FDA’s Intended Use Rule Back in Play

A number of regulatory and enforcement items have been up for grabs at the FDA over the past year, but few carry the weight of the agency’s review of the intended use rule. The FDA announced recently that it is suspending the implementation date for the rule, and is separating the tobacco-related portions of the rule from those governing drugs and devices. It’s a welcome step and one that is long overdue, but it is not clear yet where the agency will land on this matter.

Dexcom Warning Letter Pulled

To recap, this problem dates back to at least 2011, when Par Pharmaceutical Inc. sued the agency over the latter’s attempts to suppress Par’s on-label discussion of the company’s appetite stimulant, Megace ES, in a setting in which the drug was likely to be used off-label. Par agreed to pay a $45 million fine two years later, and the five-year corporate integrity agreement is finally set to expire later this year.

Glucose monitor maker Dexcom subsequently received an FDA warning letter alleging the device maker was aware that its devices had been sold for uses that fell outside the labeled indication, but the agency has since deleted that document from the warning letter database. The agency took an explicit approach to the issue in a Federal Register announcement in September 2015, a peculiar attempt to devise a rule that would cover tobacco products along with drugs, devices and biologics. The FDA said its intent was to clarify some of the related issues, but the 10-page draft included the curious observation that a lack of clarity might lead consumers to use tobacco products “in place of FDA-approved medical products.”

The final rule appeared in early 2017 and retained the plus-tobacco features of the proposed rule, but the document grew to 25 pages and included a more or less lengthy discussion of the Central Hudson test and other issues that came up in comments to the docket. However, the agency then delayed implementation of the final rule to March 21, 2017, and then to March 19, 2018, and FDA commissioner Scott Gottlieb said in the agency’s Jan. 12 statement that the final rule will be suspended yet again “until further notice.”

A Procession of Concessions Fails

The 2015 proposed rule rattled observers by stating that the agency’s determination of a product’s intended use “is not bound by” explicit claims made by the manufacturer, but can instead be inferred by “objective evidence,” including the circumstances “surrounding the distribution of the product or the context in which it is sold.” The FDA tried to assuage industry’s concerns by vowing that it would not act on distribution of a product “based solely on a firm’s knowledge” of off-label use, but this concession did little to mollify industry.

The agency took a somewhat different approach in the final rule, stating that “a totality of the evidence” would be employed to determine an intent to knowingly distribute a drug or device for off-label uses. However, the Advanced Medical Technology Association argued that an approach based on the totality of the evidence is “more outcome determinative than prescriptive,” and thus manufacturers would have little choice but to “curb important product-related communications.”

The intended use rule does not entirely capture the regulated speech problem, but it is a significant hazard, particularly since whistleblowers and the Department of Justice can readily avail themselves of fodder for prosecution. It is pertinent to note that the Par Pharma case involved multiple relators, who had netted more than $4 million when all was said and done.

States Moving Ahead

There are several questions looming for the FDA, but whether the agency is in a position to stand pat is not one of those questions. The State of Arizona passed a law last year that takes up the off-label communication issue, and there are indications that other states may soon follow suit. Gottlieb has already noted that the FDA must come to grips with recent jurisprudence on the off-label issue, and the agency can scarcely afford to be swamped by a pixelated map of state policymaking where commercial speech is concerned.

The easy answer to all this is that Gottlieb will scuttle the totality-of-evidence standard, but little beyond that is especially obvious. The FDA said it will take comment through Feb. 5 on this latest iteration of the intended use scrum, so there is still time to weigh in. Given that the docket for this issue already features nearly 2,000 comments, it’s clear that significant change is in the works.

Auld Acquaintance; 2017 Guidances and 2018 Enforcement

2017 is now a part of the past, and everyone has their own idea as to which were the most crucial developments of the year. Following is a nomination for two FDA guidances that are at least strong candidates for the title of the most important guidances of 2017, along with developments in two ongoing dramas that could prove pivotal in this new year.

What’s Old is New (yet) Again

The FDA’s Center for Devices and Radiological Health had little to offer in the way of guidances in the first half of 2017, but the center made up for that in a big way in the latter part of the year. CDRH issued 19 draft and final guidances in the last three months of the year, but the month of September was a busy one, too.

