Since the completion of the Human Genome Project in 2003, the pharmacogenomics industry has experienced waxes and wanes in reaction to healthcare dynamics and technological advancements.[i] With the continued push towards personalized medicine, pharmacogenetics offers organizations a potential solution to fine-tune therapy by helping predict the patient’s response to a medication. However, incorporating pharmacogenetics into clinical practice with high fidelity is a delicate balancing act: The lack of standardized testing methods and data analytics, poorly informed payer perceptions, and misconceptions held by both the public and healthcare industry professionals give rise to many questions and ambiguities.
“Pharmacogenomics is not the general standard of care yet,” said Ruben Bonilla Guerrero, M.D., director of medical affairs at Admera Health. “However, it’s become the standard of care for institutions and practices where they’ve seen the practical application and its health and economic benefits and have the personnel who understand how it works and how to implement it into patient care.”
Pharmacogenetics Testing Building Momentum
“There’s a conflict between ordering a few specific tests that have good evidence behind them, but the reality is that interrogating the genome is cost effectively done by interrogating hundreds of tests that have variants,” explained Mary Relling, PharmD, chair of the pharmaceutical sciences department at St. Jude Children’s Research Hospital. The negligible cost differential between ordering a single test versus a panel allows organizations to focus on actionable genomic variants without clouding clinicians’ thinking about non-actionable genetic variants.
One factor limiting the broader use of pharmacogenomic testing is inconsistent and often inadequate reimbursement of genetic testing. But organizations have devised different strategies for overcoming payer hurdles.
An institution that routinely performs pharmacogenetic testing, St. Jude Children’s Research Hospital eliminates payer barriers by automatically paying for the patient’s care regardless of reimbursement rates. However, most organizations lack such financial liberties and frequently encounter misconceptions payers may harbor regarding the actual cost of testing.
Jake Comstock, director of business development at OneOme, noted providers are reticent to adopt pharmacogenetics into practice beyond oncology where there is strong evidence supporting clinical use. He firmly believes that providing payers with clinical evidence and the benefits of pharmacogenetic testing is critical. His organization launched OneOme Institute to provide education and resources for doctors, pharmacists, and other healthcare professionals interested in expanding their knowledge of pharmacogenetics.
Michael Schuh, PharmD, assistant professor of family and palliative medicine and assistant professor of pharmacy at the college of medicine at the Mayo Clinic Florida said the organization benefits from educating payers of the potential long-term cost-savings. “We make the argument that genes and phenotype generally won’t change, so running a complete panel can uncover other problems for the same price of one.”
Bryan Dechairo, Ph.D., executive vice president of clinical development at Myriad Genetics, believes the reception to pharmacogenetic testing depends on whether the customer is a payer or a physician.
“Payers want to know whether tests are valid and whether the tests improve outcomes,” he said. “Once they make the decision that the tests help patients, we contract or negotiate with them a price a that makes sense.”
Not All Available Tests Relevant, Not All Settings Conducive to Testing
Currently, there are 262 drug labels approved by the U.S. Food and Drug Administration (FDA) to include information about variations in patient responses as a result of genetic variability, according to the FDA’s Table of Pharmacogenetic Biomarkers. [ii, iii]
Among these medications are the anticoagulant warfarin (Coumadin, Jantoven), metabolized by the VKORC1 biomarker, and codeine, along with various psychiatric and neurological medications that are metabolized by the CYP2D6 enzyme. In a more specific example, the antiplatelet drug clopidogrel (Plavix) is metabolized primarily via the CYP2C19 pathway, and people who carry the genetic mutation for poor metabolism of the enzyme have an increased risk for bleeding.[iv] For this reason, clopidogrel bears a boxed warning on the label.
Organizations typically adopt one of two forms of testing: preemptive testing, in which they test patients before initiating therapy, or reactive testing, in which tests are run after initiating therapy. As it stands, the FDA only requires pharmacogenetic testing before initiating therapy for medications identified requiring preemptive testing, as noted in the package insert.
The decision to test for variants for medications for which the manufacturer has made no specifications falls upon the discretion of the institution and healthcare provider.
“The neural space, pain control, and cancer are all areas where patients have a high chance of getting exposed to many drugs. This is where pre-emptive testing makes the most sense,” said Ulrich Broeckel, M.D., cofounder and chief executive officer of pharmacogenomic testing company RPRD Diagnostics.
In addition to the pharmacogenetic testing required by the FDA, some organizations have implemented pharmacogenetics as a routine form of testing for certain therapeutic areas; which tests are run largely varies among institutions, depending on the therapeutic area as well as industry trends.
For example, while altered drug responses in patients taking warfarin who have the VKORC1 variant have been identified, warfarin does not have a boxed warning, leaving institutions and providers the leverage to determine testing feasibility. Currently, physicians rarely test their patients for warfarin pharmacogenetic variants. But as Don Rule, cofounder and CEO of Translational Software explained, efficiency may also play a role in the lack of pharmacogenetic testing for warfarin.
