NEW YORK – In recent months, as the US Food and Drug Administration has increased regulatory scrutiny on labs marketing pharmacogenetic testing without regulatory approval, groups representing test providers, patients, and personalized medicine advocates have become increasingly alarmed that the agency's actions lack transparency and legal standing.
While some groups have communicated their concerns directly to the agency, stakeholders have also formed a new coalition — represented by law firms Hyman, Phelps & McNamara, and Epstein Becker Green — to publicly push back against the FDA's actions.
The Coalition to Preserve Access to Pharmacogenomics (PGx) Information has been gaining members over the past month in reaction to the FDA's efforts to regulate how labs communicate genetic variants associated with drug response to doctors and patients. The coalition alleges that the manner in which the agency has chosen to regulate lab activities with regard to PGx testing is illegal and may harm patients, and the group wants to create a public record of these complaints.
Hyman, Phelps & McNamara's Jeff Gibbs and Epstein Becker Green's Gail Javitt, well-known legal experts in healthcare regulation, are leading the group and are incorporating its members' concerns into a citizen petition. Any time an interested party submits a citizen petition to the FDA taking issue with a regulation or order, the agency, by law, has to respond to it.
"It may take the FDA years to respond, but we're not submitting this with the expectation that we'll get a quick response," Gibbs said, adding that a citizen petition also triggers a formal review by the agency and the creation of a public docket where other interested parties may submit comments.
"Part of our concern about what's been going on is there has not been a lot of transparency, which has limited the ability of stakeholders, who are adversely affected, to air their concerns in a public way," Javitt explained. "A public docket, we hope, will encourage people to submit comments that then can be viewed by everybody."
Members in the coalition can remain anonymous, however, since some industry players are concerned about being identified to the FDA. While Gibbs and Javitt would not detail the composition of the coalition, they plan to draft a citizen petition that reflects the concerns of a diverse group of stakeholders, including hospitals, patients, physicians, and labs. The agency's actions have worried the broader healthcare community enough that a variety of stakeholders have signed on to the coalition, the lawyers said, and new entities continue to express interest in joining.
FDA's role in regulating lab tests and processes is a divisive topic within the diagnostic industry, with test kit developers and device manufacturers typically more open to some level of agency oversight than clinical labs and pathologists. Despite these differences, interviews with the coalition's lawyers and experts from different segments of the healthcare community revealed widespread agreement on one point: the way FDA has gone about regulating PGx testing is not only bad for patients but sets troubling legal and policy precedents.
The agency has put forth guidelines on companion diagnostics, for example, where it has communicated to industry that tests claiming to predict whether patients will respond to specific drugs pose a high public health risk if results are in error and therefore must undergo premarket review. However, labs marketing multi-gene PGx tests that inform treatment for different classes of drugs for a variety of indications, may not fit within the companion diagnostic regulatory framework, experts in the field said.
Importantly, the FDA has historically practiced enforcement discretion when such tests are developed and performed within a lab, leaving it up to the Centers for Medicare & Medicaid Services to oversee lab operations under the Clinical Laboratory Improvement Amendments. Over the years, as the genetic testing industry has grown and more broadly marketed its testing services, the agency has attempted to lift its enforcement discretion over certain types of lab tests and even all lab tests. But these attempts have been stymied again and again by industry groups that maintain the agency lacks statutory authority to regulate.
Industry observers repeatedly described the FDA's latest actions against PGx testing as a backdoor attempt at overseeing a sector that has frustrated its efforts to date.
The issue began almost a year ago, when the agency issued a safety alert cautioning patients and healthcare providers against changing treatments based on PGx tests without its approval. The FDA said at the time that it was aware that doctors may have inappropriately changed patients' medications based on PGx test results, suggesting this could harm patients. The agency also said in the safety alert that it was looking into companies selling PGx testing for unapproved uses.
In April, the agency sent a warning letter to Inova Health System's genomics lab in Virginia for marketing its MediMap test without approval. Subsequently, the health system decided to stop providing PGx testing entirely.
Over the summer, the agency began stepping up regulatory actions against other labs offering pharmacogenetics services without premarket clearance or approval. As GenomeWeb reported, the agency contacted a number of labs, asking them to explain why its PGx tests lack FDA clearance or approval. After discussions with the agency, which industry sources described as vague and inconsistent, some firms, such as OneOme, decided to remove references to drugs and drug classes in test reports. Other companies began working on or seriously considering FDA review, while still others, like Myriad Genetics, engaged with the agency in the hopes of arriving at a mutually acceptable solution.
Genomind, a mental health-focused PGx testing service, is involved in the coalition and is working with the FDA. Both are important, according to Genomind CEO Shawn Patrick O'Brien, because while the coalition's efforts raise awareness of stakeholders' concerns, it will take time and collaboration with the agency to advance regulatory policy.
The company proactively reached out to the FDA to discuss clearance of its test even before it issued its safety alert last year. Based on these interactions, it became clear that the FDA wanted companies to stop mentioning drugs or drug classes associated with genetic variants in reports, and the company complied. It was also the firm's understanding that the agency was planning to take industry-wide action against all labs performing PGx testing and that it would be "a level playing field," said O'Brien.
