Boomerang: EMA Goes from Hunter to Hunted

Boomerang: EMA Goes from Hunter to Hunted

Regulatory agencies spend more time investigating others than being investigated by others, but the European Medicines Agency is now on the hot seat over what is purported to be a lack of transparency regarding premarket interactions between it and drug makers. This is quite a reversal of the typical dynamic, such as when the EMA orders drug makers to withdraw their products from the EU market, but companies in the life sciences might not think the agency’s new transparency problem is a good problem for industry.

EU Ombudsman Investigating Presubmission Meetings

Allegations that regulators are all to cozy with industry are typically leveled at the American FDA, but that problem seems to have migrated to the other side of the Atlantic Ocean. Former journalist Emily O’Reilly, who took the job of European Ombudsman in 2013, has advised the European Medicines Agency she intends to open a “strategic inquiry” into pre-submission activities between the European Medicines Agency and regulated entities.

O’Reilly is no stranger to controversy, having penned three books that struck a number of nerves, but she also took the government of Ireland to task for what she saw as a problem with transparency. The theme of transparency appears in her July 17 letter to EMA executive director Guido Rasi, which states that pre-submission interactions with EMA staff and industry “may pose some risks,” such as that reviewers at EMA may be influenced by applicants in these interactions. O’Reilly acknowledges that these pre-submission meetings are not necessarily problematic, but said there is risk that these meetings create “in the eyes of the public, at least some perception of bias,” a hazard she asserts “must be managed.”

This risk could be managed by more transparency, O’Reilly continues, stating also that “a preliminary assessment suggests that more could be done in this area” without offering any details related to that preliminary assessment.

O’Reilly inquired as to whether EMA publishes “detailed minutes of pre-submission meetings,” which may strike some in industry as incurring the hazard of loosing the lid on proprietary information. She asked EMA to provide details of such meetings dating back to 2012, and asked for a list of the 10 companies that “met most frequently” with EMA staff in pre-submission meetings.

The inquiry is certain to raise a few hackles, but it’s anyone’s guess as to how far this will go and whether EMA will find this sufficiently distractive to impede the agency’s handling of priority review applications, which are also referenced in O’Reilly’s letter. At the very least, this is a matter that bears watching.

EMA Hits Gadoliniums After FDA Stands Pat

The EMA is no stranger to imposing its will on others, as demonstrated by the fact that it has followed through on a threat to suspend the marketing authorization for three gadolinium-based MRI imaging agents, a move that was not paralleled in a similar FDA review. Among the products up for suspension is one route of administration for Magnevist, a linear gabapentin-based contrast agent (GBCA) manufactured by Bayer Schering Pharma, but the macrocyclic GBCAs escaped relatively unscathed in this review.

The FDA began its investigation into the effects of deposits of GBCAs in human tissues in 2015, but announced in May that it had no data on hand to suggest that retention of these agents in the brain is harmful for most patients. The agency affirmed the notion that linear GBCAs are more the more likely of the two types to be retained in the human body, and said the only known problem is nephrogenic systemic fibrosis, said to occur only in “a small subgroup of patients” who had been diagnosed with kidney failure. The FDA said it would continue to track these patients.

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) said earlier in July that it had confirmed “that there is convincing evidence of gadolinium deposition in brain tissues” with the use of gadolinium contrast agents, but while PRAC did not identify specific conditions in connection with deposits in the brain, the committee recommended that EMA suspend the use of Magnevist (gadopentic acid) and two other linear GBCAs, Omniscan (gadodiamide) and Optimark (gadoversetamide).

EMA’s July 21 announcement confirmed the suspension of marketing authorizations for the three linear agents cited by the PRAC, while stating that another linear GBCA, Multihance (gadobenic acid) should be restricted to use in scans of the liver. Another linear GBCA, Primovist (gadoxeticacid), was untouched by the EMA action, although it should be noted that the agency will allow Magnevist to stay on the market for intra-articular use despite the suspension of its use via intravenous administration.

Biosimilars, Biostatisticians, and the New EEU

There are very few days during which the worlds of drugs and medical devices are entirely quiescent, thanks to very active American courts and international regulatory churn. There is some good news in all this, but how good is it?

