The risks associated with ignoring genetic factors far exceed the complications of including them and going forward there will be more clinical trials having a genetic or precision medicine component to develop targeted therapies.
Today, nearly half of all therapies in clinical trials are collecting biomarker and genetic data, and that number rises to 73 percent for oncology trials. A search on Clinicaltrials.gov returns 9,300 current trials that include a genetic component. From asthma to leukemia, genetics are playing a growing role in clinical trials as clinical researchers and sponsors work to create more effective therapies targeted to the underlying cause of a disease.
But along with the widespread use of genetics in clinical trials comes added complications. When the inclusion criteria for a clinical trial includes a specific genetic variant, finding and recruiting participants becomes more difficult. Testing patients for genetic variants also necessitates the involvement of different resources, such as genetic counselors, to assist in operating the trial. Genetic testing creates complications for patients, their caregivers, clinical trial investigators and sponsors. The risks associated with ignoring genetic factors far exceed the complications of including them, though.
Recently, Biogen reported the results of a clinical trial of their experimental therapeutic BAN2401 in patients with Alzheimer’s disease. Although the study failed to meet its primary goal, it appeared to have a positive protective effect in the group of patients who received the highest tested dose. However, in the clinical trial, a significantly higher percentage of patients in the placebo group carried a genetic susceptibility allele, called APOe4, that confers a higher risk of developing Alzheimer’s disease.
The trial groups were not balanced due to concerns from regulators about possible side effects that could result from including individuals with this allele in the high-dose groups. But critics are now questioning whether BAN2401 actually slowed disease progression, or whether the treated group was less likely to develop severe Alzheimer’s disease based on underlying genetic predisposition.
The lessons from this study are clear: clinical trial sponsors must consider genetic differences in their study population, even when the therapeutic isn’t targeting a specific genetic cause of disease. So, what happens when the clinical trial ecosystem is not designed for the inclusion of genetic testing and the stratification of patients based on genetic differences? And what kind of expertise is needed to bring about a much needed change?
It starts with the patients
Clinical trials already have a patient participation problem. In a 2017 survey of more than 12,000 people, 84.5 percent of respondents thought clinical trials were important, but only 31 percent were “very willing” to participate in one. Furthermore, physicians are not talking to their patients about clinical trials frequently. Only 19.4 percent of the 2,194 clinical trial participants surveyed in the study learned about a study from their physician, although 63.5 percent cited this as their preferred method.
To further complicate matters, clinical trials sometimes focus on rare subtypes of common diseases (e.g. rare genetic variants in macular degeneration or Parkinson’s disease) that may affect only two to three percent of the overall disease population, meaning that sites would need to screen about 16,000 people to find 300 potential participants. The identification, enrollment, and retention of these participants may benefit from a level of genetics expertise and support best suited to the skillset of genetic counselors.
Since genetic counselors are uniquely poised to set expectations and explain implications to a participant before a genetic test, it is crucial that sponsors provide this resource to their investigators. These experts can also discuss results with patients after genetic testing. If the patient tests positive, the genetic counselor can explain what the results mean for them and their family. Also, the patient’s family members are often more likely to qualify for a clinical trial recruiting individuals with particular genetic variants than the general population. This means fewer people may ultimately need to be screened.
Genetic counseling can also improve participant satisfaction, which improves engagement and retention during the trial in addition to creating an overall positive perception about clinical trials. Whether or not patients qualify for the current trial, they deserve to understand their genetic test results. Recently, the National Academies of Science, Engineering and Medicine recommended that clinical studies return trial results to research participants in a thoughtful and supportive manner. Given the complexity of genetic testing, it is frequently meaningless for the patient to have the results returned in the absence of an in depth discussion on the implications of the findings.
This kind of thoughtful engagement with potential participants requires additional resources. However, it is an important and necessary step. If a participant tests negative for the current specific trial, they may still qualify for another clinical trial in the future. Patients already lack a willingness to participate in clinical trials. Providing this due diligence to patients who want to participate but do not qualify can lead to a more positive attitude toward clinical trials in the future. Options such as remote screening and telephone-based genetic counseling appointments can help to make this a practical addition to a clinical trial.
Genetic counselors can help streamline the protocol
Adding genetic testing and gene-based stratification into clinical trial design can complicate the entire protocol. The result is more of everything: more potential patients need to be screened and more resources are needed, especially to interpret the results of genetic testing. And trials in general are generating more data. All parties within this ecosystem need to be brought together to streamline trials as protocols get more challenging.
When investigators are selected to participate in a study utilizing genetic testing, they may assume that they simply need to add a genetic test to the initial screening period. However, genetics expertise and patient engagement should be considered throughout the protocol. While 67 percent of physicians in a study published in the Journal of Personalized Medicine believed genetic testing is clinically useful, only 31 percent believed that they had adequate training to care for genetically high-risk patients. When investigators lack confidence and expertise in genetic testing, genetic counselors can prove to be a valuable resource, both for patients and the physicians.
One way to help control for the complicated protocols is by determining the correct genetic tests at the beginning of the trial. Genetic counselors can be invaluable in this effort by choosing the right test panels, based on the needed patient population for a clinical trial. Importantly, this approach can reduce the need for massive screening, while focusing on a set of genes that offers the greatest benefit to the patient population and the sponsor.
In other cases, large genetic testing panels are the most appropriate choice. Broad genetic testing raises important questions though: is there a responsibility to share the results with patients who are screened? If the patient tests negative for the target variant but positive for another, is it ethical to ignore those results, or save them for future research studies?
By comparison, a small panel could be more cost effective and focus on the genetic variants critical to the current trial, but the sponsor might need to expand genetic testing efforts for the next trial to gain access to more genetic information. The expertise of a genetic counselor knowledgeable about the specific disease population can provide much-needed guidance on these complex issues.
Get ready for more genetic testing
As genetic testing is destined to play a larger role in the clinical trials process, sponsors would be wise to include more genetic counselors for their expertise in several areas. First, they can assist sponsors and CROs in the development of the protocol and selection of the right genetic test panels to be included in a trial. Next, genetic counselors can play a vital role in helping patients and their family members to understand the implications of both positive and negative results, which promotes patient empowerment and goodwill. The inclusion of genetic counselors is vital as research indicates that many investigators lack confidence or training in interpreting genetic tests.
Going forward, as more clinical trials have a genetic or precision medicine component, the goal is to create much needed therapies that are more targeted, and therefore, more effective for patients anxiously awaiting them.
Date: December 31, 2018