Genetic testing and drug development: Use cases, regulations, and misconceptions

By Melissa Fassbender

- Last updated on GMT

(Image: Getty/Nazan Akpolat)
(Image: Getty/Nazan Akpolat)

Related tags Genetic testing InformedDNA Drug development Patient recruitment Rare disease Oncology

Scientific advances and regulatory incentives are driving the use of genetics in drug development, though the industry’s ability to perform wide-scale testing has outpaced its understanding of the results, the misinterpretation of which can have “disastrous” results. This is where genetic counselors step in.

To further discuss the role of genetics in drug development, and some of the common misconceptions, Outsourcing-Pharma (OSP​) spoke to a certified genetic counselor, Karmen Trzupek (KT​), director of ocular and rare disease genetics services and clinical trial services at InformedDNA.

OSP: How is genetic testing being used across the drug development industry?

KT:​ Genetic testing is increasingly being used as a biomarker for diagnostic, prognostic, and predictive purposes. From a diagnostic perspective, genetic testing is commonly used to confirm a clinical diagnosis, or to identify the underlying specific genotype for patients with heterogeneous diseases. In a gene-based therapy, genotype is typically the most important inclusion criteria for a clinical trial.

As a marker of prognosis, genetic testing can help to identify subgroups within a disease population that are more or less likely to experience rapid or severe progression or recurrence of disease. As pharmaceutical companies target diseases with clear genetic susceptibility factors, genetic testing is becoming vital to balancing the arms of a clinical trial so that individuals at higher risk of severe progression of disease are not inadvertently enrolled more heavily into the treatment or placebo arm of the study.

As a predictive measure, genetic testing is frequently utilized in clinical trials as a secondary or exploratory outcome measure, with the goal of identifying genes that exhibit significant differences between responding and non-responding patients, to guide future development programs.

The common thread is a growing understanding that most of the variability in treatment response to therapeutics is not ​random. Genetics can have a huge impact on how drugs and therapies affect patients.

OSP: In which of these areas is it having the greatest impact?

KT: ​The two areas where genetic testing currently has the greatest impact are oncology and rare disease.

For cancer diseases, genetic testing has been utilized for decades in high-risk populations to determine inherited risk – that is, germline testing to determine predisposition to develop certain types of cancer. But today, genetic testing is also commonly used in tumor profiling to identify genetic mutations that drive cancer growth.

Targeted cancer therapies – directed against specific genes or pathways – have accounted for a significant percentage of the successes in oncology treatment in the last five years, in some cases leading to dramatic improvements in survival rates and clinical trial successes.

The PARP inhibitor story is a great example of the importance of genetic testing in the drug development pathway: Early studies of PARP inhibitors for late-stage, triple-negative breast cancer failed to show a clear benefit. These were large, well-designed randomized studies. However, later clinical trials of PARP inhibitors in patients with BRCA-positive breast cancer were very successful, leading to FDA-approval of Olaparib for patients with BRCA-related metastatic disease. The difference is that the early studies failed to stratify trial patients by their underlying genetic cause of disease.

Today, lists 113 open interventional studies for the evaluation of Olaparib in a variety of cancers. Most necessitate genetic testing as an inclusion criteria for the study, though many of the studies are now investigating genetic mutations in genes other than just BRCA1/2. 

OSP: What is driving the increased use of genetic testing in clinical research/drug development?

KT: ​A combination of scientific advances and regulatory incentives is driving an increase in the use of genetics in clinical research and drug development. From a scientific standpoint, the importance of recent successes in gene therapy cannot be overstated.

After decades of safety concerns, the FDA approval of life-changing gene therapies for the treatment of a childhood-onset type of blindness (Luxturna for RPE65​-related retinal dystrophy) and two approved gene therapies (Spinraza and more recently Zolgensma) for the treatment of infantile spinal muscular atrophy, have fueled hope, research commitment, and financial investment in gene-based therapies. 

Additional scientific advances include significant improvements in genetic testing technologies, leading to higher yield, lower costs, and ultimately better uptake of genetic testing. 

From a regulatory perspective, pharmaceutical and biotech companies enjoy multiple benefits from developing therapeutics for orphan diseases, including tax credits, clinical research funding support, and longer market exclusivity following FDA approval.

As a result, there has been a huge shift towards the treatment of rare diseases, approximately 80% of which are Mendelian (or clearly genetic in origin). 

OSP: In what ways is genetic testing specifically being used to advance drug development to treat rare diseases?

KT: ​As the utility of genetic testing becomes more widely recognized, pharmaceutical companies, patients and patient advocacy organizations, such as specific disease foundations, are beginning to support genetic screening efforts.

