United States: FDA Legal And Regulatory – 2015 Year In Review

Looking back on 2015, it's apparent that this was another very busy year for the Food and Drug Administration (FDA or Agency), whose oversight responsibilities are estimated to touch 25% of American consumers' spending on various regulated products.  There was no shortage of significant Agency actions in 2015 related to therapeutic and diagnostic products, which include traditional chemical drugs, biological products, medical devices and diagnostic tests, and even stem cell therapies and human tissue products.  Also noteworthy is that FDA is reporting that as of December 14th it had granted approval to 42 groundbreaking new drugs (called "new molecular entities" or NMEs) and therapeutic biological products during the calendar year.  The figure so far for this year beats 2014's final count of 41 approved NMEs and far exceeds the prior year's total of 27 NMEs.  This post will highlight some of FDA's significant actions this year and provide our thoughts about what next year may bring for FDA-regulated entities.

Breakthrough Year for Biosimilars

As our colleagues noted last week in their year-in-review for the pharmacy industry, 2015 saw the first marketing approval of a biosimilar product under the Biologics Price Competition and Innovation Act (BPCIA), and the subsequent market launch of that product, Zarxio (filgrastim-sndz), following a key Federal Circuit ruling interpreting several patent and notice provisions of the BPCIA.  From public reports, Mintz Levin also estimates that at least 7 biosimilar applications have been submitted to FDA and are at various stages of the review process, although this number may be higher because not all sponsors announce filings and prefer to wait until actual approval is received.  FDA also is working directly with a significant number of biosimilar developers through its so-called Biosimilar Product Development (BPD) Program, with the Agency's Dr. Janet Woodcock reporting in September to a Senate committee that "57 proposed biosimilar products to 16 different reference products were enrolled" in that BPD Program.  Dr. Woodcock also noted that sponsors of an additional 27 proposed biosimilar products have had a Biosimilar Initial Advisory meeting with the Agency, but have not yet joined the BPD Program (which can trigger biosimilar user fees).

In addition to product development and application review activities related to biosimilars, FDA has been refining its regulatory policies in this area. The Agency finalized three guidance documents in April that together set forth the evidence showing biosimilarity that sponsors must include in their biosimilar "351(k) applications." FDA also released in August a controversial draft policy on nonproprietary names for biosimilars and finalized its guidance on BPD Program meetings in November.

2016 may prove to be an even more exciting year for biosimilars with potentially several more 351(k) applications to be approved and FDA announcements expected regarding its policies on important regulatory issues, including interchangeability and labeling for biosimilar products. Indeed, FDA received two high-profile Citizen Petitions this year requesting completely conflicting requirements for biosimilar labels, so it will be fascinating to see how the Agency handles this important issue.  Next year will also begin the process of stakeholder consultation and negotiations in advance of the first reauthorization of the Biosimilar User Fee Act (BsUFA), originally passed in 2012, which will offer another opportunity for interested parties to participate in the Agency's various regulatory processes.

Regulating Digital Health While Promoting Innovation

FDA also took several actions in the "digital health" area this year that have significant implications for many different healthcare providers. The Agency uses the term digital health to cover a variety of things – from mobile health ("mHealth") and mobile medical applications ("MMAs"); health information technology ("Health IT"); wearable devices; and telemedicine.

In February, the Agency revised its final guidance on MMAs to reflect its concurrently-announced decision to exercise enforcement discretion for the specific product category of Medical Device Data Systems, which are devices that are intended to store, transfer, convert, or display medical device data.  These actions early on in the year further strengthened the risk-based regulatory framework for mHealth and MMAs, as did a new draft guidance that the Agency issued describing its policy for low-risk "general wellness" products.

In addition, following a high-profile warning over the summer regarding a potential hacking vulnerability in certain medical devices, the Agency recently announced a public workshop to be held in January 2016 on the topic of medical device cybersecurity.  The workshop will be hosted by FDA in collaboration with the National Health Information Sharing Analysis Center, the Department of Health and Human Services, and the Department of Homeland Security. One of the workshop's stated goals is to "engage the multi-stakeholder community in focused discussions on unresolved gaps and challenges that have hampered progress in advancing medical device cybersecurity." As healthcare and medicine continue to become more digital, "cloud-based," and interconnected, the legal and regulatory activities will continue to evolve as well.  So we expect increasing engagement by FDA on digital health even as many of the more widespread mHealth products are not being actively regulated by the Agency under its medical device authorities (for example, wearable fitness trackers and mobile apps to help users track their daily calorie intakes).

Advancing Precision Medicine Through Device Approvals & Policymaking

President Obama's Precision Medicine Initiative, announced in January, included $10 million for FDA to "to acquire additional expertise and advance the development of high quality, curated databases to support the regulatory structure needed to advance innovation in precision medicine and protect public health." And, indeed, the Agency has been and will continue to be at the forefront of this transformation in medicine.

Precision medicine, sometimes also called personalized medicine, at its simplest, is the treatment of a patient with the right drug, at the right dose, and at the right time. The etiology of a patient's disease is matched with an appropriately targeted product with, hopefully, few or no side effects due to the selection of a drug that fits with the patient's genetic makeup, metabolism, and other potential personal nuances. This new treatment paradigm will depend in large part on FDA and its approval of emerging technologies that would make this vision possible.

