FDA Delays Effective Date of Amended Regulations Affecting "Intended Use" Definition
One day before the final rule, "Clarification of When Products Made or Derived From Tobacco Are Regulated as Drugs, Devices, or Combination Products; Amendments to Regulations Regarding 'Intended Uses,'" would have taken effect, the Food & Drug Administration ("FDA" or "Agency") announced it was delaying the rule's effective date until March 19, 2018, to obtain public comments on issues raised in an industry petition and on any other issues raised with respect to the rulemaking.
In a 2015 proposed rule, the Agency proposed changing the existing "intended use" regulations for drugs and medical devices to clarify that FDA would not regard a firm as intending an unapproved new use for an approved or cleared drug or device based solely on that firm's knowledge that its product was being prescribed or used by doctors for such use. However, in the final rule published January 9, 2017, FDA did not to delete the language but, rather, added new language creating a new and different standard for the rule providing: "And if the totality of the evidence establishes that a manufacturer objectively intends that a drug [or device] … is to be used for conditions, purposes, or uses other than the ones for which he offers it is approved (if any), he is required … to provide for such drug [or device] adequate labeling that accords with such other intended uses."
FDA stated that adding the "totality of the evidence" standard did not change its goals under the proposed rule, and it clarified that the new language embodies its longstanding position that "intended use" can be based on "any relevant source of evidence," including a variety of direct and circumstantial evidence. (Notably, FDA's original proposed removal was "to better reflect FDA's interpretation and application of [the intended use] regulations" and "would not reflect a change in FDA's approach regarding evidence of intended use for drugs and devices.")
Notwithstanding FDA's reasoning, industry members petitioned FDA to reconsider the rule, to revert to the language proposed in 2015, and to stay the final rule indefinitely. The petitioners claim FDA's final rule violated the fair notice requirements of the Administrative Procedure Act, and that the "totality of the evidence" standard is a new and unjustified standard that would introduce significant constitutional concerns and negatively affect the public health by chilling valuable scientific speech.
Consequently, FDA has delayed the effective date of the amended regulations and is requesting comments specially related to: (i) how FDA should consider situations where companies and individuals distribute medical products and/or seek to import medical products without explicit promotional claims; (ii) the potential public health consequences and relevant policy considerations that should be considered in evaluating any approaches to intended use; (iii) how First Amendment considerations apply to the use of non-speech evidence in determining intended use, such as the circumstances surrounding the distribution of a product or the context in which it is sold; and (iv) whether stakeholders believe there is a distinction between considering "any relevant source of evidence" and "the totality of evidence," and whether there are any suggestions about what wording provides the most clarity to regulated entities.
FDA also encouraged submitting comments regarding off-label communications of approved/cleared medical products (see next story) to also submit their comments to the present docket if pertinent to the specific issues raised.
The Continuing Story of Manufacturers' Off-Label Promotion of Approved or Cleared Medical Products
Prior to the end of the previous Administration, FDA released several draft guidance documents and a white paper addressing different types of communications about medical products. On January 18, 2017, FDA published two draft guidances answering questions and providing FDA's recommendations regarding different types of communications about medical products: "Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities" and "Medical Product Communications That Are Consistent With the FDA-Required Labeling." These draft guidance documents, respectively, address:
- Firms' communication of health care economic information ("HCEI") about prescription drugs to payors, formulary committees, or other similar entities with knowledge and expertise in the area of health care economic analysis. The FDA uses a Q&A format in the draft guidance to address communication of HCEI to these groups regarding approved drugs and regarding investigational drugs and devices. The document addresses: what constitutes HCEI, how it can be presented, appropriate audiences, FDA implementation, what FDA considers related to an approved indication, and evidentiary support for HCEI, among other issues.
- How FDA evaluates firms' medical product communications that present information not contained in FDA-required labeling but that may be consistent with such labeling. The draft guidance document describes three factors it considers in evaluating whether the representations or suggestions in a communication about a product are consistent with the product's FDA-required labeling, namely: (i) how the information compares with certain conditions of use (indication, patient population, limitations and directions for handling/use, and dosing/administration); (ii) whether the information communicated increases the potential for harm relative to the FDA-required labeling information; and (iii) whether the directions for use enable the product to be safely and effectively used under the conditions communicated. Additionally, it provides examples of what communications could or could not be considered consistent with the FDA-required labeling for a product. FDA also outlines the evidence required to support these communications and provides general recommendations to help ensure the communications are not construed as false or misleading.
Additionally, on January 18, 2017, FDA posted as part of the docket on Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products, an Agency memorandum describing "Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products," at the same time reopening the docket through April 19, 2017. The FDA Memorandum specifically addresses First Amendment matters by laying out is position on case law regarding off-label communications, provides FDA's initial reactions to proposed mechanisms to address First Amendment concerns, and invites comments on the document.
