Recruiting and Retaining Clinical Trial Patients

By Dave Betz, Dana Betz and Diane Leahy – OmniTrace Corp.

What is a major area of concern and associated consequences in clinical trial conduct?

Clinical trial failure is a major concern, as 80% of failures are caused by the inability of research sites to find and enroll sufficient patients and meet timelines.¹ Failure in recruiting and retaining clinical trial patients has the greatest impact on trial costs, delays, and failures. Sites that optimize clinical trial patient recruitment so that patients are retained and not lost to follow-up (LTFU) will be more successful in the long term.²

What procedures can be implemented to recruit clinical trial patients more successfully?

Several clinical trial patient centric approaches can increase success rates. One such approach that has shown success is recruitment web-based systems.³ For potential patients, these systems offer online clinical trial information including the therapeutic area under study; inclusion / exclusion criteria; investigational drug benefits and side effects; instructions on patient consent; and site locations. For investigators, such tools can expedite the recruitment development process, collect performance metrics in real time, and streamline ongoing recruitment management.³

What approaches have shown success in retaining clinical trial patients more successfully so they are not LTFU?

Incorporating case management and clinical trial patient education approaches into the care process for study subjects has been shown to improve patient compliance and patient satisfaction,² factors that subsequently reduce clinical trial patient dropout rates. Additionally, a process to assure that patient dropouts are located expeditiously so they can be placed back into the study so as not to lose important data is essential.

 What process should be implemented to find patients LTFU?

Companies with expertise in finding people can offer a valuable service in locating clinical trial patient dropouts.  Therefore, contacting a people locate company with this proficiency, such as OmniTrace, during patient recruitment may avoid the consequences of patient dropouts becoming forever LTFU.  

Who is OmniTrace and how can it assist drug manufacturers in finding patients LTFU?

OmniTrace is a people locate company that has been in operation for 8 years.  OmniTrace has a stellar record of success in locating tens of thousands of people worldwide, servicing several sectors including the pharmaceutical  /biotechnological industry in finding clinical trial patient dropouts and those LTFU.  As mentioned, as every participant in clinical research is a valuable source of safety information, locating patients LTFU is critical to maintaining a robust risk management system.

 1. D. Myshko, “Global Development,” PharmaVoice, March 2009, 24 -29.

2. E. Moench, “The Business of Recruitment,” Applied Clinical Trials, March 2009, Trends in Subject Recruitment Insert, 8-10.

3. Streamlining Clinical Trials, www.clinicaltrial benchmarking.com (2008).

Recent reports have indicated that the Health Insurance Portability and Accountability Act (HIPAA) that went into effect in 2003 has adversely affected clinical trial conduct and patient retention by imposing significant time and cost burden and by impeding clinical trial recruiting and patient retention,¹ which in turn has deterred patient search efforts–locating patients lost-to-follow-up.  This commentary will serve as the third of a series that will discuss strategies to enhance patient retention and finding patients lost to follow-up based on evolving interpretations of the HIPAA regulations.

Challenges of Patient Retention

When conducting a clinical study on a treatment or intervention, it is imperative to retain patients throughout the entire study duration and for a follow-up period, which can be months or even a decade for longitudinal studies.  Patient retention for study duration and follow-up represents a major challenge and we must address this issue to avoid potentially devastating consequences to the clinical trial industry.² 

In fact, estimates reported in 2003, before HIPAA- impact, indicate that 85% of trials do not finish on schedule, 60% to 80% of clinical trials do not meet their chronological endpoints because of challenges in recruitment, and 30% of trial sites fail to recruit even a single participant.²  

Additionally, disappointing statistics show that 26% of patients drop out after providing consent and greater than 94% of studies are delayed due to failed enrollment / patient retention (including patients lost to follow-up).  The situation is worsening in large part due to HIPAA regulations.  In fact from 1997 to 2003, the percentage of studies completed on time decreased from 18% to 6%.^3,4  The costly consequences of trial delay are so staggering  that each day of delay can equate to  $220K, and a 2 month delay can equate to $70 million potential product sales due to postponed launch.

Strategies to Enhance Patient Retention

We can enhance retention of participants by utilizing appointment reminders with the caveat that this process must be cognizant of participant privacy.  Under HIPAA, postcard reminders are discouraged due to the possibility of a patient’s medical diagnosis being inferred by anyone seeing the postcard (by virtue of a study logo or clinic’s name). Therefore, if utilizing mail reminders, enclose in an envelope without a return address that includes the affiliated study group (e.g., the Diabetes Research Group).²   Additionally, a mail reminder should not resemble a medical bill as patients may delay opening.

