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SUBJECT RECRUITMENT IN CLINICAL TRIALS THE INDIAN PERSPECTIVE

SUBJECT RECRUITMENT IN CLINICAL TRIALS THE INDIAN PERSPECTIVE
RAVINDRA REDDY.S., DEPARTMENT OF PHARMACY PRACTICE, VISVESWARAPURA INSTITUTE OF PHARMACEUTICAL SCIENCES, BANGALORE

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    • SUBJECT RECRUITMENT IN CLINICAL TRIALS THE INDIAN PERSPECTIVE By RAVINDRA REDDY.S. Dissertation Submitted to the Rajiv Gandhi University Of Health Sciences, Karnataka, Bangalore In partial fulfillment of the requirements for the degree of MASTER OF PHARMACY In PHARMACY PRACTICE Under the guidance of Mrs. GITHA KISHORE M.Pharm DEPARTMENT OF PHARMACY PRACTICEVISVESWARAPURA INSTITUTE OF PHARMACEUTICAL SCIENCES BANGALORE 2007 I
    • Rajiv Gandhi University of Health Sciences DECLARATION BY THE CANDIDATE I hereby declare that this dissertation/thesis entitled SUBJECT RECRUITMENT IN CLINICAL TRIALS THE INDIAN PERSPECTIVE is a bonafide and genuine research work carried out by me under the guidance of Mrs. Githa Kishore M.PharmDate: Signature of the candidatePlace: Ravindra Reddy S. II
    • CERTIFICATE BY THE GUIDE This is to certify that the dissertation entitled SUBJECT RECRUITMENT INCLINICAL TRIALS THE INDIAN PERSPECTIVE is a bonafide research work done by Ravindra Reddy S. in partial fulfilment of the requirement for the degree of Master of Pharmacy in Pharmacy PracticeMr. Anirban Roy Chowdhury Mr. Milind Nadgouda Mrs. Githa KishoreClinical Research Manager Regulatory Affairs Manager Asst. Professor& GuideAstraZeneca Pharma India Ltd, AstraZeneca Pharma India Ltd, VIPS, BangaloreBangalore Bangalore(CO-GUIDE) (CO-GUIDE) (GUIDE)Date: Date: Date:Place: Place: Place: III
    • ENDORSEMENT BY THE HOD, PRINCIPAL This is to certify that the dissertation entitled SUBJECT RECRUITMENT IN CLINICAL TRIALS THE INDIAN PERSPECTIVE is a bonafide research work done by Ravindra Reddy.S Under the guidance of Mrs. Githa Kishore Asst Professor and Guide VIPS, BangaloreSeal and Signature Seal and Signature of the PrincipalMRS. GITHAKISHORE DR. KALYANI PRAKASAMGuide and HOD, PrincipalDepartment of Pharmacy Practice VIPS, BangaloreVIPS, Bangalore Date : Date : Place : Place : IV
    • COPYRIGHT DECLARATION BY THE CANDIDATE I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka shall have the rights to preserve, use and disseminate this dissertation / thesis in print or electronic format for academic / research purpose.Date: Signature of the CandidatePlace: Ravindra Reddy.S © Rajiv Gandhi University of Health Sciences, Karnataka V
    • Dedicated to my Parents VI
    • ACKNOWLEDGEMENT As I look back on the long journey that has lead to the completion of mydissertation work, I see the faces of the people who have made my voyage worthwhile.At this juncture, the least I can do is acknowledge the efforts they took to ease my task ofcompleting this thesis. If I stand here today, it is only because I have been blessed. My God has been myinvisible source of support, love and hope. It is only with His grace that I have been ableto accomplish the conclusion of this dissertation. I extend my profound thanks to my guide Mrs. Githa Kishore AssistantProfessor, VIPS, Bangalore, whose exuberance and constant encouragement havecontributed much to the successful completion of my work. I express my sincere gratitude to Dr. Kalyani Prakasam, Principal,Visveswarapura institute of pharmaceutical sciences, for her constant encouragement,valuable suggestions and timely advice. I take this opportunity to express my heart felt gratitude to my co-guides Mr.Anirban Roy Chowdhury(Clinical Research Manager) and Mr. Milind Nadgouda(Regulatory affairs Manager), AstraZeneca pharma India Ltd., Bangalore for theirinspiring guidance and keen interest shown towards this work. I am short of words tothank both of them for unlimited patience, freedom of thought, faith and affection. I would like to thank Mrs. N.K.Meera, Asst. Professor, Department of Pharmacypractice whose invaluable recommendations have helped me in perfecting my work. VII
    • I would also like to thank all the staff of department of pharmacy practice,particularly Mr. Kenneth and Mr. Shekhar for their suggestions that helped me perfectmy work. “Good friendship is a gift of God”. Words are insufficient & inefficient to expressmy whole hearted thanks to Jhina, Reenu, Rajan, Abdul and Anil for their valuablesuggestion and help offered. I express my gratitude to all teaching & non-teaching staff of VisveswarapuraInstitute of Pharmaceutical Sciences, Bangalore. I take great privilege to express my heartfelt thanks to all those who have directlyor indirectly helped me in getting through this project successfully. Last, but by no means the least, I am eternally grateful to my family for theirabiding love and encouragement.Date: Signature of the CandidatePlace: Ravindra Reddy S. VIII
    • AbstractAbstractBackground and objectivesSubject recruitment in clinical trials is considered as the major bottleneck in the new drugdevelopment pipeline and it is one of the most significant challenges faced by thepharmaceutical industry today. Currently there is a great focus on the issues surroundingsubject recruitment. The purpose of this study is to identify the issues and understand theregulatory framework surrounding subject recruitment. And compare these issues withother countries and develop new ideas and strategies to improve the recruitment rate andretain the subjects throughout the investigation.MethodsIt is a retrospective and interview based analytical and argumentative study conducted atAstraZeneca Pharma India Ltd., Bangalore. The complete data was collected fromliterature survey (journals & reports available in public domain) and data obtainedthrough questionnaire by interacting with various clinical research personnel involved inclinical trials, both nationally and internationally. Including investigators & ethicscommittee members to assess their perspective regarding subject recruitment in clinicaltrials.ResultsA strong correlation was found between the findings from literature review and thoseobtained from the questionnaire survey. The various issues that were identified can becategorized in the broad headings of cultural, demographic, economic, financial, protocolrelated, investigator related and informed consent related issues. The review and thesurvey findings not only helped us to understand more clearly the reasons why patientsdo or do not take part in clinical trials but also provided us with a good insight into thesolutions that can be employed to overcome the problems surrounding patientrecruitment.Interpretation and conclusionWe conclude that to address patient recruitment issues it is very important to understandmore clearly on an ongoing basis why patients do or do not take part in a clinical trial.Based on this understanding the clinical research community needs to come up withrobust scientific trial designs and strategies customized for each individual set ofcircumstances like disease, type of participants, type of intervention, phase of trial etc.ensuring that they are compatible with routine medical care and attractive to bothclinicians and patients.Care should also be taken to ensure that while improving recruitment, safety measures arenot weakened and ethical aspects not compromised in the clinical trial process.Key words: Clinical trials, Subject Recruitment and retention, Issues Subject Recruitment in Clinical Trials-The Indian Perspective IX
    • CONTENTSSl. No. Particulars Page No. 1 Introduction 1 2 Objectives 13 3 Review of literature 14 4 Methodology 31 5 Results 34 6 Discussion 62 7 Conclusion 69 8 Summary 70 9 Limitations 71 10 Future Directions 72 11 Bibliography 73 12 Annexures 77 X
    • LIST OF TABLESTable No. Title Page No. 1 Cost of a clinical trial per patient 4 2 Disease burden in India. 6 3 Respondent Affiliation 34 4 Respondent Nationality 35 5 Education level as a factor for retention in CT 37 6 Education level as a factor for retention in CT - a split 38 response 7 Education level as a factor for retention in CT - the country 39 wise response 8 Financial Status of patient affecting enrolment rate 40 9 Financial Status of patient affecting enrolment rate in CT - a 40 split response 10 Financial Status of patient affecting enrolment rate in CT - 41 the country wise response 11 Reluctance to enrol due to increased visits 42 12 Reluctance to enrol due to increased visits in CT - a split 43 response 13 Reluctance to enrol due to increased visits in CT - the 44 country wise response 14 Gender of the Trial recruiter – A limitation or not 45 15 Gender of the Trial recruiter in CT a limitation or not - split 46 response 16 Gender of the Trial recruiter in CT a limitation or not -the 47 country wise response 17 Internet & recruitment rates 48 XI
    • 18 Internet & recruitment rates in CT - a split response 4919 Internet & recruitment rates in CT - the country wise 50 response20 Protocol Amendments – effect on retention rates 5121 Protocol Amendments – effect on retention rates the country 52 wise response22 Recruitment Strategies – Ethnic or Cultural differentiation 5323 Recruitment Strategies – Ethnic or Cultural differentiation 54 the country wise response24 Availability of Alternative medicine 5525 Availability of Alternative medicine affects the subject 55 recruitment the country wise response26 Distrust in Science affects subject recruitment 5627 Literacy rate of clinical trial patients 5728 Literate patient percentage from Investigators response 5829 Literate patient percentage from CR professional response 5930 Rating the parameters as per their difficulty levels 6031 Key factors to motivate a subject to participate in a CT 61 XII
    • LIST OF FIGURESTable No. Figures Page No. 1 Phases of Clinical Trial 2 2 A simplified model of the cash flows of an original ethical 4 drug 3 Overall country attractiveness index to perform CT 8 4 Subject Recruitment in Clinical Trials 9 5 Respondent Affiliation 34 6 Respondent Nationality 36 7 Education level as a factor for retention in CT 37 8 Education level as a factor for retention in CT - a split 38 response 9 Education level as a factor for retention in CT - the country 39 wise response 10 Financial Status of patient affecting enrolment rate 40 11 Financial Status of patient affecting enrolment rate in CT - a 41 split response 12 Financial Status of patient affecting enrolment rate in CT - 42 the country wise response 13 Reluctance to enrol due to increased visits 43 14 Reluctance to enrol due to increased visits in CT - a split 44 response 15 Reluctance to enrol due to increased visits in CT - the 45 country wise response 16 Gender of the Trial recruiter – A limitation or not 46 17 Gender of the Trial recruiter in CT a limitation or not - a split 47 response XIII
    • 18 Gender of the Trial recruiter in CT a limitation or not - the 48 country wise response19 Internet & recruitment rates 4920 Internet & recruitment rates in CT - a split response 4921 Internet & recruitment rates in CT - the country wise 50 response22 Protocol Amendments – effect on retention rates 5123 Protocol Amendments – effect on retention rates the country 52 wise response24 Recruitment Strategies – Ethnic or Cultural differentiation 5325 Recruitment Strategies – Ethnic or Cultural differentiation 54 the country wise response26 Availability of Alternative medicine 5527 Availability of Alternative medicine affects the subject 56 recruitment the country wise response28 Distrust in Science affects subject recruitment 5729 Literacy rate of clinical trial patients 5830 Literate patient percentage from Investigators response 5931 Literate patient percentage from CR professional response 60 XIV
    • LIST OF ABBREVIATIONS USED (In alphabetical order)Sl No. Abbreviations Expansions 1 CII Confedaration of Indian Industry 2 CRO Contract Research Organisation 3 CT Clinical Trial 4 DCGI Drug Controller General of India 5 FDA Food & Drug Administration 6 GCP Good Clinical Practice International Conference on Hormonization of technical requirements for registration of pharmaceuticals for human 7 ICH use 8 ICMR Indian Council of Medical Research 9 IND Investigational New Drug 10 IRB Institutional Review Board 11 NDA New Drug Application 12 R&D Research and Development 13 RRCHF Relaxation Response Intervention for Chronic Heart Failure 14 TRIPS Trade Related aspects of intellectual property 15 TSE Tuskegee Syphilis Experiment 16 USD US Dollars 17 WHO World Health Organization 18 WTO World Trade Organization XV
    • LIST OF ANNEXURESAnnex No. Title I Subject Recruitment Investigator’s Questionnaire II Subject Recruitment Clinical Research Personnel Questionnaire XVI
    • Introduction1. IntroductionDrug Development and Clinical TrialClinical trials are essential in the development of a new medical product, device, orprocedure, in order to ensure its efficacy and safety to the general public.A clinical trial or study is defined by the International Conference on HarmonisationPrinciples of Good Clinical Practice (ICH GCP) as being any investigation in humansubjects intended to discover or verify the clinical, pharmacological and/or otherpharmacodynamic effects of an investigational product(s), and/or to identify any adversereactions to an investigational product(s), and/or to study absorption, distribution,metabolism, and excretion of an investigational product(s) with the object of ascertainingits safety and/or efficacy.Clinical trials are conducted by pharmaceutical companies or contract researchorganisations (CROs) on their behalf.Clinical development of a new drug comprises about two thirds of the total drugdevelopment costs.Transforming a discovery into a marketed medicine can take between10 and 20 years, and costs around USD 800 million.On an average screening of every 10000 molecules produces only 1000 molecules withbiological activity. Of those 1000, only around 10 advance so far as to be administered tohumans, and only one reaches the market. (See Fig 1) Subject Recruitment in Clinical Trials-The Indian Perspective 1