If you’re in the biosimilars business, the latest news is quite good, indeed.

SCOTUS rules for Sandoz

The U.S. Supreme Court ruled on June 12 that makers of biosimilars do not have to wait six months after the issuance of a biologics license application to begin marketing that product, a development that could bring some less costly biotech drugs to market more quickly and possibly take a bite out of spending on these agents.

In a 9-0 vote, the Court ruled in favor of Sandoz in Sandoz v. Amgen, a case that made a stop at the Court of Appeals for the Federal Circuit, where the outcome was quite different. Sandoz had argued that the terms of the Biologics Price Competition and Innovation Act of 2009 had essentially worked to add half a year of exclusivity to the 12 years already granted by the statute, and by some accounts, Sandoz’s Zarxio is about 15 percent less expensive than Amgen’s Neupogen, a drug for chemotherapy-induced neutropenia.

The news might not change the field dramatically in the near term, given that the FDA has approved only about half a dozen biosimilars to date, but one possible candidate for a quick entry to market is an oncology biosimilar for Avastin, which will undergo an FDA advisory committee review in mid-July. In an ironic twist, Amgen teamed up with Allergan to produce this biosimilar.

Expert witness refuted in Zoloft lawsuit

Pfizer scored a victory in the running lawsuit pertaining to the company’s flagship antidepressant Zoloft, but what may have been the most interesting part of this story is that a court rejected expert testimony relating to allegations that the selective serotonin reuptake inhibitor (SSRI) causes congenital heart defects.

The decision may have brought to a close an effort by more than 300 litigants, which absorbed a second consecutive negative outcome in the U.S. Court of Appeals for the Third Circuit. Both the appeals court and a district court decreed that the expert witness, Nicholas Jewell, a biostatistician at the University of California at Berkeley, had failed to plausibly link the drug to the birth defects. Among the problems with Jewell’s presentation is that he had rejected meta-analyses he had previously cited in a separate lawsuit pertaining to another SSRI.

Whether the plaintiffs will take this lawsuit any further is difficult to forecast, but a footnote on page 10 of the Appeals Court decision remarked that the plaintiffs’ attorneys had conceded that they are “unable to establish general causation” if the courts jettisoned Jewell’s testimony. Summary judgment was granted in favor of Pfizer.

This is not the only multi-district litigation keeping attorneys at Pfizer busy, however. A very active set of lawsuits dealing with proton pump inhibitors and purportedly associated kidney damage would seem to implicate the OTC version of Nexium, marketing rights for which Pfizer picked up five years ago in a deal with AstraZeneca. The U.S. Judicial Panel on Multidistrict Litigation (JPML) declined in January to consolidate these lawsuits, but another motion for consolidation has been filed by attorneys with Seeger Weiss of New York.

Regulations, regulatory agreements on the move

Efforts to ramp up medical device regulatory schemes in outside-U.S. jurisdictions are nothing new, but device makers can add Malaysia and the Eurasian Economic Union (EEU) to the list of national and international entities diving into deeper regulatory waters. The news for device makers is somewhat mixed, but greater clarity alone is sometimes enough to overcome other considerations.

First, Malaysia’s Medical Device Authority has declared that adverse events associated with medical devices will have to be reported to the agency within 30 days. This apparently applies to all devices that are on the Malaysian market, regardless of where the adverse event took place. Any fatalities have to be reported within 10 days, and device makers have a mere 48 hours to advise the agency of any problems that might carry a public health consideration.

The EEU continues to work toward a single market for drugs and devices, a move which if successful would capture the markets of Russia and four other nations for a total 2015 population of nearly 184 million. There are reports that Tehran is interested in a free trade agreement with the EEU, although there is no indication that Iran would take part this new med tech regulatory bloc despite the deepening geopolitical ties with Moscow. Serbia is likewise said to be interested in doing business with the EEU, but it’s not clear whether Belgrade has full-blown membership in mind, either, although the protracted and difficult negotiations for entry into the European Union might strike some as suggestive.

To date, the EEU regulatory regime lacks several critical documents, such as a framework for quality management systems. Registration requirements for this international regulatory system would be phased in over the next four years, however, giving industry a little breathing room for offerings already available in this market.

