Pharmaceutical & Medical Device Regulatory Update, Vol. II, Issue 18

Pharmaceutical & Medical Device Regulatory Update, Vol. II, Issue 18

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December 2, 2015: Maureen Bennett will give a presentation on International Clinical Research Issues to the Boston Bar Association's Health Law Education Committee.

December 10, 2015: Colleen Heisey will give a presentation on FDA Regulation and Enforcement of Social Media at the Food & Drug Law Institute's Annual Enforcement, Litigation, and Compliance Conference in Washington, D.C.

Top News

FDA Nominee Robert Califf Testifies Before Senate HELP Committee

On November 17, 2015, Dr. Robert Califf testified in front of the Senate Committee on Health, Education, Labor, and Pensions as President Obama's nominee for FDA Commissioner. Although the hearing included discussion of rising drug prices and Califf's industry ties, media reports suggest Califf "appeared to have broad support" among the Committee members. A cardiologist and clinical trial expert, Califf currently serves as FDA Deputy Commissioner for Medical Products and Tobacco. His nomination for the top FDA post must be approved by the Senate. The Senate Committee has posted a video of the hearing and prepared remarks on its website.

FDA Issues Notices to Three Makers of Direct-to-Consumer Genetic Tests

FDA recently issued untitled letters to three companies regarding certain direct-to-consumer ("DTC") genetic tests marketed without premarket clearance. FDA asserts that the companies' tests meet the definition of a "medical device" under Section 201(h) of the federal Food, Drug, and Cosmetic Act ("FDCA") but that the products have not obtained requisite clearance numbers from the Agency. According to FDA, the products are intended: "to predict how patients will respond to more than 120 of the most commonly prescribed medications" (DNA4Life); "to test for DNA genetic markers linked to thrombophia, deep-vein thrombosis, cardiovascular disease and stroke" (DNA-CardioCheck); or "to identify individuals with genetic predisposition for increased risk to diabetes and heart attack, Osteoarthritis Associated Conditions, and obesity-related genotype for weight loss" (Interleukin Genetics). Although less significant than warning letters, these notices demonstrate the Agency's continued enforcement focus in the area of DTC genetic testing. Each letter instructs the company to identify the clearance numbers for its tests or otherwise explain the basis for not obtaining premarket clearance.

AMA Proposes Ban on Advertising Prescription Medical Products to Consumers

On November 17, 2015, physicians at the Interim Meeting of the American Medical Association ("AMA") adopted a new policy calling for a ban on DTC advertising of prescription drugs and medical devices. The AMA adopted the policy position to address growing concerns among its membership that prescription drug advertisements encourage patients to seek medicine unnecessarily, resulting in pressure on doctors to write prescriptions or otherwise risk losing patients. According to the AMA, the proliferation of prescription drug advertisements also contributes to rising drug costs. The group plans to convene a physician task force and launch an advocacy campaign to promote prescription drug affordability and greater transparency in drug prices and costs. In addition, the announcement suggests that the AMA will monitor mergers and acquisitions within the pharmaceutical sector, with an eye toward the impact of such transactions on drug prices.

Although the AMA policy has no legal effect, it adds significantly to the ongoing public debate over drug prices and the regulation of pharmaceuticals by formalizing the position of an influential group within the medical community. The action also comes at a time when the traditional bounds of pharmaceutical marketing activities are being challenged in court, including the recent preliminary injunction granted in Amarin Pharma, Inc. v. FDA, which reaffirmed First Amendment protection of commercial speech involving truthful, non-misleading promotion of a prescription drug for off-label use.

FDA Holds Back-to-Back Workshops on Next-Generation Sequencing Diagnostic Tests

Last week, FDA held two workshops to gather information on developing a flexible approach for the regulation of next generation sequencing ("NGS") in vitro diagnostic tests. NGS tests facilitate the rapid sequencing and analysis of segments of DNA, yielding information that can be used to tailor medical therapies to the individual characteristics of a patient. Specifically, the workshops focused on best practices and potential standards regarding NGS tests and the use of curated databases as sources of valid clinical evidence in the evaluation of NGS tests. The workshops featured the perspectives of industry leaders and regulators and continue the dialogue from similar workshops held by FDA in February 2015.