    • IntroductionFigure 1: Phases of Clinical Trial  Phase I: During Phase I, which lasts an average of one year; the drug is tested on a small number of healthy (non-patient) volunteers. The main goal of these trials is to obtain data on the compound’s safety, appropriate dosage range, and pharmacokinetic properties.  Phase II: This phase lasts approximately two years and the drug is tested in controlled studies involving 100 to 300 patient volunteers. The purpose of this phase is to allow researchers to assess the drug’s effectiveness on patients, experiment with various doses to establish the range that produces the desired effect, and to collect additional information on safety and drug side effects.  Phase III: This is the most critical of all phases, with studies that last approximately three years. It is typical for 1,000 to 3,000 patients to be involved in these multi-centre trials. During this phase researchers more precisely determine the drug’s effectiveness, which means that information about optimum Subject Recruitment in Clinical Trials-The Indian Perspective 2
    • Introduction dosage and indications for use is refined. Placebo studies or an alternative drug are also introduced in this stage.  Phase IV: Following submission of a NDA the purpose of the phase IV studies is to provide data on the long-term safety and efficacy of a drug. Additionally, researchers collect new types of information such as the impact of the drug on quality of life and pharmaco-economic statistics, which measure the drug’s potential market value compared with available therapies. The manufacturing company and healthcare authorities will also actively monitor the drug after it has been approved to discover any overlooked or unexpected adverse reactions.Economics of Drug Research1The relative cost is high for the first stages of research (screening) when thousands ofpotential substances are being tested. These costs drop significantly in stages 2 and 3 asthe selected 20 or so substances undergo pharmacology and toxicity studies and earlystage clinical trials. However costs start to increase for stage 4, the clinical trials.Costs increase significantly in Stage 5 as the product is readied for production and themarketing campaign is being prepared. These costs, particularly marketing, continuethrough Stage 6 as the product is rolled out. It is not until Stage 6 that a positive cashflow is generated. Only three out of 10 compounds reach the final product market, andonly one generates high positive cash flow in Stage 6. Subject Recruitment in Clinical Trials-The Indian Perspective 3
    • IntroductionHowever, all the costs borne in stages 1 to 5 represent a value added and income flow tothe individuals, organizations and companies involved in the drug development process.Figure 2: A simplified model of the cash flows of an original ethical drugFor example: The average cost of running a US-based clinical trial per patient can befound below2.Table 1: Cost of a clinical trial per patient Phase of the Trial Cost per patient Phase I $5404 Phase II $6538 Phase III $7635 Subject Recruitment in Clinical Trials-The Indian Perspective 4
    • IntroductionClinical Research in IndiaClinical Research in India is an emerging business today and the potential for growth isenormous.Disease burden – India 3Firstly there is a valid database of the disease burden in India where the patientpopulation for each disease has been listed within. The WHO listing is the most reliableone although there are a lot of other databases collected by organizations involvingprivate (non governmental) research & data collection. Needless to say that the data bankis promising with the availability of sizable patient population, which makes India anideal destination for Clinical Research primarily.Disease burden in India (based on WHO World Health Reports 2002-2004 and Ministryof Health statistics). Subject Recruitment in Clinical Trials-The Indian Perspective 5
    • IntroductionTable 2: Disease burden in India. Disease Number of patients (in millions) Cancer 3 Hypertension 150 Epilepsy 8 Depression 10 Diabetes 25 Schizophrenia 10 Asthma 40 AIDS 5 Alzheimer 1.5 Parkinson 2.5 Tuberculosis 15 Malaria 15 Filariasis 50Market PotentialA report from consultancy firm Ernst & Young indicated that the total market value ofclinical research performed in India between 1991 & 2001 was an estimated USD 70-80Million. 1. According to the Confederation of Indian Industry (CII) study, clinical trials in India in 2002 generated $70 million in revenues. CII predicts that it would grow to $200 million by 2007 4. Subject Recruitment in Clinical Trials-The Indian Perspective 6
    • Introduction 2. A recent report from McKinsey indicates that total value of Indian Clinical Research Market would be around USD 1.5 billion by 2010.Factors for growth of Clinical Research in India  Development of the Clinical Research industry in India is very critically linked to the growth of the Pharmaceutical & Healthcare industry in India as well as globally. Indian government has shown an unwavering commitment to implementing the Trade Related Aspects of Intellectual Property (TRIPS) under the World Trade Organization (WTO) mandated product patent regime.  The WTO’s intellectual property agreement has triggered a significant change in India’s pharmaceutical industry encouraging firms to switch their efforts from producing generics to actively engage in research and development of their own.  In January 2005, the Government of India enacted a new rule that allows foreign pharmaceutical companies to conduct trials of new drugs in India at the same time as that of the trials of the same phase, which are being conducted in other countries. This new rule supersedes a directive of Indias Drugs and Cosmetics 5 Rules that required a "phase lag" between India and the rest of the world .  India has certain distinct advantages over many other countries, apart from facilitating regulatory support, 500,000 well-trained English-speaking doctors, 16,000 hospitals, 171 medical colleges, a large patient pool, coupled with sophisticated technological infrastructure, a heterogeneous pool of genes has Subject Recruitment in Clinical Trials-The Indian Perspective 7
    • Introduction 6,7 made it well-suited location for conducting clinical trials . India offers a 50% 7 cost savings for phase I research and 60% for, phase II and phase III research . According to Rabo India Finance report in India, clinical trials can cost up to 60% less than in the US 2.The graphical presentation of Overall Country effectiveness index ranks India at no 2,only next to China for most attractive locations to perform CT outside the USA 8.Figure 3: Overall country attractiveness index to perform CT Subject Recruitment in Clinical Trials-The Indian Perspective 8
    • IntroductionSubject Recruitment17Figure 4: Subject Recruitment in Clinical Trials Clinical Trials Preclinical Phase I Phase II Phase III FDA Phase IV Testing 12 Years 3.5 1 2 3 2.5 Total Subject Subject Subject Recruitment Recruitment Recruitment Laboratory Test and animal File Population File 20 to 80 Subject studies NDA Review IND at healthy 100 to 300 1000 to 3000 Recruitment volunteers patient volunteers patient volunteers at process / FDA FDA Approval Additional Post Verify Assess Evaluate marketing testing effectiveness, safety and Determine safety effectiveness, required by FDA Purpose monitor adverse biological and dosage look for side reactions from activity effects long-term use 5,000 Success 1 compounds 5 enter trials Rate approved evaluatedSubject recruitment is the process of enrolling participants into the study. It begins withthe identification, targeting and enlistment of participants for a research study. It involvesproviding information to the potential participants and generating their interest in theproposed study. There are two main goals of recruitment:  To recruit a sample that adequately represents the target population;  To recruit sufficient participants to meet the sample size and power requirements of the Study 9Subject recruitment in clinical trials is recognized as one of the most difficult aspects ofthe study process. With significant increases in the number and complexity of clinicaltrials, the sponsors and investigators are facing increasing difficulty finding enough Subject Recruitment in Clinical Trials-The Indian Perspective 9
    • Introductionsubjects to recruit in a timely manner to bring drugs to market within their desired timeframe. Along with subject recruitment, even retention of subjects in clinical trials iswidely recognized as another major challenge. Recruitment of subjects and retainingthem in clinical trials are considered as the major bottleneck in the new drug developmentpipeline.The trend towards producing drugs for diseases and disorders that affect a smaller sectorof the population is driving a need to reach smaller target populations for clinical trials.This problem is compounded by growing competition between trials looking for research 10patients in the same areas, which ultimately effect to recruit sufficient subjects to trial .The inability to recruit subjects according to plan has caused significant delays in theprogress of clinical trials, which ultimately lead to loss of potential sales. Most studies inthe US are delayed by at least six months.According to reports, in 2001, over 85 percent of all completed medical studiesexperienced enrolment delays, and 34 percent were delayed for more than one month.Such postponements can cost pharmaceutical companies millions of dollars in sales.Today, this cost ranges between US$800,000 and US$5.4m per day of delay, dependingon the potential blockbuster status of the product 10.Slow enrolment is the reason for the failure of clinical trials. 86% of studies slip behindschedule. Furthermore, 60% of studies have delays of at least one month and 13% ofstudies are completed six months or more behind schedule. Because most clinical trials Subject Recruitment in Clinical Trials-The Indian Perspective 10
    • Introductionon the critical path each fall into months of delays, overall development programmes fall 11into years of delays .On average, inefficient patient recruitment can cause clinical trials to last 42% longerthan expected in phase I, 31% longer in phase II, and 30% in phase III 12.Thirty percent of clinical trial time is spent for finding and enrolling study subjects, andalmost half of all trial delays result from patient recruitment problems13. Patientrecruitment consumes 27 percent of the cost of development that is US$ 5.9 billion 14,15annually around the world . Only 1in 20 recruited patients provide results that can be 15included in a regulatory dossier In fact, over three-quarters of all clinical trials 15currently fail to meet their recruitment deadlines Not having a recruitment plan is alsoa reason for moving potential participants into rival studies10.When, a clinical trial is delayed by slow subject enrolment, you need to quickly identifythe issues impacting subject recruitment & analyze them thoroughly so as to develop newideas and strategies, which are aimed at recruiting the right patients and retaining themthroughout investigation.Clinical trial participation is the self-decision, taken by the subject to participate in thestudy. A wide variety of issues shape the recruitment of subjects to trials. The issues thatdetermine recruitment of subjects is a complex process that involves conceptual,methodological, technological and practical considerations. Consideration of theinfluencing factors or issues that impact clinical trials awareness and participation is Subject Recruitment in Clinical Trials-The Indian Perspective 11
    • Introductionhelps to improve recruitment and less patient withdrawal from studies. These issues canbe classified broadly into Subject related issues, Investigator related issues, Protocolrelated issues etc.The most critical, players in a clinical trial are the humans subject themselves. Public hascome to expect and demand that the medical system develop new, safe and effectiveapproaches to the prevention and treatment of diseases. However that the same public isnot aware of the important role that public participation plays in the development ofmedical advances.It is essential for the pharmaceutical industries that the recruitment process takes intoaccount factors that will optimize the type and number of participants enrolled in astudy while minimizing time and expense required for the recruitment process. Takinga single month off a trial by improving recruitment could generate an additional $40million in sales for an average drug. Pharma companies must radically alter their R&Defforts by improving the speed and efficiency of recruitment, and this in turn willstreamline the whole clinical trial process. Finding people for trials is always hard; toomany patients don’t realize they can participate. Further, deaths and questionablepractices in isolated trials have made potential participants wary. Moreover, designersof clinical trials are now seeking more narrowly defined sets of patients, in part todistinguish new drugs from rivals on the market16. Subject Recruitment in Clinical Trials-The Indian Perspective 12
    • Objective2. ObjectiveGeneral objective:  Subject Recruitment in Clinical Trials – The Indian perspectiveSpecific objectives:  Identify the issues with subject recruitment in India  Compare the issues in India & other countries  Develop new ideas and strategies  To improve the subject recruitment rate and retain the patients throughout investigation Subject Recruitment in Clinical Trials-The Indian Perspective 13
