Volunteer recruitment in clinical trials

Patient recruitment & Retention Strategies in Clinical Studies in India

Rashmi Pant

Issues & Challenges of patient recruitment in India

The two-headed image of the Roman deity Janus reminds us of a person who talks out of both sides of their mouth at once, such as when a sponsor talks quality but means quantity.

Source: Pictured above is a Roman Republic coin from c.225 – 212 BC, showing the Laureate Head of the Roman deity Janus.

Author: Guy P. Johnson, CPA, MS

Recruitment Problems

• Although companies have brought in numerous technology and management measures to improve their clinical trials, inefficiencies in the process continue to present problems.

• One estimate suggested that despite technological advances in pharmaceutical R&D, nearly 80% of all clinical studies for new products failed to finish on time, and 20% of those were delayed for 6 months or more`

• Competing with private physicians for patients• Providing basic care rather than referring patients back to

primary care physician • Failure to maintain adequate contact with referring physician • Attempting recruitment without the support of colleagues • Access to medical records for granted• Failing to secure enthusiasm and commitment of staff • Inadequate publicity

Source: Patient recruitment in Clinical trials: Piribo Report

Recruit and retain study volunteers – The Ultimate

Challenge• There are approximately 50,000 clinical trials taking place in the United

States, 90% are delayed because of unfulfilled enrollment. (Source: Federal Drug Administration)

• An overwhelming majority of people (77%), say that they would consider getting involved in an appropriate clinical research study if asked; only 10% of those eligible to participate in clinical trials do so in the United States. (Source: Harris Interactive)

• In a recent poll, 94% of people recognize the importance of participating in clinical research in order to assist in the advancement of medical science. Yet 75% of the general public state that they have little to no knowledge about the clinical research enterprise and the participation process. (Source: Center Watch)

• There is a lack of balance in representation in popular media with two times as many negative as positive articles in 2002.

Source: http://www.mc.uky.edu/ukcro/manual/recruitment_and_retention_page.htm

Cost of Therapy: Rising R &D Costs

• Increasing Global R & D Expenditures from 1998-2001 by 121%.

• R &D spend of US Pharma. comps vs. NME approvals 1993-2003

• Pharmaceutical Industry – R &D Intensive.

• Rising Drug development expenditures

• Rising Drug Development Times

• Declining R &D productivity

Cost of Therapy: Rising Clinical developmental costs & Drug

development times

35 6 6

3

5

6 7

2

2

32

0

2

4

6

8

10

12

14

16

1960's 1970's 1980's 1990-98

Preclinical Clinical Approval

Rising Clinical Development Costs

Years

Increase In Drug Development TimesSource: Reuters Business Insights

Cost of Therapy: Increase in outsourcing

46.7 50.458.3

68.179.2

91.39.3

10.6

13.9

18.8

26

36

0

20

40

60

80

100

120

140

2001 2002 2004 2006 2008 2010

Global In House R &D Outsourced R &D

% R & D Outsourced

Source: Reuters Business Insights

Increasing Patient recruitment in clinical trials

• 23 clinical dossiers submitted between February 1995 and April 1999 to regulatory authorities in Europe, the USA and Japan

• Dossiers contained on average 35 clinical trials, involving on average more than 4,000 subjects each.

• According to another analyst, mean number of patients per New Drug Application (NDA) to be 3,233 between 1985 and 1988. 1998 to 2001 this mean number had risen to 5,303

patients per NDA.

Source: Peck, C., “Drug Development: Improving the Process”; cited by: M-J. Lamberti. The Changing Climate of Clinical Research. Presentation at the Association for Clinical Data Management (ACDM) Meeting (15-17 February 2004 Bristol, UK

Recruitment process: Pre-Screening

• Stages of research subject recruitment – Pre-screening research subjects

• Develop a recruitment strategy• Develop a plan to contact or reach patients • Contact referral groups• Utilize advertising media (IRB approval needed)

– integrate into your budget• Carefully review your patient database against

the inclusion and exclusion criteria• Is this study compatible with the practice

population

Recruitment Process: Screening Screening of research subjects

• Discuss the clinical trial with the prospective research subject

• Assess the patient’s initial interest based on study requirements and scheduling