Utilizing a mail reminder several days in advance, followed by a telephone reminder 24 to 48 hours prior to a follow-up appointment is an effective strategy for patient retention.  Utilizing this method, ensures that the patient’s protected health information (PHI) is not revealed.  For example, if an appointment reminder is recorded on a patient’s answering machine the message should only provide the date and time for the pending appointment, and a contact number if needed by the patient for questions or re-rescheduling.  While, e-mail has become another option for appointment reminders, we must recognize that older adults may not be computer savvy and some minorities may not have e-mail access.²

Reimbursement of patients is also a well-known strategy for effective patient retention.  However, the processes of reimbursement must be consistent with participant privacy.  The standard patient reimbursement process involves the research facility’s accounting department forwarding a check to the patient’s home.  Patients can also be reimbursed with gift cards, books of stamps, and other monetary equivalents.

Lastly, a critical element of patient retention strategies are plans that include patient search initiatives to locate those lost to follow-up quickly and efficiently so they return to the study in a timely manner.  It has been shown that if patients lost to follow-up are contacted expeditiously they will return to the study, either during the ongoing phase or for follow-up evaluations. This is critical because loss of patients equates to loss of data; loss of data causes trial delay; trial delay negatively affects regulatory submission and subsequent product launch; and together this debacle of events leads to an extremely high cost burden.

References:

1. Blanton, B. et al. Lessons learned in participant recruitment and retention: The EXCITE Trial. Physical Therapy. 2006; 86: 1520-1533.

2. Wipke-Tevis, D. Impact of the Health Insurance Portability and Accountability Act on participant recruiting and retention. Western Journal of Nursing. 2008;30: 399-53.

3. 5^th annual patient recruitment and retention conference September 24-25, 2007; Washington DC; Data presented by John Benbrook and Malcolm Bohm of MMG & trialytics, Inc.

4. 101 facts about clinical research (2005) Accessed at www.ciscrp.org 

5. Nature Reviews Drug Discovery 2, 851 (November 2003)

6.  DataMonitor (2004), patient recruitment online

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Please share your thoughts regarding our post on Patient Retention.  And, please do email or call us with any questions you have about our OmniTrace Corp. patient search and patient retention services:

dave@omnitrace.com (Dave Betz)
888-965-6696

THE CONTENT ON OUR OMNITRACE OWNED WEBSITES IS MERELY GENERAL INFORMATION OBTAINED BY ORDINARY PEOPLE AND NOT LEGAL ADVICE.  ONLY A QUALIFIED LAWYER CAN GIVE LEGAL ADVICE.  WE ARE NOT LAWYERS.

Recent reports have indicated that the Health Insurance Portability and Accountability Act (HIPAA) that went into effect in 2003 has adversely affected clinical trial conduct by imposing significant time and cost burdens, and by impeding clinical trial recruitment and retention,¹ which in turn has deterred finding patients lost-to-follow-up (LTFU).  This post will serve as the second of several that will discuss strategies to enhance recruitment, retention, and finding patients lost-to-follow-up based on evolving interpretations of the HIPAA regulations and will focus on initial patient contact.

Contacting eligible participants for clinical trial recruitment is a challenge and HIPAA regulations have made this process more complicated.  Pre-HIPAA, patient lists and their contact information were accessible for review, and clinical study personnel were able to identify and subsequently contact eligible participants. 

Conversely, post-HIPAA, the contact information of potential participants cannot be accessed without the participants’ explicit authorization, a clear hindrance to the contact and clinical trial recruitment process.  In this regard, the burden shifted to the health care provider (who now becomes the recruiter), already inundated with patient care responsibilities and time constraints, to introduce the study to the patient and obtain their consent for subsequent contact.² 

As a result, there have been substantial decreases in participant accrual, as well as increases in recruitment costs.  For example:  studies have reported that clinical trial recruitment has decreased from an average of 12.4 participants per week pre-HIPAA to 1.9 participants per week post-HIPAA.^3,4 Additionally, recruitment costs have increased from $49 per participant to $169 per participant post- HIPAA, a situation particularly problematic for studies already in progress at the time of the HIPAA implementation.⁴

