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 inclus...
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