    • Review of Literature3. Review of LiteratureA key determinant of the success of a clinical trial is the recruitment and retention of theresearch subjects. Low rates of recruitment and retention have a number of negativeimplications on clinical trial. To improve subject recruitment in clinical trials, the issuesto recruitment and retention need to be identified, so appropriate strategies to overcomethem can be implemented. These issues are already well recognized in the literatures.Number of research studies concludes, these issues are repeatedly affecting subjectrecruitment and retention in clinical research.These issues broadly classified in to:Socio-cultural issues:  Language & Education  Cultural programmes  Health decision-making  Race/Ethnicity & the element of distrust  Availability of alternative medicines.Socio-economic issues:  Socio-economic status  Limited access to health care  Impoverishment  Transportation  Non availability of medical facility  Long time working hours  Travel costs  Employment status Subject Recruitment in Clinical Trials-The Indian Perspective 14
    • Review of LiteratureSocio-demographic issues:  Geographic location  Age  Gender  Marital statusFinancial issues:  Transportation  Cost associated with participationProtocol related issues:  Rigid Study design  Inclusion and exclusion criteria  Lengthy study periods  Excessive visit schedules  Demanding product dosage schedules  Long gap between visits.Investigator related issues:  Lack of time  Concern for the patient  Concern for the effect on physician-patient relationship  Concern for the potential loss of clinical autonomy  Obtain informed consentInformed Consent related Issues:  Explanation of informed consent  Consent process and  Understanding of the patientOther issues:  Emotional issues  Non availability of treatment history Subject Recruitment in Clinical Trials-The Indian Perspective 15
    • Review of LiteratureSocio-cultural issues: 19Caroline Homer has emphasized on the importance of incorporating cultural diversity inresearch especially in multicultural societies. She says that many randomized controlledtrials are designed in such a way that cultural diversity is not facilitated. This can meanthat the sample is not representative of the population from which it was drawn or towhich it is applied.The different socio-cultural issues that affect trial recruitment are discussed below.Language:Language is perceived as a major barrier to participation of subjects in global clinicaltrials. The issue of language barrier in the research studies gets all the more complex inthe increasing proportion of culturally diverse groups across the globe. The nature oflanguage barrier may differ from country to country & some of them are illustratedbelow.India is a country with diverse culture across the geographic territory. Several localdialects, sub dialects & lifestyles prevail across the length & breadth of the country &thus communication is achieved through more than one major language though mostpeople understand Hindi & English language continues to be used for all officialpurposes.Many of subjects in India are illiterate, or they have limited ability to read, write andspeak in their local languages.18 Subject Recruitment in Clinical Trials-The Indian Perspective 16
    • Review of LiteratureThus communication between a potential subject & the research Investigator may nottake place effectively specially when they do not have a common language background.Inability to understand the concerns of the potential subject & failure to explain the studyspecific details to him/her due to language barrier may deter him/her away fromparticipating in the study leading to a loss of a potential subject.Zelen31 indicated that language barriers & perceived level of intelligence & understandingare potential reasons for informal exclusions of potential subjects where researcherssubtly shape their sample.This trend is clearly seen in a trial by Giles et al., which tested the efficacy of amidwives’ clinic. The trial specifically excluded women who did not speak English, as itwas felt that only English speaking women would be able to fully understand theimplications of the trial & that predictors of satisfaction would be affected when languageability was impaired.32Cultural beliefs:Cultural beliefs might influence the willingness of women to undergo cancer-screeningexaminations & these same beliefs may be relevant to clinical trials participation. Anna 20R. Giuliano et al cited an example of a group of Chinese-American women whobelieved that the female organs ceased to function when they are not being used inprocreation & therefore, examination of the breast or cervix is not necessary when they Subject Recruitment in Clinical Trials-The Indian Perspective 17
    • Review of Literatureare not bearing children. Hence it may be difficult to recruit such patients in screeningtrials for breast or cervix cancer.Kagawa-Singer20 contrasted the cultural health values of Euro-American cultural systemwith that of the Asian-American system. She observed that the Euro-American systemholds that all life is sacred and must be preserved at all cost; autonomous decision-making must be maintained and relief of suffering is a primary objective. In contrast, theanalogous three values in most Asian-American cultures are that individual life is notsacred; the welfare of the group is the primary value; and decision-making is made byconsensus. These cultural values may have impact on the individual’s decision toundergo cancer screening or participate in research and the choice of treatment oncecancer is found.Religious beliefs and spirituality also are important in understanding ideas regardinghealth, disease risk and treatment. For example, among faith communities, God isconsidered the central healer of disease. Faith communities also provide psychologicaland physical support, serving as networks for communicating health messages andpromoting research participation.20Another important socio-cultural issue surrounding unmarried female subjects is thatthey feel offended if they are asked to perform pregnancy tests, which is a commonrequirement in almost all protocols.18Additionally, for an unmarried woman (speciallyfrom a community who believes that female organs are non functional when they are not Subject Recruitment in Clinical Trials-The Indian Perspective 18
    • Review of Literaturebeing used in procreation), to have breast or cervix examinations in breast or cervixscreening trials would imply that she is sexually active and such an admission would be 20untenable.Decision to participate in the trial also depends on the gender of the trial recruiter.Anna R. Giuliano et al 20 quoted an example of a cervical cancer screening study wherethe subjects considered it important to have a female doctor do the pelvic exam. Even themale family members preferred a female doctor for their female relatives.Health Decision-making:Naranjo and Dirksen faced challenge of recruiting Hispanic women. They successfullyrecruited 50 Hispanic women for a study being conducted on breast cancer survivors butencountered a high refusal rate. The Hispanic value of “familialism” was a prominentproblem in recruitment. Hispanics have a strong feeling of loyalty to family, and manypotential subjects refused participation because of family commitments that involvedtravel. “Machismo” was also a factor because some husbands forbade their wives to 21participate.Umakanta Sahoo et al18. observed a similar trend in Indian culture as well. In Indiansociety, the male member takes charge of all decision-making processes in the families. Ifa female subject participates in a trial, she gives her consent only after consultation withthe male member of her family, who may be father or husband.In Pacific Island cultures respect and understanding of the family system, cultural valuesand the role of women are pivotal to increasing clinical cancer research participation. Subject Recruitment in Clinical Trials-The Indian Perspective 19
    • Review of LiteratureDisease, disability and death of a family member have great implications for the entirePacific Islander family. A Pacific woman who recognises the hardship and grief that herdisability or death would bring to her family may be more motivated to participate inactivities to enhance her well-being. This motivation also could promote clinical trialparticipation.20In India subjects have deep respect for study physicians & they tend to follow theinstructions of the physicians. These cultural values facilitate recruitment & retention.1Cultural Programmes:Cultural programmes have major effects on patient recruitment and retention especiallyin a culturally diverse country like India.Indians celebrate many festivals and cultural programmes, and each community has theirown set of cultural functions. During festive and harvesting seasons, patient in flow tohospitals tends to be less, thereby leading to slower subject recruitment. Culturalprograms sometimes even compel subjects to miss scheduled follow-up visits if event fall 18during those days .Availability of alternative medicines:In India the availability and wide spread practice of alternate medicines such ashomeopathy, ayurvedic, and unani affects the recruitment and retention of subjects inclinical research18. Non-availability of medical facility in rural areas, low socio economicstatus, and illiteracy might be the reason for the dependence on these alternatives in India.This is a missed opportunity for the researchers to recruit such subjects in research. Many Subject Recruitment in Clinical Trials-The Indian Perspective 20
    • Review of Literaturesubjects may have taken these forms of treatment and would not have sufficientdocumentation of their treatment history. Thus, those patients may not be considered forrecruitment in a clinical trial. And there is a chance of clinical trial subjects may migrateto these less costly alternate methods of treatments, if the trial procedure in a subjectsopinion is time consuming, lengthy study periods, excessive visit schedules and yield noresult etc.Race/Ethnicity & the element of distrust:Race and ethnicity have been major influences on individual and group of minorities inUS, which affects the research participation. Cultural and racial differences betweenrecruiter and subjects were cited as barriers to subject participation. When the recruitersare from different culture than the subjects there is a chance for lack of trust, due tobecause the recruiter will not understand the background of the specific culture ofsubject21.Past unethical medical practices like the Tuskegee Syphilis Experiment is frequentlydescribed as the singular reason behind African American distrust on the institutions ofmedicine and public health. The racial and ethnic minority groups in the US, especiallyAfrican-Americans, are less willing than non-Hispanic whites to participate in healthresearch due to the traces of these past abuses22. Subject Recruitment in Clinical Trials-The Indian Perspective 21
    • Review of LiteratureA patients willingness to participate in a trial is also affected by trial recruiter. Patientsare more likely to agree to participate in a trial if they know and trust the medicalprofessionals running the trial and their motivation to participate will also depend on thetype of information provided and the degree to which confidentiality is guaranteed 23.Socio-economic issues:Socio economic status and limited access to health care:Anna R. Giuliano et al 20 has identified socio-economic status of the subjects, as a crucialfactor that affects the participation in clinical trials. They have observed that rates ofparticipation in clinical cancer trials are especially low among the socially disadvantaged,while, white, middle class, highly educated, married men are most represented intreatment trials and cancer prevention research. In general factors like study duration,treatment schedule, cost, time, follow-up visits and side effects which overall representmore of a barrier to participation among minority groups compared with white, non-hispanics. Among socially disadvantaged individuals, whose struggle for day-to-daysurvival is a constant concern, these factors pose even larger barriers than for individualsof higher socio economic status.The group has identified three reasons that account for lower participation rates forpeople with lower socio economic status: 20 1. Limited access to health care and higher dependence on public hospitals where physicians are less likely to be involved in clinical research Subject Recruitment in Clinical Trials-The Indian Perspective 22
    • Review of Literature 2. Issues related to insurance. Patients from low socio economic background are more likely to rely on insurance; however their coverage of costs associated with participation in a clinical trial is inconsistent and often denied. 3. Concerns about economic survival take precedence over those of health and well being among people from lower socio economic background. This reality often discourages patients from engaging into clinical trialsA prospective study of the French GAZEL Cohort and its target population shows thatthe situation in France is fairly similar to those observed in most studies performed inother countries. Socio economic status is the most important individual variable: Jobgrade shows that among both men and women the highest category had a participationrate that was double that of the lowest category and the probability of participationamong male managers was 3.15 times higher than that of unskilled male workers whenall other variables were taken into account. The article stated that Socio economic statuscannot be compared easily between countries, both because different classifications areused and because this status may be assessed by membership in a social category, incomelevel or educational level. Nevertheless, whatever the variable used, the higher categoriesare nearly always overrepresented among volunteers. This trend has been observed inGreat Britain, USA and Sweden.25An article by Mah Hussain-Gambles 24 who has explored the South Asian patients’ viewsand experiences of clinical trial participation, has outlined that trial participation is likelyto be less for those who work long hours, are in manual operations or low paid jobs, are Subject Recruitment in Clinical Trials-The Indian Perspective 23
