Genetic-Based Testing Enters Clinical Trials

The biopharmaceutical industry is now making strides in gene therapies by focusing on patients with specific genetic traits. However, that approach comes with challenges, as these patients have to express the specific genes required to qualify for studies. Some methodologies are emerging to address this challenge by creating genomic libraries, and subsequently, identifying patients that would be good candidates for gene therapies. In this interview, Karmen Trzupek, Director of Clinical Trial Services at InformedDNA, will discuss how to address these challenges.

Moe Alsumidaie: What are some of the main things biopharma companies and CROs need to know about genetics-based clinical trial programs?

Karmen Trzupek

Karmen Trzupek, MS, CGC: The first thing biopharma companies should know, which often comes as a surprise the first time they incorporate genetics into a clinical trial, is that genetic test results are complex. Laboratory advances in genetic testing have led to a massive shift in the way patients are tested. Early in my career, we used to test patients for one gene at a time. It was a very hypothesis-driven approach based on our clinical suspicion. But today, the standard of care in genetic testing for many diseases is to perform extensive panel-based tests, where literally hundreds of genes can be tested at once. Of course, in many ways, this is a good thing: It's led to a considerable increase in the detection rates for many diseases, for instance. However, our ability to do that kind of genetic testing has far outpaced our understanding of the meaning of variation in the human genome. So, we get back genetic test reports with lots of variants of uncertain significance, which can be very confusing to both patients and providers.

On another related note, coming up with a plan for the return of results of genetic testing is critical in a program. Since these results can be much more complicated than many standard medical tests, there really needs to be a plan for the delivery and use of that information. Many physicians today who are ordering genetic testing for a clinical trial, never have before ordered genetic testing, or have done so in a very limited way. Physicians often tell us that they're not confident interpreting these large-scale genetic test results, or if they are comfortable with these reports, they just don't have the time in their practice to sit down and have lengthy conversations about genetics with patients and their families. Biopharma companies need a plan for someone to take the time to disclose and explain the results of testing.

MA: Can you discuss the challenges clinical trials are facing as they work to bring more than 2,500 gene therapies in their pipeline to the market? 

KT: One major challenge in the design of the actual program is that gene-based clinical trials typically target a very, very small subset of the total patient population. It makes finding patients even more difficult than usual. We see many organizations starting to think in different ways about how to face that challenge. One of the ways that we've seen a number of pharmaceutical companies address this is by developing natural history studies or patient registries. By screening patients in advance of their intended interventional trial, trial sponsors or CROs can start to build rapport in the patient community and establish a group of engaged patients prior to starting  enrollment.

Companies are also overcoming this challenge through telemedicine-based outreach and screening. When I read the article based on your interview with Barbara Lopez Kunz at DIA, I was really struck when she said that, today, ensuring that trials are accessible to patients locally is so critical to engaging them in healthcare product development. At InformedDNA, we bring specialty genetic services to patients where they are, providing them a genetic specialist with expertise in their rare disease without that patient incurring the time or the cost associated with travel.  

Another challenge that clinical trials are facing around gene therapies is heavy competition in the pharmaceutical and clinical trials space, which is well known and established. I think this competition is in direct opposition to the collaboration that we need in the rare disease world. With a rare disease, we must find ways to get industry, patient groups, patient advocacy organizations, clinical providers and even multiple industry groups to all come together for the same cause. Ultimately, we all want to accelerate the pace of clinical trial research and find meaningful treatments for these rare diseases. And I think that the competition we've historically seen in the pharmaceutical space does not serve the rare disease population well.

MA: How is the incorporation of genetic testing implicating cost and time goals? What types of best practices can biopharmaceutical companies put forth to overcome these hurdles?