Still, the most important guidances might not have been the most widely discussed. The October final guidance for 510(k) changes and the companion software 510(k) changes final guidance might not have the splash value of the agency’s moves in the digital health realm, but it’s easy to forget how long the 510(k) changes controversy has strained relations between the FDA and industry.

Thinking back to the legacy K97 guidance of 1997, this discussion has been the subject of formal regulatory interest for only 20 years despite that the Medical Device Amendments were added to the statute more than 40 years ago. The agency took a stab at rewriting K97 in 2011, but that attempt proved futile thanks to the opposition it triggered.

Traditionally, the estimates of the number of 510(k) clearances each year is somewhere between 3,500 and 4,000, a much greater number than the volume of original PMAs, which hasn’t hit 100 in recent memory, if ever. Are digital health guidances “hotter” in terms of novelty and hence media coverage?

Apparently, but make no mistake: The 510(k) program and the agency’s overarching administration thereof is easily the most important regulatory development in calendar year 2017, particularly given that the new med tech regulations in Europe could drive a lot of traffic back to American shores.

2018: Commercial Speech Comes of Age?

2017 was a regulatory banner year for med tech, thanks to the 21st Century Cures Act and the provisions of the fourth device user fee agreement, so it’s difficult to see how 2018 can measure up. Still, this new year has at least one blockbuster story in store if recent remarks by FDA commissioner Scott Gottlieb are any indication.

Gottlieb said the agency needs “a legally enforceable set of rules” where commercial speech is concerned, a nod to recent court losses, such as Caronia. Hence, Gottlieb’s said the FDA “can’t be operating from a platform where our regulations might be perpetually in conflict with the courts.”

The agency’s January 2017 draft guidance for payer communications is still in draft form, but that’s to be expected with the change in the commissioner’s office, particularly a commissioner with Gottlieb’s views on the commercial speech question. Another consideration is that a payer communication framework might be the lowest hanging of the several commercial speech questions, and there was little indication at the time that the FDA had adopted a less restrictive approach to off-label communications to physicians.

Gottlieb’s comments from September 2017 suggest he wants the agency to provide industry with some rules of the road for the entirety of the commercial speech problem, but the agency’s chief counsel, Rebecca Wood, avoided the subject in her prepared remarks to a gathering of the Food and Drug Law Institute in early December 2017. The net effect is something of a black box inside which the regulatory version of Schrödinger’s cat awaits our collective scrutiny, but Gottlieb seems determined to settle this matter by one means or another, even if there is some understandable skepticism as to the durability of any resolution. This is a matter worth watching as we move into 2018.

Yates Memo; Up for Grabs?

On the other hand, those who are concerned about a hangover from the Yates memo might be encouraged by the fact that FDA’s Woods conceded that it is time for the FDA to revisit the question of vicarious criminal liability in Park doctrine cases. The question here is whether the agency and the Department of Justice are on the same page, given that these two parties have not necessarily agreed on these issues in the past.

The corporate liability question seems ripe for review if only because Sally Quillian Yates is no longer at the Department of Justice, but deputy attorney general Rod Rosenstein acknowledged that the Yates memo is under review in a speech to the Heritage Foundation in September 2017. Although he offered no details other than to affirm that prosecution of individuals is still seen as important as a deterrent, he stated, “I do anticipate that we may in the near future make an announcement about what changes we are going to make to corporate fraud principles.”

Rosenstein confirmed in an October 2017 speech to New York University that the memo is still in play, explaining that any changes “will reflect our resolve to hold individuals accountable for corporate wrongdoing.” However, Rosenstein also said federal attorneys will not be permitted to “use criminal authority unfairly to extract civil payments.”

While there are few tea leaves to work with, the statement about the use of criminal authority to extract civil payments is at the very least some indicator as to where DoJ may be headed. On the other hand, there are those who worry that the prison sentences handed down in the case of Jack De Coster and Peter De Coster could be part of an emerging pattern despite that the De Costers’ egg businesses routinely and egregiously ran afoul of the law over a period of decades. The corporate prosecution story is clearly another story worth tracking as we work through this new year.