On November 12, 2015, the first workshop focused on a standards-based approach to evaluating NGS tests. Deputy Commissioner Califf kicked off the event with remarks on the emerging field of personalized medicine. He indicated a major regulatory challenge is that NGS testing often lacks a specific intended use, because the tests are used by clinicians who initially do not know what condition they will be diagnosing. In addition to exploring standards for these new technologies, FDA is developing open-source tools such as precisionFDA, a cloud-based platform for sharing genomic sequencing data and methodologies and for supporting the development of a data commons for evidence on the clinical relevance of genetic variation.

During a panel on bioinformatics strategies and tools, industry representatives and clinicians discussed their experiences developing and using bioinformatics and the analytical benchmarking of tests. The panelists' "wish list" for new tools includes ways to access scientific literature in a more user-friendly manner, such as semantically tagging literature to bioinformatics tools, and improved clinical education so that sequencing pipelines are actually relevant to patients' therapeutic needs. Some panelists spoke of the importance of incremental, adaptive standards to account for unique circumstances in NGS testing, while one of the clinicians expressed concern about the risks associated with relying on fully automated systems for diagnosis.

A second workshop was held on November 13, 2015, focusing on the ways that well-curated databases of genetic variants can be used to inform clinical interpretation of NGS test results and serve as a source of clinical evidence of new genetic variants identified through NGS tests. Panelists discussed the attributes of existing databases, such as the National Center for Biotechnology Information's ClinVar database, and the potential challenges of harmonizing across databases. Such noted challenges include variation in the meaning and interpretation of data points, and lack of consistency in the expression of genotypic and phenotypic metadata. Panelists also discussed the challenge of tracking and accounting for real-time changes in data, particularly data uploaded from electronic medical records, and the utility of incomplete data sets. The curation of databases was also discussed, including desired qualifications for curators, sources of information queried by curators, and standard curation procedures.

It is unclear what policies FDA will ultimately develop for NGS tests, but the Agency has stated that the meetings held this year are intended to lead to a flexible, adaptive regulatory approach for NGS tests. The deadline for public comments on both workshops is November 25, 2015.

FTC Staff Criticize FDA's Draft Guidance on Naming of Biologics

Last month, staff of the Federal Trade Commission ("FTC") submitted a comment to FDA addressing the latter's draft guidance on the nonproprietary naming of biological products. Under the recently issued draft guidance, FDA proposes that a unique, FDA-designated suffix be added to the nonproprietary name of each biological product, including biosimilars. The FTC staff's comment expresses concern that this draft guidance may hinder competition and recommends that FDA consider alternative policies. Specifically, the comment asserts that physicians may mistakenly interpret the different suffixes as indicative of meaningful clinical differences and that such perceived product differentiation would have a dampening effect on price competition between brand products and biosimiliars. The comment cites an example from Europe, where biosimilars with distinct nonproprietary names from their reference biologic experienced less market penetration relative to biosimilars with the same nonproprietary name as the brand product.

FDA Releases Report in Support of Regulatory Overhaul of LDTs

Earlier this month, FDA's Office of Public Health Strategy and Analysis published a report discussing 20 case studies that purport to support the Agency's push for greater oversight of laboratory developed tests ("LDTs"). LDTs are the subset of in vitro diagnostics ("IVDs") intended for clinical use that are designed, manufactured, and used in a single laboratory. In its report and a related blog post, FDA cites events related to 20 LDTs in which patients had been harmed or may have been harmed by tests that did not meet FDA requirements. The Agency argues the current regulatory framework is inadequate, given the increase in complexity and availability of LDTs.

Historically, FDA has stated it was exercising enforcement discretion in not applying the FDCA to LDTs. Most laboratories making these products are obligated to follow regulatory requirements of the Clinical Laboratory Improvement Amendments ("CLIA"), which are intended to regulate the operations of laboratories but not IVDs specifically. Last year, FDA released two draft guidance documents setting forth FDA's proposed framework for regulating LDTs as medical devices under the FDCA (see the Jones Day Commentary for more details). The recent report advances those efforts by asserting that the CLIA regime does not "ensure the safety and effectiveness of LDTs prior to marketing; assess the quality of the design and manufacture of devices; ensure test labeling provides adequate directions for use; require truth in marketing materials and other labeling; require adverse event reporting; permit removal of unsafe devices from the market; require informed consent for patients participating in clinical studies of LDTs; [or] establish procedures for the conduct of such studies." The report states that enhanced oversight is needed but should be appropriately tailored to avoid duplicating the CLIA regime.