    • Review of Literatureunable to take time off work and had no transport, cannot bear the cost associated withtravelling long distances, has no financial support for childcare. 21Debbie J. Daunt has shared similar views in relation to American population. Apartfrom inability to afford childcare or transportation, the other factor that has beenidentified is the lack of time to participate in research because of the need to workovertime and holding additional jobs to support family. The article also outlined anexample of a trial that requires the recruiters to make regular phone contact with subjects;this stipulation alone could singularly eliminate most potential subjects from low socioeconomic background who do not have phones.The Indian perspective has been highlighted by Umakanta Sahoo et.al.18 In the existinghealthcare system in India, the majority of the impoverished population depend on thefree or subsidized treatment from government –run hospitals and dispensaries sincehealth insurance is still not prevalent in the low socio economic society. So participatingin clinical trial may be seen by these subjects as a means to ease some of their additionaleconomic burdens in terms of medication and treatments. They have also observed thatpoor and illiterate subjects are more compliant, as they are very sincere and follow theinstructions of the physician.Socio-demographic issues:Geographic location (travel & travel cost):Geographical location can be a major impediment to participate in clinical trials in vastcountries like India. Most of the clinical research settings are limited to private hospitals Subject Recruitment in Clinical Trials-The Indian Perspective 24
    • Review of Literature 18in urban areas, which needs long distance travel by the patients from rural areas . Travelinconvenience, travel cost adds to other factors like socio economic status, whichcumulatively affect participation in clinical trials.Similar trend is noted by Anna R. Giuliano et al 20 among Native Hawaiians and Pacificislanders, for whom, geographic location is one of the main reasons for the limited accessto health care. Access to health care in urban settings is impeded by costly travel. Travelconvenience and cost add other barriers to health service and research.Goldberg et. al., with reference to the GAZEL cohort study has identified this factor toaccount for the greatest variation in the participation rate. Studies conducted in severalEuropean countries also found participation rates that differ very clearly by country 25.Ross et. al in their systematic review of literature to identify barriers to recruitment haveidentified travel & travel costs as reasons for refusing to take part, for missingappointments and for dropping out27.Age:Age is also perceived as a barrier, which can affect recruitment of study subjectsconsiderably.Recruitment among elderly patients who have chronic diseases poses particularchallenges. Studies have identified that transportation is a specific issue in recruitment ofthe elderly. A trial that requires frequent travel for a behavioural intervention at a studysite, which can be a long distance away from the patient’s residence, adds difficulties to 26recruitment among the elderly . Subject Recruitment in Clinical Trials-The Indian Perspective 25
    • Review of LiteratureParents of children are often reluctant to provide consent for their child to enter a clinical 28trial. Elder people also may reluctant to participate in a trial due to family objections .Gender:Decision to participate in the trial is also depended on the gender of the trial recruiter,especially in those trials, which are viewed as “embarrassing”. Female subjects arehesitant to take part in gynaecological trials, if they involve members of the opposite sex.Mah Hussain-Gambels has cited references, which suggests that concerns about modestyin ethnic minority women can result in poor participation in gynaecological and breasttrials. However, there is a degree of diversity in attitudes among women; there are manyfor whom modesty & preference for female trial staff are not an issue at all24.While narrating their experience with patient recruitment in “The relaxation responseintervention for chronic heart failure (RRCHF)” study Bei-Hung Chang et. al. havehighlighted that the gender of the trial recruiter, apart from appearance, personality andmanner, is an extremely important factor in the recruiting process26.Financial issues:Financial compensation to the trial subjects has always been a very sensitive aspect &review of literature suggests that there is diversity among various people in perception ofthis issue.Ross et. al while performing systematic review of literature to identify barriers torecruitment identified that people who withdrew from one study indicated that they 27believed participants should be paid . Subject Recruitment in Clinical Trials-The Indian Perspective 26
    • Review of Literature 26Some of the patients in the RRCHF study said that monetary compensation was a nicefeature and they are happy to get it. However they stressed that they would have joinedthe study even without the money.Umakanta Sahoo et. al 18 observes that in India in a few studies which demands additionalvisits for tests and procedures, the sponsor provides compensation toward theconveyance, stay, loss of wages for the subject and other earning members of the family,as well as incidental expenses. This acts as a motivation and improves subject complianceand retention. They opine that these represent genuine compensation and logisticaleconomic support for trial subjects and would not be construed as an inducement orcompulsion for enrolment.Protocol related issues:Ross et. al 27 in their review of literature has identified bibliographic references in whichprotocol itself was blamed for restricting recruitment by clinicians.Lengthy study periods, excessive visit schedules, and demanding product dosageschedules, long gap between visits are identified as issues for subject recruitment andretention in clinical trial. Protocol designs with eligibility criteria that are so tight thatpotential study subjects do not qualify for entry, and protocols that are too difficult forinvestigators to follow due to over complex study designs, also affect recruitmentprocess. This may imply that some clinical trial protocols being designed today areunrealistic, difficult to implement in reality and difficult for subjects to comply with.28 Subject Recruitment in Clinical Trials-The Indian Perspective 27
    • Review of LiteratureInvestigator related issues:As the competition to get eligible patients in clinical trials is on the rise, the need forexperienced clinical investigators who can identify and enrol qualified patients is alsosurging high. In 2001 CenterWatch had estimated that there could be as much as 15%investigator shortfall in the next five years. It was estimated that 80% of the clinical trialsare conducted by only 20% of experienced physicians33. 27Ross et. al. identified the following factors which are indicated in different publishedliterature as barriers to clinician participation in clinical trials: 1. Time constraints 2. Lack of staff and training 3. Worry about the impact on doctor-patient relationship 4. Concern for patients 5. Loss of professional autonomy 6. Difficulty with the consent procedure 7. Lack of rewards and recognition 8. Insufficiently interesting questionAs the demand for patients in clinical trials has increased, the need to find patientsoutside of medical practises has become evident. The appeal to non-investigatorphysicians to refer patients to investigational sites where studies are being conducted hasfailed due to the following reasons29. Subject Recruitment in Clinical Trials-The Indian Perspective 28
    • Review of Literature I. Practicing physicians do not to want to lose their patients to another physician. II. Most practicing physicians are not aware of ongoing clinical trials that are available to their patients. III. Physicians have no real incentives to refer patients outside of their practices.Thus it is quite evident that in order to meet the rising demand there is a crucial need tohave more physicians getting involved into clinical trials either as trial investigator or asreferring physician.Consent issues:When patients are approached about participating in a clinical trial, they are subjected toa specific informed consent procedure. A trial recruiter is legally bound to provide fairand adequate information about the trial to a patient to make a decision whether toparticipate or not. The amount and kind of information disclosure is one of the manyfactors relevant in the patient’s decision-making process of entering a trial. Subjects,participating and non-participating want more information on trials although providinginformation may reduce recruitment and alter the response to treatment 27.The process of obtaining consent is traumatic for patients at a time when sensitivity isparamount. The process can damage patient’s trust in their doctor and they can end upbeing more confused and uncertain. This can lead to low recruitment rate in clinical 19trials . Subject Recruitment in Clinical Trials-The Indian Perspective 29
    • Review of Literature 30Zulfiqar A. Bhutta has pointed out that although most guidelines emphasize theimportance of obtaining informed consent there is little emphasis on participants’understanding of the matter. Even among literate research participants, there may be arelatively poor understanding of the nature of the research study. This issue becomesespecially important among illiterate and disenfranchised populations where fulldisclosure of relevant information must be done in a way that allows potentialparticipants to understand the nature of the research and types of investigations andinterventions that will be used.Combining several information strategies like written, oral, video, support fromprofessionals may be the best solution with time to consider the information beforemaking a decision.27Emotional issues:Unwillingness to take placebo can limit subject recruitment. Patients are less likely toparticipate in a trial where they may not receive active treatment and where they have thefear of being given a placebo. Worry about uncertainty of treatments and trials also deter 27many prospective patients from joining clinical trials .Decision to join a clinical trial also depends largely on the confidence of the patient onthe doctor and the liking they have for the doctor.27Non-availability of treatment history:Another issue specific to India is non-availability of treatment histories and hospitalrecords for most of the subjects taking treatment in hospitals. The absence of proper 18clinical history becomes very difficult to identify potential subjects suitable for the trial . Subject Recruitment in Clinical Trials-The Indian Perspective 30
    • Methodology4. Methodology4.1 Study design: It is a retrospective, theoretical and interview based analytical and argumentative study designed to evaluate the effect of the issues with subject recruitment on the clinical trial industry.4.2 Ethical approval: -Not applicable- The research involves only collection of the data from published literature and interview of the different stakeholders in the industry. There will be no investigations or interventions to be conducted on humans or animals.4.3 Source of data: Data relevant to the study was obtained from the following sources.  Journals & Reports  GCP guide lines [ICH & ICMR]  Schedule Y [Drugs & Cosmetics Act 1940]  Guidelines set by different Regulatory Authorities [DCGI & IRB]  Interview of personnel from pharmaceutical companies & CROs involved in conducting and managing clinical trials.  Interview of clinical trial investigators. Subject Recruitment in Clinical Trials-The Indian Perspective 31
    • Methodology4.4 Study procedure:i. Identify the Issues: Understand the concept of subject recruitment in clinical trials and identify the issues with subject recruitment by review the published literature from different Journals & Reports from the industry, which are available in public domain.ii. Classification of Issues: From a Number of research studies and literatures concludes, the issues affecting subject recruitment and retention in clinical trials are classified under broad headings.iii. Comparison of issues: The identified issues in India surrounding subject recruitment in clinical trials has been compared with the other countries to know the effect of such issues on the clinical research industry in other countries. iv. Preparation of standard questionnaire format: A questionnaire format was prepared in English, which contained standard questions to interview (direct or through questionnaires) the various stakeholders of the clinical research industry. The purpose of the interview was to understand the perspective of the different stakeholders with regard to subject recruitment. Subject Recruitment in Clinical Trials-The Indian Perspective 32
    • Methodologyv. Collection of data: The data was collected from literature survey (journals & reports available in public domain) and by interacting with various clinical; research personnel including investigators & ethics committee members to assess their perspective regarding subject recruitment in clinical trials. Subject Recruitment in Clinical Trials-The Indian Perspective 33
    • Results5. ResultsThe survey results have been analyzed and the details are discussed below.Sample Size:Total sample size of 113 respondents include trial investigators (doctors), sitecoordinators and professionals from the pharmaceutical & Contract ResearchOrganization (CRO) industries like clinical research associates, clinical project managers,medical directors and clinical research coordinators has been considered here. Therespondents belonged to 15 countries with Indians sending in maximum responses. Therespondents are broadly classified based on their affiliations (Figure5). The country wisebreakdown of responses also has been captured (Figure 6).Table 3: Respondent Affiliation Respondent Affiliation No. Percentage Hospitals 40 35 Pharma Companies 47 42 CROs 13 12 Not Mentioned 13 12 Total 113 100Figure 5: Respondent Affiliation Respondent Affiliation 35% 12% 12% 41% Not Mentioned Pharma Company CRO Hospital Subject Recruitment in Clinical Trials-The Indian Perspective 34