FDA Issues New Guidance on 3D Printing of Medical Devices

Jordan Lipp, Esq. | Partner, Davis Graham & Stubbs

Today, the FDA issued new guidance for the industry on 3D printing of medical devices, entitled “Technical Considerations for Additive Manufactured Medical Devices.”  Considering the recent advances in 3D printing technology, especially with anatomically-matched devices that are built for individual patients, FDA guidance on this issue is welcome.  The guidance provides the FDA’s current thinking on the myriad of issues from material controls, process validation, and device testing, to cybersecurity.

This guidance also provides information on labeling considerations involving 3D printed medical devices.  With regards to patient-matched device, the FDA recommends that additional labeling be provided with:

  • patient identifier,
  • use (e.g., left distal femoral surgical guide), and
  • final design iteration or version used to produce the device.

Also, with regards to labeling, the FDA recommends both reviewing whether the expiration date is the same as the typical shelf life for a non-patient-matched device and including a precaution that the patient should be surveyed for potential anatomical changes prior to the procedure.

The newly issued guidance is just a stepping stone.  As the FDA noted in its press release, “our recommendations are likely to evolve as the technology develops in unexpected ways.”  And, of course, as this is a guidance document, so it is nonbinding.

Changes; Azar at Senate HELP and the 510(k) Dilemma

Change is constant, but some changes are easier to manage than others. The change at the office of Secretary of Health and Human Services has been a while in coming, but promises to spark partisanship on Capitol Hill. The FDA approach to changes to 510(k) medical devices, however, seem likely to provoke less anxiety than has been the case in times gone by.

Hearing Foreshadows Road Ahead for Azar

Alex Azar, the Trump administration’s nominee for the Secretary of Health and Human Services, went through the usual hazing at a hearing of the Senate Health, Education, Labor and Pensions Committee on Nov. 29, but this was a non-voting hearing. Still, the hearing gave some indication of what is likely to follow in the days ahead as the former drug company executive goes through the Senate vetting process.

Azar had served at HHS during the second Bush administration, but then was the president of a division of Eli Lilly that was involved in a doubling of the list price for Humalog, an insulin analogue. That issue arose during the hearing, but Azar said the system allows for that kind of gaming while vowing to put an end to such practices. Democrats on the panel were not persuaded, but Republicans were not critical of Azar’s past, highlighting partisan tensions that are sure to persist.

The next stop for Azar is the Senate Finance Committee, which will hold a vote at some point on Azar, but there is a substantial amount of overlap in the HELP and Finance Committee’s memberships. The fireworks are sure to increase, and this is almost certain to go down to a party-line vote in both the Finance Committee and the Senate floor.

510(k) Changes Guidances Tweaked from Drafts

The FDA’s device center finalized the guidances dealing with changes to class II devices and changes to software devices, and while the tenor of the final guidances is similar to that found in the drafts, there are a few important differences in each. One might recall, though, that the 2011 effort to rewrite the legacy K97 guidance was possessed of a much different animus, so much so that Congress forced the FDA to withdraw that attempt.

The agency held a webinar in November for these two guidances, during which members of the FDA staff said that changes to a 510(k) draft’s user interface might not require a new filing, even if that alteration merits a fresh human factors engineering examination. The final 510(k) changes guidance offers considerably more detail where labeling changes are concerned, most of which is found in a flowchart that poses questions as to the nature of the change. The additional detail should go a long way toward allowing a device maker to establish whether a labeling change will call for a new filing.

However, anyone who was looking for a shift in the discussion regarding changes to materials or to technology and performance may be disappointed to see that the final nearly replicates the language found in the draft. Still, the draft version made a concession that carries over into the final in that the withdrawal of an indication for use will not automatically call for a new regulatory filing.

Where the software 510(k) guidance is concerned, FDAers said a change of operating systems would not likely force a new filing so long as that change is within the same family of operating systems. Migrating the software device from one platform to another, however, is likely to introduce sufficient questions about the attendant functional hazards to require a new 510(k) demonstrating that the sponsor has those hazards well controlled.

One seemingly important difference between the software draft and the final is that the latter suggests that a new filing will be needed if a change to the software requires the use of new risk controls, even in instances in which those controls address an existing and known hazard.

