FDA Revisits Combination Product Controversies

The FDA’s efforts to regulate combination products have run across some legal challenges, but more often the agency finds it difficult to implement regulations for combo products because of the complexities inherent to such products. In a recent notification, the FDA said it would continue to exercise enforcement discretion for some postmarket safety reporting requirements, but the agency ran afoul of the primary mode of action question yet again in a new draft guidance that takes up the product designation problem.

Another Day, Another Reporting Delay

The agency announced in April that it would continue to exercise enforcement discretion for a number of the postmarket reporting requirements for combo products, but the policy has been lingering for at least a year. The question arose in March 2018, when the agency posted a draft guidance that attempted to provide some direction for the December 2016 final rule for the same subject. This subject ranges back at least as far as 2009, however, the year of a proposed rule for combination product postmarket reporting, demonstrating that this topic has perplexed the agency for a decade.

Much of the difficulty revolves of course around the fact that there is no single combination product type, and there are differences in how each type makes itself felt upon the regulatory burden of the makers of each constituent part. The 2018 draft’s treatment of postmarket reporting for an approved component of an investigational combination product varies from the use of that component in an already-approved combination as well, and the net effect is to present stakeholders with three very different scenarios within a single document. Thus, some have called for a separate guidance for cross-labeled combination products at the very least, a proposal the agency may be unwilling to adopt.

One of the difficulties for the FDA is that stakeholders are not entirely united as to how the agency should approach these questions, but the deadlines for adverse event reporting requirements are already different for drugs and devices. These differences have fed calls for a pan-agency approach to the question of postmarket reporting requirements, a proposition that may strike some as only slightly less ambitious than a pan-agency approach to good manufacturing practices. Either way, the latest document is an immediately-in-effect policy statement that provides enforcement discretion through July 31, 2020, for combination products that fall under Medical Device Reporting requirements, and through Jan. 31, 2021 for products that employ the Vaccine Adverse Event Reporting System.

No Cure for the Cures Act

The FDA took another stab at the combination product designation question in a February draft guidance dealing with the principles of combo product premarket pathways, but as is often the case, the agency’s effort failed to win any converts among drug and device makers, due in large part to the question of a combination product’s primary mode of action (PMOA). That particular discussion has an interesting legal history, mostly involving France’s Prevor, which fought the agency to at least a draw in two visits to the U.S. District Court for the District of Columbia.

One of the notable features of the February draft guidance is that it stipulates that applicants provide enough data in an application to allow the centers of jurisdiction to review each component as though it were a separate application. The draft seemed largely mum on the cross-labeled combination product category, however, so much so that at least one observer questioned whether the FDA had intended to exclude cross-labeled products from the scope of the draft.

More than one trade group questioned the draft’s provisions that would seem to give the FDA wide discretion in assigning a combination product to a center that would ordinarily be inappropriate for the product’s PMOA. This question has roiled relations between the agency and industry at least as far back as 2004, the year the FDA opened a docket to deal with the PMOA question. A decade and a half of further consideration does not seem to have answered some of the underlying issues despite that the 21st Century Cures Act called on the FDA to resolve these problems.

The Cures Act directed the agency to assign primary jurisdiction for a combination product to the center that would be most appropriate for the component deemed to present the PMOA. Critics of the February 2019 draft guidance seem to have determined that the agency is resisting this legislative directive with all the regulatory muscle it can muster. The view of stakeholders may be that this draft guidance is unworkable in its present form, leaving industry with the prospect of another of those lingering draft guidances that is ultimately neither finalized nor withdrawn.

Paclitaxel Focus of Device Controversy

The technology behind percutaneous treatment for the coronary arteries has advanced much more rapidly than for the peripheral vasculature, but the use of paclitaxel, a chemotherapeutic agent, as a go-to antiproliferative for any part of the anatomy could be near an end. The FDA published a letter to physicians in January stating that a medical journal article suggested that paclitaxel-bearing drug-eluting stents (DESs) and drug-coated balloons (DCBs) for the peripheral arteries had demonstrated an unexpectedly high long-term mortality rate compared to bare-metal stents and non-coated balloons. However, the conclusions drawn in that medical journal are the subject of a dispute that may determine whether paclitaxel has any future at all in the circulatory system.

