The Surprising Reach of FDA Regulation of Cannabis, Even After Descheduling.

As more states legalize cannabis, the push to "deschedule" it from the Controlled Substances Act is gaining momentum. At the same time, the Food and Drug Administration (FDA) recently approved the first conventional drug containing a cannabinoid derived from cannabis­cannabidiol (CBD) for two rare seizure disorders. This would all seem to bode well for proponents of full federal legalization of medical cannabis. But some traditional providers are wary of drug companies pulling medical cannabis into the regular small molecule drug development system. The FDA's focus on precise analytical characterization and on individual active and inactive ingredients may be fundamentally inconsistent with the "entourage effects" theory of medical cannabis. Traditional providers may believe that descheduling cannabis would free them to promote and distribute their products free of federal intervention, both locally and nationally. Other producers appear to assume that descheduling would facilitate a robust market in cannabis-based edibles and dietary supplements. In fact, neither of these things is true. If cannabis were descheduled, the FDA's complex and comprehensive regulatory framework governing foods, drugs, and dietary supplements would preclude much of this anticipated commerce. For example, any medical claims about cannabis would require the seller to complete the rigorous new drug approval process, the cost of which will be prohibitive for most current traditional providers. Likely also unexpected to some, there is no pathway forward for conventional foods containing cannabis constituents, with the (probably exclusive) exception of certain hemp seed ingredients, if those foods cross state lines. And it will certainly come as a shock to many that federal law already prohibits the sale of dietary supplements containing CBD--including those already on the market as well as those made from "hemp," which has recently been descheduled under the 2018 Farm Bill. This Article describes in detail the surprising reach of the FDA and then outlines three modest, but legal, pathways forward for cannabis-based products in a world where cannabis has been descheduled.

How Colombia’s biosimilar regulation departs from international norms

Dear editor I write in response to an article published in January 2016 regarding Colombia’s 2014 regulation governing registration of biosimilar biological products (1). In my view, the article seriously misstates international norms regarding approval of biosimilars and creates a misimpression that the new Colombian regime is consistent with the approach taken in Europe and the United States. In fact, the Colombian regulation departs significantly from international norms. Generally speaking, the consensus approach in the rest of the world involves two pathways to market for biological medicines: a full dossier with robust preclinical and clinical evidence of safety and effectiveness, and an abbreviated dossier with a robust showing of similarity to an originator product sufficient to justify reliance on the originator’s safety and effectiveness research. There is no third pathway. The consensus approach to the abbreviated dossier for a biological medicine involves a rigorous comparison of the proposed medicine with a single originator product, proceeding step-by-step through comparative analytical and functional characterization to preclinical testing and clinical testing. Clinical data are always required...

Biosimilar monoclonal antibodies: the scientific basis for extrapolation.

INTRODUCTION: Biosimilars are biologic products that receive authorization based on an abbreviated regulatory application containing comparative quality and nonclinical and clinical data that demonstrate similarity to a licensed biologic product. Extrapolation of safety and efficacy has emerged as an important way to simplify biosimilar development. Regulatory authorities have generally reached the consensus that extrapolation of similarity from one indication to other approved indications of the reference product can be permitted if it is scientifically justified. AREAS COVERED: Recently, the first biosimilar, biosimilar infliximab (Remsima/Inflectra) to the innovator monoclonal antibody infliximab (Remicade), was approved in the European Union, Canada and South Korea; the USA subsequently approved its first biosimilar, a less complex molecule (filgrastim-sndz). Based on two clinical trials of biosimilar infliximab in patients with rheumatoid arthritis and ankylosing spondylitis, the European Medicines Agency allowed extrapolation to all eight approved indications for innovator infliximab, whereas Health Canada did not permit extrapolation to the indications for ulcerative colitis and Crohn's disease. These differing decisions on extrapolation of indications for biosimilar infliximab highlight important unanswered regulatory and scientific questions. Here, we propose substantive scientific considerations for indication extrapolation. EXPERT OPINION: The preclinical and clinical criteria that are currently required to merit indication extrapolation have not been rigorously evaluated.

An unofficial legislative history of the Biologics Price Competition and Innovation Act of 2009.

