1. Enrolment of Trial Patients:
Challenges & Strategies
Presented at the NIPER Symposium on Clinical Research and Training,
February 21-22, 2009
Dr. Bhaswat S. Chakraborty
Senior VP, Cadila Pharmaceuticals Ltd.

2. Contents
1. Characteristics of Successful Trials
2. Enrolment
1. Strategies (pragmatic)
2. Variables (modelling)
3. Challenges (operational…)
3. Methodology to Study Optimum Enrolment
4. Barriers & Promoters
5. Impact of Protocol
1. I/E Criteria
6. Case Studies
7. Conclusions

3. 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

4. A Real Example of Enrolment Variations

5. 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

6. 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

7. 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 …

8. 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

9. Oversimple Solutions will not Work
Source: Anisimov et al, GSK BDS Tech Report 2003

10. Different Approaches will have
Different Completion Times
Source: Anisimov et al, GSK BDS Tech Report 2003

11. 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

12. 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 ….

13. 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

14. 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/

15. 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

16. 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

17. 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

18. 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

19. 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

20. Impact of Protocol Exclusions
e.g., Elderly trials
Source: Lewis et al (2003), J Clin Onc, 21, 1383-89

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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/

27. Thank You