The article in the Journal of the American Heart Association describes a meta-analysis covering more than two dozen randomized, controlled trials for both DES and DCB devices, all coated with paclitaxel. The authors stated that all-cause death at both two and five years for paclitaxel devices was significantly higher than for their non-eluting counterparts when used in the arteries of the lower extremities, but that more study is warranted, in part because only two of those studies ran for a full five years. The authors hypothesize that the crystalline form of paclitaxel, which has a longer half-life than other formulations, may be the culprit.

Medtronic, the Dublin-based manufacturer of the In.Pact Admiral DCB, took issue with the JAHA authors in an article in the Journal of the American College of Cardiology, stating that there is no statistically significant difference in mortality between DCBs and plain angioplasty balloons at five years. As is the case with the JAHA analysis, there are a number of moving parts in the Medtronic summary, including that the data are drawn from patients in a variety of nations that exhibit different patterns of post-procedural care, not to mention differences in the use of dual anti-platelet therapy (DAPT). The company argued that much of the difference in mortality outcomes could hinge on the more aggressive use of DAPT in patients treated with bare-metal stents and plain angioplasty balloons.

Whether any of this clinical data will translate into regulatory action is impossible to forecast, but the FDA advised that it still sees the benefit of these devices as outweighing the risks. If Medtronic’s view – that the mortality rates at five years out, at least in statistical terms – wins the day, device makers might be on the hook for nothing more than a somewhat greater post-market surveillance liability. Makers of DCBs might already be on that track, as the Centers for Medicare & Medicaid Services (CMS) declared it will pay what clinicians and device makers see as a sub-optimal rate for these devices, unless and until CMS sees some compelling data that the difference in cost between DCBs and plain balloons is justified by outcomes.

FDA Meets Pushback on Product Jurisdiction

The FDA may have intended the draft rule for product jurisdiction for combination products to clarify the agency’s approach to how it will deal with such products, but the draft has proven unpopular so far, suggesting the agency has its work cut out for it.

The draft rule, which was prompted in part by the 21st Century Cures Act, proposed to eliminate a step in the appeals process, a step the agency suggested was superfluous. As previously discussed, the FDA also oddly cited the prospect that the proposed rule would save lives, but stakeholder see a lot of problems in the draft. For instance, the Washington Legal Foundation said stakeholders might have expected the draft to explain how the agency would “place the dividing line between drugs and devices,” but that the draft fails to do so.

WLF’s Richard Samp and Corey Andrews, respectively the organization’s chief counsel and senior litigation counsel, said the draft rule deviates from the statute with regard to determining a product’s primary mode of action. Samp and Andrews said the statute defines PMOA as “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.” In contrast, they said, the draft rule proposed to evalute the primary mode of action for each of the constituent parts rather than determining the PMOA of the product as a whole, an approach they said “improperly skews” those determinations toward a determination that the product should be reviewed as a drug application.

Several organizations recommended that the FDA allow requests for designation to run to 30 pages rather than the current 15-page limit, but attorneys with the D.C.-based law firm Hyman Phelps & McNamara had other critiques of the draft rule as well. HPM’s Jeffrey Gibbs and Jennifer Thomas said the agency’s position appears to be that a combination product “is a drug or biologic rather than a device if it exhibits any chemical action that contributes to the therapeutic effect.” Thomas and Gibbs said FDA regulations pertaining to combo products dictate that any component of a combination product may have only one mode of action, and that the net effect of these two conditions is to “bias FDA’s jurisdictional evaluations significantly in favor of determining that products composed of multiple distinct components should be regulated as drugs or biologics, rather than [as] devices”

Thomas and Gibbs cited the well-known conflict between the FDA and Prevor of Valmondois, France, over the diphoterine application – which led to a lawsuit that twice appeared in the District Court for the District of Columbia – as an example of the FDA’s propensity for determining that a combination product is a drug despite “very minimal chemical action.” They stated also that the agency’s requirement that the applicant prove the combination is primarily a device within 15 pages is further evidence of a bias against a determination that the product operates principally as a medical device.

Another FDA draft document pertaining to medical devices has provoked concerns among those in industry, the multiple function draft guidance released by the agency in mid-April. The intent in developing the draft was to clarify how FDA staff would deal with applications that embody components that meet the regulatory definition of a device along with components that do not meet that definition, but stakeholders expressed concerns over what seems to have come across as a regulatory slippery slope.

