By Karmen Trzupek, InformedDNA
Conducting a clinical trial of any kind is complex and including genetic screening can introduce nuances and complications that raise the complexity even more. Before embarking on a genetics-based clinical trial, pharmaceutical companies should fully appreciate the unique challenges genetic information presents and implement strategies to navigate potential pitfalls. Otherwise, trial progress may slow or stall, resulting in costly study delays or even trial failures.
What Are The Challenges?
There are several hurdles that top the list of issues to watch. Here are five of the most common:
- Small population size. The patient population for a genetics-based (mutation-based) trial is smaller than that of a standard disease-based clinical trial, as genetic testing effectively excludes many potential clinical trial participants. This is especially true for a rare disease trial where the population is already small. In some cases, experimental therapies are targeted to a single specific genetic variant or group of genetic risk variants.
- The patient population may be hard to identify. There are several factors that make patient identification difficult. For many diseases, diagnosis is made based on clinical findings. For these diseases, many patients have not undergone genetic testing as part of their clinical workup. When the inclusion criteria for a clinical trial includes mutations in a particular gene, physicians generally don’t know which patients will qualify for the study. In addition, while identifying trial candidates through academic medical centers is the traditional method for patient recruitment, this approach is not as successful with a rare disease trial due to the extremely small population size at any given site. Trial sponsors must think differently about how to broaden their search to increase the likelihood of finding candidates.
- Genetic results add a layer of complexity. Clinical trial staff are often unfamiliar with the complexity of genetic mutation data, and they may not accurately interpret genetic test results. This lack of expertise can result in inconsistencies in the way genetic information is reviewed and used for study screening. Ultimately, errors in genetic results interpretation can lead to misinformation being provided to patients and families, as well as the misidentification or under-identification of potential candidates for trial inclusion.
- Comprehensive informed consent is required. There are numerous national regulations and standards regarding genetic testing informed consent, results disclosure, and trial participation. Before agreeing to testing, patients need to fully understand what’s involved and how their genetic information could be used. This requires trial staff to engage in conversations with patients about what’s being tested, what the results will show, what the results could mean for their care, who the information could be shared with, and how the results could be used, both in current and future programs. Many clinical staff don’t have the time or expertise for this level of detailed discussion of genetic information. And yet it is necessary to obtain and meet regulations for informed consent.
- Without continuous engagement, patients can lose interest. The timeline from patient recruitment, screening, natural history study enrollment, and interventional trial participation can be long. Without a plan for regularly engaging patients, a trial sponsor may find its participants lose interest before the clinical trial even begins. This may cause individuals to pull out of the study or possibly seek a different trial that’s on a faster schedule. After enrollment for a Phase 3 study closes, sponsors must find ways to continue to identify and engage patients so that once FDA approval occurs, there are patients interested and qualified to receive therapy.
Strategies To Overcome Challenges
Although the above-mentioned challenges are present in most genetics-based clinical trials, they are not insurmountable. By following some key best practices, trial sponsors can mitigate the risks posed by these roadblocks and enable a smooth process.
Pursue a multifaceted approach to patient identification.
It’s important to cast a wide net when identifying patients for a genetics-based clinical trial. One common approach is to work with patient foundations related to the disease, because these organizations often have patient registries that can serve as a starting point for recruitment.
To prompt more patient testing, it is essential to engage physicians not only in academic medical centers but also at the community level. This involves educating primary and specialty physicians about the value of genetic testing for particular conditions. To gain community physician support, programs must be put in place to enable effective screening by physicians in their clinics or in patient homes. Then, only the patients who meet inclusion criteria are referred to the academic medical center for on-site evaluation. This allows community physicians to retain stewardship of the majority of their patients, which can encourage physician buy-in and support.
Think strategically about genetic testing.
This requires looking beyond the logistics of the immediate trial. For example, a sponsor may want to avoid testing for only one particular gene, as this may not be as appealing for patients and providers, making recruitment more challenging. It can be challenging to get a genetic test, and patients may opt not to do it if there is only a small possibility they could qualify for a trial. Similarly, physicians may not be as interested in suggesting testing to their patients if the test targets a single gene, and most patients would receive negative results. Instead, sponsors should consider expanding genetic testing to benefit the patients, physicians, and clinical research broadly while still identifying the specific genetic data needed for the study. Not only does this support the wider patient community, it cultivates buy-in and trust from patients and providers. In addition, it can identify possible participants for future studies.
Conduct a skills assessment to identify gaps in genetics expertise .
As mentioned before, clinical trial staff are in some cases lacking in genetics knowledge. To get a sense of these gaps, it is helpful to conduct a thorough skills assessment. Once you know about possible shortfalls, you can work to address them. This might entail defining clear processes for how genetic data is captured and analyzed; providing additional training and education to staff about genetics and how to interpret test results; and extending trial timelines to allow for more in-depth review and quality spot-checking. Organizations should also consider periodically auditing the interpretation of genetics test results to avoid errors that can lead to misidentification problems. Such audits may also catch situations where certain variants were overlooked, which could negatively influence the individual’s response to the therapy.
Develop a rapport with patients.
To maintain enthusiasm and interest for the trial, it is important to bridge the time between when a patient is identified as a candidate and when the trial begins. Thorough patient education and regular communication are necessary here, so patients know what the genetic test results mean and what their options are. During this time, trial sponsors can also address options for family members who have the same condition or may share risk for it.
Have a plan for post-FDA approval.
To realize solid market performance, it is essential to think ahead. This will involve maintaining patient excitement and enthusiasm for the therapy throughout the trial, so patients remain interested in the treatment once approved. Sponsors should also start thinking about payer issues early. Since rare disease drugs are typically expensive, it is critical to consider reimbursement policies and any preapproval logistics.
A genetic component adds many nuances to a clinical trial. Patient identification and engagement require strategic thinking and appropriate expertise and resources. Genetic results can also be challenging to decipher for clinical trial staff. By acknowledging these potential pitfalls and being proactive about addressing them, a trial sponsor increases the likelihood of trial success and can gain clearer and more impactful insights from the study.
About The Author:
Karmen Trzupek, MS, CGC, currently directs clinical trial services at InformedDNA. She first began working as a genetic counselor in 2001 at OHSU (Oregon Health & Science University), specializing in inherited eye diseases and managing clinical research studies. In 2009, Trzupek joined InformedDNA, where she developed the first national telemedicine program for ocular genetic counseling and genetic test coordination services. She has a longstanding passion for supporting patients with rare diseases and has managed multiple rare disease outreach programs in collaboration with patient foundations and pharmaceutical companies. Karmen now develops strategies and programs to increase efficiency of patient identification and enrollment initiatives for clinical trials.