However, the company soon learned that there were companies like Myriad and others that had been in talks with the FDA and submitted data on their PGx tests, but had not yet removed references to drugs in test reports. "The FDA has data [on our test], and in the spirit of fairness, we resumed putting medications on test reports to doctors," O'Brien said.
Patient reports still do not include references to drugs, only detected genetic variants. Information on the variants are uploaded to the patient portal 30 days after they are reported to the physician portal. This gives patients time to discuss the test results with their doctors, who are free to communicate to patients the drugs they may or may not respond well to based on detected variants.
Genomind's experience illustrates how FDA's inconsistent approach is creating regulatory uncertainty among labs. One of the main issues, as Gibbs sees it, is that FDA has said very little publicly about how it wishes to regulate PGx tests beyond the safety alert and the Inova warning letter. "FDA has not articulated a clear policy, and that's a fundamental problem," he said. "Companies have been told individually that they can no longer offer a test."
Other labs have stopped mentioning drugs in test reports based on their interactions with the agency, which many stakeholders have interpreted as the agency trying to suppress all communication by labs about the role PGx variants play in metabolizing drugs. This is an appropriate characterization, Gibbs said, based on the fact that the FDA appears to be taking an "extremely strong position" against labs conveying any information about specific drugs in test reports. "There may be some uncertainty about exactly how FDA plans to apply its regulations, but that's because the agency has so far chosen not to articulate clearly what its policy is," he said.
Adding to the confusion, Javitt noted, there has also been a disconnect between what the FDA has publicly communicated and what it has been telling companies privately. "While I had concerns when I read FDA's safety communication from November 2018, it was by no means obvious that [regulators] meant what they now appear to be telling labs, which is that they can't say anything about a drug in a test report, regardless of what the drug label says," she said.
Experts interviewed for this article all noted that a major worry for the agency seems to be that unapproved PGx tests will be used to make off-label prescribing decisions. However, the agency has had trouble figuring out the right way to address this concern with regulation, according to pharmacogenomics expert Howard McLeod.
For example, the agency states in guidance that a companion diagnostic's label should mention the drug it predicts response to, and the drug's label should mention the testing needed to identify the subset of patients who have a differential therapeutic response. That approach, which assumes that the drug and test are studied and approved together, may be useful for getting new drugs through the FDA, but it doesn't facilitate efficient use of diagnostics in the real world where labs are constantly tweaking and changing tests according to technological advances. This is further exacerbated with increasing use of next-generation sequencing panel tests that gauge hundreds of genes associated with a multitude of drugs.
The agency has tried to address these challenges in reviewing and approving certain NGS panels for directing cancer treatments, but McLeod has encouraged the FDA to take a more comprehensive approach. "This coalition, combined with internal efforts at the FDA to face the realities of the limits of current diagnostics regulation, may lead to a more meaningful and longstanding resolution," said McLeod, medical director of Moffitt Cancer Center's personalized medicine institute.
McLeod hasn't joined the coalition yet because he wants to continue to independently work with the FDA on these issues, but if those efforts are unfruitful, he may join in the future. "The coalition's mission is a good one, but it's not the only one that's going to help us make progress," he said.
Beyond the efforts of the coalition, other groups have also issued statements or met with the agency to communicate their objections to how FDA is moving to regulate PGx tests. "The more people that express their concern over FDA's current approach the better," Javitt said. "It shows that that this is bigger than any one individual, organization, or effort."
American Clinical Laboratory Association is hoping to meet with the agency soon to discuss these issues and encourage it to be more transparent in its interactions with labs, said ACLA President Julie Khani. "The recent actions by the FDA are absent any new statutory authority or any type of public process," she said. "It's really been a process where FDA has contacted individual laboratories by phone and by email. Something that would open this up for the public … is a priority for ACLA."
Because of the way the FDA has taken actions, it's been hard for ACLA to gauge the scope and impact of the agency's regulatory actions on the lab community, particularly labs that aren't association members. "What we have now is a lack of transparency, uniformity and clarity for labs that offer testing in this space," Khani said.
ACLA has challenged the agency's legal authority to regulate LDTs, and in a recent letter, asked FDA Acting Commissioner Ned Sharpless and other leaders in the agency's device division to reconsider how they've gone about regulating PGx testing. Specifically, the industry group pointed out that Sharpless' predecessor, Scott Gottlieb, had supported advancing a new regulatory framework for all diagnostics, including those developed and performed at a single lab, through legislation. Although members of Congress have been working with stakeholders to fine tune a draft bill in this regard, the FDA's latest actions on PGx tests may make it harder to convince industry stakeholders to work with the agency to advance a legislative solution.
The FDA's targeting of a subset of the lab testing space exemplifies why diagnostic regulations need to be comprehensively addressed through legislation, according to Khani. "This type of ad hoc enforcement undermines that process and that progress," she said. "We urge the agency to reconsider its approach to PGx testing and commit to working with stakeholders in Congress."