    • ResultsTable 4: Respondent Nationality Country Name No of respondents Percentage UK 4 4 Vietnam 1 1 USA 5 4 Taiwan 3 3 Singapore 2 2 Philippines 2 2 India 77 68 Hongkong 1 1 China 1 1 Bulgaria 1 1 Australia 5 4 Germany 1 1 Thailand 3 3 Malaysia 2 2 Sweden 5 4 Total 113 100 Subject Recruitment in Clinical Trials-The Indian Perspective 35
    • Results`Figure 6: Respondent Nationality Respondent Nationality UK 4 Veitnam 1 5 USA Taiwan 3 2 Singapore 2 Philippines 77 India 1 HongKong China 1 Bulgaria 1 5 Australia Germany 1 3 Thailand 2 Malaysia 5 SwedenEducation Level as a factor for retention: Do you think education level of subject affects the retention of the subject in a clinical trialData collected from both Investigators and CR professionals showed that 81% of clinicalresearchers felt that education level definitely affects the retention rates in trials; where asthe remainder thought it was not significant as a factor for retention. The results aredepicted (Figure 7). Subject Recruitment in Clinical Trials-The Indian Perspective 36
    • Results Table 5: Education level as a factor for retention in CT Response No of Respondents Percentage Yes 91 81 No 22 19 Total 113 100Figure 7: Education level as a factor for retention in CT 19% YES NO 81%A detailed analysis on the responses received from the CR professional as against theInvestigator showed a similar trend in the consideration of this factor for retention.Although the CR professional response seems more skewed towards the affirmation ofthe factor, the investigators are not far behind statistically on the same. This has beendepicted (Figure 8). Subject Recruitment in Clinical Trials-The Indian Perspective 37
    • Results Table 6: Education level as a factor for retention in CT - a split response No of No of CR investigators Personels Response Responded Percentage Responded Percentage Yes 38 78 53 83 No 11 22 11 17 Total 49 100 64 100Figure 8: Education level as a factor for retention in CT - a split response 17% NO 22% 83% YES 78% Investigator Response CR Professional ResponseFurther analysis of the data on classification of respondents from India against Rest ofAsia & a combination of UK, USA Australia & EU has shown that in India the educationlevel mattered a lot for patient retention in a Clinical Trial (Figure 9). Subject Recruitment in Clinical Trials-The Indian Perspective 38
    • Results Table 7: Education level as a factor for retention in CT - the country wise response Countries Yes Percentage No Percentage UK/US/Aus/EU 17 81 4 19 Asia 12 80 3 20 India 62 81 15 19Figure 9: Education level as a factor for retention in CT - the country wise response 62 17 15 12 4 3 YES NO UK/ US Aus/ EU Asia IndiaThe understanding for the need for follow up, filling up patient diaries, followingmedication regimens are affected by the low education levels of a patient. Since it iseasier to understand by the more educated patients as to why he /she wants to participatein a trial and be regular in their scheduled visits and also inform the investigator whateveris happening during the course of trial through appropriate records.Financial Status of patient affecting enrolment rate: Is the finiancial status a major reason that most patients volunteer for trial enrolmentSince many of the participants in the phase 2, phase 3 trials in India do not receive anyfinancial incentive to participate; financial motivation is only applicable to the phase1trial. Subject Recruitment in Clinical Trials-The Indian Perspective 39
    • Results50 % of the total respondents opined that the financial status might be a major reason forpatients to volunteer for a Clinical Trial (as shown in Figure 10). The investigators andthe CR fraternity have voted in similar statistical values on this question (as shown inFigure 11). Table 8: Financial Status of patient affecting enrolment rate Response No of Respondents Percentage Yes 57 50 No 56 50 Total 113 100Figure 10: Financial Status of patient affecting enrolment rate 50% YES 50% NOTable 9: Financial Status of patient affecting enrolment rate in CT- a split response No of CR No of investigators Personels Response Responded Percentage Responded Percentage Yes 25 51 32 50 No 24 49 32 50 Total 49 100 64 100 Subject Recruitment in Clinical Trials-The Indian Perspective 40
    • Results Figure 11: Financial Status of patient affecting enrolment rate in CT - a split response 50% NO 49% 50% YES 51% Investigator Response CR Professional ResponseThe response is skewed across the globe. The data from India shows a 51% of Indianrespondents believe that financial status of patients could be a major reason, where as it isonly 38% in developed nations and 67% in Asia (Figure 12).Most of the Patients in India can’t afford their cost of medication, for example; the costof chemotherapy. So if we are providing financial assistance through a clinical trial,patients will be most likely to participate in the trial. Table 10: Financial Status of patient affecting enrolment rate in CT - the country wise response Countries Yes Percentage No Percentage UK/US/Aus/EU 8 38 13 62 Asia 10 67 5 33 India 39 51 38 49 Subject Recruitment in Clinical Trials-The Indian Perspective 41
    • Results Figure 12: Financial Status of patient affecting enrolment rate in CT- the country wise response 39 38 13 8 10 5 YES NO UK/ US Aus/ EU Asia IndiaReluctance to enrol due to increased visits:Do you see getting reluctant about the number of visits they have to make during a trial either to the lab for investigations or to the clinic for diagnosisFigure 13 shows that 77% of the total respondents felt that there is reluctance inenrolment due to increased visits. The CR professionals have responded in an affirmativein large numbers than the investigators for this analysis (Figure 14). Table 11: Reluctance to enrol due to increased visits Response No of Respondents Percentage Yes 87 77 No 26 23 Total 113 100 Subject Recruitment in Clinical Trials-The Indian Perspective 42
    • ResultsFigure 13: Reluctance to enrol due to increased visits 23% YES NO 77% Table 12: Reluctance to enrol due to increased visits in CT - a split response No of investigators No of CR Personels Response Responded Percentage Responded Percentage Yes 35 71 52 81 No 14 29 12 19 Total 49 100 64 100 Subject Recruitment in Clinical Trials-The Indian Perspective 43
    • Results Figure 14: Reluctance to enrol due to increased visits in CT- a split response 19% NO 29% 81% YES 71% Investigator Response CR Professional ResponseFurther analysis of the data on geographical classification has shown insight on the factthat all the respondents agree that the number of visits could be making the patients thinktwice on the recruitment in clinical trial (Figure 15). Table 13: Reluctance to enrol due to increased visits in CT -the country wise response Countries Yes Percentage No Percentage UK/US/Aus/EU 19 90 2 10 Asia 9 60 6 40 India 59 77 18 23 Subject Recruitment in Clinical Trials-The Indian Perspective 44
    • Results Figure 15: Reluctance to enrol due to increased visits in CT- the country wise response 59 UK/ US Aus/ EU Asia India 19 18 9 2 6 YES NOGender of the Trial recruiter – A limitation or not:Do you feel Gender of the trial recruiter play a role in patient recruitment in clinical trialBoth the groups were sounding off the fact that gender of the trial recruiter is not alimitation for recruiting subjects into trial. only 27% of the investigators and 22% of CRprofessionals thought that it could be a limiting factor. (as shown in 17). Table 14: Gender of the Trial recruiter – A limitation or not Response No of Respondents Percentage Yes 86 76 No 27 24 Total 113 100 Subject Recruitment in Clinical Trials-The Indian Perspective 45
    • ResultsFigure 16: Gender of the Trial recruiter – A limitation or not 24% YES NO 76% Table 15: Gender of the Trial recruiter in CT- a limitation or not - a split response No of investigators No of CR Personels Response Responded Percentage Responded Percentage Yes 13 27 14 22 No 36 73 50 78 Total 49 100 64 100 Subject Recruitment in Clinical Trials-The Indian Perspective 46
    • ResultsFigure 17: Gender of the Trial recruiter in CT a limitation or not - a split response 78% NO 73% 22% YES 27% Investigator Response CR Professional ResponseThe responses is skewed across the globe the data shows that, 23% of Indian respondentsfelt that it was a limiting factor where as it is 33% in developed countries and 13% inAsia. (Figure 18).Table 16: Gender of the Trial recruiter in CT a limitation or not - the country wise response Countries Yes Percentage No Percentage UK/US/Aus/EU 7 33 14 67 Asia 2 13 13 87 India 18 23 59 77 Subject Recruitment in Clinical Trials-The Indian Perspective 47
    • ResultsFigure 18: Gender of the Trial recruiter in CT a limitation or not - the country wise response 59 UK/ US Aus/ EU Asia India 18 14 13 7 2 YES NOInternet & recruitment rates: Do you think internet plays a major role in patient recruitment73 % of the total respondents (113) mentioned that the Internet has not been a major toolfor recruitment of patients in the close past, and only 27 % total responses affirmed thatInternet was a major enrolment factor for patients in trial. Although the CR professionalresponse seems more skewed towards the affirmation of the factor, the investigators arenot far behind statistically on the same. The results are depicted (Figure 19 & 20). Table 17: Internet & recruitment rates No of Response Respondents Percentage Yes 31 27 No 82 73 Total 113 100 Subject Recruitment in Clinical Trials-The Indian Perspective 48
    • ResultsFigure 19: Internet & recruitment rates 27% YES NO 73% Table 18: Internet & recruitment rates in CT - a split response No of investigators No of CR Personels Response Responded Percentage Responded Percentage Yes 12 24 19 30 No 37 76 45 70 Total 49 100 64 100Figure 20: Internet & recruitment rates in CT - a split response 70% NO 76% 30% YES 24% Investigator Response CR Professional Response Subject Recruitment in Clinical Trials-The Indian Perspective 49
    • ResultsThe respondents from developed countries highlight a 50-50 probability of the use ofInternet in patient recruitment, where as 66% respondents from Asia felt that it did notplay a role and in India it was a majority who suggested that it did not play any role at all(Figure. 21). Table 19: Internet & recruitment rates in CT - the country wise response Countries Yes Percentage No Percentage UK/US/Aus/EU 10 48 11 52 Asia 5 33 10 67 India 16 21 61 79Figure 21: Internet & recruitment rates in CT - the country wise response 61 UK/ US Aus/ EU Asia India 16 11 10 10 5 YES NOProtocol Amendments – effect on retention rates: Do you think that number of protocol ammendements would affect the retention Of the patients in a trialConsidering the fact that the drop out rate would directly affect the trial data collectionfor the CR professionals this question was posed to the CR professionals only. Just over Subject Recruitment in Clinical Trials-The Indian Perspective 50
    • Results62 % of the sample surveyed felt that protocol amendments did not affect the retention,where as 38% respondents felt that protocol amendments did indeed affect the drop outrates & patient retentions was thus a concern. (Figure 22 for details). Table 20: Protocol Amendments – effect on retention rates Response No of Respondents Percentage Yes 40 62 No 24 38 Total 64 100 Figure 22: Protocol Amendments – effect on retention rates 38% YES NO 62%Indian respondents have shown a fifty-fifty response to this question, but the counterpartsfrom other geographies especially US/UK/EU & Australia have reported a negative oneffect of protocol amendment on retention of patients in the trial (Figure 23). Subject Recruitment in Clinical Trials-The Indian Perspective 51
    • Results Table 21: Protocol Amendments – effect on retention rates - the country wise response Countries Yes Percentage No Percentage UK/US/Aus/EU 3 14 18 86 Asia 6 40 9 60 India 15 54 13 46 Figure 23: Protocol Amendments – effect on retention rates - the country wise response UK/ US Aus/ EU Asia India 18 15 13 9 6 3 YES NORecruitment Strategies – Ethnic or Cultural differentiation: Do you think that recruitment strategies that are effective with one ethnic orcultural group might not be successful for recruting subjects from another group of culture or ethnicityA question again included only in the survey of the CR professionals was intended toanalyse the response on Ethnic or Cultural differentiation when it comes to recruitment Subject Recruitment in Clinical Trials-The Indian Perspective 52
    • Resultsstrategies across different geographies & cultures. This resulted in a 77% responsefavouring that different strategies are needed as per the ethnic or cultural differentiationof patient population. (See Figure 24). Table 22: Recruitment Strategies – Ethnic or Cultural differentiation Response No of Respondents Percentage Yes 49 77 No 15 23 Total 64 100Figure 24: Recruitment Strategies – Ethnic or Cultural differentiation 23% YES NO 77%Further analysis of the data on geographical classification has shown insight on the factthat majority of respondents agree that different strategies are needed as per the ethnic orcultural differentiation of patient population (Figure 25). Subject Recruitment in Clinical Trials-The Indian Perspective 53
    • ResultsTable 23: Recruitment Strategies – Ethnic or Cultural differentiation - the country wise response Countries Yes Percentage No Percentage UK/US/Aus/EU 16 76 5 24 Asia 13 87 2 13 India 20 71 8 29Figure 25: Recruitment Strategies – Ethnic or Cultural differentiation - the country wise response 20 UK/ US Aus/ EU Asia India 16 13 8 5 2 YES NOAvailability of Alternative medicine: Does the availability of alternative medicines (such as Homeopathy, Ayurvedic& Unani) affect the recruitment & retention of subjectsThe availability of alternative medicine was considered as a factor affecting patientrecruitment in trials by 38% of respondents. 19% opined that this alternative medicinetreatment was not applicable to their working geographies where as the rest (43%)responded that it did not affect recruitment rates at all (As shown in Figure 26 & 27).This question was posed only to CR professionals. Subject Recruitment in Clinical Trials-The Indian Perspective 54
