Progress report Why we still don’t have a reliable gold standard for in vitro diagnostic genetic testing

Pharmacogenomics is an important tool that offers the promise for doctors and patients of an era of personalized medicine. Testing patients for underlying genetic factors that may predict their reaction to medicine is one of the fastest growing segments of the in vitro diagnostics industry. Adoption of this new approach, however, has by most measures been slow and long in coming. Certainly the practice of medicine does not change overnight, and this particular industry has been burdened with the usual obstacles.

The hurdles for full adoption of this rational approach to patient care are still numerous, including the need for widespread physician education, reimbursement by insurers, translation of testing outcomes into patient care, and the important mandate of the U.S. Food and Drug Administration (FDA) to drive testing patients prior to drug therapy.

Many drugs have a recommendation from the FDA printed on the prescription label, telling doctors and patients which in vitro tests can help in prescribing the right dose to the right patient. In some cases, these labels help to tell us when a patient might not benefit from a certain drug, thus avoiding serious adverse drug reactions, a major cause of morbidity and mortality in the U.S.

In the May 2008 issue of Medical Laboratory Observer, I published a short article entitled, “Why is there not a de facto gold standard for genetic-testing controls? One of the main points I made was that there was a need for a U.S. government-led action to require the same quality assurance standards for reference controls as for the other components we rely on to ensure reliable and accurate genetic testing in the U.S. Unfortunately, the questions and concerns raised in the article still remain, and the ideal solutions still remain elusive.

This situation is surprising on a number of fronts. For one, the FDA has been working diligently to reverse its previous “enforcement discretion” when it comes to the oversight of Laboratory Developed Tests (LDTs). The FDA wants to influence the domain of Clinical Laboratory Improvement Amendment (CLIA) in the oversight of clinical diagnostic laboratories in the U.S. Specifically, the FDA wants laboratories (and their suppliers) to implement similar Quality System Regulations (QSR, 21CFR820) as those already imposed on the medical device industry and FDA-cleared in vitro diagnostic products. There have been a number of public meetings, announcements, and seminars hosted by the FDA to explain to the clinical laboratory industry just what needs tighter oversight and better regulation.

The use of Research Use Only (RUO) products is a significant concern of the FDA. There is a lack of quality assurance standards for these reagents because they are not manufactured using QSR. Yet such products are put together by laboratories to make many of the tests currently offered for patient testing under the banner of LDTs. Surprisingly, there has been almost no discussion of the FDA imposing similar regulation for products that laboratories use as positive controls during the implementation of LDT testing.

In our regulatory consulting practice, as we try to guide test manufacturers and clinical laboratories, the question clients ask most often is, “How will the FDA’s new enforcement of LDTs affect my business?” Our answer is simple: the same quality system regulations that the FDA enforces on in vitro diagnostic manufacturers will now apply to clinical laboratories when developing “kits” to formulate their own LDTs.

Ironically, if the FDA is successful in implementing its new enforcement, the only exception to requiring QSR in all aspects of in vitro diagnostic manufacturing and testing would be the source and type of manufacturing used to obtain stand-alone positive reference or quality controls. As in 2008, laboratories can still use leftover patient material, research-grade products originally intended for academic research, and products bought from repositories such as independent research foundations.

The main policy issues that have to be resolved in order to force a mandate to require QSR for reference standards include the following:

  • Recognition by the government and industry that quality is as important (or more important) for the controls used to verify and ensure accurate test development and testing as it is for all test components, regardless of source or regulatory compliance used in manufacturing.
  • Differentiation of lower level reference standards from Certified Reference Materials. The latter includes traceability and the high-level quality control we demand in most medical device products approved by the FDA.
  • Financial incentives for the manufacture and commercialization of control standards to compensate for the cost of implementing QSR systems.
  • Reimbursement to clinical diagnostic laboratories that utilize the products by designating common procedural terminology (CPT) codes that reflect the cost of purchasing and using higher-quality material for patient testing.
  • A government mandate that forbids the use of research-grade materials in human testing when a viable commercial source of QSR-grade material is readily available.
  • Designation of the use of leftover patient material used as a source of reference material as “the commercial use of a patient’s biological material.” Given that controls in a clinical diagnostic lab allow the company to derive an income from testing, we should take the ethical high road and inform patients of this possible commercial use of their sample. Too many in the industry still view “free” patient materials as having little value because they are readily available and “donated” by the patient, even when the informed consent originally used to obtain the sample did not spell out the potential for the laboratory to use it at a later date for commercial purposes (e.g., testing).
  • Institutional Review Boards (IRBs) and the FDA should update and correct previous guidance on the de-identification (“anonymization”) of patient samples to clarify the need to explicitly inform patients that their “leftover” material may be used for commercial purposes. Certain exceptions might be allowed for extremely rare cases since there would likely never be a commercial source for these materials.

As mentioned previously, since 2008 very little has changed in building an incentive for commercial suppliers to step up and offer QSR-grade controls. In fact, due to the lack of a government-led mandate, several companies that were attempting to provide these materials have since gone out of business or been shuttered by investors. If the FDA does not step up and force the implementation of regulations to demand only the sale and use of QSR-grade controls, it will be up to the clinical laboratory industry to police itself. We should advocate for the highest quality standards possible for testing the U.S. patient population or risk giving our industry a black eye. In not doing so, we risk the inevitable errors that cause serious harm to patients when false negative or positive results go undetected because the controls themselves were flawed.

Many in the industry fear new regulations imposed by the FDA on reagent manufacturers who might be selling research-grade components to laboratories making their own LDTs. Laboratory directors are rightly concerned about the cost and difficulty of setting up quality control and quality assurance on the procedures used to “manufacture” LDTs. In the meantime, unless the FDA starts to pay significant attention to one of the most critical aspects of in vitro diagnostic testing in the U.S., the entire industry will continue to use less than ideal products as quality controls and standards as a means of deciding if testing is being done in an accurate and reproducible manner.

Michael P. Murphy, MSc, is president of Conatus Consulting, assisting clinical diagnostic laboratories with CLIA requirements and certification and also assisting medical device clients with their submissions to the FDA for marketing clearance. Previously he was president and CEO of ParagonDx. He serves on a number of advisory panels involved in developing future policy around human genomic reference controls, including EuroGentest (EU) and “GetRM,” sponsored by the Center for Disease Prevention and Treatment.

This column addresses compliance, regulatory, legal, certification, and additional concerns in the lab. Readers can submit questions to [email protected].