Notably, the FDA Memorandum rejects 12 alternative approaches to address off-label promotion suggested in Caronia and by some commentators, stating it "is concerned that none of them appear to integrate the complex mix of numerous, and sometimes competing, interests at play and thus do not best advance those multiple interests." Some of the alternatives included creating ceilings or caps on the number of prescriptions for an unapproved use, limiting Medicare and Medicaid reimbursement to approved uses, or educating health care providers and patients to differentiate false and misleading promotion from truthful and nonmisleading information. FDA has requested comments on its review of the alternatives.
This activity follows the November 2016 public hearing regarding a number of specific questions related to off-label communications of approved or cleared medical products to support the Agency's engagement "in a comprehensive review of its regulations and policies" governing these communications. Although FDA has committed since 2011 to evaluate its related policies, FDA has not yet published any other guidance on the matter except for a 2014 draft guidance that recommended practices to distribute scientific and medical publications on unapproved new uses.
As a side note, on March 21, 2017, Arizona Governor Doug Ducey signed HB 2382, the Free Speech in Medicine Act, into law. The state law allows drug companies to communicate with doctors and other health-care providers about safe and effective off-label uses for approved medical products but does not permit advertising of off-label uses directly to consumers.
Cures Corner: FDA Launches Regenerative Medicine Advanced Therapy Designation Program
In late January 2017, FDA took the first steps to implement certain provisions of the 21st Century Cures Act ("Act"), signed into law on December 13, 2016, by launching a new designation program for regenerative medicine therapies. Implemented pursuant to Section 3033 of the Act, the Regenerative Medicine Advanced Therapy ("RMAT") Designation program aims to help foster the development and approval of regenerative medicine products. Despite the program's newness, on March 20, 2017, FDA issued one of the first RMAT designations to Humacyte's investigational human acellular vessel, "Humacyl."
Under the new program, a drug is eligible for RMAT designation if: (i) the drug is a regenerative medicine therapy; (ii) the drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and (iii) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition. A drug constitutes a "regenerative medicine therapy" if it is a cell therapy, therapeutic tissue, engineering product, human cell and tissue product, or any combination product using such therapies or products. The term does not include certain human cells, tissues, and cellular or tissue-based products regulated solely by Section 361 of the Public Health Service Act and Part 1271 of Title 21 of the Code of Federal Regulations. To determine whether a disease or condition is serious or life-threatening, or whether a drug is intended to treat such disease or condition, FDA refers to its existing guidance on Expedited Programs for Serious Conditions—Drugs and Biologics.
The RMAT designation offers a few important benefits to drug sponsors. First, sponsors of RMAT-designated products are eligible for increased and earlier interactions with FDA to expedite development and review of the therapy, similar to those interactions currently available to sponsors of products with a breakthrough therapy designation. In addition, RMAT-designated products may be eligible for priority review and accelerated approval by FDA. Finally, once approved, sponsors of RMAT-designated products can satisfy post-approval requirements through the submission of real-world clinical evidence, such as through clinical studies, patient registries, and electronic health records, the collection of larger confirmatory data sets, or post-approval monitoring of all patients treated with the therapy prior to its approval.
Sponsors of regenerative medicine therapies can request RMAT designation from FDA's Office of Tissues and Advanced Therapies either concurrently with, or at any time after, the submission of an Investigational New Drug ("IND") application or an amendment to an existing IND application. The FDA will not grant RMAT designation if an IND is on hold or is placed on hold during the designation review. In addition, although FDA does not expect sponsors to submit primary data sets, the request for RMAT designation should describe the preliminary clinical evidence and include a brief description of any available therapies for the disease or condition, the study design, the population studied, and the endpoint(s) used, and a description of the study results and statistical analysis. Once an RMAT request has been received, the FDA has 60 days to determine whether a drug meets the criteria.
President Trump Proposes Dr. Scott Gottlieb as FDA Commissioner
According to a White House statement, President Trump intends to nominate Scott Gottlieb, M.D., as FDA Commissioner. Dr. Gottlieb has previously served in government in various capacities, including as deputy commissioner for medical and scientific affairs, and as a senior official at the Centers for Medicare and Medicaid Services during the Bush Administration.
He is currently a venture partner at New Enterprise Associates, where he specializes in health care investments, and, according to his American Enterprise Institute ("AEI") biography, is a "resident fellow at the American Enterprise Institute where he studies the FDA and the Centers for Medicare & Medicaid Services ("CMS"). He also focuses on health care reform and political and clinical trends in medicine, including medical innovation and the development of new technology. He is concurrently a clinical assistant professor at New York University School of Medicine and advises the U.S. Department of Health and Human Services as a member of the Federal Health IT Policy Committee."
Dr. Gottlieb has financial interest in many companies, including American Pathology Partners or Medavante, and is a member of GlaxoSmithKline's Product Investment Board. Dr. Gottlieb recently stated that, if confirmed, he would divest his interests from any of the companies where he currently holds a financial interest, would resign from his positions at companies where he provides consulting work and would not participate initially in any particular matter involving these companies. The confirmation hearing for Dr. Gottlieb occurred on April 5, 2017.