    • Results Table 24: Availability of Alternative medicine Response No of Respondents Percentage Yes 24 38 No 28 43 NA 12 19 Total 64 100Figure 26: Availability of Alternative medicine 19% 38% YES NO NA 43% Table 25: Availability of Alternative medicine affects the subject recruitment - the country wise response Countries Yes Percentage No Percentage NA Percentage UK/US/Aus/EU 4 19 13 62 4 19 Asia 7 46 4 27 4 27 India 13 47 11 39 4 14 Subject Recruitment in Clinical Trials-The Indian Perspective 55
    • ResultsFigure 27: Availability of Alternative medicine affects the subject recruitment - the country wise response UK/ US Aus/ EU Asia India 13 13 11 7 4 4 4 4 4 YES NO NADistrust in Science: Do you face distrust in science from any of the potential trial subjectsAn assessment on distrust in science from any potential trial subjects revealed that only37% of the respondents have faced it. This question was targeted only to the Investigators(Figure 28).Table 26: Distrust in Science affects subject recruitment Response No of Respondents Percentage Yes 18 37 No 31 63 Total 49 100 Subject Recruitment in Clinical Trials-The Indian Perspective 56
    • ResultsFigure 28: Distrust in Science affects subject recruitment 37% YES 63% NOLiteracy rate of clinical trial patients: What percentage of the clinical trial patients is literateThis question was posed to both investigators and CR professionals. 53% of therespondents felt that the literacy rate of trial patients is above 75%.Table 27: Literacy rate of clinical trial patients What percentage of the clinical trial patients is literate Response No of Respondents Percentage 0-25 3 3 25-50 11 10 50-75 19 17 75-100 61 53 No Idea 12 11 Others 7 6 Total 113 100 Subject Recruitment in Clinical Trials-The Indian Perspective 57
    • ResultsFigure 29: Literacy rate of clinical trial patients Overall Literate patient percentage 11% 3% 10% 6% 17% 0-25 % 25-50 % 50-75 % 75-100 % 53% No Idea OthersWhen compared across CR professionals from the industry and investigators, 66% ofinvestigators feel that literacy rate of clinical trial patients is above 75% (Figure 30) and45% of the CR professionals feel that literacy rate of clinical trial patients is above 75%(Figure 31).Table 28: Literate patient percentage from Investigators response Response No of Respondents Percentage 25-50 5 10 50-75 11 22 75-100 32 66 No Idea 1 2 Total 49 100 Subject Recruitment in Clinical Trials-The Indian Perspective 58
    • ResultsFigure 30: Literate patient percentage from Investigators response Literate patient percentage from Investigators response 2% 10% 22% 66% 25-50 % 50-75 % 75-100 % No IdeaTable 29: Literate patient percentage from CR professional response Response No of Respondents Percentage 0-25 3 5 25-50 6 9 50-75 8 13 75-100 29 45 No Idea 6 9 Others 12 19 Total 64 100 Subject Recruitment in Clinical Trials-The Indian Perspective 59
    • Results Figure 31: Literate patient percentage from CR professional response Literate patient percentage from CR professional response 5% 19% 9% 13% 9% 0-25 % 25-50 % 50-75 % 75-100 % 45% No Idea Others Rating the parameters as per their difficulty levels  The parameters mentioned in Table 30 were surveyed among the investigators that were included in the questionnaire survey and the average response rates against each parameter was considered to arrive at the following result. The most difficult is rated as 1 and the easiest is rated as 5. A majority of the investigators felt that Explaining the legal requirements of the trial (Informed consent / financial details etc) to the patient is the most difficult parameter that they faced. Table 30: Rating the parameters as per their difficulty levels PARAMETER RANKINGExplaining the legal requirements of the trial (Informed consent / financialdetails etc) 1Delivering scientific rationale & understanding of the study 2Explaining the details of placebo / active drug 3The need for follow up diagnosis, tests etc through the entire trial. 4Language of communication with patients 5 Subject Recruitment in Clinical Trials-The Indian Perspective 60
    • Results Table 31: Key factors that motivate a subject to participate in a CTThe key factors that have been asked as a descriptive question type in the questionnaire tobe commented by the respondents have given us a revelation as shown in Table 31. Thescore is based on the number of times each factor appeared in the response Sr. Factor Score No 1 Free medications 42 2 Free treatment (Inadequate or no health insurance coverage) 36 3 Unmet need 6 4 No other therapeutic option/last resort in case of rare 21 diseases and terminal diseases 5 Request by the investigators- Inability to say no to 13 physician’s request 6 Faith/Trust/Confidence on the investigator 40 7 Extra care and attention by investigator 39 8 Reduced waiting time at clinic visits 7 9 Transportation allowance/ meal allowance reimbursement 12 10 Financial incentives/Gifts 26 11 Family/friend encouragement 4 12 Recommendation from the family physician 7 13 Full disclosure by the PI about study, total information about 17 risk benefit 14 Professional and caring approach from study team 12 15 Patient friendly protocol design. The patient should feel 29 he/she has been well cared and treated 16 Ease of travel to study sites 7 17 Willingness to help (altruism)/Humanitarian grounds 13 18 Curiosity/Research orientation 23 Contribution to medical science 19 Education/literacy level of patient 6 20 Chance to get better treatment 13 21 Web advertisement 1 22 Availability of latest research molecule 9 Subject Recruitment in Clinical Trials-The Indian Perspective 61
    • 6. Discussion:The project undertaken by us is an interview based analytical and argumentativestudy.The initial data on problems relating to patient recruitment in clinical trials iscollected through careful review of published literature. This was followed byinteraction with various members of the clinical research domain, which includedexperienced trial investigators, site coordinators, clinical research professionals frompharmaceutical companies and contract research organisation across the globe.The review of literature and the feedback from the respondents identified manybarriers to patient recruitment into clinical trials; these issues have been broadlyclassified as Socio cultural, Socio economic, Socio demographic, Financial, Protocolrelated, Investigator related and Informed consent issues. However, the findings ofour review should be read with some caution. There are several sources of potentialbias in the method, which is employed. Firstly the review methodology is subject tobiases of publishing and reporting. Some issues may have been missed because theywere not reported and some over estimated by over-reporting. Secondly, thefeedbacks from the respondents represent the personal opinion of each respondent,which are based on their own experience in their own domain and does notnecessarily represent the overall picture. For example, the viewpoint of an oncologistmay differ largely from that of a cardiologist. Similarly, the viewpoints may differgreatly among professionals across the developed and developing nations.
    • At the same time, it should also be noted that in our study we have tried to minimisethis diversity by collecting responses from across the globe by including trialinvestigators from various disease areas (oncology, psychiatry, endocrinology,cardiology, pulmonology etc.) and clinical research professionals from US, UK,Australia, Europe, countries in Asia and India.Despite the limitations of the study, in many cases a strong correlation was foundbetween the findings from literature review and those obtained from the questionnairesurvey.Some of key findings are discussed below:  Review of literature revealed that there is a difference in the perception among various group of people on the issue of financial compensation to trial 9, 10 participants . Similar trend is seen in the result from our questionnaire survey, where the ratio between people considering financial status a major reason for participation to those considering not is around 1:1 (Fig 11) and when analysed across geographies the response is highly skewed. The data from India shows a 1:1 response, where as majority from developed nations (13 out of 23 respondents) say that financial status is not a major reason and a majority respondent from Asia (10 out of 15) suggests to the contrary (Fig 13). We should note that the perspective of the group from developed nations is different from that of those from developing nations. In developed nation trial participation is less from socially disadvantaged groups due to various reasons
    • like inability to afford childcare or transportation, lack of time to participate in research because of the need to work overtime and holding additional jobs to 3,4,7,8 support family .Whereas in India, participating in clinical trial may be seen by subjects from low socio economic status as a means to ease some of their additional economic burdens in terms of medication and treatments due to the fact that the majority of the impoverished population depend on the free or subsidized treatment from government – run hospitals and dispensaries since health insurance is still not prevalent in the low socio economic society1.Similar response is also obtained from the respondents were asked about the key factors motivating subjects to participate in a clinical trial. The results are tabulated in Table 5 where it is evident that free medication and Faith/Trust/Confidence on the investigator got very high scores (42 & 40 respectively). An article1 suggested that communication between a potential subject & the research Investigator may not take place effectively specially when they do not have a common language background. Inability to understand the concerns of the potential subject & failure to explain the study specific details to him/her due to language barrier may deter him/her away from participating in the study leading to a loss of a potential subject. However, India, despite being a country where communication is achieved through more than one major language, the investigators don’t find language of communication a major barrier to patient recruitment. (Table 4). This is probably due to the fact that most people understand Hindi & English language continues to be used for all
    • official purposes. Also, the investigators take the effort to translate the information in a language which the patient comprehends. Lengthy study periods, excessive visit schedules, and demanding product dosage schedules, long gap between visits are identified as issues for subject recruitment and retention in clinical trial. 11This is very much endorsed by the respondents of the questionnaire survey. 81% of the clinical research professionals from industry and 71% of the investigators tend to agree to the fact that patients get demotivated about excessive visit schedules (Figure 15). However majority of the respondents (62%) feel that protocol amendments don’t affect retention of patients in a clinical trial (Figure 23). Availability of alternate medicines such as homeopathy, ayurvedic, and unani has been perceived to affect the recruitment and retention of subjects in clinical research1. When this question was put forward to the respondents, the response is mixed. 38 % of Clinical Research professionals said Yes, 43% said no whereas 19% said not applicable (figure 27). When analyzed across geographies, the result is interesting- a majority of respondents from Europe/USA/Australia says no where as a mixed response is obtained from India & other Asian countries. This varied response can be attributed to the fact that the practise of alternative medicine is restricted to certain specific locations. Other aspect is that treatment with alternative medicine is not always very well documented and they come into light only by proactive probing by the trial investigator. Though some of the published literature suggests gender of the trial recruiter as a factor affecting recruitment 9,11, the survey result shows that 76% believes
    • that gender does not affect trial recruitment (Figure 17). It should be noted that the published literature represents only a few selected groups and even there we did notice a degree of diversity in attitudes towards this issue.  81% of the respondents believe that education level of subject affects the retention of the subjects in a clinical trial (Figure 8). This view is consistent among both the investigators and Clinical Research professionals from the industry. In India many of the subjects are illiterate, or they have limited ability to read and write and this may be perceived as a major issue in terms of patient recruitment and retention. We feel that Investigator and research team can overcome this barrier through constant communication and counselling of the subjects and the family members.The review and the survey findings not only helped us to understand more clearly thereasons why patients do or do not take part in clinical trials but also provided us witha good insight into the solutions that can be employed to overcome the problemssurrounding patient recruitment. 2Caroline Homer has suggested particular techniques to improve participation ofculturally diverse groups. These include obtaining community support, using agegender and culturally matched research assistants in recruitment, translatingdocuments in all regional languages and acknowledging and being appreciative of theparticipants’ involvement. Other strategies include a systematic approach to samplingand recruitment and design of flexible and sensitive protocols.
