Retention of Subjects

The question of informed consent

J Findlay Walker,  Vice President, Administration, Daiichi Sankyo Development Ltd., UK

Although the factors that lead to the loss of subjects in clinical trials are poorly understood, lost to follow-up" is still too frequently recorded as an outcome. This article explores the issues involved in the planning and conduct of clinical trials, and suggests a number of practical and relatively simple steps that may be taken to enhance the retention of clinical trial subjects.

These days, pharmaceutical development is increasingly becoming an area where "high- tech" solutions exist for every difficulty encountered. Genomic analyses and biomarkers are required for enrolment in an ever increasing proportion of studies. Contract Research Organisations (CROs) have electronic files of potential investigators and patients for many diseases, and Electronic Data Capture (EDC) and electronic filing are the modern way to go. For all of the seeming sophistication, one issue, the retention of subjects in clinical trials, has not changed much in decades. The abbreviation LTFU (lost to follow-up) is still used all too frequently!

In addition to patients being entirely "lost" to follow-up, there is another group who will have their assigned medication discontinued for known or unknown reasons, but who can still be located to ascertain their vital status. In a study of say, three to five years' duration, it is likely that 25 per cent or more of patients will fall into this category. The actual proportion will vary depending on the initial indication: life-threatening conditions, like acute myocardial infarction attract better persistence with therapy than perceived low-risk diseases like hypertension.

Retention of Subjects
There are both scientific as well as financial benefits of retaining subjects after randomisation. Scientifically, the answer to the question being asked in the specific study may be jeopardised, but the credibility of the company involved, the generalisability of the results generated and their regulatory persuasiveness are also at stake. Financially, the cost of qualifying a replacement can be high, especially if that requires diagnostic interventions, genomic analyses or the validation of costly biomarkers.
Over a number of years, various strategies have been employed to enhance compliance and persistence with assigned medication. These have included automated and manual telephone reminders, as well as medication containers that emit an alarm or a vocal message reminding the subject that the dose is due or that a follow-up visit is pending. Some people have mixed feelings about being reprimanded by a pill bottle. With the widespread availability of Internet access and cell phone technology, these tools are increasingly in use despite the limited geographic penetration, especially in non-traditional sites (e.g. India, South-East Asia, etc.) where drug development studies are now increasingly being conducted.

Unacceptable practices

Before dealing with ways to enhance retention, some unacceptable ways of patient retention are considered briefly. The first of these is financial coercion. While the payment of expenses incurred by the patient in participating is permitted (e.g. actual travel costs and reimbursement of lost wages), higher payments are not. One has to bear in mind that a payment that is not objectionable in the US or Western Europe (say US$ 50) may be considered coercive if offered to an impoverished subject in India or elsewhere.

In a recent case reported by the US FDA, a psychiatric investigator was cited for keeping a patient in a locked ward against her will, an obvious infringement of acceptable practice (except under specific circumstances in which the patient may be "sectioned" under the Mental Health Act).

Making continued treatment dependent upon return to the investigator is also unacceptable, but this prohibition should be a part of the informed consent procedure. Using family members to persuade patients to continue in study may also be questionable, as it may undermine the view of a subject as a "free agent".

Acceptable practices

The acceptable ways to enhance retention are mostly "low-tech" and may be considered "boring", since they incorporate practices that have been widely used for many years by experienced investigators and their research staff. For the patient, the prospect of participating as a subject in a clinical trial may be a little daunting, and the first step to take is to make the patient feel comfortable in the new situation.

How is the informed consent procedure handled? Problems with the adequacy of informed consent are among the most commonly identified issues during regulatory audits by the FDA and other agencies. Sometimes it seems as if the signing of the Informed Consent Form (ICF) is a formality to be dispensed with as quickly as possible, so that the real business of the investigator can be engaged: physical examination, special diagnostic testing and bloodletting!

For the average patient, for whom this may be a first experience as a subject, the ICF is a complex document, incorporating as it does, the details of the study, frequency of evaluations, consequences of non-participation, likelihood of adverse events, availability of care for any adverse event, as well as details of indemnification for resulting in any injury. It is a good practice to have the prospective subject review the document with a study nurse or coordinator to answer any question. The study personnel must be fully aware of the details of the study and must answer all questions fully and honestly. Sometimes it may take more than one visit before the patient feels sufficiently informed to give consent.

Once the patient is enrolled, there are a number of simple steps that can be taken to reduce the likelihood of drop-out. A telephone reminder of each visit is recommended, preferably not by an automated calling system, since a personal call can positively motivate the patient who is equivocal about continuing. As far as possible, the subject should be seen by the same study personnel at each visit so that he / she may build trusting relationships that will facilitate the solving of any problem that arises in the course of the study.

Ways to retain study subjects or retaining study subjects

• Ensure that each visit is a pleasant experience • Ensure that punctuality is maintained • Make certain that appointment times are suitable to the subjects • Call the subjects personally to remind them about their upcoming visits • See that the number of study personnel is limited • Make sure that questions posed by subjects are answered honestly • Ensure that the personnel are always available to subjects

Additionally, the waiting area for appointments should be pleasant, although, little used, since appointment times will be punctually adhered to. The timing of available appointments may also be critical with regard to the subject's willingness to participate and comply. A 7.00 a.m. appointment may be ideal for a subject in full-time employment, but may be unattractive to a retired person who may prefer to wake up late. Unless the protocol calls for a trough reading of blood pressure, pharmacokinetic or other variables, such early morning appointments may be counter productive in some cases.

Finally, the subject should be given the name and contact details of the appropriate contact person(s) if difficulties or questions occur in the course of the study or if suspected adverse effects of treatment arise.

In summary, the subject is more likely to continue in the study if the overall experience of participation is positive, if relationships with study personnel are open and honest and if the subject is treated with dignity and fairness in all respects.

May LTFU be banished from the clinical study lexicon!

Author Bio

J Findlay Walker
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