Patient recruiting is the backbone of any clinical trial, and retina clinical trials are no exception. If sites are unable to recruit enough subjects to complete the study, the entire project's timelines will likely be put in jeopardy. Furthermore, it is not enough to simply recruit patients; they must remain in the study throughout its duration to generate usable data for the trial. Although each clinical trial has specific requirements for subjects, careful patient selection increases retention and compliance rates and thus facilitates a study's success. In this issue, we tackle subject enrollment by looking at a theoretical retina study, specific recruiting timelines, and the elements that lead to robust subject recruitment.
WHERE TO BEGIN:
A THEORETICAL RETINA STUDY
In a randomized, multi-center, placebo-controlled
phase 2 study of a therapy to treat geographic atrophy
(GA), 160 patients will be recruited at approximately
25 sites in the United States. The eligibility requirements
include having a GA lesion that meets specific size criteria
and visual acuity of at least 20/200 or better in the
study eye. Although the most meaningful efficacy endpoint
for a dry age-related macular degeneration
(AMD) study might at first appear to be preservation of
visual acuity or the prevention of conversion of the disease
to the wet form, the slow, progressive nature of dry
AMD would make it difficult to complete such a study
in a reasonable time frame. For that reason, study sponsors
are now investigating novel clinical endpoints that
may allow investigators to evaluate a drug's efficacy in a
shorter time frame. These developments may also help
with subject recruiting because patients may be more
willing to participate in shorter trials. However, for the
purposes of this exercise, the primary efficacy endpoint
for this study will be the rate of change in area of GA in
the study eye and fellow eye at 2 years compared with
baseline.
Numerous designs for GA clinical studies have been advanced, but the average duration for study subject participation is generally expected to be between 18 and 24 months. For our hypothetical study, a total of 36 months has been budgeted for its completion: 12 of these months have been set aside for recruiting and the remaining 24 for the study patient participation. Sites are often provided approximately 12 months to recruit patients, although some sites may be given either a shorter or longer window to recruit, depending on the specific trial parameters and the specific requests of the sponsor.
UNDERSTANDING THE NUMBERS
When planning any study, some key factors must be
taken into account, in addition to some general
assumptions:
Enrollment period. If we want to complete enrollment in 12 months or less, this means that sites would have anywhere between 12 months and a much shorter period to actively enroll patients in the study. The active time depends on how fast a site can obtain the necessary approvals and the necessary setup, including drug supply and qualifications, and be ready to enroll patients. As a rule of thumb, it may be reasonable to assume that sites can take up to 4 months to start. They may actually take longer, but such delays must to be avoided if at all possible. This activation period leaves an average of only 9 to 10 months of enrollment time. This cuts the planned enrollment period of 12 months by approximately 25%, which is critical information for any site beginning enrollment.
Screened patients and screen failure. How many patients can the sites screen for participation in the study at any given time? What proportion of the screened patients will not be eligible for the study? The more challenging the enrollment criteria are, the more patients will be found ineligible to participate in the study. The design of the inclusion and exclusion criteria is an art of balancing the need for scientific and biostatistical rigor with the “real world” of patients. Many trials have lagged in enrollment simply because the inclusion and exclusion criteria have made it almost impossible to find suitable patients. It is best to design the criteria with close interaction with researchers who are active in the field and can bring in their experience in facing these particular recruitment challenges.
Enrolled patients. How many patients will actually start the study? Is there an “entry” period? What assessments are required for baseline measurements?
Retention. Some patients will inevitably not complete the study for various reasons. Patients volunteer to participate in the study; they can opt out at any point for any reason and are not required to justify their decision. Patients can also be withdrawn from the study by the investigator if the investigator feels it is in the best interest of the patient, or by the sponsor if the sponsor determines that the patients is under some specific increased risk or unable to comply with the study visits and procedures.
Patients per site per month is the “magic number” that reflects the enrollment rate. In our theoretical study, for 160 patients and at 25 sites and 9 months as average enrollment time, we will need an average of 0.71 patients/site/month to complete enrollment within the 12-month specified period. Note that this assumes enrolled patients, so screen failure rates must be factored in also. It is unlikely that sites will enroll 0.71 patients, but as a calculated average rate this number is a good reflection of the enrollment rate.
ARE WE BEING REALISTIC?
After calculating the numbers, it is time to make a
careful feasibility assessment, and to do this it is best to
have the answers from potential sites. These sites are in
an opportune position to determine whether the projections
are realistic or if we are overestimating the recruitment
capacity. Recruiting for any retina study actually
begins with the initial feasibility questionnaire, as many
sites are originally selected based on their stated access
to certain patient populations. Sites are often given preliminary
details about what the study might look like or a
preview of the inclusion/exclusion criteria. For larger retina
studies like our theoretical GA trial, an investigator's
meeting may be held, permitting the sponsor and clinical
research organization (CRO) representatives to outline
the specific types of patients they hope to recruit.