If confirmed by the Senate, Dr. Gottlieb would replace Robert Califf, who resigned in January 2017. Stephen Ostroff, M.D., has been acting Commissioner.
Ten Years of Conditional Marketing Authorizations
The European Medicines Agency ("EMA") published a report ("EMA report") concerning the data collected over 10 years—between July 2006 and June 2016—on the so-called "conditional marketing authorizations" ("CMAs").
CMAs allow pharmaceutical companies in the European Union to obtain the authorization to place a medicinal product on the market provided they subsequently fulfill certain conditions. CMAs were designed for the purpose of speeding up access to various categories of medicinal products that address unmet medical needs of patients, including orphan products. They are regulated by Regulation 507/2006 on the conditional marketing authorization for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004 of the European Parliament and the Council ("CMA Regulation").
The CMA Regulation allows the authorization of medicinal products if the public health benefit of the immediate availability to patients of a concerned medicinal product is deemed to outweigh the risk of an authorization granted on the basis of less comprehensive data than normally required for the purpose of obtaining a standard marketing authorization. A CMA is valid for one year. As part of the CMAs, companies marketing medicinal products are obliged to carry out further post-authorization studies to obtain more comprehensive safety, quality, and efficacy data.
The EMA's Committee for Medicinal Products for Human Use ("CHMP") assesses the data generated by these specific post-authorization obligations and, at the end of its assessment, provides an opinion on the renewal or not of the CMA or its conversion into a standard marketing authorization.
The EMA report highlights that, since 2006, 30 medicinal products were granted a CMA. Fourteen of the medicinal products that were granted a CMA were orphan medicinal products. The report also indicates that approximately 70 percent of the CMA holders completed their specific post-authorization obligations within the timelines specified by the EMA.
The EMA report also shows that it takes an average of four years to generate the additional data needed to convert a CMA into a standard marketing authorization. Based on 10 years of experience with the CMA Regulation, the EMA report also identifies a number of possible areas for improvement, including the prospective planning of CMAs and early dialogue with EMA to support the generation of high-quality data and the timely discussion of additional post-authorization studies and their feasibility.
EMA Consultation on the Revised Policy on Access to Documents
The EMA has launched a public consultation on the proposed revision to its policy on access to documents. The policy describes the rules EMA applies to grant access to the documents that it holds, in accordance with Regulation (EC) No 1049/2001 ("FOI Regulation"). The FOI Regulation gives citizens a right to access EU documents. Comments from stakeholders may be submitted until May 18, 2017.
GCP Renovation ICH Reflection on "GCP Renovation"
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ("ICH") has released a reflection paper on Good Clinical Practice ("GCP") "Renovation," which contains the ICH proposal for further modernization of the ICH Guidelines related to clinical trial design, planning, management, and conduct. Comments were solicited through March 11, 2017. ICH will review the comments received to determine whether to make revisions to the currently proposed approach. The aim is to proceed with initiating needed renovation work as soon as practical, for example, within the next year.
EU-U.S. Agreement for Mutual Recognition of GMP Inspections Entered Into Force
On March 4, 2017, the "Decision No 1/2017 of March 1, 2017, of the Joint Committee established under Article 14 of the Agreement on Mutual Recognition between the European Community and the United States of America, amending the Sectoral Annex for Pharmaceutical Good Manufacturing Practices (GMPs)" was published in the Official Journal of the EU.
The Agreement amends the Sectoral Annex for Pharmaceutical GMPs of the initial EU-U.S. Mutual Recognition Agreement signed in 1998 to include the reciprocal recognition of GMP inspections of manufacturing sites for medicinal products for human or animal use conducted in the European Union and the United States.
The express inclusion of mutual recognition of GMPs in the EU-U.S. Mutual Recognition Agreement of 1998 allows EU and U.S. regulatory authorities to rely on each other's assessments and official findings resulting from inspections conducted in manufacturing facilities in the European Union and the United States. The mutual recognition of GMP inspections and documentation resulting from such inspections will apply from November 1, 2017.
The Agreement also includes a provision for the waiver of requirements for batch testing of medicinal products for human and animal use on entry of imported products into the European Union and the United States, after a transition phase. The transition phase will last until the United States and the European Union conclude an evaluation of the regulatory and procedural frameworks for GMP inspections of each other's regulatory authorities. On the basis of the Agreement, the European Union must complete its assessment of the U.S. Food and Drug Administration ("FDA") by July 1, 2017, and the United States must assess at least eight EU Member States' competent regulatory authorities by November 1, 2017.
The Agreement provides that the Joint Sectoral Committee must maintain an updated list of all the recognized authorities and serve as a forum to discuss issues related to the Sectoral Annex, such as disagreements on the determination of reciprocal recognitions.
The Agreement's stated purpose is to facilitate cross-border trade of medicinal products and benefit public health by allowing each party to reallocate its inspection resources, including by avoiding duplication of inspections, so as to improve oversight of manufacturing facilities, better address quality risk, and prevent adverse health consequences.
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