In March 2010, Congress passed the Biologics Price Competition and Innovation Act of 2009 (BPCIA). This law established a statutory pathway for approval of "biosimilars," follow-on versions of innovative biological products. This article traces the history of the BPCIA, beginning with a discussion of the origins of federal regulation of drugs and biologics, including passage of the Hatch-Waxman amendments, in Section I. Section I also describes the development of the European approval framework for biosimilars in the mid-2000s and how this increased interest in creation of a pathway in the United States. The article then provides, in Section II, an overview of early stakeholder discussions in the United States regarding legal and scientific issues relating to biosimilars, spanning the years 1998-2006. The legislative debate began in earnest in late 2006, when the first biosimilars bill was introduced. Section III of the article examines introduced bills, other legislative proposals, and related stakeholder discussion in detail, leading up to enactment of the BPCIA. Section IV describes the BPCIA as enacted, and the paper ends with the authors' concluding observations about the legislative negotiations and their implications for interpretation of the Act.

A new history and discussion of 180-day exclusivity.

Congress created 180-day exclusivity for generic drug applicants in the 1984 Hatch-Waxman amendments to the Federal Food, Drug, and Cosmetic Act (FDCA) and amended the provision substantially in the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). The fundamental goal behind 180-day exclusivity was to provide an incentive for generic drug applicants to challenge innovator patents, and the core of the concept--as it has been applied by the Food and Drug Administration (FDA) and the courts--is that the first generic drug applicant to challenge an innovator's patent is entitled to six months of exclusivity against subsequent patent challengers for the same innovator drug. 180-day exclusivity is governed by sections 505(j)(5)(B)(iv) and 505(j)(5)(D) of the FDCA. In this article, the authors provide a comprehensive resource on 180-day exclusivity for old abbreviated new drug applications (ANDAs) (but less detail in some places where the 2007 article may be referenced) but focus more discussion on the new provisions as well as some policy and legal issues related to 180-day exclusivity that have not previously addressed.

Advisory committees at FDA: the Hinchey Amendment and "conflict of interest" waivers.

In approving the Food and Drug Administration's (FDA) Fiscal Year 2007 budget, the House approved an amendment that would prevent the agency from using appropriated funds to waive certain conflicts of interest identified by members of its advisory committees. The amendment, introduced by Representative Hinchey and known as the Hinchey Amendment, provides that no funds may be used to: waive a conflict of interest under Section 505(n)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA) for any voting member of an FDA advisory committee or panel; or make a certification under Section 208(b)(3) of Title 18 of the U.S. Code for any such voting member. This creates a problem, as ties to industry create the very expertise that FDA values in its outside advisors-under the Hinchey Amendment, these very ties would prevent them from serving as advisors to FDA during the drug approval process. The author opposes this change in the law and argues that the Hinchey Amendment would undermine congressional efforts in 1962 and 1989 to carefully balance the goals of attracting qualified experts and protecting agency decisionmaking. Further, the author argues, this change is unnecessary at FDA, because experts on FDA advisory committees divulge their connections to the industry, because the committees offer only advice and do not make agency decisions, and because the agency is under the watchful eye of Congress, the public, and public interest groups. The Article concludes that although FDA's advisory committee conflict-of-interest process can be improved, congressional action is unnecessary, and a change in the law through amendment to an appropriations bill that does not go through the ordinary legislative process (as an amendment to the FDCA or Title 18 would) is inappropriate. Instead, recommendations from organizations studying FDA practice, such as the OIG, GAO, and IOM, should be used to carefully and reflectively amend the process at the agency level, within the existing statutory framework.

A brief history of 180-day exclusivity under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act.

This article summarizes the history of the 180-day exclusivity provision on the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act (FDCA). Part II presents the statutory language, as amended in the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA), and summarizes the law that applies to new abbreviated new drug applications (ANDAs) (those filed after December 8, 2003, provided there was no paragraph IV certification to the listed drug prior to December 8), as well as the law that applies to all other ("old") ANDAs. Part III describes the legislative history of the original 1984 provision and traces its judicial and administrative history through the present. Part IV describes the history of the 2003 amendments and describes the key changes made in 2003. While Congress addressed in 2003 a number of the interpretive issues that had arisen since 1984, the new law is intricate and undoubtedly will give rise to new interpretive questions in the months and years ahead.

2004 update--180-day exclusivity under the Hatch-Waxman amendments to the federal Food, Drug, and Cosmetic Act.

This article updates the author's previously published article on the topic, provides some insight into recent events in this area of the law, and specifies a few minor items that were noted incorrectly in the earlier work.