    • Debbie J. Daunt 4 has suggested that education, language, geographic, cultural andeconomic barriers can all be overcome or minimized by careful planning. Researchersneed to invest time and money into performing proper feasibility studies. Withadequate knowledge common recruitment problems can be minimized. Whilerecruiting patients from diverse populations it may be necessary to employrecruitment techniques that address ethnic and cultural differences. This question wasput forward to our respondents and 77% of the respondents tend to agree with the factthat recruitment strategies that are effective with one ethnic or cultural group mightnot be successful for recruiting subjects from another group of culture or ethnicity(Figure 25).The factors that motivate a subject to participate in a trial which have been collectedfrom the survey results are listed in Table 5. Addressing these factors appropriately,keeping in mind the regulatory and ethical framework will surely enhance subjectrecruitment and retention in clinical trials.Even though 73% of the survey respondents (Figure 20) believe that Internet don’tplay a major role in patient recruitment, we feel that with the growing popularity ofinternet appropriate Internet portals and websites promoting and providinginformation on clinical trials can be used to both boost recruitment and provide detailsof investigators to potential patients.Apart from the techniques discussed above we would also like to make the followingrecommendations to improve patient recruitment and retention:
    •  Improve public knowledge and perception about clinical trial through educational campaigns targeting the public  The recruitment strategy should be well thought out and realistic  The study design should mimic the regular clinical practice and should be consistent with the scientific purpose of the study  The protocol should be as clear and simple as possible  Dedicated research staff from sponsor should be present to provide support and encouragement to the clinical staff  Patients should be supported in the process of decision making and should not be placed under pressure to participate  The trial information to the patients should be clear and conciseConclusionWe conclude that to address patient recruitment issues it is very important tounderstand more clearly on an ongoing basis why patients do or do not take part in aclinical trial. Based on this understanding the clinical research community needs tocome up with robust scientific trial designs, which are compatible with routinemedical care, which are attractive to both clinicians and patientsThe rewards for a properly designed protocol based on incremental changes to patientprocesses are immense. However, care should also be taken to ensure that inimproving recruitment safety measures are not weakened and ethical aspects notcompromised in the clinical trial process.SummaryPatient recruitment is one of the most difficult aspects of clinical trials, especiallythose involving diverse population as in India. The purpose of this study is to
    • understand the various factors associated with participation in clinical trials which isachieved through careful review of published literature and questionnaire basedsurvey of various members of the clinical research domain, which includedexperienced trial investigators, site coordinators, clinical research professionals frompharmaceutical companies and contract research organisation across the globe. Inspiteof the inherent limitations of the study we could still understand the problemsexperienced in patient recruitment and could make recommendations from thefindings.LimitationsThe main limitations of the trial are discussed below:There are several sources of potential bias in the method, which is employed. Firstlythe review methodology is subject to biases of publishing and reporting. Some issuesmay have been missed because they were not reported and some over estimated byover-reporting. Secondly, the feedbacks from the respondents represent the personalopinion of each respondent, which are based on their own experience in their owndomain and does not necessarily represent the overall picture. For example, theviewpoint of an oncologist may differ largely from that of a cardiologist. Similarly,the viewpoints may differ greatly among professionals across the developed anddeveloping nations.We have tried to minimise this diversity by collecting responses from across the globeby including trial investigators from various disease areas (oncology, psychiatry,endocrinology, cardiology, pulmonology etc.) and clinical research professionals fromUS, UK, Australia, Europe, countries in Asia and India. However due to interest oftime we had to stop collecting data once we reached 45 responses. Responses frommore respondents will certainly make the study more robust. However, even with the
    • limitations we could find a strong correlation between the findings from literaturereview and those obtained from the questionnaire survey.Future DirectionsWhile some of the strategies are likely to be useful for a wide range of trials, it isimportant to tailor strategies for each individual set of circumstances like disease, typeof participants, type of intervention, phase of trial etc. The future endeavour will be todelve deeper into various disease types and phases of trial and understand the issuessurrounding each so that effective strategies can be customized based on the specificnature of the trial.
    • Discussion6. Discussion:It is an interview based, analytical and argumentative study.The initial data on problems relating to patient recruitment in clinical trials is collectedthrough careful review of published literature. This was followed by interaction withvarious members of the clinical research domain, which included experienced trialinvestigators, site coordinators, clinical research professionals from pharmaceuticalcompanies and contract research organisation across the globe.The review of literature and the feedback from the respondents identified many barriersto patient recruitment into clinical trials; these issues have been broadly classified asSocio cultural, Socio economic, Socio demographic, Financial, Protocol related,Investigator related and Informed consent issues.Despite the limitations of the study, in many cases a strong correlation was foundbetween the findings from literature review and those obtained from the questionnairesurvey.Some of key findings are discussed below:  Review of literature revealed that there is a difference in the perception among various group of people on the issue of financial compensation to trial participants 26, 27 . Similar trend is seen in the result from our questionnaire survey, where the ratio between people considering financial status a major reason for participation to those considering not is around 1:1 (Fig 10) and when analysed across Subject Recruitment in Clinical Trials-The Indian Perspective 62
    • Discussion geographies the response is highly skewed. The data from India shows 1:1 response, where as majority from developed nations (13 out of 23 respondents) say that financial status is not a major reason and a majority of respondents from Asia (10 out of 15) suggests to the contrary (Fig 12). We should note that the perspective of the group from developed nations is different from that of those from developing nations. In developed nation trial participation is less from socially disadvantaged groups due to various reasons like; inability to afford childcare or transportation, lack of time to participate in research because of the need to work overtime and holding additional jobs to support family 20, 21,24,25 .Whereas in India, participating in clinical trial may be seen by subjects from low socio economic status as a means to ease some of their additional economic burdens in terms of medication and treatments due to the fact that the majority of the impoverished population depend on the free or subsidized treatment from government – run hospitals and dispensaries since health insurance is still not prevalent in the low socio economic society18. Similar response is also obtained from the respondents who were asked about the key factors motivating subjects to participate in a clinical trial. The results are tabulated (Table 31) where it is evident that free medication and Faith/Trust/Confidence on the investigator got very high scores (42 & 40 respectively). Subject Recruitment in Clinical Trials-The Indian Perspective 63
    • Discussion 18 Umakanth Sahoo , suggested that communication between a potential subject & the research Investigator may not take place effectively specially when they do not have a common language background. Inability to understand the concerns of the potential subject & failure to explain the study specific details to him/her due to language barrier may deter him/her away from participating in the study leading to a loss of a potential subject. However, India, despite being a country where communication is achieved through more than one major language, the investigators don’t find language of communication a major barrier to patient recruitment (Table 30). This is probably due to the fact that most people understand Hindi & English language continues to be used for all official purposes. Also, the investigators take the effort to translate the information in a language which the patient comprehends. Lengthy study periods, excessive visit schedules, and demanding dosage schedules, long gap between visits are identified as issues for subject recruitment 28 and retention in clinical trial . This is very much endorsed by the respondents of the questionnaire survey. 81% of the clinical research professionals from industry and 71% of the investigators tend to agree to the fact that patients get demotivated about excessive visit schedules (Figure 14). However majority of the respondents (62%) feel that protocol amendments don’t affect retention of patients in a clinical trial (Figure 22). Subject Recruitment in Clinical Trials-The Indian Perspective 64
    • Discussion Availability of alternate medicines such as homeopathy, ayurvedic, and unani has been perceived to affect the recruitment and retention of subjects in clinical 18 research . When this question was put forward to the respondents, the response is mixed. 38 % of Clinical Research professionals said Yes, 43% said no whereas 19% said not applicable (figure 26). When analyzed across geographies, the result is interesting- a majority of respondents from Europe/USA/Australia says no where as a mixed response is obtained from India & other Asian countries. This varied response can be attributed to the fact that the practise of alternative medicine is restricted to certain specific locations. Other aspect is that treatment with alternative medicine is not always very well documented and they come into light only by proactive probing by the trial investigator. Though some of the published literature suggests gender of the trial recruiter as a 26,28 factor affecting recruitment , the survey result shows that 76% believes that gender does not affect trial recruitment (Figure 16). It should be noted that the published literature represents only a few selected groups and even there we did notice a degree of diversity in attitudes towards this issue. 81% of the respondents believe that education level of subject affects the retention of the subjects in a clinical trial (Figure 7). This view is consistent among both the investigators and Clinical Research professionals from the industry. In India many of the subjects are illiterate, or they have limited ability to read and write, this Subject Recruitment in Clinical Trials-The Indian Perspective 65
    • Discussion may be perceived as a major issue in terms of patient recruitment and retention. We feel that Investigator and research team can overcome this barrier through constant communication and counselling of the subjects and the family members.The review and the survey findings not only helped us to understand more clearly thereasons why patients do or do not take part in clinical trials but also provided us with agood insight into the solutions that can be employed to overcome the problemssurrounding patient recruitment. 19Caroline Homer has suggested particular techniques to improve participation ofculturally diverse groups. These include obtaining community support, using age genderand culturally matched research assistants in recruitment, translating documents in allregional languages and acknowledging and being appreciative of the participantsinvolvement. Other strategies include a systematic approach to sampling and recruitmentand design of flexible and sensitive protocols. 21Debbie J. Daunt has suggested that education, language, geographic, cultural andeconomic barriers can all be overcome or minimized by careful planning. Researchersneed to invest time and money into performing proper feasibility studies. With adequateknowledge common recruitment problems can be minimized. While recruiting patientsfrom diverse populations it may be necessary to employ recruitment techniques thataddress ethnic and cultural differences. This question was put forward to our respondentsand 77% of the respondents tend to agree with the fact that recruitment strategies that are Subject Recruitment in Clinical Trials-The Indian Perspective 66
