The second installment of Ropes & Gray’s new podcast series, Non-binding Guidance, addresses the departure of former FDA Commissioner Scott Gottlieb, who resigned from his position last month. During his time at FDA, Commissioner Gottlieb employed an ambitious policy agenda, taking significant steps to combat the opioid crisis, improve access to generic drugs and biosimilars, confront the use of e-cigarettes by minors, and more. In this episode, Ropes & Gray lawyers Greg Levine, Kellie Combs, and Beth Weinman explore several areas of uncertainty that remain in the wake of Dr. Gottlieb’s resignation: the regulation of laboratory developed tests, dietary supplements, and off-label communications. Tune in to this discussion to learn more about the unfinished business of the Gottlieb administration, the impact of his resignation, and how the agency will move forward under Acting Commissioner Ned Sharpless.
Kellie Combs: Hi, I'm Kellie Combs, a partner in the life sciences practice group at Ropes & Gray and based in our Washington office. Welcome to Non-binding Guidance, a podcast series from Ropes & Gray focused on current trends in FDA regulatory law as well as other important developments affecting the life sciences industry. I'm here today with my colleagues Greg Levine, partner and co-chair of the life sciences practice group, as well as Beth Weinman, counsel in the life sciences group who joined us late last year from FDA's Office of Chief Counsel. On today's episode, we'll be talking about the tenure of former Commissioner Scott Gottlieb, who unexpectedly resigned from his post earlier this month. In the wake of Dr. Gottlieb's departure, a lot has been said about his achievements during his two years as commissioner. He had an ambitious policy agenda and his resignation letter touted accomplishments such as his work to confront use of e-cigarettes by minors, to combat the opioid crisis, and improve access to generic drugs and biosimilars. While there's no doubt that he and his staff made progress on a number of his policy priorities, he also leaves behind a significant amount of unfinished business. And that's what we'll be discussing on today's episode – some of the key items on Gottlieb's to-do list that have not yet been crossed off and how we think the agency may proceed now that Ned Sharpless, former director of the National Cancer Institute, is the acting commissioner. Now, of course, we won't be able to cover all of Dr. Gottlieb's unfinished business today, but we'll focus on a few topics that we've been following closely.
Let's kick off the discussion with you, Greg. One of the big policy areas left unresolved at the end of the Obama Administration was how laboratory-developed tests will be regulated in the future. Under former Commissioner Gottlieb, the FDA proposed a very different model than the previous administration had outlined, one that would almost certainly require Congress to act, which is not an easy feat. Where do you see the issue going after Commissioner Gottlieb's departure?
Greg Levine: Thanks, Kellie. As you mentioned, under the prior administration, FDA had developed a proposal on regulation of laboratory-developed tests. Under that proposal, FDA would phase in the regulation of in vitro diagnostic tests, using its current statutory authorities. That effort was highly controversial. In fact, a clinical laboratory trade association had hired a former solicitor general as well as Professor Laurence Tribe from Harvard Law School to argue why FDA lacked the legal authority to take that step. Eventually, FDA abandoned its proposal after the last presidential election and the FDA, under Commissioner Gottlieb, has conceded the future regulation of LDTs must be addressed by Congress. I don't see that changing under a new commissioner, regardless of whether it's acting Commissioner Sharpless, permanent Commissioner Sharpless, or someone else. At the same time, FDA's sense of urgency around the widespread use of complex laboratory tests marketed as LDTs, which is outside the normal framework of FDA regulation of in vitro diagnostic tests, is unlikely to diminish. The importance of how to regulate such tests optimally will only continue to grow as diagnostics become increasingly central in the delivery of healthcare due the amazing developments we're seeing in genomics and related scientific disciplines and in the increasing pace of FDA approvals of precision-guided drug therapies. And despite the views of some critics, the FDA believes that it has the expertise to regulate both the clinical validity and the analytical validity of these types of tests based on its extensive history of regulating in vitro diagnostic tests marketed by test manufacturers that do not themselves operate laboratories, but instead sell IVD tests to laboratories that purchase and run them. Given this view of its expertise, it's not surprising that FDA has been very active in the legislative debate over LDT regulation.