• Conduct initial screening questions using inclusion/exclusion as guide, use checklist, part of source documents

• Conduct initial history, physical, and clinical laboratory screen (also special laboratories)

• Re-screen or conduct a more detailed secondary screen to confirm labs, ask detailed questions, schedule additional tests

• Obtain patient’s informed consent

Aims of Ethics Committee in Subject recruitment

• Protect the rights and welfare of research subjects

• Protect the rights of researchers to conduct studies

• Minimise the potential for claims of negligence against the researchers or the University

Drugs Controller General of India (DCGI)

• The Drugs Controller General of India (DCGI) is responsible for regulatory approvals of clinical trials in India (7). The DCGI’s office depends on external experts and other government agencies for advice. Additional permissions are required for the export of blood samples to foreign central laboratories.

• Certain recent changes in regulatory affairs encourage clinical trials in India. In 2005, the Schedule Y of the Drugs and Cosmetics Act was amended. Earlier, foreign drugs trials could be conducted only at one phase below the highest phase of testing abroad. Now, parallel global clinical trials are possible in India. Permission is granted for concomitant phase 2 and phase 3 trials.

Ethical recruitment of subjects in India

• Low literacy levels- can delay in enrolment of subjects due to lack of understanding

• Drop out rates may be high if the subject has to travel a long distance.

• Confidence in an investigator makes a difference in enrolment

• Help from Social worker could enhance the enrolment

Source: www.chillibreeze.com

Subject retention – Treating Study Volunteers as Customers

Retention Strategies are rooted in principles of customer service:1. respect & honesty = retention 2. being informed 3. convenience 4. perceived value in care 5. education and counseling 6. special treatment – holiday cards, token gifts 7. availability & responsiveness (24/7 access for high risk trials) 8. connection – get to know the volunteer 9. Utilize compliance enhancers (study drug logs, pill dispensers,

appointment reminder cards, wallet cards with study information, etc.) 10.Follow-up on open adverse events to both sponsor and subject

satisfaction 11.Document and track reasons for volunteer drop-out 12.Utilize an end-of-study feedback questionnaire 13.Follow-up after the trial - 79% of study volunteers report NO follow-up

after study completion (un-blinding or results when available, volunteer newsletters to past subjects, etc.)

Long Term Follow Up- After study

Retention is 1/5 the cost of recruitment so it is a worthwhile investment.

Source: http://www.mc.uky.edu/ukcro/manual/recruitment_and_retention_page.htm

1. Attempts to contact subjects lost to follow up to complete a termination or final visit should be documented.

2. Document in subject’s progress notes attempts to contact subject via phone.

3. Send registered letter, keep a copy of letter and postal receipt.

4. E-mail attempts if applicable

Recruitment Errors

• Competing with private physicians for patients• Providing basic care rather than referring patients

back to primary care physician • Failure to maintain adequate contact with referring

physician • Attempting recruitment without the support of

colleagues • Access to medical records for granted• Failing to secure enthusiasm and commitment of

staff • Inadequate publicity

Recruitment Concerns-1

• Patient attitudes – community standards, individual psychosocial factors about healthcare research, and negative publicity

• Provider attitudes – pressure from sponsor to recruit, inclusion/exclusion criteria, uneven recruitment planning

• Sponsor attitudes – unaware of research subject attitudes, pressure to develop new drugs in a timely and cost effective manner

Recruitment Concerns-2

• Ethical contradictions in the context of sponsoring, monitoring, and evaluating a clinical research program

• Inclusion/exclusion criteria

• Wide concerns from FDA and DHHA

• Growing concern over clinical trial recruitment strategies and tactics for ensuring adequate enrollment and retention

Common errors in the consent process

1. Inadequate time

2. Failure to specify required procedures

3. Inadequate documentation

4. Vague or inaccurate statements

5. Making commitments which cannot be met

6. Use of false statements to protect study design

7. Consent after the fact

8. Speaking for the patient

Critical Factors in recruitment

• Identifying, Recruiting, Enrolling patients is the most challenging part of any clinical trial…

• Participation rates are low 3% to 20% of potential subjects who are screened

• Oncology patients enroll in clinical trials ~8% of the time

Volunteer recruitment “Flaws”

• Investigators overestimate the pool of available patients who meet inclusion criteria that are willing to participate in clinical research.