Liability in EU Market Promises to Grow

Device makers doing business in the U.S. don’t always care for the current state of tort law, but at least they know what to expect. The legal environment in other markets is undergoing some changes that promise to up the ante where financial liability is concerned.

The European Parliament recently voted on the overhaul of device regulations for the European Union, bringing to a close an effort of several years’ duration. As has been previously described at this blog, the notified bodies have their own recent issues with liability in the EU nations, but one of the less conspicuous features of the new Medical Device Regulations is that device makers will have to ensure they can make compensation to all patients who have been harmed by defective medical devices.

The version of the new regulatory framework adopted by the EP includes a requirement that device makers develop “a robust financial mechanism” that will compensate patients who “receive defective products.” There are several factors that go into the calculation of that “robust” mechanism, including the class of the device and the associated risk, but the legislation also points to the size of the manufacturer as a factor. The legislation further stipulates that device makers put themselves in a position to “rapidly and effectively” compensate patients, even when the company has gone out of business.

It requires no reading of tea leaves to realize this provision was sparked at least in part by the silicone gel breast implant scandal, which gained momentum in 2009 when implant rupture rates began to spike. The manufacturer, Poly Implant Prothèse, went bankrupt the following year. The metal-on-metal hip implant problem might also have figured into this provision.

The summary for this legislation is not specific about the nature of this financial mechanism, so it would appear that liability policies will serve in the stead of cash reserves. Whether a manufacturer opts to self-insure or cover this requirement by other means, one thing companies cannot do is leave themselves open to a raft of lawsuits without some sort of plan in place to deal with any claims.

Company beats shareholder suit despite CIA

Minnesota-based Cardiovascular Systems, Inc., persuaded a federal judge to toss out a class-action shareholder lawsuit based on alleged illegal sales tactics, but the suit may be refiled. District Court judge Donovan Frank dismissed the suit (Shoemaker v. Cardiovascular Systems) due to the absence of information specific enough to support the allegations, but Frank left the door open to a reopening of the suit. Cardiovascular had already settled a qui tam lawsuit with the federal government in the amount of $8 million, but the company is also working under a five-year corporate integrity agreement with the Office of Inspector General at the Department of Health and Human Services, which went into effect in June 2016.

PTO to revisit controversial AIA program

Holders of patents who have grown fatigued with the inter partes review process at the U.S. Patent and Trademark Office may be relieved to know the PTO is undertaking a retrospective review of this and other procedures handled by the agency’s Patent Trial and Appeals Board (PTAB). The inter partes review, one of several functions added to the PTO’s to-do list via the America Invents Act (AIA) of 2012, has been widely blasted as doing little to slow down the stream of cases landing at the Court of Appeals for the Federal Circuit, but also for allowing parties with no direct interest in a patent to damage or destroy the patent.

Hedge fund billionaire Kyle Bass has not been uniformly successful with the inter partes process, losing a challenge to the patent for Shire’s Lialda (mesalimine) late in 2016, but Bass has managed to invalidate a number of important patents via the process. PTO director Michelle Lee has instructed PTO staffers to review issues such as multiple petitions, motions to amend, and claims construction. The PTO announcement did not identify a date by which the review would be complete, however.

Life Science News Roundup, 2/14

  • Mexico Proposes Changes to Medical Device Regulations in 2018 – Emergo Group
  • GSK on America First: US Will Not Be Able to Own Every Part of Supply Chain – In-Pharma Technologist
  • Digital Health Startups Should Raise Awareness of Health Issues, Not Flaunt Tech – Medcity News
  • ATA Releases State-by-State “Report Card” of Telemedicine Policies; Texas Finds Compromise – MobiHealthNews

Hits & Misses: Top Stories for 2016

Some years look better in the rear view mirror, but it’s tough to make that call in other instances. Let’s take a look at some of the developments in 2016 and consider what kind of year it was.