KT: For most genetic diseases, genetic testing is not the standard of care. There are some exceptions like with cystic fibrosis, the most common recessively inherited genetic disease in the U.S. population. Most patients in this country with cystic fibrosis have previously undergone genetic testing, so they already know the genetic cause of their disease; but this is not the case for most rare diseases. When a pharmaceutical company or a CRO is starting to target a rare disease, they have to think about how to incorporate genetic testing into their own clinical development program. They can't just rely on reviewing medical records and finding the genetic test results to determine whether or not that patient might qualify. They have to ask questions such as, "How do I find patients who might have this particular genetic disease?” And then, “How do we implement a genetic testing program to support those patients in obtaining and understanding genetic testing?"

Obviously, finding the right patients for the trial impacts cost and time because both are going to be increased when you think about implementing that second testing step. While that may be an added expense and it does take some time, if the clinical development program can find ways to incorporate screening remotely, it will actually decrease total costs by identifying patients remotely who are more likely to be engaged, and then more likely to travel to the clinical trial centers for evaluation.

MA: What implications do genetic testing and genomics have on clinical trial and protocol design? 

KT: I’ve spoken with a number of different sponsors regarding how they think about incorporating genetic testing into their protocols or into their clinical development program. To me, any genetic testing program should do two things: One, it should benefit the patient population broadly, and not just the patients who are going to qualify for that study eventually. Two, it should ideally benefit the sponsor in ways that go beyond that first trial. Earlier, I talked about how we see these large-scale panel-based tests, and there is a benefit to that in many cases. While we don't always want the most extensive test, panel-based testing can sometimes address both of these needs. 

If you have a patient population where there are many different underlying genes that can cause disease, a pharmaceutical sponsor could say, "Well, we're only going to test for this one gene that we're currently targeting for our clinical trial." However, let’s say only 5% of your patient population has that particular gene as the cause of their disease. If you only target that one gene, you are excluding 95% of those patients, which over time, can lead to fatigue and lack of engagement in that patient population. Instead, if the sponsor utilizes a more substantial test that has a much broader appeal to the patient population, many more patients will find answers to questions about their disease. The program will still identify the genetic cause of disease in that initial 5% but will support other patients simultaneously. This can then benefit the sponsor as well, because they're engaging the broader patient population and, for the next therapy they develop in that disease group, they have already identified a set of potential clinical trial candidates. 

MA: A big challenge in the new era of genomic therapies is identifying patients who have a particular mutation in their genes. As this field starts to evolve, would you expect genetic testing to play a role in recruitment? 

KT: I'll give you an example of something that we're currently doing that I think really shows a model we should be working toward in genetics. We're currently supporting a program in collaboration with the Foundation Fighting Blindness, a patient advocacy organization that supports patients with inherited retinal disease. In that patient community, there are more than 200 different causative genes. All of these patients have degenerative forms of retinal disease, but the underlying genetic cause varies. When the first FDA-approved gene therapy came along for the treatment of a genetic disease, which was LUXTURNA by Spark Therapeutics, it only targeted one of those 200+ genes, for which a very tiny portion of the patient population qualified. Now, we’re seeing many other clinical trials pop up, sponsored by different biopharma companies, and targeting different genes.   

To meet this challenge, the Foundation Fighting Blindness is hosting and sponsoring a genetic testing and genetic counseling initiative, with well over 300 providers participating all over the country. This is a big contrast to five to ten years ago, when there were fewer than 30 physicians routinely ordering genetic testing in this patient population, and they were primarily located in academic research centers. Now, utilizing the Foundation Fighting Blindness program, we see genetic testing being initiated at the community level with local retina physicians, and not solely at large academic medical centers, which patients may have to travel hundreds of miles to reach. Patients get tested, and the test results come directly to us since we’re providing telemedicine-based genetic counseling. We interpret the test results and provide medical management information to the patient, as well as provide the needed guidance for family members who might also be at risk and may consider testing. Finally, all of that data goes into the registry through the Foundation Fighting Blindness, which acts as a central resource for clinical trial information for patients in this community. 

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.