Healthy Skepticism Library item: 17975

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: Journal Article

Wadhwa T
Clinical Trials – Still many miles to go ahead
NetRUM Newsletter 2010 Jun; 3:(2):5-13

Abstract:

(Recruitment & Retention of participants)

Full text:

‘Ethical behavior is the ethical way of adopting good ethical practices……..’
Clinical trials stand on two major pillars for efficient execution and successful completion i.e. recruitment and retention. Participant recruitment and retention are major factors in running and completing a successful clinical trial. Timelines can be tight due to both financial issues and the responsibility of answering a scientifically important question. Meeting recruitment targets is one of the keys to achieving the projected timelines. Therefore, when designing a trial, consideration needs to be given to how participants will be recruited, as well as to the science behind the protocol. Clinical research participants are not easy to find; a 2001 report from CenterWatch stated that over 85% of all medical research studies that were completed experienced enrollment delays, and 34% were delayed for more than one month.1
When reviewing an offer to participate in a clinical trial, PI need to consider whether enough eligible participants are possible to recruit. Inevitably, some target populations will be met more quickly than others e.g., recruitment times have been shown to be two to three times quicker for the therapeutic classes of anti-infective and antiviral treatments compared with those for cardiac therapies.2
Estimation of participant numbers:
The inclusion/ exclusion criteria serve as the starting point for targeting potential participants. Posters summarizing inclusion/ exclusion criteria can act as a prompt for staff and your institution to contact the study team if they see a suitable participant. Remember that any such materials/ information will usually need to be approved by institutional review board (IRB)/ independent ethics committee (IEC) prior to use.
Some hospitals have large research teams who review the eligibility of all participants admitted for participation in a trial. At other sites, there may only be the principal investigator (PI) and clinical research coordinator (CRC) managing one or more trials. Three important questions that enable a focused approach to looking for eligible participants are mentioned below.
QUESTIONS TO HELP YOU TO IDENTIFY WHERE TO LOOK FOR ELIGIBLE PARTICIPANTS
Question
Explanation
What is the severity of the condition being studied?
Will your participants be found in physicians’ surgeries or will they be hospital in-patients or out-patients?
Is the condition acute or chronic?
Participants with acute diseases are likely to be admitted as hospital in-patients.
Is there a specific location where you may find this participant population?
For example, you are most likely to find renal participants in a dialysis unit and post myocardial infarction participants in rehabilitation clinic.
FUNNEL EFFECT:
There is an almost invariable phenomenon called the ‘funnel effect’, whereby a likelihood of potential participants who are contacted about entering a clinical trial becomes progressively smaller as it passes through successive screens and the informed consent process. The funnel effect illustrates the progressive shrinking of the patient population prior to enrolling in a trial.3
The end result of the funnel effect is the number of participants who enter the clinical trial, and this number can be expressed as a percentage yield of those screened or initially contacted. It has been stated that a general loss of 90% of participants can be anticipated, although the screening yield probably depends on the type of trial population sought. The yield is primarily related to the inclusion criteria plus the protocol plus the motivation of participants to enroll.
This funnel effect could be extended to include dropout and discontinuation during the clinical trial, but these events are separate and relate to the clinical trial and not to the process of patient recruitment. Typically, participants either dropout on their own or are discontinued by the investigator. If some or all dropouts are to be replaced in a trial then additional participants must be recruited.3
Dropout rates vary widely (1- 50%) and are influenced by the following factors:
• outcome measure being used
• length of follow up
• type of study intervention
• the trial population itself
Dropout and discontinuation rates that are greater than anticipated threaten the successful completion of any clinical trial; anticipated dropout and discontinuation rates must be incorporated in sample size projections to determine the number of patients that should be recruited.
RECRUITMENT:
Generating interest in the study
It is important to remember that clinical research is a team effort. Before starting a study it is useful to make a list of everyone who will be involved in the trial. Good relationships need to be maintained with all members of the multidisciplinary team at all times in order to enable smooth running at the study site.
Examples of the multidisciplinary team members at a clinical research site:
• Pharmacists
• Transfusion specialists
• Ward nurses, doctors and administrators
• Medical records staff
• Accident and emergency department, and admission wards
• Other departments relevant to your study (e.g. X-ray, physiotherapy, dietetics)
• Out-patient staff
One of the important aspect for the research study is that all the study staff should be trained in relevant study procedures (this is a requirement of the ICH-GCP).