“Everyone expected that warfarin would be the poster child for pharmacogenetic testing—especially because it’s rat poison,” he said. “When prescribing a medicine, it’s not unusual to get the INR back before you get the lab test back.”
Pharmacogenetics tests average a seven-day turnaround; INR results are usually available within 24 hours.
Patient settings and health status also affect the ability to perform tests and implement regular testing. For example, pharmacogenetics testing can be performed in outpatient settings such as community pharmacies and ambulatory care clinics. However, testing eligibility becomes a more arduous task in the hospital setting—especially for patients who lack cognition such as incapacitated patients in intensive care or comatose patients.
“Genetic testing requires consent forms, so a patient in the ICU will have to be in an alert and communicative status to understand and consent to testing,” Admera’s Bonilla Guerrero said. “Comatose patients need a Power of Attorney or Advanced Directive.”
Pharmacogenetics May Improve Mental Health by Countering Patient Adherence
An estimated 33% to 50% of all patients do not take their medications according to their prescribers’ instructions, costing the United States an estimated $300 billion annually.[ii] However, actual costs may be higher than recent estimates, as the definition of adherence and how it is measured vary greatly in the literature.
Patients may have numerous reasons for not adhering to their medication regimens. Reasons include high medication costs, lack of involvement in treatment decisions, negative perceptions regarding medication efficacy, doubting medication need, inadequate or incorrect understanding of medication instructions, forgetfulness, poor social support, and side effect concerns.
Managing and reducing nonadherence remains a challenge to treatment success that requires an arsenal of resources depending on the barrier a patient may face in treatment. In situations where an inability to tolerate side effects or even the potential for life-threatening side effects may threaten a patients ability to take his or her medications according to instructions, pharmacogenetics may prove an instrumental resource in ensuring therapeutic success by helping to facilitate appropriate drug choice as well as dose initiation and titration.
In the psychiatric realm, Myriad Genetics focuses on testing diagnostic markers for depression medications. Dechairo considers tapping into this therapeutic area a beneficial feat in helping to address adherence challenges by focusing on patients who are being treated for depression in which the consequences of failed antidepressant therapy adds $20,000 in additional healthcare spending.
As mental health issues continue building momentum, Zohra Ali-Khan Catts, LCGC, director of genetic counseling at Christiana Care’s Helen F. Graham Cancer Center & Research Institute, foresees pharmacogenetics as another element in treating depression and anxiety.
“With mental health, it’s not just monogenetic—it’s more complex involving multifactorial environmental factors with genetic factors playing a role. “I think the biggest area of shift we’re going to see is in caring for the mental health population,” Ali-Khan said.
Inconsistencies, Ambiguities, and Misunderstandings Abound
Both Relling and Broeckel warn against relying solely on pharmacogenetics testing as the panacea in personalized medicine. Pharmacogenetics testing is just one ingredient in a complex, multifactorial soup in solving the puzzle of treating a patient. A prudent healthcare provider must consider numerous factors when designing a treatment plan for his or her patient—of which pharmacogenetics is one of many tools.
Additional factors such as body mass index, age, height, weight, disease status, renal function, liver function, and volume of distribution all contribute to the patient experience. Dechairo agreed, stating, “When you only have one piece of the information, you can often make the wrong decision.”
To overcome this hurdle, Myriad Genetics and Admera Health employ testing strategies that take into account pharmacokinetic, pharmacodynamic, and pharmacogenetic results to produce results that are a composite of the three—a concept called combinatorial pharmacogenetics. Myriad uses clinical evidence using a combinatorial algorithm that adds compensation to each of these values to produce weighted results.
Relling warns that even pharmacogenetics has some limitations. “One of the issues with combinatorial testing approaches is some companies don’t provide information on the algorithms they use or the data testing,” said Relling. “A lot of them are divorced from information from the patients.”
Resources Offer Providers Actionable, Evidence-Based Guidance
In 2009, the National Institutes of Health funded the Pharmacogenomics Research Network to provide reliable data and guides to help facilitate the implementation of pharmacogenetics. From that partnership, Relling and Teri Klein, Ph.D., of Stanford University, cofounded Clinical Pharmacogenetics Information Consortium (CPIC) aimed at facilitating the use of pharmacogenetics in the clinic to provide what Relling defines as “peer-reviewed, freely available updatable, expert- and evidence-driven guidelines for specific gene-drug pairs.” The consortium uses four categories to rank recommendations based on evidence—”strong,” “moderate,” “optional,” and “no recommendation.” CPIC started as a joint venture in partnership with PharmDGKB, a database hosted by Stanford and curated by industry professionals.
“An important underlying assumption is that we’re trying to provide guidance on how to use genomic information to guide [what to] prescribe—not whether to order a genetic test,” Relling explained. “A major dilemma is how to use the information at their fingertips to provide the prescribing, which is useful because it helps us bypass the issue of cost-effective prescribing of avoiding a test.”
Pharmacists and Genetic Counselors Complementary, not Interchangeable
While perfecting the patient care model remains somewhat of an enigma, experts recommend organizations and healthcare professionals can still enhance the quality of personalized treatment a patient receives.