Last summer, FDA circulated its own draft legislation that proposed a pre-certification approach for developers of some in vitro clinical diagnostic tests. That approach is similar to the approach FDA has been exploring for software products that are regulated as medical devices. This aspect of FDA's proposal was then picked up and included in a bipartisan draft bill circulated on Capitol Hill last December by members of Congress who had been prominent players on this issue. They requested feedback on the draft through February 15th of this year. That draft bill, the VALID Act, would establish a tiered system of FDA regulation of in vitro clinical tests. Those that are high-risk would require pre-market approval by FDA. Low-risk, grandfathered and certain other tests, such as tests for rare diseases, would not require prior FDA approval. Nearly all tests would need to be designed and manufactured under an FDA-compliant quality system and subject to other general FDA requirements. And then on top of that structure, the proposal would be that test developers could choose to participate in an optional pre-certification program in which once they are pre-certified by the FDA, they would no longer need FDA approval to introduce an in vitro clinical test that falls within the scope of their pre-certification order. In a blog post last year, Commissioner Gottlieb had discussed this concept and said he thought that 40-50% of laboratory tests could ultimately fall in the pre-certification category. This will continue to be unfinished business until Congress is able to act. Timing-wise, I think the outside date to get this issue resolved would be the next round of User Fee Act legislation, which would be 2022, but many would like to get this done much sooner. One question in my mind is whether Commissioner Gottlieb's departure might weaken FDA's hand in this legislative debate. There are numerous stakeholders who have responded to the call for comments on the draft legislation and some have raised serious concerns about FDA's proposed pre-certification approach, in particular, the lack of details on what protocols, policies and experience a developer would be required to demonstrate in order for the FDA to grant pre-certification application and how the FDA would ensure under this model that these tests are safe and effective. One has to ask whether a new commissioner will have as high a likelihood as Commissioner Gottlieb might have had to succeed in persuading Congress not only that FDA's the right agency to regulate these types of tests in the future, but also that its proposed model is the best one.
Kellie Combs: Great. Thanks, Greg. And given the concerns you mention that FDA has, what is FDA actually doing about regulation of LDTs in the meantime?
Greg Levine: For the most part, as FDA has been developing its proposed regulatory model and now as the legislative debate has been going on, FDA has largely not been seeking to enforce current law against manufacturers of tests being marketed as LDTs. FDA has always said it thinks it has the legal authority to do so and has reserved the right to do so on issues where it sees a significant public health concern. Where FDA has been using this authority to date has been with respect to tests marketed directly to consumers, which as a definitional matter, FDA has said, falls outside the boundaries of a traditional LDT. Interestingly on April 4th, which was Dr. Gottlieb's second to last day, FDA issued a warning letter that potentially can be seen as a slightly more aggressive use of its legal authority. That letter went to Inova Genomics Laboratory, which is associated with the Inova Health System, and the letter alleged that the company was illegally marketing several genetic tests, the MediMap ADHD, MediMap Heart and MediMap Baby test without required FDA approvals or clearances. According to the warning letter, the tests are marketed as genetic tests for predicting medication response, reducing negative side effects from certain medications, discovering the right drug and the right dose for a patient, and avoiding trial and error prescribing by healthcare providers. FDA in this letter says it was concerned that the clinical validity of the tests had not been established, and that healthcare providers or patients may make inappropriate treatment decisions based on inaccurate results. In the written response, the firm stated its belief that they were properly operating within the scope of FDA's LDT exemption, and therefore the tests were not subject to FDA pre-market review. But in the warning letter, the FDA responded, saying it had not created a legal carve-out for LDTs and that the agency always retains discretion to act, to address significant public health concerns. The most interesting feature of this letter, though, is that the test does not seem to be a direct-to-consumer test of the same type FDA has objected to in the past. FDA states that according to the company's website, the MediMap tests may be ordered by a lab physician, in which case test results are provided directly to patients. So there is an ability for the results to be provided to the patient, but this is apparently not a test where the test itself is purchased directly by the patient without the involvement of any healthcare provider, or where the consumer is involved in collecting a specimen, such as blood or urine, and sending it to the testing company for analysis. This looks more like a traditional laboratory test. FDA's particular concern, though, is that the laboratory director is not the patient's doctor, and therefore there's not the same level of ability to consult with your own doctor about test results. There's definitely a direct-to-consumer-ish element to this test, but it does seem to be different in some ways from other tests to which FDA's objected. We'll see what the FDA does on this issue going forward.
Speaking of FDA enforcement, we'll now turn to our former FDA enforcement litigator, Beth Weinman. Beth, I know one of the issues you've been looking at involves dietary supplements. Earlier this year, Dr. Gottlieb announced a new plan to modernize the regulatory framework for dietary supplements. Why now? And do we have a sense of what that might look like?
