvarna says, “Based on the study protocol and therapeutic area there could be slight differences in the approach. The system begins with careful selection of the right investigator, training of the investigator and team, and continuous oversight/regular monitoring, to ensure the right patients are recruited. The study is done only if it meets current unmet medical need of Indian patients, benefit is more than risk, and the new drug has the potential of being a significant advance over current standard of care.·

    Marthak stresses on the procedures depending upon complexity of a disease, “There are different strategies for different indications. e.g. oncology patients also need assurance for continuing the chemotherapy along with marketed product. HIV patients need confidentiality and also the right combination of drugs. TB patients need confidentiality and also additional nutritional support. If their needs are taken care of the patients do participate in clinical trials.”

  • Invest in training: Bhatt suggests, “Indian hospitals have to invest in training of the investigators/staff in science, ethics and regulation governing clinical research, create computerised patient databases, and develop research infrastructure to improve overall conduct of clinical trials including recruitment of patients.”

Conclusion

If implemented, these recommendations would resolve the issues plaguing the footsteps of the clinical trials segment in India, including patient recruitment, and help to retrieve the country’s reputation as a clinical trial hub.

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