hot topics in the regulation of pharmaceuticals and med ... · – pre v. post ppaca blas ....
TRANSCRIPT
Hot Topics in the Regulation of Pharmaceuticals and Med Devices: Challenges and Opportunities
Association of Corporate Counsel - SD November 3, 2011 Scott L. Cunningham Covington & Burling LLP
Topics
New Developments in Regulation of Drugs New Developments in Regulation of Devices Enforcement Trends
New Developments in Regulation of Drugs
Drugs: Current Topics
Biosimilars Accelerated Approval PDUFA V
Biosimilars: Hot Topics
• FDA implementation • Biologics “drift” • When can FDA waive data requirements • “Skinny” BLA • Potential changes with PDUFA V and
potential Constitutional issues
FDA Implementation
• Public docket opened late 2010 • Part 15 hearing in November 2010
– Lots of views expressed – Scarce feedback from FDA on key issues
• FDA emphasis on, e.g.: – Data requirements – Naming requirements – Pharmacovigilence requirements – Interchangeability issues
• Draft guidance documents by end of year?
7
“Skinny” BLAs
• Abbreviated BLA filed under PHSA 351(a) – Contains comparative data – Therefore really should be considered a 351(k)
“biosimilar application”
• FDA may nonetheless accept – Dr. Woodcock has stated that the agency cannot
prevent biosimilar applications under § 351(a) • Flexibility of § 351(a)
• End-run around exclusivity and patent provisions
8
Skinny BLAs (cont.)
• Potential counterarguments: – Permitting skinny BLAs moots PHSA 351(k)
• Supported by FDA pre-BPCIA statements
– PHSA does not give FDA authority to rely on prior findings when reviewing a 351(a) application
– Policy arguments
PDUFA V & Potential Constitutional Issues
• Obama & 12 year exclusivity (PDUFA V?)
• Patient Protection & Affordable Care Act challenges and severability of BPCIA
• 5th Amendment “takings” limitations on biosimilars? – Approval of a biosimilar is a government “taking,”
which requires “just compensation” – Pre v. post PPACA BLAs
Accelerated Approval: Avastin
• CDER Position – Post-approval studies failed to verify benefit – Marginal PFS improvement with no OS or QOL
improvement – Changes risk/benefit analysis
• Genentech Response – Post-approval studies showed PFS benefit – No new safety signal – FDA should permit further study/patient choice
• Awaiting Decision From FDA Commissioner
Accelerated Approval After Avastin
• A more conservative FDA approach? – Priority review ≠ accelerated approval – Accelerated approval may be granted less
frequently – Effect on use of surrogate endpoints?
• Possible legislative response?
PDUFA V
• PDUFA set to sunset in 2012 • “Must pass” legislation • Previous PDUFAs have brought significant
change, e.g.: – 1992: User fees – 1997: Pediatric exclusivity, clinicaltrials.gov – 2007: Drug safety provisions
• Significant opportunity for additional change
FDA PDUFA V Proposed Performance Goals/Procedures
• Issued 08/2011, public meeting in October • New review program for NCE NDA/BLAs
– Pre-submission meeting – + 30 day submissions – Mid and late-cycle meetings – Revised review goals (triggered on filing date)
• Changes to effect of major amendments • Science/rare disease oriented provisions
PDUFA V Legislative Possibilities • Changes to biosimilars legislation? • Comparative effectiveness? • Antibiotic incentives? • Drug imports? • More drug safety authority? • Other changes?
New Developments in Regulation of Devices
Medical Device: Current Topics
510(k) Process Reform Software/Mobile Medical Apps Laboratory Developed Tests (LDTs) Companion Diagnostics
17
FDA’s Review of the 510(k) Process
• In response to criticisms, recently FDA commissioned two reviews of the 510(k) process
• FDA Working Group issued a report and solicited comment – Wide array of reforms initially proposed – FDA backed off more controversial ideas, referred to IOM
• Institute of Medicine (IOM): – Report issued August 2011 – Recommended that 510(k) program be scrapped – Did not address issues referred from working group
• FTC in the mix? – Recent comments re adequate substantiation
“Least Burdensome”
• Letter from Congress to FDA expressing concern that the agency is not following the “least burdensome” provisions of the statute
• Industry concerns that FDA is not considering least burdensome alternatives in imposing requirements for device studies, 510(k) clearance, PMA approval, etc.
• FDA interest in applying current scientific standards and not being bound by precedents it considers outdated
18
FDA Regulation of Software • When does software become a “medical device”?