Beth Weinman: Thanks, Greg. That's right. In February of this year, former Commissioner Gottlieb announced a new goal of significantly modernizing the dietary supplement regulation and oversight. It's a good question, "Why now?" And I guess the answer's probably that it's been 25 years since DSHEA was passed – that's the Dietary Supplement Health and Education Act of 1994 – and a lot's changed since then. That law was intended to be a comprehensive regulatory framework for dietary supplements, but it was passed at a time where there were only about 4,000 products on the market. And it was passed in a context of specific congressional findings that dietary supplements were generally safe and problems were relatively rare. And the goal of the law in some sense was to protect consumer access to supplements that were deemed safe. And a lot's happened in 25 years. Since 1994, the dietary supplement industry has grown to a $40 billion industry with anywhere from 50,000-80,000 unique products on the market. And over time, we've seen a number of safety issues that seem to be challenging older assumptions that these products are categorically safe and don't need to be scrutinized. The current regulatory framework does not involve a true pre-market review process for supplements or for their ingredients. Manufacturers are required to notify FDA of their intention to introduce new dietary ingredients to the market 75 days in advance of doing so, but that notification process is not a substantive pre-market approval process like we see with other products. The notification must include the basis on which the manufacturer has concluded that the dietary supplement containing the new dietary ingredient will reasonably be expected to be safe. And FDA can object – it can highlight safety concerns, it can complain that the notification itself is lacking in some way, but it doesn't have the authority to approve or deny approval to a new dietary ingredient. I’ll note, the notification process for new dietary ingredients is significantly less robust than the petition process for food additives, which are in contrast deemed unsafe until they are proved to be safe to FDA's satisfaction through the approval of the food additive petition. And DSHEA specifically excluded dietary ingredients from the food additive definition.
Greg Levine: So, Beth, given that framework, what does FDA do if it has a concern about a dietary supplement or an ingredient in a dietary supplement?
Beth Weinman: Under the current framework, if FDA has concerns, it has essentially two options. One is to take post-market enforcement action, and the other is to use its sort of bully pulpit to issue safety alerts or consumer advisories that it has concerns about particular products. We’ve seen both and I expect we'll see more of both. To take post-market enforcement action, the agency has to show that the product in the market is adulterated or misbranded. It also has the option of trying to demonstrate that the product isn't actually a dietary supplement, but that it's a drug and then to pursue drug theories. But in this framework, the burden on the agency is high.
For example, to show that a dietary supplement is adulterated under Section 402(f)(1)(A) of the Act, one of the primary adulteration theories for dietary supplements, the agency has to show that the supplement or a dietary ingredient that it contains, presents a significant or unreasonable risk of illness or injury if used as contemplated by the labeling or under ordinary conditions of use. Another option for showing adulteration is that the product contains a dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury. Both of these theories are complicated to pursue, though the agency certainly does try.
The existing framework also governs the kinds of claims that a dietary supplement can make in its labeling – it can make structure function claims, it can make certain kinds of health claims with the appropriate level of evidence and support. And failure to adhere to the requirements for allowable claims or failure to disclose all ingredients in the labeling, or labeling that's otherwise misleading, can render dietary supplements misbranded as well. And as I said before, the government can also charge a dietary supplement as a drug if it is, in fact, making drug claims which are not allowed for dietary supplements. But again, the burden is on the agency to prove that the product is adulterated or misbranded once it's already on the market. And enforcement, while a priority, is sort of whack-a-mole. There are thousands of products on the market, and they are accessible to consumers everywhere--in retail stores and online-- and without the intervention or need for a healthcare practitioner or prescription.
So the question now is, "What is reform going to look like, and how far it will go?” Former Commissioner Gottlieb didn't give us a lot of information about what his thoughts were on that front. He noted that the agency needed to do communication better and faster. And we talked about, you know, safety alerts, consumer advisories – there's some suggestion that the agency will come up with a rapid alert system, and that's one way to get the message out when there are problematic products.
Former Commissioner Gottlieb also discussed the need to develop better toxicological tools to evaluate dietary ingredients and botanicals. At the moment, there is not a robust pre-market review process for dietary supplements, and developing such a process would require statutory change. And the question is whether now FDA will be in a position to be able to do that, whether our Congress will have an interest in doing that…
Former Commissioner Gottlieb also discussed the need to promote better compliance with the new dietary ingredient notification process. And perhaps we'll see change in regulations that discuss what kind of information needs to be in those notifications… I think what we definitely will see, and what former Commissioner Gottlieb suggested we should see, is more enforcement.