Advertising and marketing
Advertisements can be used to publicize study and can help to increase recruitment rates. However, there are many country- specific ethical, regulatory, and institutional regulations surrounding how and where studies can be advertised. Every advertisement needs to be approved by the IRB/ IEC before use.
Advertising should be carefully planned as part of the recruitment strategy and can be targeted directly to potential participants, encouraging them to volunteer, or to physicians so that they will refer suitable participants. It is important to decide on the characteristics of the target audience (e.g. age, race, gender) and to prepare the strategy accordingly. For example, a different strategy
would be required when targeting elderly people with heart disease than it would if the target population was young, healthy females.4
Advertising can be costly, and it is useful to look at the potential benefits before deciding on a strategy. Sponsors will often have an advertising program in place. Advertisements can be placed in newspapers, on the radio, TV, or internet, or delivered as handouts, e.g. in doctors’ surgeries, out-patient clinics, supermarkets, or other public places.5
It is important not to offer a ‘wonder cure’ or to be coercive. It is also essential to consider the size of an advertising campaign with regard to the facilities available for handling the responses generated and for scheduling appointments within a timely manner. In 2003, an analysis of prequalified study volunteers for phase II and III projects found that 13% of potential volunteers did not enroll because there was no conveniently located investigative site, 14% lost interest following their initial interactions with call center or study staff, and 23% were never randomized because no one contacted them after the initial phone screen.6
METHODS OF INCREASING RECRUITMENT RATES
METHOD
EXPLANATION
Increase the screening area
Review participant notes and hospital databases
Visit patient areas (e.g. wards, clinics) daily, if possible
Review screening logs from previous trials
Ensure colleagues are aware of the study
Regularly present the study at education meetings at your site
Regularly distribute information about the study (i.e. newsletters, posters)- remember that ethical approval is required for this material
Consider presenting the study at local research meetings
Use advertising and marketing
Target participant support groups
Write articles
Consider giving presentations to support groups
ADVERTISING GUIDELINES IN CLINICAL TRIAL RECRUITMENT7,8
US Food and Drug Administration (FDA)
Advertisements should not
• Be unduly coercive
• State or imply a certainty of benefit, beyond what is outlined in the informed consent document and the study protocol
• Claim that the treatment under investigation is safe or effective
• Claim that the treatment under investigation is known to be equivalent or superior to any other treatment
• Use terms such as ‘new treatment’, ‘new medication’, or ‘new drug’ without explaining that the test article is investigational
• Promise ‘free medical treatment’ when the intent is only to say that participants will not be charged for taking part in the investigation
Advertisements may:
• State that participants will be paid, but should not emphasize the payment or the amount to be paid by means such as bold type.
UK Association of the British Pharmaceutical Industry (ABPI)
Advertisements should not:
• Imply or express claims of safety or efficacy
• Place undue emphasis on reimbursement, although mention of reimbursement is permitted
• Express or imply that the research is FDA or MCA* approved
• Use the term ‘new’ unless qualified, i.e., ‘new research medicine’, ‘new investigational medicine’
• Use the compound’s name
In addition:
• Care should be taken to ensure that advertisements are in no way promotional for the medicine concerned *MCA: Medicine Control Agency.
COMPLIANCE AND RETENTION
What motivates participants?
Once a participant has been randomized into a study and has been allocated a treatment it is important to keep them in the study from this point on, both for their safety and for the integrity of the study results. Understanding the reasons that people have for participating should help you to retain participants. Two of the main motivations are:
• Many participants will have been ill for a long time and might not be getting much relief from their routine medical care. Such participants hope that the chance to be involved with a new therapy might improve their condition.
• Many prospective participants are aware that their own condition might not change, but are willing to take part in the hope that better treatment options will become available in the future, thereby decreasing the suffering of others.
Dispelling the myths
Often, participants comment that by taking part in the study they are receiving a better level of care through additional check-ups and in some instances, tests. While this might be true, it is essential that participants are aware that their care will not suffer in any way should they decide to withdraw their consent during the study.
Whatever their motivation, it is vital that potential participants fully understand that there may be no direct benefit to themselves. It is important to ensure that, if they decide to participate, they have no misconceptions- they must be aware that they might receive a placebo rather than the active drug, and that they might not get the ‘choice’ of treatment they would have preferred (e.g. surgery instead of a minimally invasive procedure).
Follow-up visits
