In an effort to target the right patients, genetic screening is becoming more common in clinical trials. But incorporating it can be complex and add a significant burden for both patients and clinical trial sites. Genetic counseling can streamline that process and help drug and gene therapy developers expedite the recruitment of genetically-eligible participants for their trials and use genetic testing results to accelerate the speed and success of clinical trials.
Genetic testing serves multiple purposes in the clinical trial process.
For one, it helps identify individuals who have specific genetic variants that make them eligible for a particular trial. These variants may be detected in the germline, meaning they were inherited and are present in all cells of the body. Or, they may be present in tumor tissue, but not in other cells of the body.
The interpretation of the results is also crucial to enroll participants who truly meet enrollment criteria. For example, if the inclusion criteria require participants to have a specific disease-causing variant within a gene (because the therapy is gene-based), trial staff must be able to accurately interpret and document the results to ensure only eligible patients are enrolled. It’s not uncommon to identify patients who were enrolled in error due to misinterpretation of the genetic test report.
Genetic testing also helps stratify participants based on their genetic characteristics. This enables researchers to study the impact of genetic variants on treatment response and disease progression. Consider these two examples:
- Researchers conducting a cancer clinical trial knew their drug altered Apolipoprotein E expression, which inhibited tumor growth. Apolipoprotein E is encoded by the APOE gene and all participants had APOE genetic testing to evaluate how APOE allele status may have impacted treatment response. Certain APOE alleles can also significantly increase risk for Alzheimer’s disease. Genetic counseling was integrated into the trial to properly explain that risk to participants.
- Another trial was treating individuals with an inherited metabolic disorder. Individuals with a variant in the target gene were eligible, and then they were stratified by variant and phenotype severity. In this trial, genetic counselors thoroughly reviewed and adjudicated variants and performed genotype-phenotype analyses to appropriately stratify these individuals.
Genetic testing helps assess the safety and efficacy of investigational drugs in specific genetic subpopulations. Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. There is an ever-growing list of FDA-approved therapeutic products with pharmacogenomic information found in the drug labeling.
One example is abacavir, which goes by the brand name Ziagen. It is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with Ziagen.
When designing clinical trials, underlying causes or biomarkers of the condition also need to be taken into consideration. Trials employing preselection biomarkers have higher success rates. As such, biomarkers, and in this case, genetic data, need to be captured accurately for clean data analysis and FDA review.
For example, accurately entering the specific coding DNA and protein level variant nomenclature can help determine whether participants with specific variants have different drug responses. However, clinical trial staff without genetic training are unlikely to understand the nuances of genetic data. Variant nomenclature is prone to documentation error. Interpreting whether the variant is disease-causing can also be quite nuanced. In these cases, genetic counselors can ensure accurate data entry into electronic case report form platforms.
To date, genetic testing has been predominantly performed in individuals with rare disease. According to the National Organization of Rare Disorders, one in 10 Americans have a rare disease or lifelong condition—or approximately 30 million people. Of those diseases, 80% have an underlying genetic component, yet only 5% have available treatments. However, there are a growing number in the development pipeline, and genetic counseling can help get more of those treatments to market faster.
How genetic counseling overcomes obstacles in the clinical trial process
Readers of this article are likely very aware of the obstacles when enrolling patients in clinical trials for genomic-based therapies. Genetic counseling can help address these challenges in multiple ways.
First and foremost, genetic counselors are highly skilled professionals with advanced training in both medical genetics and counseling. They work in a variety of settings, including university medical centers, private and public hospitals, diagnostic laboratories, nonprofit organizations, and government agencies. And they are involved in multiple areas of medical practice including pediatrics, prenatal, cancer, metabolic disease, neurology, cardiology, infertility, pharmacogenetics, genomic medicine, and others. All that expertise can help navigate some of the biggest obstacles in the end-to-end clinical trial process.
Planning & Feasibility: At this stage, clinical genomics expertise can inform eligibility criteria. Mechanism of disease and variant interpretation can be complicated. Genetic counselors can serve as consultants to instruct genetic inclusion/exclusion criteria and research and vet genetic testing laboratories.
Patient Identification: Targeting patients with rare genetic variants is difficult. Some candidates may not have received a diagnosis yet, while others may have a clinical diagnosis that has not been confirmed with genetic testing. Furthermore, academic medical centers, and even entire states, may only have a couple patients with the rare disease.
Clinical genomics experts may already have a relationship with individuals with the rare disease as well as patient advocacy groups. They can leverage these relationships to expand identification. Additionally, telehealth genetic screening can confirm eligibility criteria regardless of where the patient lives and eliminate the time, cost, and coordination of patient travel.
Provider Engagement: Clinicians have a lot on their plate and screening for clinical trials may not be a top priority. Their clinics may also not have the bandwidth or staffing resources to provide genetic screening to patients.
Genetic counselors are equipped to engage patients in clinical trial screening (in person or via telehealth) with minimal impact to the clinic while the local provider retains patient stewardship. Counselors can facilitate patient genetic testing, communicate genetic results and implications, discuss trial eligibility, and then share this information with the provider. Furthermore, they can develop condition-specific and genomics resources for providers with varying levels of involvement in the clinical trial.