Diagnostics in churn in 2016

One item of particular interest to makers of diagnostics was the FDA’s draft co-development guidance, a companion piece to the agency’s companion diagnostic (CDx) guidance. Granted the co-development draft came to light only in July 2016, but it lags the CDx guidance (which was itself in mothballs for 37 months) by a couple of years, which is a problem in that the CDx guidance requires a companion diagnostic for many new drugs. Regardless of how long it takes the agency to wrap up the co-development guidance, it is well past due.

Makers of in vitro diagnostics performed in clinical labs received two good bits of news in 2016, including that CMS suspended its lab fee schedule overhaul until 2018. This development allows industry to avoid what some feared would be a massive gouging of reimbursement rates, but Medicare crosswalk procedures for 2017 might still ding the rates paid for a few tests.

Of perhaps greater importance was that the FDA officially withdrew its proposed framework for regulation of LDTs in 2016, but the agency vowed that would not be the end of the matter. Indeed, the FDA has published another document addressing regulation despite that Congress is crafting legislation that would carve out a unique regulatory regime for these tests.

Oddly, the new discussion draft, which appeared at the FDA website on Jan. 13, declares that its contents do not reflect the agency’s official position on the matter, perhaps an unavoidable concession. This document proposes that the agency would not attempt to regulate tests that are already in practice, tests deemed to be of the low-risk variety, and tests used for purposes of tissue matching.

The future of FDA’s regulation of LDTs is still up for grabs, but it seems certain that any regulatory regime will be less stringent than the one initially proposed. One wild card in this discussion is the timing of Congress’s efforts to deal with this predicament, given the need to deal with the overhaul of the Affordable Care Act and the tax reform imperative, not to mention the debt ceiling and continuing budget resolution dilemmas. The agency’s declared intent to let already-marketed tests go through unmolested could trigger a stampede of applications, however, and developers with the best sets of evidence for clinical validity may find their applications impeded by those with evidentiary foundations of lower quality.

Bundled payments in the crosshairs

One huge development was, of course, the election of millionaire Donald Trump to the White House, which doesn’t seem to bode well for current FDA commissioner Robert Califf. On the other hand, foes of the Affordable Care Act might be pleased to see Sen. Tom Price as Trump’s nominee for the Secretary of Health and Human Services job, given Price’s well-known animosity toward the law. Price is also averse to some of the recent bundled care payment programs rolled out by the Centers for Medicare & Medicaid Services over the past two years, programs that have some in industry worried about doctors stinting on care in order to avoid cost overruns.

Device makers were quite pleased to see passage of the 21st Century Cures Act, a bipartisan crowd pleaser if ever there was one. The legislation puts Medicare administrative contractors on notice regarding disclosure of local draft coverage determinations, but also requires some training of FDA staff on the least burdensome standard. The legislation doubled the number of devices that can be sold under the humanitarian device exemption from 4,000 to 8,000 a year, but the additional monies for more expedited drug and device reviews may prove a mixed blessing if any of the products thus approved are associated with severe or lethal adverse events.

Getting back to the discussion of taxes, the big question for 2017 is whether the device tax repeal will be handled separately from the ACA repeal-and-replace program. There are a lot of reasons to think the ACA repeal-and-replace imperative will prove unmanageable, but a permanent repeal of the currently suspended device tax comes across as an instance of lower-hanging fruit, particularly if the status quo holds through the congressional recess in August (recall that the suspension of the device tax expires at the end of 2017).

ISO-ing on the cake

The FDA wrapped up a couple of guidances of some standing in 2016, including the Section 522 post-market studies guidance, which gives sponsors 15 months from the date of an order to come up with a compliant postmarket study. The agency also exhibited what might seem a grudging concession on ISO 14971 in several final guidances, not to mention the agency’s adoption of the International Medical Device Regulators Forum standard for software as a medical device (SaMD).

Overall, the FDA gave more explicit ground to regulatory harmonization than ever, even if the term “regulatory convergence” might be a more apt characterization. On the other hand, the notion that the FDA is still the center of regulatory gravity isn’t exactly discredited when one considers the massive changes to the European Union’s Medical Device Directives. Recall that Jeff Shuren, director of the Center for Devices and Radiological Health, famously described EU clinical study enrollees as guinea pigs in 2011, a comment he had to retract after hearing from his higher-ups at HHS.