Relling and Ali-Khan urge organizations to eliminate silos and compartmentalization among healthcare professsionals and encourage intra- and inter-disciplinary collaboration. Ulrich recommends engaging pharmacists to play an intermediary role between the physicians and the patients—especially those in the community sector. Bonilla Guerrero pointed out that while many organizations tend to rely on either a pharmacist or a genetic counselor, organizations stand to benefit from the complementary skill sets of having both professionals on board.
Genetic counselors specialize in rare and life-threatening diseases, while pharmacists specialize in drug information and dosing, according to Rule.
“Pharmacists can be helpful in [analyzing, translating, and interpreting] the results of pharmacogenetic tests, but genetic counselors are very important in assisting providers and patients when a test result could be severe and potentially life-threatening,” Rule said.
For example, patients who have the HLA-B*15:02 wild type variant have a greater risk for developing a life-threatening skin reaction called Stevens’ Johnson’s syndrome if administered the antiepileptic drug carbamazepine.[v] In addition to supporting this area, genetic counselors frequently support cardiologists treating patients who have familial hypercholesterolemia, according to Ali-Khan Catts.
“Not only do we want the providers to utilize the information we provide to help them make better decisions, but we integrate the information we provide so the pharmacist can see which drugs are contraindicated and the drug information shows when the patient presents to the ER,” she said.
Genetic counselors can also collaborate with pharmacists to tailor therapy. Ali-Khan Catts cites the relationship between Huntington’s disease and potential therapy as an opportunity for genetic counselors to collaborate with pharmacists. An autosomal recessive disease caused by a mutation in the HTT gene, genetic counselors can notify the pharmacist if a patient who has Huntington’s disease is a poor metabolizer of CYP2D6. Doing so could alter the course of treatment or dosing considerations, as some medication used to treat Huntington’s are metabolized via the CYP2D6 pathway.
While recognizing that the complementary skills of genetic counselors and pharmacists can add value to the overall treatment, Rule’s organization has focused on engaging pharmacists—particularly those in community practice.
Pharmacists receive more training in pharmacology than any healthcare professional, uniquely positioning them to provide drug information. Additionally, many pharmacy schools incorporate pharmacogenetics into their curriculum, but the degree of training students receive varies greatly among schools of pharmacy. However, a study published in Pharmacy Teaching and Learning in 2019 found that 76.9% of responders participating in a survey evaluating pharmacogenomics training in pharmacy schools felt that pharmacists lacked sufficient knowledge in the area, yet only 30.7% of responders expressed plans to expand the amount of pharmacogenomics training in their school’s curriculum.
Despite the potential benefit of incorporating pharmacists into the patient treatment scheme, Schuh says payor challenges may hinder pharmacists’ ability to provide these specialized services.
“They still don’t pay the pharmacists for the sit-down with patients to explain the testing of the panels,” explained Schuh. “It’s kind of a disservice to the patient because the public needs to understand the difference between a CLIA-certified lab from which a clinical decision can be made, and a direct-to-consumer lab, like a 23andMe, that is more for information, education, and entertainment.”
The Future
Bonilla Guerrero said a recurring question pharmacogenetics companies get from physicians is “Why is my gene or medication of interest not listed in your report?”
“Pharmacogenetics is about the genes’ ‘pharmacogenes’ function and medications interaction as predicted by the molecular findings, and the impact that complex has on the potential medication response in a particular patient,” Bonilla Guerrero noted.
For that reason, the specific gene-variant and drug combination must have a sufficient level of clinical evidence to produce an actionable clinical statement. Gene-drug pairs failing to meet such criteria are omitted from reports. Regardless, testing companies could include these findings in an informative but not clinically actionable fashion.
Genes deemed as important could change with continued discovery of new genes and technological advancements.
“Pharmacogenomics is not about the molecular findings of the so-called pharmacogenes alone but rather the combined effect of the interactions between a drug and pharmacogenes’ function,” said Bonilla Guerrero. “As time passes, there’ll be new genes and variants associated with the same medications we use right now, and there will be new genes and variants associated with medication that we cannot foresee.”
Sources
[i] Drozda K, Paconowski M, Grimstein Z, Zineh I. JACC Basic Transl Sci. 2018 Aug; 3(4): 545–549. Published online 2018 Aug 28. doi: 10.1016/j.jacbts.2018.06.001.
[ii] Haga S, LaPointe N. The potential impact of pharmacogenetic testing on mediation adherence. 2013 Dece; 13(6):481-483. Doi: 10.1038/tp0j.2013.33.
[iii] www.fda.gov/drugs/science-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling
[iv] www.accessdata.fda.gov/drugsatfda_docs/label/2019/020839s072lbl.pdf
[v] Guo C, et.al. Pharmacogenetic signatures: A novel strategy on the individual differences in drug response. Cancer Letter. 410(2018) 190e194
[vi] ghr.nlm.nih.gov/condition/huntington-disease#inheritance
