Life Sciences News Roundup, 6/22

Courtney S. Young, Esq. | Senior Attorney, Medmarc Risk Management

MedPAC Calls for Action to Reduce Number of PODs 

On June 15, the Medicare Payment Advisory Commission (MedPAC) issued its annual report, which enumerated problems with PODs and outlined actions that could be taken to reduce their prevalence. You can read more here.

FDA Seeks Comment on Two New Drug Promotion Studies

The FDA published two notices in the Federal Register on Monday articulating its plans to undertake new studies on drug promotion: (1) Experimental Study on Risk Information Amount and Location in Direct-to-Consumer Print Ads; and (2) Disclosures of Descriptive Presentations in Professional Oncology Prescription Drug Promotion.

 

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.

FDA Introduces Portal for Public Reporting of Regulatory Misconduct

Kate T. Klaus, Esq. | Staff Attorney, Medmarc Loss Control

Earlier this week, FDA launched a new program in which individuals can report, directly to FDA’s Center for Devices and Radiological Health, allegations of regulatory misconduct on the part of medical device manufacturers and marketers. The agency understands very well the vast reach of the medical device industry, but its limited resources have allowed bad actors to market their products while attempting to remain below FDA’s radar. In addition to creating potential risks for patient safety, this flouting of regulations has long been a source of frustration for medical device companies that do operate within the bounds of the law and feel unfairly disadvantaged when competitors skirt the rules.

Examples of reportable misconduct include:

  • Advertising or promoting a device beyond the bounds of its indications for use;
  • Marketing a device without the necessary clearance or approval;
  • Failing to implement or comply with necessary Quality System requirements;
  • Importing devices that do not meet U.S. legal criteria;
  • Failing to register and list with FDA, thus preventing FDA from properly overseeing operations; and
  • Knowingly deceiving FDA in some fashion, whether falsifying documents or hiding information.

Reports are accepted through the FDA webpage, as well as by mail and email. While FDA encourages reporters to include their name and contact information in the event that additional information is required, reports can be filed anonymously. FDA will review the reports, evaluate potential risks to public safety, and determine the appropriate intervention or enforcement action.

What is the takeaway for medical device firms? For those already operating in compliance with FDA regulations, there should not be a burdensome impact. Even if FDA chooses to investigate an allegation, frivolous claims will likely be dispensed with easily when met with strong quality systems and thorough recordkeeping practices. However, for those firms attempting to fly beneath FDA’s radar, they may find themselves on the receiving end of a Warning Letter in short order. Your competitors have been watching your practices for years, but FDA has now empowered them to act.

For more information on compliance with FDA regulations, please see our Life Sciences Guidebook, available for sale on Amazon.

New Guidance from FDA: When to Submit a 510(k) for a Change to a Cleared Medical Device

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

FDA’s newest guidance for medical device manufacturers, Deciding When to Submit a 510(k) for a Change to an Existing Device, issued August 8, addresses a question manufacturers commonly face,—when a 510(k) is necessary for a change to an already cleared device. Manufacturers’ failures to submit 510(k)s are frequently cited in warning letters as rendering a device adulterated. As such, it’s an issue medical device companies can’t be too careful in scrutinizing. Thankfully, this guidance does provide such much-needed clarity on exactly when a 510(k) is necessary, and when processing the change in accordance with Quality System (QS) requirements (e.g., documentation of changes and approvals in the master record, verification and revalidation, etc.) is sufficient.

The confusion over whether a 510(k) is necessary is largely due to the subjective, relative language in the regulations, requiring device-makers to submit a 510(k) when a change “could significantly affect the safety or effectiveness of the device.” (21 CFR 807.81 (a)(3)). The Agency tried to clarify its interpretation of that language in its first guidance document on this issue, published in 1997, but clearly, as evidenced by the frequency with which the manufacturers’ determination of “significant” changes differed from the Agency’s, greater clarity was needed still. (Once finalized, this draft guidance will supersede the 1997 Guidance on the subject.)

This guidance document improves upon its predecessor by providing a number of exacting flow chart-decision trees to guide manufacturers through the determination of a 510(k)s’ necessity with regard to different types of changes.

It begins by setting out the guidance principles to be first considered in determining the propriety of a 510(k), which I briefly summarize here:

  • Modifications made with intent to significantly affect safety or effectiveness of a device. This is the same language as is found in the regulations, and its meaning is fleshed out in the remainder of the document.
  • Could “significantly affect” evaluation and the role of testing. In order to determine significance of the effect, manufacturers must conduct risk-based assessments.
  • Unintended consequences of changes. One component deemed to make up a “significant effect” is if the change would result in unintended consequences or effects. The draft guidance provides sterilization as an example which may affect device materials, thereby affecting performance of the device.
  • Use of risk management. Here, the draft refers to ISO 147981: Medical devices – Application of risk management to medical devices, and instructs manufacturers to utilize an assessment combining the probability of occurrence of harm and the severity of that harm in determining “significant effect.”
  • Evaluating simultaneous changes. Even though changes may occur simultaneously, each change should be assessed individually and in combination.
  • Appropriate comparative device and cumulative effect of changes. In making the determination of a 510(k)’s propriety, manufacturers need to consider (1) how different a change makes the device from its initial or most recent iteration as described in their most recently cleared 510(k); and (2) the cumulative effect of all changes since the last 510(k) cleared for this device. That is, though previous changes did not require a 510(k) when made in isolation, does the cumulative effect of this change with those previously made nor warrant a 510(k), even if it, by itself, would not?
  • Documentation required. Even if a manufacturer determines a 510(k) is appropriate for a particular change, this does not alleviate them from compliance with all existing QS requirements, including all documentation, verification, and validation duties.
  • 510(k) submission for modified devices. When a 510(k) is submitted for a device with multiple modifications since its last cleared 510(k), the 510(k) should describe not only the most recent change that warranted the 510(k), but also all previous modifications even though they did not merit the submission of 510(k)s in and of themselves.
  • Substantial equivalence determination. Manufacturers need understand that submission of a 510(k) for a change pursuant to everything outlined in the regulation and this guidance document does not assure that a substantial equivalence determination will be provided.

 

With these considerations in mind, manufacturers may proceed to the different parts of the guidance instructing them on decision-making for different kinds of changes—labeling, control mechanisms, operating principles, etc. In each of these, manufactures will find the aforementioned decision trees to guide them through submission criteria.

An example of the flow charts included in this draft guidance:

8.16 - guidance flowchart

In addition to charts guiding decision making, the guidance also provides examples of documenting changes and written regulatory change assessments.

This should go a long way in facilitating manufacturers’ understanding of when 510(k)s for changes are necessary, and reduce the number of warning letters for companies’ failure to submit them, accordingly.

FDA Pushes Back the Date for Issuing Generic Drug Labeling Rule to April 2017

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

On Thursday, the FDA again pushed back the date it expected to issue its final rule on generic drug labeling.  The final rule is now expected in April 2017.  The highly controversial proposed rule, as discussed in more depth in earlier posts, would permit generic drug manufacturers to unilaterally change their labels under the changes-being-effected (“CBE”) process.  Besides likely creating a bureaucratic headache and allowing generic and brand-name labels to differ (potentially in violation of the Hatch-Waxman Act), the proposed rule would also threaten to undermine the generic drug preemption decisions by the U.S. Supreme Court.  The proposed rule has generated significant political heat for these reasons, and the date for the final rule has already been pushed back several times.  Although the FDA did not state a reason for pushing back the announcement of its final rule again, the new date of April 2017 is, of course, after the next election.  Whether the final rule will ever be issued, and what it may look like, are open questions.  In any event, the wait continues.

 

FDA Settles with Amarin in Off-Label Promotion Free Speech Lawsuit

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

As discussed more in an earlier post, Amarin Pharma sued the FDA in May 2015 asserting that under the First Amendment’s free speech protections, it could engage in truthful and non-misleading speech promoting the off-label use of its drug, Vascepa, for the treatment of patients with persistently high triglyceride levels.  On August 7, 2015, a federal judge in New York granted Amarin’s preliminary injunction in the case, and held that under the First Amendment’s free speech protections, the FDA could not bring a misbranding action against Amarin for Amarin’s off-label promotion.  As the Court stated:  “Where the speech at issue consists of truthful and non-misleading speech promoting the off-label use of an FDA-approved drug, such speech . . . cannot be the act upon which an action for misbranding is based.”

Yesterday, Amarin and the FDA settled this lawsuit.  The settlement largely mirrors the Court’s preliminary injunction order – with the FDA agreeing “to be bound by the Court’s conclusions that Amarin may engage in truthful and non-misleading speech promoting the off-label use of Vascepa®,” and Amarin agreeing that it “bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa® remain truthful and non-misleading.”  The settlement also sets forth a preclearance procedure between Amarin and the FDA on other future off-label promotion of Vascepa.

This settlement cements Amarin’s victory on its preliminary injunction.  The course of this lawsuit has provided a roadmap for drug and device manufacturers looking to promote their products off-label – in terms of how to raise such promotional plans with the courts to obtain court approval and FDA agreement on such off-label promotion.

What Scalia’s Passing Means to Life Sciences Companies

Courtney A. Stevens | Senior Attorney, Loss Control | Medmarc Insurance Group

The recent passing of Justice Antonin Scalia, the Court’s longest-serving justice, means more than just political scuttlebutt over who will get to appoint his replacement. For life sciences companies, it means the loss of a real ally in matters of tort liability and a powerful force in intellectual property.

Preemption

Scalia authored the 8-1 majority opinion in Riegel v. Medtronic, 552 U.S. 312 (2008), a pivotal decision in preemption jurisprudence that held that the Medical Device Amendments to the Food, Drug and Cosmetic Act (FDCA) preempted state-law claims relating to the safety and effectiveness of pre-market approval (PMA) devices. This effectively shields makers of PMA devices from products liability claims.

In Wyeth v. Levine, 555 U.S. 555 (2009), which undermined preemption in holding that FDA approval of a medication does not preempt state law failure-to-warn claims, Scalia joined the dissent (authored by Justice Samuel Alito). The dissent argued that this holding was inconsistent with their previously-adopted “conflict preemption” analysis.

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