We have seen enforcement in a variety of areas in dietary supplements. And, in fact, on the day of the former commissioner's announcement in February, FDA sent a slew of warning letters to companies whose products made claims about treatment or prevention of serious diseases or conditions, which is not permissible for a dietary supplement. In particular, those supplements were claiming to prevent or treat Alzheimer's disease. And we've also seen action in the dietary supplement space with respect to unlabeled ingredients, cGMP issues, misleading claims – and I expect that we'll see more of that.
Another open question is whether modernization will also add to or amend the enforcement toolbox– and I don't think we yet know the answer to that question.
Let's go back to you now, Kelly. Several years ago, in the wake of First Amendment cases like Caronia, Amarin and Pacira, FDA committed to modernizing the regulatory framework for advertising and promotion. Early in his tenure, former Commissioner Gottlieb acknowledged the First Amendment case law and stated that FDA needed to develop clearer standards for manufacture communications, consistent with First Amendment principles. So, what did FDA accomplish under Dr. Gottlieb's leadership? And what remains left to do?
Kellie Combs: Thanks, Beth. Last summer, FDA finalized two important guidance documents related to manufacturer communications. The first relates to communications consistent with the labeling and the second relates to communications with payers, including both communication of healthcare economic information as well as information before a new drug or a new use of a drug or device goes to market. These guidance documents together provided significantly more flexibility to companies who wanted to convey truthful, non-misleading information that did not appear within the four corners of the product labeling. And it also gave companies a lot of clarity around when communications with payers were appropriate, either before approval of a new product or a new use of a product. Now at the time of issuance of those guidance documents, former Commissioner Gottlieb took the rather unusual step of issuing a press release to accompany the guidance. And in that press release he expressly tied the guidance documents and increased flexibility in manufacture communications to a broader governmental effort related to value-based care and the effort to curb rising drug costs, which is really interesting at the time because you have a former commissioner specifically tying off-label or out-of-label communications to things like patient choice and payer decision-making. You know, I think universally we thought that those were great steps and were generally happy with the way that the guidance documents turned out, particularly because they provided so much clarity to industry and areas that had been previously unclear. That said, there are several open items left related to off-label communications and the First Amendment
So number one, FDA in 2014 committed to what it called a comprehensive review of the regulatory framework for manufacturer communications. And the goal of that comprehensive review was really to modernize the framework and to harmonize it with constitutional requirements. The agency a couple of years ago held a public hearing and then solicited comment from industry and others, but hasn't taken any further action, so we don't know the status of the comprehensive review or where things stand in the broader effort to really modernize the regulatory framework and guidance. The agency still hasn't given a timeline. The second item of unfinished business in the ad/promo space relates to scientific exchange. There have been repeated calls from industry over a number of years, for the agency to issue guidance on scientific exchange, which exists as a safe harbor in the investigational drug regulations, but has never fully been defined by FDA. The agency, in fact, promised in 2014 that it would issue guidance on scientific exchange and provide some clarity to companies around when they could communicate regarding off-label uses or investigational products with a variety of audiences, including prescribers, payers and patients. However, the FDA still hasn't acted and has not given a timeline for when they actually might release guidance.
The third aspect of unfinished business in the ad/promo space relates to the intended use rulemaking. In September of 2015, FDA proposed to revise the intended use regulation for drugs and devices, and to make clear through that revision that the agency would not consider knowledge of off-label use by a manufacturer as sufficient evidence to demonstrate that a manufacturer had actually intended to promote its products off-label. When FDA finalized the revision to the intended use regulation about a year and a half later, however, they didn't stick with this removal of the knowledge prong. Instead, the agency offered the totality of the evidence standard, for the first time – essentially saying that the agency would consider anything and everything, including knowledge, to determine whether a company had promoted its product off-label. Industry groups, including PhRMA, BIO, and the Medical Information Working Group, opposed FDA's finalization of that rule, arguing that the totality of the evidence standard was brand new and not the same one that was initially proposed, and then also taking the position that the totality of the evidence standard wasn't supported by the case law or by FDA's statutory authority. The agency initially delayed the rule and then indefinitely stayed the final rule, so the intended use rulemaking at this point is a little bit in flux. We still have that old regulation on the books – that at least by the plain language, seems to allow the agency to consider knowledge as sufficient to demonstrate that a company had promoted off-label, but FDA has also said that as a practical matter it will not consider knowledge in and of itself to be sufficient.
Greg Levine: Thanks, Kellie. That's all the time we have for today. Thanks for tuning in to our podcast, Non-binding Guidance, brought to you by our FDA regulatory attorneys in the life sciences practice at Ropes & Gray.
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