Enrolment of Trial Patients: Challenges & Strategies

Dr. Bhaswat S. Chakraborty

Senior VP, Cadila Pharmaceuticals Ltd.

Presented at the NIPER Symposium on Clinical Research and Training,February 21-22, 2009

Contents

1. Characteristics of Successful Trials

2. Enrolment1. Strategies (pragmatic)

2. Variables (modelling)

3. Challenges (operational…)

3. Methodology to Study Optimum Enrolment

4. Barriers & Promoters

5. Impact of Protocol1. I/E Criteria

6. Case Studies

7. Conclusions

Enrolment & Recruitment

• Enrolment– All patients who are found eligible to participate in

a trial

• Recruitment – Those enrolled patients who actually participate to

complete the trial

A Real Example of Enrolment Variations

Successful RCTs

• Well designed• Timely recruitment of the required number of

patients (N)• Low drop outs & lost to follow up• Adequate effect size• Low SAEs• Compliant to applicable guidelines• Cost effective• Convincing positive results

Enrolment Strategies

• Hospitals, specialized hospitals• The use of occupational and targeted screening• Registers of trials• Clinicians • Mass media• Direct mailing to access patients• Specialized interventions• Community camps

Enrolment Variables

• N– Adequate to include design, dropouts …

• Time to complete recruitment

• Response to treatments– Effect size, variability, power

• Risks– Costs of enrolment, centre initiation & overheads,

treatment conduct, cost of delay …

Main Challenges

• Understanding the nature and extent of true variability– Seasonal, due to disease itself, probabilities of success for

different approaches• Risks as described in a previous slide• Some trials, e.g., Cancer RCTs, require years to

complete, and subject recruitment can be a lengthy process

• Irrational or untested recruitment methods• Monitoring of patient accrual with respect to a priori

targets• Development of a risk management plan to respond to

failure to achieve targets

Oversimple Solutions will not Work

Source: Anisimov et al, GSK BDS Tech Report 2003

Different Approaches will haveDifferent Completion Times

Source: Anisimov et al, GSK BDS Tech Report 2003

Cancer Trial Enrolment Issues

Only 3% of adults with cancer participate in clinical trials

far fewer than the number needed

Up to 80% of clinical trials are estimated to experience problems with recruitment

Source: American Society of Clinical Oncologists, Press Release 1999

Methodology to Particular Study Recruitment Issues and Solutions

• Identify patient recruitment barriers through an extensive review of the factors that hinder recruitment and retention – eg. complicated protocols, over-rigorous inclusion and exclusion

criteria, professional and cost barriers etc.

• Identify solutions that work – illustrated by extensive review and numerous case histories of

strategies and tactics that have been shown to improve recruitment and retention

• Understanding of cost-effective means– Advertizing– Technological and other innovations introduced by CROs – Strengths of emerging hubs like India, their cost benefits, large

populations, pharmacogenetic profiling ….

Barriers & Promoters

• Barriers mainly 3 types– barriers to opportunity to participate (most)– barriers to awareness or acceptance of clinical

trials– cultural factors

• Promoters mainly 3 types– awareness– transport– altruism

A Survey on Clinical Trial Barriers

• A survey of almost 6,000 people with cancer conducted in 2000– 85% were either unaware or unsure that participation in clinical

trials was an option– 75% said they would have been willing to enroll had they known – of the aware ones of clinical trial option, most declined to

participate because of common myths about clinical trials:• The medical treatment they would receive in a clinical trial would be less

effective than standard care• They might get a placebo• They would be treated like a "guinea pig"• Their insurance company would not cover costs

Source: www.harrisinteractive.com/harris_poll/

Main Barriers to Enrolment

• Patient age • Comorbidity• Disease stage• Mistrust of research method and researchers• Lack of physician/care giver awareness about trials• Communication• Method of IC presentation • Community based approach versus Institution based

approach

Specific Barriers • Long-standing fear, apprehension, and skepticism

• Doctors may not mention clinical trials as an option for cancer care.