Patient Engagement: Many patients have mixed feelings about their clinical trial experiences—for example, feeling removed from the process, wary of the pharma industry, or fatigued from a lack of qualifying studies. In these cases, high-touch, expert clinical genetic counseling can build trust and rapport with patients, resulting in higher levels of study recruitment.
Data Regulations: Accurate genetic data is absolutely critical for ensuring eligibility criteria, patient stratification, and FDA review. Genetic counselors have research experience, understand the IRB and FDA processes, and importantly, are able to ensure accuracy of genomic data within electronic case report forms. They can recommend best practices for accurate entry, help rectify incorrectly entered data, and even enter the data if needed to ensure accuracy.
Post Market: Genetic counselors can help determine data points to demonstrate clinical utility so payers will have policies to ensure coverage for patients.
Telehealth genetic counseling
Telehealth genetic screening was mentioned above as a way to eliminate obstacles in the patient identification phase. Here’s how telehealth genetic counseling and provision of care for patients in the clinical setting can work:
- Once a provider or patient-initiated referral is placed, the patient is registered, and an appointment is scheduled.
- In pre-test consultation, genetic counselors obtain family and medical history, address psychosocial concerns, and discuss the risks, benefits, and limitations of genetic testing.
- Genetic counselors then facilitate genetic testing. They are uniquely trained to identify the best lab and test that is targeted to meet the patient’s needs.
- When test results are available, there is a post-test consultation where the genetic counselor discusses the results. These may be diagnostic for a genetic condition, negative, or the results may be uncertain. Genetic counselors are uniquely trained to discuss implications of these results for the patient and their families.
- A formal summary report of the information discussed during consultation is shared with the patient and/or healthcare provider.
Telehealth clinical trials
The telehealth model for genomics-based clinical trials is quite similar to the clinical telehealth model described above. The key difference is that the patient or provider is making a referral for a specific clinical trial program. Often the referring provider is involved in the clinical trial somehow, but that is not a requirement. There may be some initial screening questions to confirm the patient meets the basic eligibility criteria.
Clinical genomics experts may already have a relationship with individuals with the rare disease as well as patient advocacy groups. They can leverage these relationships to expand identification. Additionally, telehealth genetic screening can confirm eligibility criteria regardless of where the patient lives and eliminate the time, cost, and coordination of patient travel.
During the pre-test consultation, the genetic counselor will discuss the testing process. This is typically sponsored genetic testing, where a specific lab vendor and test are utilized. Sometimes the sponsor has a lab in mind, but genetic counselors can also identify the most appropriate lab and tests for the patient and sponsor’s needs.
During the post-test consultation, the genetic counselor will discuss results. For clinical trials, a positive, or disease-causing result does not mean the patient meets the genetic criteria for the trial. The positive result may need to be in a specific gene or even a specific type of gene variant. So, there is an added consideration that needs to be considered and discussed.
Variants of uncertain significance add another layer of complexity. The lab does not have enough evidence to determine whether these variants are disease-causing, so these patients are typically not eligible for gene-based trials.
Some diseases have a high rate of VUSs. For example, approximately half of individuals with a clinical diagnosis of a form of muscular dystrophy are found to have a VUS. In these cases, genetic counselors can engage in several VUS resolution services sponsored by biopharma where they work with the reporting lab to determine what additional information is needed to resolve the VUS. This may involve genetic counselors tracking down medical records and facilitating family member testing.
If the patient does meet genetic eligibility, the genetic counselor will discuss the clinical trial in more detail and, if the patient is interested, a referral will be made to the clinical trial site.
The patient and/or referring provider will also receive a summary report so they are aware of the results and clinical trial plans.
Once the patient is referred to the site, they are prescreened and trial-ready.
Building patient trust and engagement
Patient trust is an essential part of the clinical trial process—and genetic counseling can play a critical role throughout.
In pre- and post-test genetic counseling appointments, genetic counselors discuss complicated and sensitive topics with patients. Counselors can perform family member outreach, which has been a successful method of recruitment, especially for trials targeting rare and ultra-rare conditions. They are also able to facilitate resolution of VUSs. This is a time-intensive step that is extremely valuable for patients and clinicians.
Lastly, genetic counselors collaborate with multiple labs and are able to identify labs and tests that meet both the patient and sponsor’s needs.
Genetic counseling adds both quality and speed to the clinical trial process—by identifying qualified patients, leveraging telehealth to screen a higher volume of patients while reducing the burden on patients and clinical staff, facilitating genetic testing with remote sample collection, consent and pre- and post-genetic counseling, and genetic data integrity to ensure accurate patient eligibility criteria and data collection within the eCRF.
Ashley Cannon is a clinical program manager responsible for coordinating and managing the delivery of clinical programs for the Life Sciences division at precision health company InformedDNA. She earned a PhD in neuroscience from Mayo Clinic as well as an MS in genetic counseling from the University of Alabama at Birmingham. Her clinical and research experience focuses on neurogenetic conditions, including neurofibromatosis type 1 and frontotemporal degeneration.
