Reducing patient dropouts

Is India's patient pool showing the first signs of drying up? Or is it a case of a lack of investigators to get to the right patients? Usha Sharma analyses... (Extracted from Express Pharma, 1-15 September 2008)

Faster patient recruitment which increases the speed of running clinical trials is the biggest advantage that pharmaceutical companies consider when they outsource studies to India. Patient recruitment and retention has always been a challenge in the West. In fact, it is estimated that only 15 percent of clinical trials are completed on time, with over 50 percent of delays attributed to patient recruitment and 30 percent of investigator sites failing to recruit a single patient.

There are various ways of reducing patient dropouts. The very famous Louis Lasagna rule or 'Muench's Third Law' indicates, that the recruitment strategy should be to enrol a greater number of potential participants, since only a fraction of potential participants progress through to the screening phase, a subsequently smaller number get randomised and not all randomised participants complete the study. But, according to a CenterWatch survey of 1050 study volunteers, the most common reason for participation was to find relief (60 percent) followed by an urge to advance science (23 percent), to earn extra money (11 percent), and to receive better medical care (six percent). Almost 50 percent of trial delays result from patient enrolment problems. 86 percent of all US clinical studies fail to recruit the required number of subjects on time. As against in specialty drugs trials segment the delays can translate to $288 million in potential lost revenue over a 12 month period. Industry-wide, there is a 20 to 30 percent patient dropout rate in Phase II/III studies.

Multiple pain points

According to a recent study from McKinsey, global pharma majors would spend around Rs 4,000-6,000 crore ($1-1.5 billion) for drug trials in the country in the next three to four years, up from the current spend of about Rs 1,200 crore, ($300 million). More trials would mean the need for more patients as well as Indian investigators (the doctors who conduct the study) and some industry observers are already predicting challenges in this area.

The challenges of patient recruitment in India could stem from multiple reasons like access to fewer, busier investigators in a given therapeutic area where there could be competition to do trials since investigators may be working on multiple studies. The problems are faced as a result of poor awareness about the importance of clinical trials among volunteers (patients). Also in some cases, the communication skills of professionals concerned with patient recruitment in a clinical research organisation (CRO) need to be scaled up.

Currently as per industry estimates, more than 350 trials are being conducted in India involving 25,000 volunteers. The majority of these studies are in oncology, infectious diseases and type 2 diabetes. This is obvious since the global drug development pipeline primarily addresses these therapeutic areas. Hence there is an acute need to have more investigators in these areas as more and more companies would approach sites where such therapeutic area expertise exists. In addition, there are good number of studies in India for ophthalmology, neuropsychiatry conditions, respiratory disorders and vaccines.

As per projections, clinical trials sponsored by US pharma companies account for 374 sites presently recruiting patients in India. But the number of on- going trials at this point of time should be much more, since many domestic pharma companies also conduct clinical trials within the country and there would be also some trials from countries other than the US.

The other major challenges identified as impediments to patient recruitment in India are lack of awareness within the public and patient community of on-going clinical trials, media misinforming the public via negative write-ups, refusal of doctors to refer patients to on-going trials with the fear of losing a patient to the other physician/investigaator, and a belief that the existing therapy is the best. Also, some busy clinicians believe recruitment would only add to the documentation workload which deters them from enrolling.

From the patient/volunteer side, the frequently cited reasons for refusing to sign up for clinical trials are practical/ personal obstacles which would imply issues like difficulty in reaching the site, inability to be away from work, family obligations, festivals, extreme weather conditions etc. There is also a social stigma associated with participation in clinical trials in our country as also the fear of being treated as a 'guinea pig' especially since Indians do not have a long history of participation in clinical trials. In a country having 22 official languages, even language acts as a significant barrier leading to ineffective communication between investigators and patients.

In India there is no systematic guideline for reference while recruiting human subjects for clinical studies. It has been observed that while pharma companies invest heavily in marketing approved drugs, they often do not employ that same market research when it comes to positioning and

communicating the value of clinical trials to study sites and patients. Neither the pharma companies nor the CROs are prepared to make investments towards training and developing new investigators and new sites.

Vijay Moza, Chairman, CREMA	Kavita Singh, Director Business Development and Project Management, Fortis Clinical Research
Venkat Jasti, Vice Chairman and CEO Suven Life Sciences	Dr Ramanad Nadig, Deputy Dean and President Operations CREMA

A method in the strategy

It is possible to sidestep or at least reduce these pitfalls. Kavita Singh, Director Business Development and Project Management, Fortis Clinical Research says, "Every clinical trial should be subject to feasibility assessment, with a primary focus on patient attitudes. Carefully planned implementation and follow-through of sound recruitment and enrolment strategies will contribute to the success of clinical research trials. It is possible that effective recruitment strategies in the West might not be relevant to our set-up. We need to have approaches which could even differ between states. Cultural and social factors have to be given their due importance. Even factors like patient's medical profile, emotional drivers, values, tastes and other key factors such as family support play an important role."

Dr Ramanad Nadig, Deputy Dean and President Operations, Clinical Research Education and Management Academy (CREMA), avers, "What I have seen from my experience is that a lot of CROs over-project the number of patients they have recruited in their trials. As a result, the actual recruitment always falls short of the projection in front of the sponsors. A decade ago, Indian CROs were able to select 100 percent patients for clinical trials. Today it has dropped down to 90 percent."

