Although the human Genome was mapped nearly two decades ago, we are just now beginning to enter the real era of Personalized medicine . With the knowledge that the genetic makeup of a patient can impact the effectiveness of a drug for that individual, many researchers are now working to develop drugs targeted to different underlying causes of diseases, rather than the disease as a whole. Through personalized medicine, researchers have begun to incorporate into their research the underlying principle that the same disease can be caused by many different genetic variants.
 
Rare genetic diseases such as Huntington’s disease and cystic fibrosis stem from mutations in a single Gene , which makes genetic data the key to drug development. An increasing number of drugs developed to treat rare diseases specifically call for the use of genetic data during development. With rare diseases affecting 25 to 30 million Americans, there is a strong need for drugs developed with specific genetic profiles in mind.
 
Recently, Luxturna, a drug for a specific subtype of inherited retinal dystrophy, was approved by the FDA . Inherited retinal dystrophy leads to vision loss and in some cases, complete blindness. Over 200 different genes are currently known to cause inherited retinal dystrophy. To benefit from Luxturna, patients must have two identified mutations in the RPE65 gene, which only occurs in 0.5 percent of cases. This drug would not have made it through development if all patients with retinal dystrophy were included in the clinical trial, due to the very small percentage of retinal dystrophy patients who have this specific genetic subtype. But the development and recent approval of this drug is life-changing for that subset of patients.  
 
Despite the great potential genetics offers to Clinical Trials , the need for genetic expertise is often forgotten. Clinical trialists may think adding a genetic screening is as simple as including any other type of test or screening. However, genetic testing and screening is much more complicated than that.
 
There are many challenges that arise when a trial implements genetics. From the beginning stages of determining the appropriate genetic panel make-up to the issue of retaining patients throughout the trial, genetic expertise is crucial. As personalized medicine becomes more necessary for areas such as rare-disease drug development, genetic expertise is increasingly becoming a necessity.
 
Challenges
The complexities of genetics in clinical trials begin in the planning stage. When searching for a single-gene mutation, it may seem evident that the genetic test should only test for that one gene, however, there is a Lot to consider. A small test will require less resources, but it may also mean less buy-in from patients and providers. Patients are likely to test negative on a specific test. After a few such negative results, they may even be discouraged from participating, feeling it is unlikely they will find a cause of their disease state or ever qualify for a trial. This can Lead to significant future challenges if the sponsor later develops a therapy targeting a different gene. When researching Orphan Drugs , sponsors can’t afford to decrease patient and provider buy-in or discourage patients from undergoing testing. With a large test encompassing many genes,however, results are more likely to be inconclusive or complex, and additional resources are needed to explain the results to patients. The design of the genetic panel should balance the demand and resources of the trial, the future and current needs of the patient population, and the importance of patient and provider engagement.
 
Once the genetic test is chosen, patients need to be screened. With rare diseases or rare subsets of a common disease, many patients will need to be screened to find a sufficient patient sample required for the clinical trial. When only one to two percent of the population possesses the variant researchers are seeking, thousands of patients will need to be screened to find enough patients testing positive. Those patients need to be educated about the clinical trial and determine whether or not they would like to consider participating.  Even if patients want to participate, they may not fully qualify for the study according to the Protocol ’s inclusion/exclusion criteria.   
 
When patients are identified for genetic screening, investigators need to also consider the sensitivity of the results. Genetic data can be confusing, and not only for the patients who test positive. Patients who test negative may erroneously think they have no risk for the disease, if the results are not properly explained. Based on a recent recommendation from the National Academies of Science, Engineering, and Medicine clinical researchers should routinely consider whether and how to return individual research results to patients through an informed and thoughtful decision-making process.
 
The traditional clinical trial model does not usually concern itself with patients who test negative and therefore do not qualify for the trial. However, when dealing with such small patient populations, engagement and retention are crucial. Continuing to engage with patients who test negative is important for future trials, in which a patient who initially tested negative may end up testing positive for a different genetic variant and qualifying for a future trial
 
These challenges can be overwhelming, but there is one key piece to facing them all: genetic counselors.
 
The missing piece
When incorporating genetics into clinical trials, genetic counselors have the expertise necessary to help effectively identify, engage and retain patients.
 
When identifying patients with a specific genetic variant even for a common disease, a lot of people will need to be screened. New models such as virtual counseling, via telemedicine, make it easier for genetic counselors to reach a large number of patients regardless of their physical location. Patients can be screened remotely, and only those who screen positive will need to travel to the study site. Complications also arise because all patients need education about their results. This can be overwhelming for a trial to handle, but genetic counselors can help with this. Genetic counselors are trained to interpret complex genetic test results, and to explain those results to patients. Decisions need to be made on how to handle all of the patients who are tested. For example, education materials could be developed for all patients who test negative, and genetic counseling appointments could be made for all patients who test positive or whose results are inconclusive.
 
If a patient tests positive, the genetic counselor can discuss what that result means for both the patient and their family. A more lengthy and personal conversation than would typically occur during a “normal” doctor visit may allow the counselor to learn more about the patient’s family history. This could lead to identifying family members of the patient who may also be eligible for the clinical trial, even if that individual is in a different location, since the same genetic counselor can speak with family members across the country. Genetic counseling also helps keep the patients engaged in a trial, by helping them more fully understand the implications of their results and their options.
 
Patients who test negative will remain engaged because of the high-touch component that genetic counselors provide directly or through the educational materials they provide. This will help patients who test negative continue to think positively about clinical trials in case they qualify for a future trial. Explaining a negative result and its implications may not be possible without a genetic counselor serving the trial.
 
Genetic counselors are also aware of the types of concerns that patients will have pre- and post-screening. They can set appropriate expectations about the length of time it may take to get a test result returned or the likelihood of testing positive. Patients who are well informed will know what to expect from the process and are more likely to remain engaged in the study.
 
The future
This expertise is important as we become more aware of the possibilities that genetic studies provide. After Luxturna, the drug for inherited retinal dystrophy, was approved last December, the FDA Commissioner Scott Gottlieb, M.D., expressed optimism about the future of genetic research.
 
“I believe Gene Therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses,” Gottlieb said.
 
With so much potential to be found through the proper utilization of genetics, genetics expertise is becoming increasingly important. Without this expertise, the potential for successful development of a targeted drug — the only chance of finding an effective drug for many illnesses—is greatly diminished.

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Karmen Trzupek is the Director of Clinical Trial Services and the Director of Ocular & Rare Disease Genetics Services at InformedDNA. She is a certified genetic counselor and specializes in identifying and supporting patients with rare genetic diseases. Karmen has worked in genetics for more than 15 years.
 




Jill Johnston is the President of Site Activation Solutions at WCG Clinical Services. Here, she is responsible for creating transformational site activation solutions that stimulate growth, accelerate study starts, and maximize efficiency for those who perform clinical trials. She has more than 25 years of clinical research experience.