Fears of Regulatory Mission Creep

In that draft, the agency coined the term “device-function-under-review” to distinguish between the regulated and non-regulated functions, and the FDA said the term “function” means “a distinct purpose of the product.” Definitional issues aside, some who commented for the docket indicated that the draft could be applied to combination products, possibly leading to regulatory mischief. Another concern is that any function fulfilled by a component that qualifies as a device that is under enforcement discretion might nonetheless fall under premarket scrutiny if the agency determines that the component in question could provoke questions regarding the safety and/or effectiveness of the entire product.

Another point of consideration is how the FDA’s field investigators would handle inspections of a facility when these non-device components are involved in a product, but there are also lingering questions revolving around recalls and field corrections. Those in the field of in vitro diagnostics may be concerned that controls and calibrators might be swept up in a premarket review if the agency fails to make explicit that these components would not be seen as subject to review despite that the agency has explicitly exempted them from such scrutiny.

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.

Of Combo Products and High Courts

Tourists to our nation’s capital can always find plenty to do, and the same can be said for those in the life sciences with an ear for crucial policy matters. Following are two items of interest to makers of FDA-regulated products, one of which may have a significant influence over FDA regulation over an increasingly important class of medical products, while the other addresses federal prosecution under the responsible corporate officer doctrine.

Misgivings regarding the FDA’s CPPC

The FDA’s Combination Products Policy Council (CPPC) has a pretty serious lift in front of it, not the least of which is the thorny problem of differences in culture and attitude at the various centers that will be caught up in these combo product applications.

For some time, it has been known that many reviewers at the Center for Drug Evaluation and Research are no fans of the 510(k) program, apparently seeing it as an unforgivably fast track to market. Of course, the notion of substantial equivalence is a stranger in a strange land at CDER, which might explain a lot of the antipathy toward 510(k) devices there.

The agency opened a docket at regulations.gov in January, seeking feedback on topics the CPPC might address, and as might be expected, some of the consternation has to do with the process for determining a combo product’s primary mode of action. One concern in particular is how the agency will go about determining what sort of evidence will be needed to establish a product’s PMOA.

Other concerns relate to procedures for handling inter-center disputes regarding PMOA when the Office of Combination Products seems unable to broker a conflict. On the other hand, some have indicated that the interactive review process at CDER is more cumbersome than at the Center for Devices and Radiological Health, and thus would add time to what already promises to be a difficult review process.

One issue that was not conspicuous in comments to the docket was that of user fees. A sponsor will obviously have to pay more if the product’s PMOA is declared to be that of a drug, but what about fee sharing between centers? Will the lead center share user fees with the other center or centers? That’s not clear, and while reviewers at CDRH might find the drug user fees more than adequate, reviewers at CDER might find the device fee schedule unacceptably miserly.

SCOTUS says no to DeCoster

In one of the more interesting Park doctrine cases of recent vintage, the Supreme Court has opted not to hear arguments in the case of Decoster v. U.S., which allows to stand a three-month jail sentence imposed on the father-son ownership team in the egg business.

Many members of the bar see DeCoster as an outlier in that it entailed a jail sentence for Jack and Peter DeCoster, who are said to have been unaware of the violative behavior going on at their company, but more important is the prospect that this case will serve as a precedent for federal prosecutors who want to imprison those in the food, drug and device industries for problematic products. The high court’s decision to pass on the case means the two men will serve their jail sentences, but it also suggests that the Supreme Court will not hear this case until an appeals court other than U.S. Eight Appeals renders a different verdict in a similar case.

It may be an odd source of comfort to note that federal prosecutors will likely try out this new enforcement tool fairly promptly, which suggests that a different appeals court will have a crack at this question in fairly short order. Understandably, nobody in the food, drug or device business wants to serve as the subject of that case, but industry as a whole might want to see this question resolved as quickly as possible.

There is some question as to whether the current composition of the Supreme Court makes this the ideal time to take up such a case, but it’s difficult to predict which of the justices will be the next to leave the Court. Ruth Bader Ginsberg is a leading candidate for retirement because of her age (84), but Anthony Kennedy is no kid, either, as his 81st birthday is fast approaching. A Trump administration replacement for Ginsburg would seem to guarantee DeCoster will be overturned, but those in search of a predictable legal environment might say sooner is better, regardless of the prospects for churn at 1 First St. NE in our nation’s capital.