When your site is beginning to formulate its recruiting strategy, it is best to keep in mind that the number of subjects that must be recruited depends on powered statistical calculations. Typically, the formal expectations for subject recruitment and research participant goals are established far in advance of trial startup, and these are topics that should be adequately discussed with the sponsor or CRO. Both the Louis Lasagna rule1 and Muench's Third Law2 suggest that the recruitment strategy for clinical trials should be one that reaches a greater number of prospective subjects than the anticipated patient enrollment, as a portion of the potential patients will progress to the screening phase, and a smaller subset of these individuals will eventually enroll in the study.
SPREADING THE WORD
Now that you have established baseline criteria for
recruiting, it is time to make your need for eligible
patients known to both patients from your practice
and colleagues in the vision care community.
A number of recruitment tactics that can be employed,
some of which include searching electronic medical
records (EMRs) databases, doctor-to-doctor letters,
quick reference guides in offices for staff members, and
patient-directed materials such as posters and other
institutional review board (IRB)-approved internal and
external advertising. The most appropriate recruitment
tactics will undoubtedly depend on your site's prior
recruiting experience and ability to use resources wisely.
These recruitment measures obviously depend on the
type of indication to be studied. Is it a chronic condition
or an acute condition? What is the window from onset
of symptoms to inclusion in the trial? Are the patients
allowed other treatments and medications, or are they
disqualified from participation if they have been previously
treated?
Perhaps the best time to recruit is long before you even need patients. Building a database of patients by the disease state in anticipation of an imminent study allows your site to recruit patients faster. Some sites have EMRs that allow coordinators to run searches of existing patients. Patients with GA are likely to have significant visual acuity symptoms and may already be in your EMR database. In contrast to other, more laborintensive recruiting methods, EMR database searches help identify patients who are already part of your practice and may meet some basic inclusion/exclusion criteria; utilizing today's technology can expedite the screening process and speed recruitment timelines. In some cases, patient charts can be flagged for follow-up during a chart review, and quick reference guides detailing inclusion/exclusion criteria are good reminders for staff to assess whether patients potentially qualify.
Another successful recruiting strategy is through doctor-to-doctor letters. If your site knows the type of subjects likely needed for a study, querying referral sources may open a wide range of options. For example, patients with dry AMD may make frequent visits to their general ophthalmologist as opposed to retina specialists; sometimes the general ophthalmologist is the first eye care professional to diagnose the condition. Letting your colleagues know about an enrolling study is an opportunity to gain access to a larger patient population. In addition, anything unique to your site may bring in patients as well. For example, hearing a novel surgeon speak about the benefits of a particular study may be of interest to patients who may consider participating.
In some cases, patient-directed materials can work toward the benefit of the study simply by generating interest. Any formal advertising done to spark the interest of potential subjects will require IRB approval. Because many retina studies do not offer monetary incentives other than travel expense reimbursement to patients, be sure to highlight the qualities of the trial that are appealing to patients. Examples of these include access to cutting-edge experimental therapies, and close attention and follow-up. For some patients, cost-free treatment alone can often be an incentive. Patients with sight-threatening conditions, particularly if treatment options are limited, appreciate the opportunity opportunity to receive novel investigational treatments.
Finally, regardless of the recruitment tactics used, the ability of the investigators and study coordinators to be able to adequately explain the study to the subjects during the screening process is of utmost importance. Sites with enthusiastic, knowledgeable, and researchkeen investigators and coordinators are much more likely to successfully recruit patients than sites whose staff members seem uninterested.
CONCLUSION
For all site staff members in a retina clinical trial, a
deep understanding of the study's inclusion and exclusion
criteria is paramount to success. With a grasp on
the requirements to be eligible to participate, sites are
given access to desirable patient populations. If your
site does not have immediate access to a large pool of
patients, you can expand your research through the
aforementioned recruiting strategies. Keep in touch
regularly with your CRO and sponsor representatives
to update them on your site's recruiting progress. An
open line of dialogue allows access for all parties to a
plethora of recruiting strategies. An ample patient
population lays the foundation for anticipated participant
retention, making way to assessable patient data.
Most importantly, actively showing your site's enthusiasm
for the study will create a successful basis for
recruiting patients. Enthusiasm is contagious in any
retina study, and if your site shows excitement at the
prospect of a potential new treatment your patients
will likely follow suit.
Avner Ingerman, MD, MSc, is Senior Vice President and General Manager of Retina at Ora, Inc., in Andover, MA. He states that he has no financial interests to disclose.
Ashley Lafond is a medical writer at Ora, Inc.
David Waters-Honcu is a Manager of Retina Clinical Operations at Ora, Inc.
Sunita Saigal is a Clinical Research Specialist at Ora, Inc.
POSSIBLE RECRUITMENT
AND REFERRAL STRATEGIES
• Private practice referrals
• Interdepartmental referrals
• Newspaper and radio advertisements
• Local patient association advertisements
• Health fairs
• Patient mailings
• Doctor-to-doctor letters
• Posters in office
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