Despite the burden the HIPAA privacy rule has placed on contacting patients for clinical trial recruitment, deliberation of the seemingly logical intent of these regulations, along with prior planning can facilitate these efforts.  In response to the HIPAA privacy rule, routine clinic visits by study personnel such as medical directors, nurses, etc., now speak directly to patients about their eligibility and study participant interest vs. identifying their names from lists.  Clinical collaborators and staff liaisons now obtain patient authorizations with their contact information and provide this data to the appropriate persons for study recruitment.  Additionally, clinical collaborators write letters on the clinicians’ letterhead including clinicians’ signature to potential eligible patients of interest, informing them of the study.⁵

Further, a number of other innovative-HIPAA compliant strategies have been implemented to make initial contact with participants, subsequent to local IRB approval.  These include:  flyers, advertisements, and electronic media.  Flyers are posted at health care institutions such as hospitals and clinics, as well as in community locations including pharmacies, public libraries, and senior and community centers.  

Most academic health sciences centers have a web page advertising current clinical trials that are designed to include contact information of the study coordinator, or to include a study sign-up form embedded on the page to be completed by those interested.  An example of this form is located at https://apps.muhealth.org/clinical_research/.²  

Subsequent to receipt of participant information, the study site calls respectively to gain additional eligibility criteria, or PHI per HIPAA.  It’s important to note that no specific HIPAA guidance is available on this last contact approach, therefore logic should prevail and many institutes interpret this contact NOT to require additional HIPAA or alternative authorization because the person is freely volunteering to provide his or her health information.

Because the challenges imposed by HIPAA for clinical trial recruitment, retention, and finding patients lost to follow-up are ambiguous, logical interpretation and processes must guide the clinical trial conduct process until further clarification and guidance are made available.

A future post will focus on processes compliant to patient retention and long-term follow-up.
References:

1. Blanton, B. et al. Lessons learned in participant recruitment and retention: The EXCITE Trial. Physical Therapy. 2006; 86: 1520-1533.

2. Wipke-Tevis, D. Impact of the Health Insurance Portability and Accountability Act on participant recruiting and retention. Western Journal of Nursing. 2008;30: 399-53.

3. Ness, R. B. (2005). A year is a terrible thing to waste: Early experience with HIPAA [Editorial]. Annals of Epidemiology, 15, 85-86.

4. Wolf, M. S., & Bennett, C. L. (2006). Local perspective of the impact of the HIPAA privacy rule on research. Cancer, 106, 474-479.

5. Olsen, D. P. (2003). HIPAA privacy regulations and nursing research. Nursing Research, 52, 344-348.

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Please share your thoughts regarding our post on Addressing Clinical Trial Recruitment and Retention Issues Imposed by HIPAA.  And, please do email or call us with any questions you have about our OmniTrace Corp. patient search and patient retention services:

dave@omnitrace.com (Dave Betz)
888-965-6696

THE CONTENT ON OUR OMNITRACE OWNED WEBSITES IS MERELY GENERAL INFORMATION OBTAINED BY ORDINARY PEOPLE AND NOT LEGAL ADVICE.  ONLY A QUALIFIED LAWYER CAN GIVE LEGAL ADVICE.  WE ARE NOT LAWYERS.

Subsequent to our recent post that focused on these factors that hinder the conduct of clinical trials as a consequence of the HIPAA, this commentary will serve as the first of several that will discuss strategies to enhance recruitment, retention, and finding patients LTFU based on evolving interpretations of the HIPAA regulations.  

The first of these series will focus on initial procedural practices to facilitate participant recruitment–considered the most difficult aspect of the research process¹–and made even more difficult due to HIPPA.  Estimates reported in 2003, before HIPAA- impact, indicated that 85% of trials do not finish as scheduled because:

• There is low participant accrual.
• Sixty to eighty percent of clinical trials do not meet their chronological endpoints because of challenges in recruitment.
• Thirty percent of trial sites fail to recruit even a single participant.²

Despite the burden that the HIPAA privacy rule has placed on participant recruitment, retention and finding patients lost to follow-up (LTFU), deliberation of the seemingly logical intent of these regulations, along with prior planning, can facilitate clinical research efforts.  Consider one initial important process in study planning–preparatory research.  It is a necessity to identify potential sample populations available for recruitment and estimate those who will meet inclusion criteria.³   This task obviously requires the need to review individuals’ health information and the ability to subsequently contact these respective individuals.