The Association for Molecular Pathology, another group that hasn't supported FDA oversight of lab processes, hasn't directly commented on the agency's latest actions on PGx testing, but recently released a statement recommending labs report drug-gene associations backed by "well-established clinical validity" from peer-reviewed literature, practice guidelines, or FDA-approved drug labeling. The document is notable precisely because AMP has historically maintained that FDA lacks statutory authority to regulate lab processes. In the statement, AMP urged labs to follow CLIA regulations but didn't mention the need for FDA approval or clearance of tests. AMP declined to further comment for this article beyond its statement.
The FDA has previously said that it is committed to advancing legislation on diagnostic regulation, but that it has the authority under the Federal Food, Drug, and Cosmetic Act to remove from the market tests, including lab tests, that raise public health concerns. In response to a request for comment, an FDA spokesperson said that the agency supports "valid pharmacogenomic testing" and "that it is important to assure that the claims made for such tests are based on sound science and the information provided to clinicians and patients should be truthful, not misleading, and understandable." The agency took action, the spokesperson said, after identifying concerns that particular PGx tests lacked evidence supporting certain claims labs were making in marketing them.
Also in its safety alert the agency indicated it is aware of doctors who made inappropriate adjustments to patients' medications based on PGx test results. Industry players have countered that the agency has not provided evidence that lab tests without the agency's approval or clearance have harmed individuals. "We are unaware of any adverse events in this space," ACLA's Khani said. "If the FDA has evidence to the contrary, I think it's essential that information be shared clearly and transparently."
Genomind's O'Brien similarly said that the company looked at its internal database and FDA's adverse events database and didn't flag any safety concerns related to PGx testing.
On the contrary, stakeholders interviewed for this article said there is widespread concern that FDA's tactic of having labs remove references to drugs in PGx test reports is actually putting the public health at risk by making it more difficult for doctors to interpret genetic test reports. "This is a major concern we've heard again and again … I've been struck by how many people have been deeply troubled by what FDA has done," Gibbs said.
It's more often the case that stakeholders are concerned that FDA isn't doing enough to protect the public health, he said, citing the opioid crisis as an example. "But, here, it's the affirmative action of blocking information that's causing concern due to it being contrary to public health," Gibbs said. "In my experience that's pretty unusual."
Moffitt, which has expertise in cancer pharmacogenomics, has had to help physicians from other large, well-known institutions interpret test results after certain labs, facing regulatory pressure, stopped referencing drugs in reports. "The lab reports no longer give adequate guidance, [and] that's resulting in physicians having to rely on Google to make recommendations," McLeod said.
Upon review of some of these reports that McLeod and his colleagues helped interpret, they identified clinically significant drug-gene associations that the physicians hadn't flagged. "[This] has now gotten to a point that it will not be surprising at all if patients end up being harmed," he said.
The National Alliance on Mental Illness, National Council for Behavioral Health, the Depression and Bipolar Support Alliance, and Mental Health America jointly wrote to the FDA and HHS that the agency's actions restricting labs from mentioning drugs in lab reports "may in fact inflict greater harm on patients."
Doctors typically rely on trial and error when prescribing medication for depression patients, and only 50 percent of patients respond to the first drug they're prescribed. Few patients with depression achieve remission, and more commonly, patients relapse or develop treatment resistance.
"[H]ealthcare providers treating mental illness are in desperate need of the promise of personalized medicine — getting the right treatment to the right patient at the right time," the organizations said in their letter. "The FDA should not stand in the way of this emerging and exciting field of science. Physicians must be able to continue to receive information about the impact a patient’s genetics may have with medication choices."
For supporters of personalized medicine, FDA's recent actions go against fostering a system that would enable greater precision and accuracy in patient care. The Personalized Medicine Coalition held a meeting in mid-September with Jeff Shuren, director of FDA's device division, and his team, and made clear that its members wanted better communication and clarity from the agency on this issue.
"There was concern among many people that this was a backdoor way to regulate LDTs," said PMC President Ed Abrahams. "They assured us that it was not their intention to broadly walk back enforcement discretion over [PGx] tests."
During the meeting, the PMC raised some of the same worries that other groups have, and the FDA acknowledged it needs help figuring out how to regulate PGx tests that it considers to be making "off label" claims and is open to the input from the healthcare community. The PMC has invited the FDA to a Dec. 10 public policy meeting to discuss this topic with its members.
With industry and patient-focused groups airing their objections and the formation of the coalition, "we're seeing a unification of many different types of stakeholders all in favor of the FDA getting this right," McLeod said. "That needs to be the goal."
An FDA spokesperson also said that the agency is open to discussing with test developers and other stakeholders "the evidence that can support specific pharmacogenomic claims." Whether such a discussion will happen in a public forum remains to be seen. Certainly, the agency will soon hear from the Coalition to Preserve Access to Pharmacogenomics Information through the citizen petition.
The coalition is still accepting members and has started drafting the petition. "Perhaps one of the things the citizen petition will do is help crystalize the issues and we'll get a more thoughtful explanation from the FDA about what they're doing and why," Gibbs said.