Consider, however, that the EU will henceforth require more routine use of clinical studies for marketing applications and more stringent oversight of notified bodies. Clearly, the FDA is still the standard-bearer for global medical device regulation, regardless of breathtakingly impolitic wordplay offered up by FDAers.

Breathing Room but Hefty Fines: NIH’s Final Rule for Study Registration

The National Institutes of Health has finalized the rule for registration of drug and device trials at, one of the most commercially important documents the agency has published in decades. While the NIH did relent on a couple of points essential to industry, it appears that the requirements will be retroactive, thus exposing device makers to a fine of $10,000 per day per violation for any studies that are not up to date regardless of when those studies first appeared at the clinical studies website.

The NIH notice of proposed rulemaking (NPRM) came to light in 2014, and the docket for this proposal drew more than 900 comments, some of which was reflective of a considerable amount of consternation by those in the life science industries. Among the concerns expressed by industry early on was that the draft rule would have forced the disclosure of confidential information that could compromise a drug or device maker’s competitive position. However, industry was not the only target of the rule. By some accounts, most of the failures to register a study are accounted for by researchers working on studies not sponsored by industry. In any case, members of the NIH team said in an article in the New England Journal of Medicine that only about 10% of the studies registered at include results data from the registered study.

The retroactive nature of the mandate suggests the FDA will be on the look-out for violations of the final rule by drug and device makers. There does seem to be a split on the question of Section 522 post-market surveillance studies, however. The NIH flowchart regarding clinical trial compliance under the Food and Drug Administration Amendments Act of 2007 – the law that gave rise to the NIH rule – suggests that Section 522 studies are only required to register at the NIH site if those studies are of devices in pediatric populations

Nonetheless, any laggardly performance in these non-pediatric Section 522 studies might show up on the FDA radar screen if the agency starts hearing from the public, or from Capitol Hill, about clinical trial compliance generally.

Makers of combination drug-device products were none too happy to see that the NIH draft had stated that trials of combination products would be treated as pharmaceutical agents for the purposes of trial registration. The NIH heard from a number of entities that the final rule ought to reflect the designation applied to the product by the FDA’s Office of Combination Products, which itself has come under a barrage of criticism of late. The final NIH rule conceded the point

On the point of disclosure of trade information, the NIH opted to give sponsors of clinical studies of unapproved drugs and devices a year after the study’s primary completion date to register the results of the study, although sponsors can avail themselves of an additional two years if they certify that they intend to continue development of the product in question. Disclosure of dead-end studies would be required upon the sponsor’s notification of abandonment of the study.

As for timelines, the NIH said the final rule goes into effect on Jan. 18, 2017, and that compliance will turn into enforcement three months later, on April 18, 2017. That leaves sponsors less than six months to determine which of their studies are subject to the final rule and get those studies’ data updated. After all, $10,000 per violation per day can add up quickly.

Nadcap-like Program Holds Promise for Recall Reduction and Enhanced Quality Assurance for Medtech Industry

Courtney A. Stevens, Esq. | Senior Attorney, Medmarc Loss Control

The Performance Research Insitute (PRI), the not-for-profit organization responsible for spearheading the Nadcap program in the aerospace industry, is now turning its focus on medtech and hoping to have the same dramatic results in quality improvement and supply chain management there that is attributed to it for aerospace.

Despite the multitude of standards and regulations that medical device and component part manufacturers are subject to, and indeed the corresponding barrage of audits to which they are subjected, leaders in the medical device industry working with PRI identified a real gap left by all—critical processes. That is, the specific, crucial processes manufacturers use to create their products—heat treating, welding, sterilization, plastics molding, printed circuit board assemblies, cable and wire harness, etc.—are not the focus of quality management system audits. Suppliers can pass all audits imposed on them by the FDA and their OEM-customers without ever having the integrity of their critical manufacturing processes assessed by subject matter experts. PRI’s MedAccred program endeavors to change that, and has already been adopted by some of the largest medical device OEMs (original equipment manufacturer) in the industry, including Johnson & Johnson, Stryker, and Philips Healthcare.

This article, Bringing Nadcap to the Medical Industry, discusses the prospects for the program in greater detail.