One of these emerging technologies is so-called Next-Generation Sequencing (NGS), which allows labs to rapidly sequence large portions of an individual's DNA at a low cost, potentially offering great rewards (but also risks) to patients. FDA hosted workshops in February and November of this year to discuss options for an appropriate regulatory scheme for NGS platforms and tests that would allow flexibility and innovation, as the traditional approach to diagnostic tests in which the Agency reviews data on each test result is not feasible for NGS.  The workshops examined possible approaches to analytical standards that would ensure the reliability and accuracy of the technologies and to clinical validation of the tests through external curated databases that developers could use to establish clinical relevance of a particular test.

In addition to its policy work in the area of NGS and high-throughput genomic technologies, FDA has been working to advance precision medicine in other areas as well. This year, those regulatory activities included the approval of the first autosomal carrier screening gene mutation test and the Agency's decision to make any future autosomal carrier genetic tests low-risk  and exempt from premarket review.  Further, although originally announced last year, FDA's revised regulatory framework for laboratory-developed tests (LDTs) continued to generate commentary, controversy, and alternatives in 2015.  LDTs should be a persistent topic next year as well, due to the expectation that the Agency's LDT proposal will be finalized in 2016, and then regulators' focus will shift to implementation.

Renewed Focus on Human Cells and Tissue Products

As the American stem cell and human tissue industry has gained attention over the past few years, FDA has begun to sharpen its regulatory focus commensurate with the potential risks it considers these products to pose to consumers. At the end of 2014, FDA published three important draft guidances regarding the scope of various criteria required for human cells, tissue, and cellular and tissue-based product (HCT/Ps) to be regulated solely under the Public Health Service Act (that is, not as a "drug" or "device" as well). Specifically, those drafts elaborated upon the "same surgical procedure" exemption, the meaning of "minimal manipulation" of cells and tissue, and fat-derived stem cells.  In February of this year, it also released a draft guidance document that discusses how HCT/P manufacturers should investigate and report adverse reactions due to communicable diseases experienced by recipients of HCT/Ps.

More importantly, however, in October FDA re-opened the comment period for the three draft guidances published a year ago and also released another draft guidance related to the PHS Act exemption for human cells and tissues – this one on the meaning of "homologous use" of HCT/Ps. Concurrently, the Agency also announced a public hearing scheduled for April 13, 2016, intended to obtain input on all of the draft HCT/P policies that have been developed over the past 14 months. FDA's recent activity in this area, combined with the increasing media reports (both promotional and skeptical) of patients treated successfully by for-profit stem cell clinics that may or may not be adhering to the Agency's regulatory requirements for HCT/Ps, lead us to conclude that 2016 could be a watershed year for this industry.  We will certainly keep our readers apprised of any interesting developments in the area of human cells and tissues.

Rethinking Off-Label Uses and Promotion

Last, but certainly not least, FDA was also busy this year defending itself in First Amendment lawsuits involving its long-standing policies related to the off-label marketing of prescription drugs and the meaning of "intended use," as that term is used in Agency regulations. After FDA threatened Amarin Pharma Inc. with misbranding charges if the company made truthful statements regarding off-label uses of the drug Vascepa (icosapent ethyl) to doctors, in August Amarin successfully obtained a preliminary injunction based on its First Amendment challenge to FDA.  Although the court agreed that Amarin should be able to provide truthful and non-misleading information to doctors about the drug without running afoul of the Federal Food, Drug, and Cosmetic Act, the decision was limited to truthful statements only.  At least one other plaintiff drug company has sued the Agency in federal court in reliance on the court's discussion and criticism of FDA in the Amarin injunction.  There will certainly be a lot more litigation in this area next year as well.

Moreover, shortly after its defeat in Amarin, FDA published a proposed rule that would update its regulations that define the term "intended use," which is important because a product's intended use determines whether and how the product is regulated by FDA. For decades, FDA has used an objective intent standard that focuses on how the product is advertised and labeled to the public, rather than what the manufacturer's subjective intent may have been with respect to that product, to determine the "intended use."  Going one step further, FDA's existing regulations also purported to require the manufacturer to provide adequate directions to doctors for off-label uses of a product if the manufacturer "knows, or has knowledge of facts that would give him notice" that the product is actually being used for such off-label uses, even if the manufacturer does not promote the product for those uses.  Although rarely enforced, this provision has had a chilling effect on manufacturers who have been wary about informing physicians in any way regarding products that the manufacturers know are being used off-label.  FDA's proposed rule deletes this last part of the regulations' definition of "intended use" with very little explanation.

What is clear from this proposed regulatory change, as well as the First Amendment cases, is that industry and judicial opposition to FDA's broadly construed view of off-label promotion has begun to have an impact on the Agency's decision- and policymakers. It remains to be seen exactly how FDA responds to the swell of challenges it is now facing with respect to off-label promotion, but we will be reporting out on those future Agency moves and their potential wider implications.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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