Pre-HIPAA, these activities were not regulated by the Investigation Review Board (IRB), however, in the post-HIPAA era accessing this information– protected health information(PHI)–requires IRB or privacy board approval.⁴

Keeping in mind that logic must prevail, the initial fears of HIPAA caused institutes not to allow medical record access without patient consent.  This led to increased interruption in recruiting patients, and following the realization of no patients, no study interpretations, were adjusted to allow HIPAA waivers of authorization to facilitate this process.

Although logical interpretation can reign in situations of HIPAA non-clarification/guidance, abiding to regulatory standards such as completing a Preparatory to Research form and submitting to the local IRB or privacy board has been clearly confirmed.  The form must answer the following questions:   

• What is the purpose of the review?
• What PHI will be used or disclosed?
• Why is the PHI necessary for the research?
• Where is the information located?
• How will the information be assessed and by whom? ³

Only the minimal PHI from the covered entity (i.e., health plan, health care clearinghouse, or health care provider who transmits any health information in connection with a HIPAA transaction) is utilized to answer the questions on the form.  If no treatment relationship exists between the institute and prospective participants, the institute should work with the hospital or clinic staff to contact potential trial participants identified in the preparatory research. ³

Because the challenges imposed by HIPAA for recruitment, retention, and finding patients lost to follow-up (LTFU) are ambiguous, logical interpretation and processes must guide the clinical trial conduct process until further clarification and guidance are made available.

Our next post will focus on processes compliant to initial contact of participants and the consent process.

References:

1. Blanton, B. et al. Lessons learned in participant recruitment and retention: The EXCITE Trial. Physical Therapy. 2006; 86: 1520-1533.

 2. Nitkin R. Patient recruitment strategies. Training workshop conducted by National Institutes of Health, Bethesda, MD, 2003.

 3. Wipke-Tevis, D. Impact of the Health Insurance Portability and Accountability Act on participant recruiting and retention. Western Journal of Nursing. 2008;30: 399-53.

 4. U.S. Department of Health and Human Services. (2004). Protecting personal health information in research: Understanding the HIPAA privacy rule. Retrieved March 15, 2006, from http://privacyruleandresearch.nih.gov/HIPAA_Booklet_4-14-2003.rtf

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Please share your thoughts regarding our post.  Also, please email or call us with any questions you have about our OmniTrace Corp. patient search and patient retention services:

dave@omnitrace.com (Dave Betz)
888-965-6696

THE CONTENT ON OUR OMNITRACE OWNED WEBSITES IS MERELY GENERAL INFORMATION OBTAINED BY ORDINARY PEOPLE AND NOT LEGAL ADVICE.  ONLY A QUALIFIED LAWYER CAN GIVE LEGAL ADVICE.  WE ARE NOT LAWYERS.

Conducting clinical trials is becoming increasingly arduous for drug manufactures due to several factors including: (a) heightened food and drug (FDA) regulatory scrutiny based on recent safety concerns; (b) inefficiencies and/or unclear guidance imposed by Health Insurance Portability and Accountability Act (HIPAA) guidelines in the research, design, enrollment and follow-up processes; (c) and increased demand and competition for patients due to a plethora of investigational products under study, as well as the increased scope and design of studies.¹ 

An obvious critical determinant of successful clinical trial research and subsequent product approval is to assure full compliance of regulatory/guidelines mandates of governing authorities throughout the entire clinical process. Other key determinants associated with the success and efficiency of clinical trials are recruitment, retention² and return, especially when drop-outs of a study become lost to follow-up (LTFU). This is particularly important because a patient LTFU, if found, may be willing to return to the study. Therefore, effective retention initiatives require means to find those LTFU.  Additionally, participants in clinical studies are invaluable for poststudy pharmacovigilance programs, so retention strategies that include LTFU is imperative, especially as it relates to an adverse event or other development affecting the safety or efficacy of the product either under study, or post marketing.² 

Low rates of recruitment and retention and high rates of patients LTFU have a number of negative implications including longer durations of the clinical trial and a costlier clinical trial, since extra resources may need to be dedicated to the recruitment effort; and there is less statistical power for both the study and the validity of the results.  In fact, almost 90% of trials are delayed, primarily due to patient recruitment and retention / LTFU problems.  Depending on the investigational drugs potential, every day of delay can cost a pharmaceutical company $600,000 to $8,000,000 dollars.¹

Overall, poor clinical trial recruitment, retention / LTFU initiatives is therefore likely to impede the successful evaluation of new and existing interventions, and prevent greater efficiency and safety in clinical development.³ 

Summary:  Efficiency of clinical trials requires strategic iniatives that favorably affect recruitment, retention and lost to follow-up processes. 