• FDCA definition of device: “an instrument, apparatus, implement, machine, contrivance … or other similar or related article… which is . . . intended for use – in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or – prevention of disease, in man or other animals . . . .“
• If considered a device, FDA requirements may apply: – Premarket Notice or Approval – Quality Systems Regulations (QSR)
FDA Guidance on Software in Devices
• Original software guidance scrapped
• FDA has issued guidance on using software in devices: – Content of Premarket Submissions for Software Contained
in Medical Devices (May 2005) – Cybersecurity for Networked Medical Devices Containing
Off-the-Shelf (OTS) Software (January 2005) – General Principles of Software Validation (January 2002) – Off-the-Shelf Software Use in Medical Devices (September
1999)
• But despite FDA’s guidance, substantial ambiguities exist
Mobile Medical Applications • July 2011 FDA Guidance • “Mobile app”: Software application (including
web-based) executed on a mobile platform • “Mobile medical app”: A mobile app that
meets the definition of “device” and either: – Is used as an accessory to a medical device; or – Transforms a mobile platform into a med device
• Regulation by classification? – Maybe not always for accessories – Creation of new lower classification level?
Examples of Mobile Medical Apps
• Extensions of devices for control, display, analysis, etc. – Apps for viewing images for diagnosis – Apps that control zoom, resolution, etc. of medical
image servers • Apps transforming platforms into med device
– EKG leads on mobile devices – Apps with sensors to monitor glucose levels
• Apps for inputting patient-specific information and use algorithm for diagnosis/treatment – Apps for computing pain index score
Laboratory Developed Tests (LDTs) • Historically, two pathways:
– IVDs: kits regulated by FDA as devices – LDTs: services regulated by CMS under the Clinical Laboratory
Improvement Amendments of 1988
• FDA asserted in the 1990s that it had authority over LDTs, but would exercise enforcement discretion
• In 2010, FDA announced its intention to begin regulating LDTs under device authorities – Including premarket clearance/approval of the tests, and regulation
of laboratories as “device manufacturers”
• Differing views between clinical laboratories and IVD manufacturers
• Legislative fix, e.g., Burgess “clinically valid” bill?
23
Enforcement Trends
Changing Trends in Drug Promotion Enforcement
Key Developments
• May 2009: FDA releases Guidance on presentation of risk information
• August 2009: FDA “streamlines” warning letter process – Limited OCC review
• May 2010: DDMAC launches “Bad Ad” program
– Goal is to improve surveillance
• October 2011: DDMAC elevated to Office of Prescription Drug Promotion (OPDP)
Issues to Watch in 2011
• Indications and safety
• Disease awareness
• Unbranded websites
• Substantial evidence
• Individual enforcement
Disease Awareness: GSK/Arzerra Untitled Letter
“The characteristics of the product promoted in the ad can only describe Arzerra. Not only is Arzerra the only recently approved drug marketed by GSK for CLL, but no other product approved for the treatment of CLL has an indication that is limited to this specific population.”
Unbranded Websites: Novartis/Gleevec Warning Letter
Unbranded Websites (cont’d)
“The [unbranded] websites are clearly marked with the Novartis Oncology name and logo and/or the Novartis name and logo and discuss sponsorship by Novartis Pharmaceuticals Corporation.”
Unbranded Websites (cont’d) “The [unbranded] websites present data from imatinib clinical studies, and provide the corresponding literature references, which include the drug name in the listed publication titles. At least one of the publications [DeMatteo et al.] recounts the pivotal clinical trial submitted to FDA in support of the approval of Gleevec in the treatment of adjuvant GIST.”
Letters to Individuals
Enforcement Against Individuals
The Park Precedent
• U.S. Supreme Court case from 1975 • Defendants: grocery retail corporation and its
CEO • Charge: food adulteration • CEO warned of problems by letter from FDA • Subsequent inspection revealed that
deficiencies had not been corrected fully
Park Holdings
• Strict individual liability for FDCA violations
• Prima facie case for individual liability: – “had, by reason of his position in the corporation,
responsibility and authority either to prevent in the first instance, or promptly to correct, the violation complained of, and that he failed to do so.”
• Objective impossibility defense
Post-Park Case Law • Scope of Park liability is broad
– No individual knowledge – No intent – No negligence
• But, 1975 to 2007 Park cases usually involve: – Negligence or intentional violations – Actors up the chain of command
New Precedent: Purdue
• Gov. alleges false and misleading statements that OxyContin was: – less addictive – less subject to abuse and diversion – less likely to create tolerance and withdrawal
• 502(a) misbranding violation
Individual Liability in Purdue
• Three individual defendants: – Former President and CEO – Executive VP and Chief Legal Officer – Former Chief Scientific Officer
• All plead guilty to misdemeanor – $34.5 million in fines – No jail time
• no personal knowledge, no intent to defraud
Subsequent FDA Comments
• 2008 FDLI Enforcement Conference (Rick Blumberg): – Park doctrine is broad – Nothing new with Purdue – Directors potentially liable
• 2010 FDLI Annual Conference
Hamburg Letter to Sen. Grassley (March 2010)