Those who are looking for additional clarity surrounding the meaning of the term “significant risk” in connection with changes are likely to be disappointed. The significant risk dilemma is present in both guidances, but FDA staff on the conference call indicated that the agency believes that some flexibility on its part – which comes across to sponsors as uncertainty – is called for in dealing with its regulatory oversight of these devices.

DTC Gene Tests, Tax Reform in the News

2017 is starting to wind down as evidenced by the resurgence of holiday-themed music and Christmas jingle-riddled television commercials, but Washington is nonetheless making good use of these last few weeks of the year. In one of the more significant regulatory concessions in recent memory, the FDA said it will use a more streamlined approach to direct-to-consumer genetic tests, but the current state of tax reform seems headed for game-stopping controversy unless significant concessions are made.

‘Precert’ the New Approach to DTC Gene Risk Tests

The notion of pre-certification, or “precert,” has gained a lot of momentum at the FDA this year. First, the FDA said in July it would use a precert program for some moderate-risk digital health applications, and now the agency is making use of that same concept in connection with direct-to-consumer genetic tests that disclose the customer’s risk for diseases. The announcement affirms yet again that the agency has adopted a much less militant approach to its regulation of the life sciences under the new leadership.

Readers will remember the controversy over DTC marketing of such tests shortly after Margaret Hamburg took the commissioner’s chair in 2009, which led to a warning letter to several makers of these DTC genetic propensity tests. The agency wrote a warning letter to 23andMe of Mountain View, Calif., in 2010 about this kind of activity, but even two years ago, the FDA was still trying to keep a lid on such activity as indicated by a Sept. 21, 2015 warning letter to Pathway Genomics Inc. of San Diego for the company’s marketing of its Cancer Intercept test.

FDA commissioner Scott Gottlieb said in a statement that these tests do carry some risk, but he also cited the need to devise a regulatory regime that avoids strangling innovation in technological spaces that move at a more rapid pace than the agency can hope to match. Gottlieb made reference to a de novo filing for the 25-hydroxyvitamin D test system by AB Sciex LLC of Redwood City, Calif., but the FDA also announced it had approved a de novo application by 23andMe for the company’s Personal Genome Service (PGS) test on the same day the agency announced the precert program.

The net effect is certainly a positive change for makers of these tests, but any allegations that a false negative cost a consumer their life will undoubtedly spark a severe case of whiplash, at least on Capitol Hill. The real test in this scenario is how the FDA would respond to such criticism.

Tax Reform Gains Momentum

The push for corporate tax reform is heating up on Capitol Hill, and both the House and the Senate have legislation in the works. While neither proposal seems to include a repeal of the medical device tax, both versions eliminate at least some of the credit for orphan drug development, a move that seems certain to drive resistance among drug makers and patient groups alike.

The House Ways and Means Committee passed its tax reform vote on Nov. 9 in a party-line vote, perhaps a predictor of how this issue will play out on both sides of the Capitol. Section 3401 of the Tax Cuts and Jobs Act of 2017 completely eradicates the tax credit for clinical testing for orphan drugs, which the authors of the legislation say will save the taxpayer roughly $54 billion over 10 years.

The Senate took a less stringent but more convoluted approach, with the net result that drug makers will lose $30 billion in tax credits over 10 years. At least one patient group, the American Cancer Society Cancer Action Network, voiced its opposition to several features of the House bill, stating that the majority of cancer drugs qualify for orphan drug status “at some point in their lifecycle.” The group also said a study conducted in 2015 suggested that elimination of the orphan drug tax credit “would be to decrease orphan drug development by one third.”

The issue of the device tax is not necessarily dead despite the failure of both chambers to include a repeal in their respective bills. Much of the conversation about a device tax repeal seems to revolve around the reauthorization of the Children’s Health Insurance Program, which must be completed by Dec. 31. Ways and Means chairman Kevin Brady lent credence to that expectation, stating recently that temporary relief from the device tax will arrive via an unidentified legislative vehicle “before the end of the year.”

Of Patents and the Parsing of Words

Makers of FDA-regulated products usually have a lot to keep track of, and the last few weeks are no exception. Recently, the FDA seemed to tell industry, “do as I say, not as I do” in connection with combination product classification, while a federal court breathed new life into a lawsuit that could badly damage a very expensive patent for a cholesterol statin.

