1. THE REGULATORY HORIZON Michael A. Swit, Esq. Vice President Pharmaceutical Education Associates Skin Summit Philadelphia February 20, 2008

2. 2 Standard Disclaimers Views expressed here are solely my own and do not necessarily reflect those of my firm or any of our clients. These slides support an oral briefing and may not be relied upon solely on their own to support any conclusion of law or fact.

3. 3 ANCIENT (Possibly Chinese) CURSE May You Live in Interesting Times …

4. 4 These Are Interesting Regulatory Times September 30, 2004 – the beginning of the current era of drug regulation –Vioxx –SSRI’s and suicidal ideation Since then: –Tysabri –Avandia New Lynchpin of Regulatory Process – Drug Safety

5. 5 Interesting Regulatory Times … FDA Leadership –Top -- In disarray 2004 -- McClellan left to go to CMS; Crawford interim Commissioner Summer 2005 – Crawford confirmed by Senate Sept. 2005 – Crawford abruptly resigns 2006 – Andrew von Eschenbach becomes acting December 2006 – von Eschenbach confirmed Sept. 2007 – General Counsel resigns –Deputies & Associates – many leave at end of 2006

6. 6 The Perfect Storm? The Current FDA Regulatory Equation -- (Drug Safety Lynchpin) + (Leadership Vacuums) = an approval process mired in uncertainty, fear and decision paralysis PLUS A Democratic Congress PLUS September 30, 2007 – Deadline Day –PDUFA Reauthorization Sunsets –Pediatric Exclusivity and Pediatric “Rule” Sunsets EQUALS Congress in driver’s seat to drive change?? –But, still have 2 more years of Bush

7. 7 The Result – FDAAA FDAAA -- Food and Drug Administration Amendments Act of 2007 -- H.R. 3580 (422 pages) Originally H.R. 2900 – –Introduced in House on June 28 by John Dingell –Passed House on July 16 Negotiated compromise – passed House on September 20 and Senate on September 21 Signed by President on Thurs., September 27, 2007 Public Law 110-85

8. 8 Key Provisions for Drug Industry PDUFA Reauthorization Prescription Drug Advertising Review Fees DTC Advertising Penalties Drug Safety Provisions Clinical Trials Registry & Results Data Base Critical Path Initiative – Reagan-Udall Foundation Pediatric Exclusivity and Pediatric “Rule” Reauthorization Citizen Petitions – limits FDA authority to delay approvals Biosimilars – NOT COVERED by FDAAA

9. 9 PDUFA Reauthorization – Title I Goals –Expedite drug development process –Expedite application review process –Postmarket Drug Safety Gross Fees (not including inflation adjusters) –$393 MM annually in User Fees –Drug Safety Fees Over 5 Years -- $225 MM (starting at $25 MM; increases $10MM per year thereafter)

10. 10 Prescription Drug Advertising “Advisory” Review Fees FDAAA Section 104 -- Must pay if you submit a TV ad for “advisory review” (but, don’t have to submit for review) “Advisory review” = “reviewing and providing advisory comments regarding compliance of a proposed advertisement If required to submit, you do not have to pay, unless you say it’s for “advisory review” –No separate authority given FDA to require submission

11. 11 Prescription Drug Advertising “Advisory” Review Fees … Annual Fees Generated Under DTC Review Authority -- $6.25 MM FY 2008 – maximum fee is $83,000 per ad submission Sunsets – October 1, 2012 Problem – the necessary user fees for the program were not "provided in advance in appropriations Acts" as required by FDAAA; thus, FDA scratched program

12. 12 “Required” Drug Advertising Reviews New Section 503B of Federal Food Drug, and Cosmetic Act (FFDCA) -- added by Section 901 of FDAAA (the Drug Safety provisions) FDA “may require” submission 45 days before dissemination FDA “may make recommendations” on changes –“necessary to protect the consumer good and well-being”, or –Consistent with prescribing information –And, if available, to address specific populations FDA can not require changes Constitutionality ???