EMA Supports Antibiotic Resistance Awareness Day 2015

On November 17, 2015, the European Medicines Agency ("EMA") reinforced its commitment to help combat antimicrobial resistance by announcing support for a "European Antibiotic Awareness Day 2015." The EMA outlined its three-pronged approach to addressing the issue as follows: (i) speed up development of new treatments; (ii) promote responsible use; and (iii) collect robust data to inform public health policies. According to the EMA, antimicrobial resistance is one of the most serious public health threats globally, with infections caused by multidrug-resistant bacteria estimated to kill 25,000 people in Europe every year.

White House Releases Privacy and Trust Principles Supporting Personalized Medicine

President Obama's Precision Medicine Initiative ("PMI") continues to move forward with the release of Privacy and Trust Principles, developed by an interagency working group of the White House Office of Science and Technology Policy, U.S. Department of Health and Human Services Office for Civil Rights, and National Institutes of Health. The principles are intended to establish parameters for future PMI activities, including governance; transparency; participant empowerment through access to information; respect for participant preferences; data sharing, access, and use; and data quality and integrity. On November 9, 2015, the White House announced it had considered more than 100 comments submitted by individuals, groups, academic research institutions, and advocacy organizations in crafting the final principles. Key comments included consideration and adoption of standards for data security; PMI is still evaluating this policy, which it hopes to release in the coming months.

Other News

HHS Hosts "Pharmaceutical Forum" Focused on Innovation, Access, and Affordability

CBER/CDER Issue Final Guidance Outlining Procedures for Meetings Between FDA and Biosimilar Sponsors or Applicants

FDA Orders Recall of Certain Automated Endoscope Reprocessors

Pharmaceutical Company Pleads Guilty to DOJ Charges of Health Care Fraud

FDA Approves Nasal Spray to Treat Opioid Overdose

EMA Review Concludes No Evidence that HPV Vaccines Cause CRPS or POTS

EU Improves System for Electronic Reporting of Suspected Adverse Reactions

FDA to Hold Public Meeting on "Clinical Trials—Assessing Safety and Efficacy for Diverse Populations" (December 2, 2015)

FDA to Hold Public Workshop on "Eighth Annual Sentinel Initiative" (February 3, 2016)

Regulatory Updates

FDA Issues Partial Stay on IND-Related Guidance

In the October 30, 2015, Federal Register, FDA announced a stay of portions of the final guidance for clinical investigators, sponsors, and institutional review boards titled "Investigational New Drug Applications—Determining Whether Human Research Studies Can Be Conducted Without an IND." Specifically, FDA is staying portions of subsection VI.D.2, "Conventional Food," and all of subsection VI.D.3, "Studies Intended to Support a Health Claim," except as to studies intended to evaluate whether a food substance reduces the risk of a disease in individuals less than 12 months old, those with altered immune systems, and those with serious or life-threatening medical conditions. FDA took the action in response to public comments submitted in 2014, which raised questions about application of the IND requirement to certain clinical studies of conventional foods, dietary supplements, and cosmetics being investigated for uses covered by the drug definition in section 201(g)(1)(B) or (C) of the FDCA. Pursuant to the stay, FDA will allow for further consideration of the issues raised by these comments. The partial stay is effective immediately.

FDA Opens Public Dockets for Lists of Bulk Drug Substances Used in Compounding

In separate notices in the October 27, 2015, Federal Register, FDA announced it has established public dockets for the purpose of developing lists of bulk drug substances (active ingredients) that can be used to compound drug products in accordance with Section 503A or Section 503B of the FDCA, as applicable. The Agency previously solicited nominations for the list, but some nominated substances were not supported by sufficient information for FDA to evaluate them. For purposes of gathering additional information, FDA has opened Docket No. FDA-2015-N-3534 for "Bulk Drug Substances That Can Be Used To Compound Drug Products in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act; Establishment of a Public Docket" and Docket No. FDA-2015-N-3469 for "Bulk Drug Substances That Can Be Used To Compound Drug Products in Accordance With Section 503B of the Federal Food, Drug, and Cosmetic Act; Establishment of a Public Docket."