The hard work continues even after a participant has been enrolled into a study. In order to ensure that participants make a useful contribution to the research, make sure that they feel comfortable taking part and where possible, withdrawal before the end of the study should be avoided.
The process of retention starts in the recruitment phase. If a potential participant feels pressurized into entering the study or does not fully understand what participation involves, then he/she is more likely to become unhappy and withdraw.
The PI is responsible for ensuring that participants are followed up according to the study protocol, but often this is delegated to the CRC. In order to follow-up successfully, there are several aspects to consider:
• Choose participants carefully (ie, consider whether the participant is likely to be reliable).
• Involve the family or friends of participants in the process- understand who the participant listens to, and who they take advice from.
• Make sure that PI or any other clinical trial personnel can be contacted.
Follow-up visits are an essential part of clinical research, but preparation is necessary to ensure they run smoothly:
• Ensure the PI is available if there are any queries to be resolved.
• When necessary, have a translator available and ensure that all study materials are translated into the languages required (all these materials must be approved by the IRB/IEC).
• Send a reminder letter or phone the participant 2- 3 weeks before the follow-up visit.
• Phone the participant between follow-up visits to maintain contact.
• Ensure that the participant remains happy regarding their involvement in the study and answer any questions at each follow-up visit.
• Ensure that all study related procedures are completed at follow-up visits and that adverse event reporting is performed as specified in the protocol.
Some tips for ensuring a successful follow-up visit are listed below:
• Schedule appointments realistically, but do not rush participants.
• Liaise with colleagues in other departments to ensure that appointment times can be met.
• Consider seeing participants for follow-up out of normal working hours, if required.
• Consider transport issues, e.g. car parking facilities, bus times, and booking taxis for participants. The informed consent process must make it clear whether participants travelling costs can be reimbursed.
• Make sure that participants know how to contact PI or other team members.
• If the site allows, have some light refreshments available, especially if fasting blood samples must be taken.
• Be sure to establish several possible channels of contact for the participant (e.g. family or a friend at a different address).
• Reconfirm appointments close to the booked date.
Participant withdrawal
In real instances nobody wants a participant to withdraw from a study but in certain circumstances it happens. It is the participant’s right to withdraw at any time and without giving a reason. It is possible that the participant may decide to withdraw consent for all or part of the study. e.g.
• The participant will not take the study medication, but is prepared to continue with follow-up visits and/or procedures. Most protocols will define how data from such participants should be analyzed.
• The participant does not wish to undergo follow-up tests (e.g. an angiogram), but is prepared to continue all other follow-up procedures, which may or may not include continuing with the study medication.
• The participant wants no further contact whatsoever, and no further data can be obtained from the participant. In some instances the participant might consent to allow the CRC to obtain survival data from his/her general physician or the national statistics office.
If a participant does withdraw from a study, their safety must always be considered and any standard care must be carried out as usual.
CONCLUSION:
Recruitment of participants and their retention are necessary for a clinical trial to work. It depends on the efficiency of PI or other clinical trial personnel how efficiently or effectively they manage both recruitment and retention.
To conduct a successful clinical trial that provides an answer to a scientifically important question, it is important to follow all rules and regulations as per regulatory requirements and try hard to recruit and retain participants for smooth running and completion.
REFERENCES:
1. Gamache V. Minimizing volunteer dropout. CenterWatch Monthly 2002;Dec:9-12.
2. Kermani F. Japanese R&D: branching out. Applied clinical trials 2004;Aug. Available from: www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=109174. Accessed February 10, 2005.
3. Spilker B, Cramer J. Patient recruitment in clinical trials. Philadelphia, PA: Lippincott-Raven Publishers, 1996.
4. Beasley D. Perfect harmony. Applied clinical trials 2004;Nov. Available from: www.actmagazine.com/appliedclinicaltrials/article/articledetail.jsp?id=129272. Accessed February 10, 2005.
5. Cavalieri RJ. Effective advertising strategies for clinical research sites. Clinical Researcher 2003;3(5):12-17.
6. Never A. Treating study volunteers as customers. CenterWatch Monthly 2003;Mar:1-7.
7. Goggin MJ. Introduction to the work of research ethics committees. 2nd edition. London: the association of the British Pharmaceutical Industry. Available from: www.abpi.org.uk/publications/pdfs/intro_research_ethics.pdf.
8. FDA information sheets. Guidance for institutional review boards and clinical investigators: recruiting study subjects. Update. Food and Drug Administration, 1998. Available from: www.fda.gov/oc/ohrt/irbs/toc4.html. Accessed February 10, 2005.