    • Discussioneffective with one ethnic or cultural group might not be successful for recruiting subjectsfrom another group of culture or ethnicity (Figure 24).The factors that motivate a subject to participate in a trial which have been collected fromthe survey results are listed in Table 31. Addressing these factors appropriately, keepingin mind the regulatory and ethical framework will surely enhance subject recruitment andretention in clinical trials.Even though 73% of the survey respondents (Figure 19) believe that Internet does notplay a major role in patient recruitment, we feel that with the growing popularity ofinternet appropriate Internet portals and websites promoting and providing informationon clinical trials can be used to both boost recruitment and provide details of investigatorsto potential patients.Apart from the techniques discussed above we would also like to make the followingrecommendations to improve patient recruitment and retention:  Improve public knowledge and perception about clinical trial through educational campaigns targeting the public  The recruitment strategy should be well thought out and realistic  The study design should mimic the regular clinical practice and should be consistent with the scientific purpose of the study  The protocol should be as clear and simple as possible Subject Recruitment in Clinical Trials-The Indian Perspective 67
    • Discussion Dedicated research staff from sponsor should be present to provide support and encouragement to the clinical staff The trial information to the patients should be clear and concise Patients should be supported in the process of decision making and should not be placed under pressure to participate. Subject Recruitment in Clinical Trials-The Indian Perspective 68
    • Conclusion7. ConclusionWe conclude that to address patient recruitment issues it is very important to understandmore clearly on an ongoing basis why patients do or do not take part in a clinical trial.Based on this understanding the clinical research community needs to come up withrobust scientific trial designs, which are compatible with routine medical care, which areattractive to both clinicians and patientsThe rewards for a properly designed protocol based on incremental changes to patientprocesses are immense. However, care should also be taken to ensure that in improvingrecruitment safety measures are not weakened and ethical aspects not compromised in theclinical trial process. Subject Recruitment in Clinical Trials-The Indian Perspective 69
    • Summary8. SummaryPatient recruitment is one of the most difficult aspects of clinical trials, especially thoseinvolving diverse population as in India. The purpose of this study is to understand thevarious factors associated with participation in clinical trials which is achieved throughcareful review of published literature and questionnaire based survey of various membersof the clinical research domain, which included experienced trial investigators, sitecoordinators, clinical research professionals from pharmaceutical companies and contractresearch organisation across the globe. Inspite of the inherent limitations of the study wecould still understand the problems experienced in patient recruitment and could makerecommendations from the findings. Subject Recruitment in Clinical Trials-The Indian Perspective 70
    • Limitations9. LimitationsThe main limitations of the trial are discussed below:There are several sources of potential bias in the method, which is employed. Firstly thereview methodology is subject to biases of publishing and reporting. Some issues mayhave been missed because they were not reported and some over estimated by over-reporting. Secondly, the feedbacks from the respondents represent the personal opinion ofeach respondent, which are based on their own experience in their own domain and doesnot necessarily represent the overall picture. For example, the viewpoint of an oncologistmay differ largely from that of a cardiologist. Similarly, the viewpoints may differ greatlyamong professionals across the developed and developing nations.We have tried to minimise this diversity by collecting responses from across the globe byincluding trial investigators from various disease areas (oncology, psychiatry,endocrinology, cardiology, pulmonology etc.) and clinical research professionals fromUS, UK, Australia, Europe, countries in Asia and India. However due to interest of timewe had to stop collecting data once we reached 45 responses. Responses from morerespondents will certainly make the study more robust. However, even with thelimitations we could find a strong correlation between the findings from literature reviewand those obtained from the questionnaire survey. Subject Recruitment in Clinical Trials-The Indian Perspective 71
    • Future Directions10. Future Directions  While some of the strategies are likely to be useful for a wide range of trials, it is important to tailor strategies for each individual set of circumstances like disease, type of participants, type of intervention, phase of trial etc.  The future endeavour will be to delve deeper into various disease types and phases of trial and understand the issues surrounding each so that effective strategies can be customized based on the specific nature of the trial. Subject Recruitment in Clinical Trials-The Indian Perspective 72
    • Bibliography11. Bibliography1. Pharmaceuticals Industry Action Agenda (Discussion Paper), September 2001 The Action Agenda Team.2. Kirsty Barnes. “ Balancing the clinical scales”. in-Pharma Technologies.com. Url: http://www.in-pharmatechnologist.com/news/printNewsBis.asp?id=662133. Krishan Maggon. “ Regulatory reforms and GCP clinical trials with new drugs in India”. Clinical Trials 2004; 1: 461-467.4. De Minakshi. India, ideal destination for clinical trials. Current Science, 2005; 89 (4): 5975. Bryan Jenny. Look east, for the future development of new drugs and speedy clinical trials. The Pharmaceutical Journal, 2005; 275:6586. Bhatt Arun. “Clinical trials in India: Pangs of globalization”. Indian Journal of Pharmacology, Vol. 36, No. 4, August, 2004, pp. 207-208.7. Jeff Berens and Jason McCoy. Offshoring in the Global Pharmaceutical Industry: Drivers and Trends. August 30, 2005.8. Pharma Focus Asia - White Papers - Make Your move: Taking Clinical Trials to the best location.9. Maxine X. Patel, Victor Doku & Lakshika Tennakoon. “Challenges in recruitment of research participants”. Advances in Psychiatric treatment(2003), Vol.9, 229-238.10. Next Generation Pharmaceutical Article: Trials And Tribulations. Url: http://www.ngpharma.com/pastissue/article.asp?art=25517&issue=143 Subject Recruitment in Clinical Trials-The Indian Perspective 73
    • Bibliography11. Nick Sinackevich, Jean-Pierre Tassignon. Skyscape Content: Speeding the Clinical Path. January 1, 2004.12. Donna Beasley. “Applied Clinical Trials- Recruitment Special population” June 1, 2006.13. Kristy Barnes. “ Use ‘The Net’ to catch your fish”. On Drug Research.com. Url: http://www.drugresearcher.com/news/printNewsBis.asp?id=6617914. Bowden, DR. Michel. “Accelerating patient recruitment.” Pharmafocus. August 2002.15. IBM Institute for Business Value analysis.16. Janice Cruz Rowe, Martin E. Elling, Judith G. Hazlewood, and Randa17. Dale E. Wierenga, C. Robert Eaton. Drug Development and Approval Process. Url: http://www.allp.com/drug_dev.htm.18. Umakanth Sahoo, Vimal Sanghavi, Faiz Kermani. Applied Clinical Trials - Subject Recruitment: An Indian Perspective. Feb 1, 2006.19. Caroline Homer. Incorporating cultural diversity in randomised controlled Trials in midwifery. Midwifery(2000) 16, 252-259.20.Anna R. Giuliano, McCaskill Stevens. Participation of Minorities in Cancer Research: The Influence of Structural, Cultural, and Linguistic Factors. Ann Epidemiol 2000; 10, S22-S34.21. Debbie J. Daunt. Ethinicity and Recruitment Rates in Clinical Research Studies. Applied Nursing Research, Vol. 16, No.3 (August), 2003: pp 189-195. Subject Recruitment in Clinical Trials-The Indian Perspective 74
    • Bibliography22. David Wendler, Ezekiel Emanuel. Are Racial and Ethinic Minorities Less Willing to Participate in Health Research? PloS Medicine, February 2006, Vol 3, Issue 2, e19, pp 0201-0210.23. Lara Marks, Emmett Power. Using technology to address recruitment issues in the clinical trial process. Trends in Biotechnology, Vol 20, Issue 3, 1 March 2002, pp 105-109.24. Hussain-Gambles M. South Asian patients views and experiences of clinical Trial participation. Family Practice 2004; 21: 636-642.25. Marcel Goldberg, Ellen Imbernon. Socioeconomic, Demographic, Occupational, and Health Factors Associated with Participation in a Long-term Epidemiologic Survey: A Prospective Study of the French GAZEL Cohort and Its Target Population. Annals Journal Of Epidemiology, Vol.154, No.4, 2001, pp 373-384.26. Bei-Hung Chag, Ann M Hendriks, Mara T Slawsky and Joseph S Locastro. Patient recruitment to a randomized clinical trial of behavioural therapy for chronic heart failure. BMC Medical Research Methidology 2004, 4:8.27. Sue Ross, Robin Prescott. Barriers to Participation in Randomised Controlled Trials: A Systemic Review. J Clin Epidemiol 1999, Vol. 52, No. 12, pp. 1143-1156.28. Jean Sullivan. Subject Recruitment and Retention: Barriers to Success. Applied Clinical Trials, Apr 1, 2004.29. Katheleen B. Drennan. Patient recruitment: the costly and growing bottleneck in drug development. DDT Vol. &, No. 3 February 2002.30. Zulfiqar A. Bhutta. Beyond informed consent. Bulletin of the World Health Organisation 2004;82:771-777. Subject Recruitment in Clinical Trials-The Indian Perspective 75
    • Bibliography31. Zelen M. A new design for randomized controlled trials. New England Journal of Medicine 1979;33:1242-124532. Giles W, Collins J, Ong F et. al. Antenatal care of low risk obstetric patients by midwives.1992;157:158-16133. CenterWatch (2001) Anticipating a clinical investigator shortfall. 8 (April),pp.1, 5-13 Subject Recruitment in Clinical Trials-The Indian Perspective 76
    • Annexures ANNEXURE – I Subject Recruitment Investigator’s QuestionnaireName:Designation:Country:  Could you list down in ascending order of importance the 5 key factors you think that motivate a subject to participate in a clinical trial? (Most important =5, Least important = 1) Rating Factors  Please rate these parameters as per their difficulty levels (the most difficult being rated as 1 and the most easiest rated as 5) Language of communication with patients Delivering scientific rationale & understanding of the study Explaining the legal requirements of the trial (Informed consent / financial details etc) The need for follow up diagnosis, tests etc through the entire trial. Explaining the details of placebo / active drug Subject Recruitment in Clinical Trials-The Indian Perspective I
    • Annexures Do you think education level of subject affects the retention of the subject in a clinical trial? Yes/No To what extent do you think that the family of a subject is responsible in the decision making process for inclusion in a trial? High/Low Is the financial status a major reason that most patients to volunteer for trial enrolment? Yes/No Do you see patients getting reluctant about the number of visits they have to make during a trial either to the lab for investigation or to the clinic for diagnosis? Yes/No Is it easy to handle a patient who is illiterate when it comes to enrolling him / her in the trial? Yes/No/Not applicable Do you feel that gender of the trial recruiter play a role in patient recruitment in Clinical Trial? Yes/No Subject Recruitment in Clinical Trials-The Indian Perspective II
    • Annexures Do you face distrust in science from any of the potential trial subjects? If so what are their views? Yes/No Do you think Internet plays a major role in patient recruitment? Yes/No Subject Recruitment in Clinical Trials-The Indian Perspective III
    • Annexures Annexure – II Subject Recruitment Clinical Research personnel QuestionnaireName:Designation:Company:Country:  Could you list down in ascending order of importance the 5 key factors you think that motivate a subject to participate in a clinical trial? (Most important =5, Least important = 1) Rating Factors  Do you think education level of subject affects the retention of the subject in a clinical trial? Yes/No  In your opinion is financial status a major reason for patients to volunteer for trial enrolment? Yes/No Subject Recruitment in Clinical Trials-The Indian Perspective IV
    • Annexures Do you see patients getting reluctant about the number of visits they have to make during a trial either to the lab for investigation or to the clinic for diagnosis? Yes/No Do you think that number of protocol amendments would affect the retention of patients in trial? Yes/No Does the availability of alternative medicines (such as homeopathy, ayurvedic, and unani) affect the recruitment and retention of subjects? Yes/No/Not Applicable What percentage of the clinical trial patients is literate? Do you feel that gender of the trial recruiter play a role in patient recruitment in Clinical Trial? Yes/No Do you think that recruitment strategies that are effective with one ethnic or cultural group might not be successful for recruiting subjects from another group of culture or ethnicity? Yes/No Do you think Internet plays a major role in patient recruitment? Yes/No Subject Recruitment in Clinical Trials-The Indian Perspective V