• People from various cultural or ethnic backgrounds hold different values and beliefs that may be different than principles of Western medicine.

• Language or literacy barriers may make it difficult for some people to understand and consider participating.

• Additional access problems confront many people

Barriers for Researchers & Clinicians• Lack of awareness of appropriate clinical trials

– not always aware of available clinical trials, local resources

– may assume that none would be appropriate for their patients

• Unwillingness to "lose control" of a person's care

– relationship with patients is very important

– doctors fear they may lose control of the person's care

• Belief that standard therapy is best or participating in a clinical trial adds an administrative burden

• Concerns about the person's care or how the person will react to the suggestion of clinical trial participation

Cost Barriers

• The costs associated with clinical trials can be a barrier for many professionals and the public

• Physicians are often concerned about reimbursement related to the expense of either caring for people enrolled in trials or offering trials within their practice

• Potential trial participants often fear that their insurance company will not cover participation

• Those who are uninsured will need to know how their participation in a trial will be covered

Successful Recruitment

• Detailed understanding of the stages in the recruitment process

• Identification of steps where potential patients are lost

• Development of alternative tactics to enhance recruitment.

• Timeliness & cost containment• Ability to detect subtle treatment effects • Meeting ethical responsibilities to patients and

clinicians• Employment of an enthusiastic, committed and

talented staff• Initiative and adaptability to recruitment problems

Impact of Protocol Exclusionse.g., Elderly trials

Source: Lewis et al (2003), J Clin Onc, 21, 1383-89

Successful Recruitment of Hospitalized Patients

• Provide checklists on patient charts with eligibility criteria

• Placing posters with open protocols listed• Using abridged "protocol pocket cards" with key

inclusion and exclusion criteria• Dedicate one research nurse or research assistant– to identifying and screening participants– coordinating pre-enrolment tests– educating participants about the protocol and process– and initiating the informed consent and enrollment process

• Access funding for clinical trial support

Successful Recruitment

• One particular study– the study nurse being employed for longer hours (P<0.001)– the use of a coronary care register to identify eligible

patients (P=0.001)– a systematic recruitment plan with targets and timetable

(P=0.02)– the invitation of patients by both a personal letter and

follow-up phone call (P=0.09)– regular contact with the patients' usual doctors and

adequate funding of centres

Source: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia

Another Study: Recruitment Facilitation Factors

• Interest in the research question, participation did not require any unusual management practices

• Toll-free telephone randomisation and a simple one-page outcome form each took only a few minutes to complete

• Well-organised and committed principal nurses• Ongoing staff training• Investigators’ meetings• Regular communication and target setting• Barrier

– minimal financial recompense for staff time– many potentially eligible patients could not be recruited because of the lack of staff time

to dedicate to research

Source: Clinical Trials Research Unit, University of Auckland, Auckland, New Zealand

Effect of an Intervention Program

• Intervention program consisted of the installation of a rapid tumor-reporting system – to improve data quality and to expedite the receipt of information on

cancer patients from physicians– a nurse facilitator who would notify physicians of clinical trials– a quarterly newsletter mailed to physicians about cancer treatment and

clinical trials– a health educator who trained lay health educators and provided

community-based information about cancer screening, treatment, and clinical trials

• The rates of enrollment into clinical treatment trials did not improve significantly in the intervention communities

Source:Ford Met al Clinical Trials 2004;1:343-51

Differences Between Passive and Active Recruitment

• Patients were employees• In the passive employee contact arm– employees were contacted from a list of employee names

and telephone numbers provided by the company• In the active employee contact arm– employees actively signed up to participate

• While lower enrollment and higher attrition were observed in the passive recruitment arm, the passive method enrolled a more diverse group of participants than did the active recruitment method

Source: Linnan LA et al Ann Behav Med 2002;24(2):157-66

Participation – Can be a very Positive Experience

– In an International Poll

– 97% – treated with dignity and

respect

– quality of care excellent or good

– 86% – treatment was covered by

insurance

Source: www.harrisinteractive.com/harris_poll/

Thank You