From The Editor | August 17, 2018

Is Genetic Testing Creating a Moral Dilemma For Clinical Researchers?

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

Gene Therapy

With the mapping of the human genome, some thought that we would immediately have treatments targeting patients with a specific genetic profile. Obviously, it has taken longer than expected for genomics to begin to impact pharma pipelines. At the 2018 DIA Annual Meeting, Ken Getz, director of sponsored programs, Center for the Study of Drug Development, Tufts University School of Medicine, stated we are now getting to this point. About half of all drugs, across all therapeutic areas, are now collecting biomarker and genetic data. In the area of oncology, that figure is over 80 percent. It is also an area where companies are increasing their investment.

Karmen Trzupek, director of ocular & rare disease genetics services at InformedDNA (an independent provider of clinical and genomics expertise), notes that in the area of medicine, biomarkers can be used for diagnostic, prognostic, or predictive purposes. Genetic testing is now being used in all three areas as well. In a trial, it is used to stratify patients into more personalized therapies.

Clinical trials are complex, but adding genomics to the equation has the potential to make them even more complicated. Getz notes almost any new scientific innovation will create additional operating complexity. “We are collecting more data than ever before,” says Getz. “Historically, a Phase 3 trial would collect about a million data points of information for a chronic disease. In a study with genetic tests there could be three million to five million data points for a single protocol. The number of procedures we are performing has also been growing dramatically – increasing 60 percent over the last decade. This creates a greater burden on sites, patients, and those who have to gather and analyze the data.”

Genetic Tests Raise Concerns

Much of the genetic testing that is now being performed in the clinical space is done before a trial begins. It typically involves pre-screening patients before they are admitted to a trial. But Jill Johnston, president of site activation solutions at services provider WCG Clinical, cautions that companies need to do some thinking before adding a genetic test to the protocol.

“We need to think about how patients will be prepared for that genetic test and what the possible outcomes of the test might be,” says Johnston. “This needs to be considered from a high level and there is a lot more thinking that needs to be put into it. I think there are some companies not fully thinking through all of the challenges that can arise when including genetic testing into a clinical trial setting. Pharma needs to plan appropriately for these tests and the associated data that it generates.”

For example, when screening a potential patient to take part in a trial, information could be uncovered from a genetic test that the patient may not be prepared to hear not even related to the trial itself. Johnston notes that if the patient’s physician is involved in the upfront genetic testing, they may not be prepared on how to read the results or the non-conclusive outcomes that often are returned. Knowing how to manage patients in these scenarios is something relatively new for the industry as a whole, and physicians may not be fully prepared for how to provide the support and care these patients may need through the genetic testing process. Even the clinical investigators participating in clinical research may not have experience in speaking to patients about the results of these tests. In these instances, it is helpful to have experts (such as genetic counselors) to call upon who do this every day of the week.

“The results of a genetic test can be very complex,” says Trzupek. “Interpreting those tests and presenting the results to patients can be a very daunting task for those who are not used to doing it.  Genetic counselors who are used to doing this will spend a considerable amount of time with patients explaining the implications of the results and risks that may exist to them as well as to other family members.  It is a huge benefit to patients, but can often also assist in identifying other patients within that family who may qualify for a clinical trial.”

Locate The Right Patients

Involving genetic data in trials means there is a higher probability of getting the right cure to the right patient. But this also makes recruitment a bit more difficult. In oncology, trials can no longer simply accept a patient with a certain type of cancer. Some patients will have to be rejected based on genetics, and finding the right patients will require more work and more screening.

Travis Quigley, senior director of clinical development at bluebird bio, notes a lot of patient screenings are performed at the academic centers his company partners with. “When a patient is diagnosed with a disease, they are checked for a certain genotype,” says Quigley. “The therapies produced by bluebird could work differently for each patient, based on their genotype. The data received is then used to assign patients to different cohorts to better understand the various outcomes.”

By using the patient information that has already been obtained in a hospital setting, bluebird does not have to perform the screening itself. Pre-emptive screening can also help to identify potential trial participants much earlier. Those patients can then be directed toward marketed or experimental treatments for their disease. Quigley notes that currently, many diseases will go undiagnosed until patients are too far along to have a treatment make a meaningful impact. Genetic testing is something that can be used to match patients to a potential treatment much sooner.

Finding those patients, and doing it sooner, will continue to be a challenge for pharma. Trzupek notes this is especially critical in the rare genetic disease space where patients can be more difficult to locate. The move towards precision medicine has companies seeking these patients, but the old methods of recruitment (going to the major clinical research centers) may no longer be sufficient.

“Companies are going to have to spread a wider net,” she says. “Companies will need to perform greater outreach to those patient communities. That will mean bringing genetic expertise to more community physicians and hospitals. This will enable pharma to find a greater population of potential patients, which can then be funneled down to those who qualify for a specific trial. To put this in a clearer perspective, if a trial requires 300 patients, with a variant of just one to two percent, a company will need to screen more than 15,000 patients.”

The problem isn’t just finding the patients. Companies will need to find them, engage with them, and convince them to submit to a genetic test and participate in a clinical trial. Those patients are suffering with a condition and are going to require education and information. And, even if they don’t qualify for this trial, they may qualify for another trial at a future date. Johnston adds, “Once you engage those patients to potentially participate in a trial, you want to keep them engaged for a long period of time.”

Be Careful With What You Collect

Trzupek states we are seeing an increase in the number of clinical trials where sponsors opt to perform a large genetic panel test that collects more patient data upfront that can be used in the future to screen for additional trials. When that happens, she cautions there must be mechanisms in place to provide necessary counseling to patients and families.

Including patient input in trial design will help to determine what tests are and aren’t acceptable to patients. Regulatory agencies are increasingly asking for patient reported outcomes and patient input. For that reason, Trzupek states incorporating patient input early in the trial design process can help to guide testing, plan future stages of trials, and increase the success of gaining trial approval from the regulatory agencies. 

In the course of conducting genetic testing, researchers will learn a lot about a patient. Oftentimes they will discover things about a patient’s health that was not the primary source of investigation. In those instances, what is the obligation of researchers to disclose that information to patients? Do you tell them that while you were looking for one indication, you discovered that they have an indication or propensity for two or three other disorders?

“This is definitely something we need to talk about early,” says Trzupek. “We have to be thoughtful about what tests we are offering, how narrow or broad they are, and what are the potential implications. We have to be thoughtful in our protocol design to know what is on the panel, what we are testing for, and to have a plan for managing incidental findings.” 

“This really has a lot to do with patient centricity,” adds Quigley. “Our knowledge and understanding of genetics has evolved over the last 20 years, but it is still very nascent. We are still unsure of how to handle all of the data we are gathering and how best to act on it moving forward. We will need to have a lot more conversations like this one to understand how we can best help patients and caregivers.”