CDRH Solicits Requests for Participation in 2015 ELP General Training Program

In the November 16, 2015, Federal Register, FDA's Center for Devices and Radiological Health ("CDRH") announced the 2015 Experiential Learning Program ("ELP") General Training Program. The training is intended to provide CDRH staff with an opportunity to understand the policies, laboratory practices, and challenges faced in broader disciplines that affect the device development life cycle. Members of industry, academia, and health care facilities are invited to participate in the ELP for FDA's medical device review staff. Areas of interest are broken down by the Office of Device Evaluation and the Office of In Vitro Diagnostic Devices and Radiological Health. Selection of potential facilities will be based on CDRH's priorities for staff training and resources available to fund the program. Comments or requests for participation must be submitted by December 16, 2015.

FDA Announces Withdrawal of Hearing Requests Regarding Nitroglycerin Drug Products in Transdermal Systems

In the November 16, 2015, Federal Register, FDA announced that all outstanding hearing requests regarding nitroglycerin drug products in transdermal systems under Docket No. FDA-1977-N-0356 (formerly 77N-0240) (DESI 1786) have been withdrawn. Accordingly, shipment in interstate commerce of any nitroglycerin drug product in a transdermal system identified in this docket, or any identical, related, or similar product, that is not the subject of an approved new drug application or abbreviated new drug application is unlawful as of the effective date of the notice.

FDA Publishes List of Approved PMAs

In the November 18, 2015, Federal Register, FDA published a list of premarket approval applications ("PMAs") that have been approved between July 1, 2015, and September 30, 2015. By regulation, FDA is required to publish a quarterly list of available safety and effectiveness summaries of PMA approvals and denials. There were no denial actions during this recent quarter.

FDA Issues Priority Review Voucher for Strensiq

In the November 17, 2015, Federal Register, FDA issued a priority review voucher to the sponsor of a rare pediatric disease product application for Strensiq (asfotase alfa), manufactured by Alexion Pharmaceuticals, Inc. FDA determined the application satisfied certain criteria to merit a priority review voucher pursuant to the Food and Drug Administration Safety and Innovation Act. The rare pediatric disease priority review voucher program is in its sunset period, which was triggered on March 17, 2015, with FDA's issuance of a third voucher under the program. Unless reauthorized by Congress, FDA may not issue pediatric vouchers after the one-year period following award of the third voucher.

FDA Issues Reproposal of Proposed Rule to Classify Certain Diagnostic Devices for Bacillus Detection into Class II

In the November 17, 2015, Federal Register, FDA issued a reproposal of a proposed rule to classify IVD devices for Bacillus species (spp.) detection into class II (special controls) after considering, among other information, the recommendations of the Microbiology Devices Advisory Panel. In addition, FDA is again proposing to restrict use and distribution of the devices. Comments are due February 16, 2016.

FDA Classifies Gastrointestinal Multiplex Assay into Class II

In the November 2, 2015, Federal Register, FDA issued a final order classifying a gastrointestinal microorganism multiplex nucleic acid-based assay into class II (special controls). The order is effective immediately.

FDA Classifies Autosomal Recessive Carrier Screening Gene Mutation Detection System into Class II

In the October 27, 2015, Federal Register, FDA issued a final order classifying an autosomal recessive carrier screening gene mutation detection system into class II (special controls). The special controls that apply to this device are identified in this order and will be part of the codified language for the autosomal recessive carrier screening gene mutation detection system classification. The order is effective immediately.

FDA Issued the Following Draft and Final Guidance Documents:

Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants, November 18, 2015, Federal Register.

Guidance on Qualification of Biomarker—Galactomannan in Studies of Treatments of Invasive Aspergillosis, November 13, 2015, Federal Register.

Guidance for Industry: Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment, November 3, 2015, Federal Register.