FDA; Devices are Drugs, too

Some systems of justice say you are innocent until proven guilty, but the FDA guidance for combination product classification has a different approach, stating that in conceptual terms, “all FDA-regulated medical products meet the definition of a drug.” The passage seems to resurrect industry concerns that the primary mode of action (PMOA) controversy is not over yet after all.

The 21st Century Cures Act purportedly fixed a number of problems with combination products, including the PMOA problem as seen in Section 3038 of the Cures Act. That portion of the legislation stated that the PMOA is “the single mode of action of a combination product expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.”

Granted that this passage is no novelty where the regulation is concerned, but the inclusion of this language in the statute might be seen as putting the FDA’s Office of Combination Products on notice that would get away with no adventurism on the PMOA question. As is widely known, the FDA has locked horns with industry, in and out of the courts, on a number of occasions over the agency’s product classification process, partly because the agency seemed to develop a penchant for seeing any chemical mode of action at all as necessarily categorizing the product as a drug.

This bias toward categorization  of a combo product as a drug was a significant bone of contention with industry in the 2011 draft guidance for determination of product classification. One of the arguments raised by industry at the time was that the text and the legislative history of the Food, Drug and Cosmetic Act suggested that if anything, the bias should be that a medical product is a device, not a drug. However, the final guidance states, “conceptually, all FDA-regulated medical products” meet the definition of  a drug “due to the broader scope of the drug definition.”

For what it’s worth, the agency addressed the chemical action question a bit more forthrightly than it has in the past, vowing that it will not assume that a product with a chemical action in the body is necessarily a drug, but that passage may prove to be of little consolation when the next inevitable close call shows up at OCP’s doorstep.

Patent Scrum Over PCSK9s Not Over Yet

Amgen v. Sanofi is headed back to a district court after the Court of Appeals for the Federal Circuit overturned a couple of determinations by a district court, and upheld a couple of others. The Federal Circuit lifted an injunction the district court placed on one of these cholesterol statins, but the more interesting matter may be how the Federal Circuit ruled on whether evidence developed after the patent priority date can be used to invalidate a patent.

Amgen’s lawsuit against Sanofi and Regeneron alleged infringement of Amgen’s patents for Repatha, the PCSK9 inhibitor that hit the market a couple of years ago with an eye-popping price tag that had payers in an uproar. Prior to the hearing at the Federal Circuit, the case was heard in a district court in Delaware, where U.S. District Judge Sue Robinson affirmed Amgen’s argument that the patent was not obvious, and ordered the defendants to pull Praluent off the market.

Robinson also excluded evidence about the patents for Repatha that was based on data developed after the patent priority date of January 2008. The question here seems to revolve around whether Amgen was required to characterize all the species of antibodies that bind to the PCSK9 enzyme, a bit of biochemistry that is necessary to achieve the cholesterol-lowering effect of this class of drugs.

Amgen is said to have screened 3,000 species of antibodies to arrive at the two that are used in the drug, but Robinson had ruled that Sanofi and Regeneron could not introduce evidence that the written description for Repatha failed to comport with the statute governing patents. The passage in question, Title 35 of the U.S. Code (§112), states that a patent applicant must characterize the patented item in “full, clear, concise and exact terms,” a standard the sponsors of Praluent said Amgen had failed to fulfill.

Robinson’s rationale was that the evidence offered by Sanofi and Regeneron would not have served to “illuminate” the state of the art at the time of the filing of the Repatha patent, but the Federal Circuit saw otherwise, essentially concluding that the question is not whether the evidence was illuminating, but rather whether Amgen’s written description of these antibodies was sufficient to support a patent.

The Federal Circuit also said Robinson’s instructions to the jury led the jurors to believe that a description of a novel antibody would suffice to cover the requirement that a patent describe a correlation between structure and function. The net effect of all this is that the case will head back to the district court, but a date has not been set, and Robinson is said to have left the court. Her absence will likely be felt, given that TC Heartland v. Kraft will soon load the court with a large volume of cases thanks to that decision’s effect on the long-standing forum question and the presence of a huge number of LLCs in the Blue Hen State.