Prior preparation

The patient recruitment process involves extensive training of investigators (doctors at hospitals involved in the clinical study) to identify potential patients for a specific study who may benefit from involvement in such a clinical study. However, prior to enrolment of such subjects in the study, there has to be extensive explanation about the study, including both risks and benefits of participation. The process involves providing an opportunity for the patient and their relative (or their counsel) to understand the Informed Consent Form (ICF) and get explanations and clarifications from investigators as may be required. Once the patient has agreed to participate in the trial by signing the ICF, the investigator enrols the patient and conducts the study as defined by the sponsor in the study protocol.

Vijay Moza, Chairman, CREMA, says, "Launch of new drugs is delayed by two to three years due to delay in recruitment of suitable patients. Problems are also faced in the retention of patients. The costs of clinical trials have gone up by about 15 percent as a result of this. Since India is considered as a hub of trials, the issue may impact its future prospects."

There has to be a well co-ordinated effort among the different components of a CRO like the principal investigators, site investigators, and trial monitors over proper recruitment of patients and keeping them motivated throughout the trial. The selection of trial sites must be appropriate. The CROs should closely monitor the trial staff to ensure that committed numbers are met and those whoever is recruited is retained.

Citing more reasons, Singh adds, "The two most frequently cited reasons for dropping out of the study are either an adverse event or lack of response to the study drug. Trial sponsors must make an educated guess and accordingly compensate for subject dropouts by increasing the number of enrolled subjects, as well as the supplies and resources for these additions. It is also possible that the subject who reports no response to the investigational medication is due to non-compliance or poor compliance with protocol directions. It is estimated that subject dropout rates range from 15-40 percent of enrolled participants."

Different routes

Different enrolment practices are followed for conduct of Phase I (which requires healthy volunteers), for Phase II-III (which are pre-registration studies in patients) and Phase IV (which includes studies performed after drug approval and related to approved indication). For the Phase I studies, the Phase I unit of the CRO maintains a database of healthy volunteers. The database is built by different modalities like person to person contact, advertisements and by distribution of flyers. In the West the most preferred modality is internet advertisement.

For Phase II to IV clinical trials the responsibility of patient recruitment is on the investigator and the investigator's site team. The sponsors and the CROs rely solely on the investigators for recruitment. The investigator himself/herself or the site team members usually approach patients already visiting the clinic/hospital with medical histories/new diagnosis of the target drug indication. In addition, methods like advertisements, referrals from other physicians and holding medical camps are practiced by Indian investigators.

The backlash of dropout of enrolled patients is actually felt by the pharma company. This is so because even if the treatment is effective but non-adherence is substantial, the analysis following the intention-to-treat principle underestimates the magnitude of the treatment effect that will occur in adherent patients. Though alternative strategies are available that impute outcomes to those lost to follow-up, these strategies in general make unverifiable assumptions that may introduce bias in the estimates of treatment effect. Hence, inferences from studies with appreciable loss to follow-up are usually weaker.

Going by the rule book

While enrolling subjects in the trial the investigator should comply with the Schedule-Y requirements, and should adhere to Good Clinical Practice (GCP) and to the ethical principles that have their origin in the declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the Institutional Review Board (IRB)/Independent

Ethics Committee (IEC) written approval/favourable opinion of the written ICF. Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial. Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. The written ICF should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.

Ajit M Nair, President, SIRO Clinpharm, says, "Patient recruitment challenges could also come in due to protocols being very complex, requiring very specific patient types to meet the inclusion criteria for patients to participate. Many studies which are very complex come to India as rescue studies for sponsors since recruitment timelines were not met as predicted by sponsors in other countries. Other reasons could be patient related due to the complexities of the protocol requiring invasive procedures, frequent visits to clinical sites etc, which may dissuade the patient from participating in such studies."

Suven Life Science's Clinical Research Services division, Asian Clinical Trials (ACT) assists global pharma, biotechnology and medical device companies in clinical research. Venkat Jasti, Vice Chairman and CEO, Suven Life Sciences, says, "I think more drug development addressing the needs of India under diseases like dengue, malaria, rota-virus and other infectious diseases always helps. The therapeutic areas covered predominantly include oncology, cardiology, endocrinology and neurology. We as a CRO provide services like regulatory consulting, clinical trial management, safety management, monitoring, project management, data management and biostatistics. In the current scenario, (issues affecting any clinical trial) are declining productivity of investigators as they tend to undertake more trials for the same indications, patient dropout rates and not reaching rural and semi-urban populations due to logistic problems. Hence these populations provide unrealistic promises on target enrolment in the beginning. We were able to bring trials providing healthcare for needy patients in therapeutic areas like oncology and cardiology for which no alternative remedies are available."

The issue can be tackled with proper planning of trials, proper recruitment of patients, proper communication to patients over the steps involved and clarification of doubts in their minds. Special attention needs to be given to train and re-train clinical trial teams including principal investigators and co-investigators, clinical research associates and nursing staff along with continuous patient education and training.

Highlighting this issue Nadig further avers, "In India, CROs often face recruitment and retention issues in the areas of oncology, diabetology, cardiology and neuro-psychiatry. If it is not tackled immediately, Indian CROs may gradually lose their credibility, which they once enjoyed. The only solution is to follow the rules strictly. And ensure that the committed numbers are delivered on time."

The question often given immense importance in the site feasibility questionnaire, is prior experience of the site. A positive answer to this often overrides the fact that the site has conflicting studies ongoing.

Also, after completing site feasibility assessments, the CROs should inform the non- selected sites of the reason for rejection. This will help those sites to work upon their deficiencies; somehow this learning is not happening currently. There has to be intense effort from not only the CROs but also the regulatory, healthcare providers, clinical trial sponsors, the media, and the public to overcome factual and perceived obstacles to clinical research participation, concludes Singh.

u.sharma@expressindia.com