(Revised) Guidance for Industry: DSCSA Implementation: Product Tracing Requirements for Dispensers—Compliance Policy, November 2, 2015, Federal Register.

Draft Guidance on Progesterone, November 2, 2015, Federal Register. Comments are due January 4, 2016.

Draft Guidance for Industry and FDA Staff: Information to Support a Claim of Electromagnetic Compatibility (EMC) of Electrically-Powered Medical Devices, November 2, 2015, Federal Register. Comments are due December 17, 2015.

Draft Guidance for Industry and FDA Staff: Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products, October 30, 2015, Federal Register. Comments are due April 29, 2016.

Draft Guidance for Industry: Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation, October 30, 2015, Federal Register. Comments are due December 29, 2015.

Draft Guidance for Industry: Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act, October 27, 2015, Federal Register. Comments are due December 28, 2015.

Draft Guidance for Industry: Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act, October 27, 2015, Federal Register. Comments are due December 28, 2015.

FDA Announced the Opportunity to Comment on the Following Proposed Information Collections:

  • Adverse Event Reporting; Electronic Submissions
  • Electronic Submission of Medical Device Registration and Listing

FDA Announced that the Following Collections Have Been Submitted to OMB:

  • Guidance for Industry on Tropical Disease Priority Review Vouchers
  • Prescription Drug Product Labeling; Medication Guide Requirements
  • Financial Disclosure by Clinical Investigators

FDA Announced that the Following Collections Have Been Approved by OMB:

  • Guidance for Industry and Food and Drug Administration Staff: Class II Special Controls Automated Blood Cell Separator Device Operating by Centrifugal or Filtration Separation Principle
  • Impact of Ad Exposure Frequency on Perception and Mental Processing of Risk and Benefit Information in Direct-to-Consumer Prescription Drug Ads
  • Guidance for Industry on Controlled Correspondence Related to Generic Drug Development
  • Survey of Pharmacists and Patients; Variations in the Physical Characteristics of Generic Drug Pills and Patient Perceptions
  • Guidance for Industry on Formal Meetings Between the Food and Drug Administration and Biosimilar Biological Product Sponsors or Applicants
  • Guidance for Industry on Adverse Event Reporting for Outsourcing Facilities

EU Regulatory Notices

Guido Rasi Assumes Office as Head of EMA

On November 16, 2015, Guido Rasi assumed the position of executive director of the EMA. He was appointed following his statement to the European Parliament's Committee on Environment, Public Health and Food Safety last month. Rasi will outline his priorities for the next five years at a virtual press briefing scheduled for December 9, 2015.

EMA Issues Draft Guidelines on Post-Market Studies

On November 6, 2015, the EMA published a draft scientific guideline that outlines how post-authorization efficacy studies ("PAES") should be designed by companies to support regulatory decision-making in the EU. PAES are conducted within the authorized indication after a medicine has been granted a marketing authorization, and they collect data on aspects of the product's benefits that can only be explored or otherwise need to be addressed once the medicine is marketed. PAES may be imposed by regulators or carried out voluntarily by companies, and the draft scientific guideline applies to both scenarios. Comments are due January 31, 2016.

Upcoming Meetings, Workshops, and Conferences

For comprehensive listings of FDA meetings, please visit the following web pages:

Meetings, Conferences, and Workshops (Drugs)

Workshops, Meetings, and Conferences (Biologics)

Workshops & Conferences (Medical Devices)

FDA Advisory Committee Calendar

Recent Notable Drug and Device Approvals/Clearances

FDA moves quickly to approve easy-to-use nasal spray to treat opioid overdose (November 18, 2015)

FDA approves Darzalex for patients with previously treated multiple myeloma (November 16, 2015)

FDA approves modified antihemophilic factor for hemophilia A (November 13, 2015)

FDA approves new pill to treat certain patients with non-small cell lung cancer (November 13, 2015)

FDA approves Cotellic as part of combination treatment for advanced melanoma (November 10, 2015)

FDA approves new treatment for HIV (November 5, 2015)

FDA approves Nucala to treat severe asthma (November 4, 2015)

For additional information on drug and device approvals and clearances, please visit FDA's web pages on Drug Approvals and Databases (includes biologics) and Device Approvals, Denials, and Clearances.

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