• “Funnel Effect” of recruiting research subjects – “dwindling returns” when screening

• Illustrates the progressive shrinking of the research subject population prior to enrollment--Usually related to the clinical trial

• End result is the number of research subjects who enter the clinical trial

Volunteer “Myths”

• Survey of oncology patients (Harris Feb 2001)• 5972 cancer patients surveyed about clinical trials• 85% unaware or unsure that participating in clinical

trials was a treatment option• 75% said they would have been willing to participate• 33% said they would be better off taking standard

treatment• 29% feared they would receive placebo• 20% feared they would be treated like “guinea pigs”• 18% feared doctor would not be able to choose best

treatment

“Funnel Effect”

• 8027 research subjects screened– 3103 unavailable during key hours– 4254 preliminary exclusion– 21 not screened for various reasons– 258 rejected prior to interview– 53 rejected after interview– 92 not consenting– 146 not medicated

100 research subjects enrolled

Emerging trends In Volunteer recruitment

• The number of multi-centre clinical trials being carried out in the Central and Eastern Europe (CEE) is growing on average at an annual rate of 30%.

• High patient recruitment rates and cheaper costs associated with the CEE region have led to various companies attempting to develop their drugs in these countries.

• However, CEE is a very large area, comprising of many different countries with their own customs and systems, and it is important that the sponsor carefully selects which individual countries will best suit their needs .

Emerging trends In Volunteer recruitment-1- Wyeth

• Recent increasing trends in volunteer recruitment are observed countries in Latin America, Central & Eastern Europe & Asia-Pacific.

• Traditional Methods of patient enrollment were placed aside.• Factors taken into consideration during patient recruitment were outlined

based on the following:– Collection of historical clinical trial data from the year 2000 (roughly

5 Years data).– Evaluation of patient enrollment data country by country.– Evaluation of patient enrollment data country by country in terms of

typical timelines needed for regulatory bodies/ ethics committee approvals in various regions.

– No of drug indications: 50-100• Data extraction in a usable form for the end user.• Final output: web based SAS application.• Launched 6 Months ago.

Source: Scrip Magazine April 2006

Emerging trends In Volunteer recruitment -2- Wyeth

• Advantages: Helps in patient enrollment forecasting:

– Example of a Phase II Trial covering 20trial sites; 10 in USA & 10 in Europe.

– No of volunteers required to be enrolled are=100

– Time line for 100 volunteers to be enrolled: 243 days.

– For the above hypothetical model, for US, France & Spain, selection criterion for volunteer selection would exceed 243 days.

– However if the Czech republic & Estonia were taken for the study with 50 & 40 volunteers each & 10 in the study, the same can be completed in the required time.

• Country regulatory approvals, time required for patient enrollment etc. are the important simulations employed for this application

Source: Scrip Magazine April 2006

Case Presentation

Phase II Study-Oncology Product

Phase II Study-Oncology Product----1

A ) Challenges Faced

1.DCGI

2.Evaluation of an IND (Time, Manpower)

3.Permission to conduct the study

4.Restriction in number of Sites-Example- Centres & referral sites


B )Challenges Faced with I.E.C.

1.Existence & composition

2.Training-G.C.P., General

3.Approval of material for media

4.Reporting of serious adverse events


C )Challenges Faced with Patients

1. Understanding the importance of a study

2. “Guinea-pig” syndrome

3. Organizing the camps

4. Visit Issues-Distance

5. Reporting of sADR


Challenges at the site:

A)Investigator Training- To Make patient understand

the trial.- Benefit/Risk ratio- Counseling of patients- Reporting of ADRs


• Challenges at the site:B) Paramedical - Importance of trial

- Appointments resulting into drop outs

-Training of paramedics -Reduction in Drop out rate.


B) Recommendations- Coordinated approach- Regulatory

Understanding- Creating awareness- Retention in the trial

by: - 1)Regular follow up - 2)Handling of sADR - 3)Family Physician

involvement

`

Thank you