A Festival of Device Guidances

Now that the first half of 2017 is vanishing in the rear-view mirror, the FDA’s device center has resumed its steady production of draft and final guidances. Thanks to the 21st Century Cures Act and the FDA Reauthorization Act of 2017, there’s much more to come, but regulatory geeks can now celebrate the end of a long guidance drought at the Center for Devices and Radiological Health.

Data Disharmony on Display

Between regulatory harmonization and regulatory convergence, the latter is the less implausible, but the FDA final guidance for demographic representation and reporting in clinical trials does not mesh well with the current state of affairs in the European Union, which may complicate the conduct of multinational clinical studies.

The CDRH final guidance for enrollment and reporting of different demographic groups in clinical studies stems at least in part from congressional mandates, but the statute in several European jurisdictions may complicate the gathering of demographic information for participants in those studies. For instance, Article 8 of the European Data Privacy Directive 95/46/EC states that EU member nations “shall prohibit the processing of personal data revealing racial or ethnic origin” and a number of other pieces of information, including anything pertaining to “health or sex life.”

At least two EU nations, France and Portugal, have similar laws on the books, so it’s not as if the problem can be handled in its entirety in Brussels (although by some accounts, the updated French statute carves out an exception for clinical studies). Because of the congressional mandates, the FDA also has little room to breathe.

Whether the authors of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) realized there was an impasse in the offing for multinational clinical studies is not clear, and it should be noted that the EU directive does not kick in until May 2018. Nonetheless, consent is likely to be more worksome in these instances, particularly since the EU law also addresses de-identified sources of data.

FDA Rejects Five-Year Follow-Up in HPV Final

The term of follow-up is always a bone of contention between the FDA and device makers, but the agency resisted calls from clinicians to tack on a five-year follow-up requirement in the final guidance for diagnostics for the human papillomavirus.

This is a document with some history behind it, including a 2009 draft that drew fire for its insistence that all precision studies be conducted at one site. The final guidance allows a sponsor to use two external and one internal testing sites for reproducibility studies, which typically encompass evaluations of precision.

Perhaps of greater importance is that the final guidance requires that sponsors follow patients for a shorter span of time than was recommended by several professional societies. The American Society of Cytopathology and the College of American Pathologists were among those who urged the agency to require that sponsors follow a subset of women with negative co-testing results for five years, but the agency indicated no interest in such a requirement despite the societies’ argument that this would comport with their guidelines for co-test screening intervals.

In a somewhat related development, CDRH announced in the Sept. 8 issue of the Federal Register that it has scheduled a Jan. 11, 2018, workshop for self-collection devices for pap tests. Clearly the agency’s primary interest is in public health – the agency remarked that there are still gaps in screening for cervical cancer – but the development might also seem to portend a more relaxed approach on the agency’s part to home sample collection going forward. It’s too soon to anticipate where this particular conversation might be headed, but testing labs would probably have to more vigorously demonstrate the reliability of their tests than is currently the case, and designers of collection kits might be charged with usability studies to ensure those kits can be reliably used by those with limited familiarity with such things.

Cosmetic Industry on Oodles Of Needles

Those who are in the business of making microneedling devices for cosmetic purposes might want to take heed of the draft guidance recently issued by the FDA’s Center for Devices and Radiological Health, which appears to take on a burgeoning set of offerings from the cosmetic industry. The agency clarified the characteristics that would distinguish items that are and are not regulated as devices, explaining that the length and sharpness of the needles in these needle arrays is one indicator of whether such an instrument is indeed a medical device.

Another factor is whether the item in question achieves its primary intended purpose through chemical action within or on the human body, which if so would constitute a medical device. Claims that suggest the device is intended to do nothing more than remove the outermost regions of the epidermis, (the stratum corneum) would not be subject to regulation, but anything suggestive of penetration or delivery of an effect “beyond the stratum corneum into living layers of skin” would likely make that item a medical device.

As of yet, no microneedling devices have gone through regulatory review, and thus anyone who files for a premarket review faces either a class III designation or must file a de novo application. De novo filings are now subject to $93,000 in user fees under the fourth device user fee agreement, although the agency is on the hook for a turn-around of 150 days under this new de novo paradigm. In this first year of the MDUFA IV, only half of de novos have to meet that 150-day turn-around, however.