 
1. Datamonitor. Online recruitment is streamlining clinical trails. July, 2008. Available at: www.datamonitor.com

 2. J. Weschler. Applied Clinical Trials Oneline. Privacy Restrictions Alarm Clinical Researchers (July. 2002). Available at: www.datamonitor.com

 3. B. Spilker and J.A. Cramer, Patient Recruitment in Clinical Trials (Raven Press, New York, 1992).

Please share your thoughts regarding our post on Efficiency of Clinical Trials.  Also, please email our call us with any questions you have about or OmniTrace Corp. patient search and patient retention services:

dave@omnitrace.com (Dave Betz)
888-965-6696

THE CONTENT ON OUR OMNITRACE OWNED WEBSITES IS MERELY GENERAL INFORMATION OBTAINED BY ORDINARY PEOPLE AND NOT LEGAL ADVICE.  ONLY A QUALIFIED LAWYER CAN GIVE LEGAL ADVICE.  WE ARE NOT LAWYERS.

Anxiety lurks among manufacturers of type 2 diabetes drugs, especially those manufacturers who have drugs in late clinical development. 

Recent FDA advisory committee recommendations have created an ongoing debate over whether Investigational diabetes agents should be subject to long-term cardiovascular safety. ¹   A firm consensus has not been reached,  however, several manufacturers are already scurrying to develop plans and design studies addressing impending implications of a confirmative study requirement.

There are 131 diabetes pipeline drugs, including 80 in phase 2 and phase 3 development.  Obvious consequences relating to study conduct will be increased competition among the many sponsors to recruit the appropriate patient type for safety assessment-subsequently retaining these patients in the study long-term and preventing lost to follow-up. 

For those agents in late stage development, slow recruitment, poor retention and ultimate study delay could potentially cause loss of a first-to-market position.  This could cost a drug manufacturer millions in revenue over the lifestyle of the drug.

Background

Several drugs in this therapeutic area raised cardiovascular safety concerns (rosiglitazone [Avandia, GalaxoSmithKline] and muraglitizar are recent examples). ¹ Compounding these concerns are:

• The recent results of the ACCORD trial-patients had increased mortality when patients underwent intensive glucose lowering. ³ 
• Unexpected results from ADVANCE, VADT and HEART2D-no CV benefit shown with intensive glucose lowering. ⁴-6

This apprehensive setting has led to FDA committee recommendations to increase the level of evidence of cardiovascular safety of new therapies for type 2 diabetes based on the requirement to conduct long-term trials or provision of equivalent evidence to rule out an unacceptable cardiovascular risk. ¹

There are several specific issues still under discussion:  (1) whether these cardiovascular assessments should occur pre- or post- approval and (2) several design considerations. ¹  However, there is no doubt that the clinical development process, approval time and cost of developing and marketing type 2 diabetes agents will dramatically increase. 

1, FDA Advisory Committee Recommends Cardiovascular Safety Studies for Diabetes Drugs [press release]. July 3, 2008. Available at: www.theheart.org.

2. Pipeline Insight: Non-insulin antidiabetics Incretin mimetics – leaders in a diverse pipeline.  Datamonitor [Reference Code: DMHC2395]. May, 2008.

3. Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.

4. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.  N Engl J Med. 2008;358:2560-2572.

5. The Veterans Affairs Diabetes Trial (VADT). Panel discussion at the American Diabetes Association 68th Scientific Sessions; June 6-10, 2008; San Francisco, CA.

Large, long-term Veterans Affairs diabetes trial (VADT) reveals important cardiovascular safety news on Avandia [press release]. PharmaLive. June 8, 2008.

6. HEART2D Study Produces No Cardiovascular Benefit by Targeting Postprandial Glucose Levels [press release]. Medscape Medical News. June 11, 2008.

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Please share your thoughts regarding our post on clinical trial recruitment / retention issues for manufacturers of diabetes agents.  Also, please email or call us with any questions you have about our OmniTrace Corp. patient search and patient retention services:

dave@omnitrace.com (Dave Betz)
888-965-6696

THE CONTENT ON OUR OMNITRACE OWNED WEBSITES IS MERELY GENERAL INFORMATION OBTAINED BY ORDINARY PEOPLE AND NOT LEGAL ADVICE.  ONLY A QUALIFIED LAWYER CAN GIVE LEGAL ADVICE.  WE ARE NOT LAWYERS.