The Foundation Fighting Blindness, for example, currently sponsors a genetic testing and genetic counseling program for individuals with inherited retinal diseases. Patients with one of these conditions can undergo genetic testing and receive genetic counseling through this program. The primary purpose of the study is to accelerate the pace of clinical trial research by identifying large groups of patients who might qualify for gene-specific interventional trials and natural history studies. 

Increasingly, pharmaceutical companies are also beginning to sponsor genetic testing for patients and looking for ways to partner with the patient community.

OSP: Why is it not enough to merely incorporate genetic testing? Specifically, what is the importance of a genetic counselor?

KT: ​Contrary to the expectations of patients and many providers, genetic test results can be complex, and despite the advances that have been made in our understanding of the human genome, patients often have a limited understanding of basic genetic concepts. As a result, some patients may incorrectly interpret test results if they receive them directly.

Unfortunately, this can lead to disastrous results, such as unnecessary surgeries and/or inaccurate risk identification for family members. Utilizing genetic counselors to help interpret and explain genetic test results can both support patients in this unfamiliar world of genetics and mitigate risk for the sponsor.

From a sponsor’s perspective, genetic counseling can also lead to greater physician utilization, increased patient engagement, and the identification of family members through family outreach activities. 

As sites are being selected for a clinical trial, genetic counseling support may make the difference between whether or not a community-based PI chooses to participate in a study. Even physicians with a strong understanding of genetic testing have very limited time in their clinic to sit down and explain the implications of test results to patients and families.

Working with a genetic counselor with deep subject matter expertise enables that physician to screen their patients for a clinical trial and provide subspecialty level genetic services to their patients, while retaining stewardship of their patients and maintaining their clinic schedule. 

Of course, genetic diseases carry a risk for family members, as well. Patients frequently cite that one of the benefits of genetic counseling is gaining a better understanding of the potential impact of the disease to their family and developing the tools to discuss that risk.

Sponsors may benefit from another consequence of family member support: By identifying at-risk family members with the same genetic mutation(s), additional patients can be recruited into the study.

OSP: What are some of the most common misconceptions surrounding genetic testing/counselors?

KT: ​The most common misconception about genetic testing is probably that, following the conclusion of the Human Genome Project, we gained a deep understanding of the function of all our genes, and the impact of all of the genetic variation within the genome.

But in fact, the sequencing of the human genome was just the first step in a long road towards appreciating the consequence of human genetic variation, as today the clinical utility is understood for less than two percent of our genes.

Today, our ability to perform wide-scale genetic testing has far outpaced our understanding of the meaning of the results.

This means that most patients who undergo “panel-based” genetic testing of >50 genes will have multiple genetic variants identified, for which data is currently insufficient to provide proof of relationship to disease. 

Misconceptions about genetic counseling also exist. Genetic counseling began as a profession that primarily supported prenatal patients with at-risk pregnancies. The field has grown and stretched in many ways since then, but patients and clinicians still frequently associate genetic counselors with prenatal clinics or believe that the purpose of genetic counseling is solely to explain inheritance patterns.

Increasingly, genetic counselors now work in subspecialty fields, where their deep subject matter expertise complements the efforts of the referring physicians and provides patients with a resource to turn to for information about the utility of genetic testing and the potential impact of identified genetic variants.

Counselors also provide a better understanding of the underlying pathology of the disease, and current and upcoming approaches to treatment.

OSP: How has the proliferation of at-home genetic tests added to these misconceptions and/or misunderstandings as it pertains to genetics?

KT: ​The ease of ordering direct-to-consumer (DTC) genetic tests has led to the perception that genetic information is simple and accurate – for the prediction of everything from ancestry to the risk of developing complex diseases such as Parkinson’s disease. 

This is, of course, not true, as over the last couple of years the media has covered numerous instances where DTC genetic testing led to confusion on the part of the individual tested, with no clear path of where to turn for help.

Physicians who did not order the test typically do not want a role in interpreting the results, and patients without clear medical or family history indication typically do not meet insurance guidelines to repeat testing in a clinical laboratory. 

OSP: Conversely, what are some of the benefits to at-home testing?

KT: ​The DTC genetic testing market has made the public much more aware of the use of genetics, and, in general, more open to undergoing genetic testing.

The ease of using DTC genetic test kits has also spurred a significant change in clinical genetic testing labs, which have developed test kits to make sample collection more accessible to patients.

Just a few years ago, sample collection typically entailed a blood draw at a clinic, with specific storage and shipping requirements. Today, sample collection can be as easy as spitting in a tube and sending it through the US mail. For patients who struggle to travel, either for health or logistical reasons, this is very convenient.

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