13. 13 DTC Advertising – Civil Penalties Adds Section 303(g) to FFDCA – civil penalties for false or misleading DTC ads for a prescription drug (not a device) Penalty – –Up to $150,000 on first offense in a 3-year period –Up to $300,000 on later offenses FDA must give a chance for a hearing “Safe Harbor” – if you complied with all FDA recommendations given in a review of the ad

14. 14 FDAAA & Enhanced Authorities Regarding Postmarket Safety Originally S.484 or Kennedy-Enzi (Feb 1, 2007) Designed to improve drug safety monitoring and evaluation Applies to Drugs and Biologics Subtitle A: Postmarket Studies and Surveillance Subtitle B: Other provisions to ensure drug safety and surveillance

15. 15 Drug Safety – Phase IV Studies FDAAA Section 901 – adds power of FDA to require post-approval “studies” or “clinical trials” – per new Section 505(o) of the FFDCA Allows the FDA to require a post-approval clinical study or trial to assess: –A known serious risk –A “signal” of a serious risk –To identify an unexpected serious risk when available data suggests one Study -- May not be required if available surveillance methods are adequate – FDA must make an “affirmative negative” (my words) determination before requiring Clinical Trial – May not be required unless a Study is not adequate – “affirmative negative” determination also required Already approved drugs – can only require if “new safety information” is available

16. 16 New Safety Terminology Serious Risk – the risk of a serious adverse drug experience Unexpected Serious Risk – not in labeling or related to a labeled risk, but differs due to “greater severity, specificity, or prevalence.” Signal of a Serious Risk: information related to a Serious Adverse Drug Experience associated with use of a drug derived from - –A clinical trial, adverse event report, postapproval study, peer-reviewed biomedical literature, from a postmarket risk identification system, or other scientific data New Safety Information – relates to a serious risk or unexpected serious risk; may be based on new analysis of existing data or even an assessment of the effectiveness of an approved REMS (see next slides).

17. 17 Drug Safety – Risk Evaluation and Mitigation Risk Evaluation and Mitigation Strategies (“REMS”) –Section 901 of FDAAA – adds a new Section 505-1 to FFDCA – If a REMS is OK’d for an application, must follow it or sale of drug is illegal You can voluntarily submit a REMS FDA may require if viewed as needed to ensure benefits of drug outweigh risk –Must be provided within 120 days of request –Can be required later, after initial approval, if new safety info exists Decision to require a REMS must be made at or above the division director level in CDER

18. 18 CONTENT OF A REMS Minimal – a timetable for assessments –18 + 36 months –During seventh year Additional Potential Elements –Medication Guide, Patient Package Insert –Communication Plan, such as: Disseminating info about the REMS to ensure REMS is being done correctly (e.g., medical monitoring elements)

19. 19 Content of a REMS … Assuring safe use … –Requiring specialized training or certifications for health care providers –Required certifications of dispensing pharmacies –Dispensing only possible if certain info supplied regarding patient (e.g., lab tests) –Patient monitoring –Patient registry enrollment

20. 20 Civil Penalties for Drug Safety Violations Section 902 of FDAAA -- If fail to conduct required post-approval studies or trials, or to follow a REMS, can face civil monetary penalties: –$250,000 per violation –$1,000,000 maximum in “single adjudication”

21. 21 FDAAA & Clinical Trials Registries Current U.S. Law – FDAMA §113 – –Since Feb. 2000 –All persons conducting clinical trials of experimental treatments for “serious or life-threatening” diseases and conditions –Where the trial is to test “effectiveness” – i.e., Phase 2, 3 or 4 studies with efficacy endpoints –Must register certain information with U.S. government, within 21 days of study enrollment opening –Done via ClinicalTrials.gov No requirement for Clinical Trials Results

22. 22 Limitations of ClinicalTrials.gov Only applies to –“serious or life-threatening” diseases –Drugs – not devices No mechanism to ensure compliance by all performing clinicals Inconsistent information in required data fields Only applies to studies under INDs Does not include actual results

23. 23 FDAAA & Clinical Trials Registries … Section 801 -- Expands Trial Registry System Much more detailed information required on the clinical studies Applies to drugs and devices –Devices – under 510k’s, PMAs or PDPs and HDEs or Section 522 Postmarket Surveillance –Drugs – “controlled clinical investigation” other than a Phase I study Not pegged to serious or life threatening

24. 24 FDAAA & Clinical Trials Registries … Where “applicable clinical trial” is ongoing on date of enactment or initiated after enactment –90 days after enactment if ongoing –21 days after first patient in if initiated Posting of data – –Drug – within 30 days of submission –Device – If not previously cleared, not earlier than date of clearance or approval If previously cleared, not until 30 days after clinical trial results data is to be submitted

25. 25 FDAAA & Clinical Trials Results Linking to FDA Data –For clinical trials that form “the primary basis for an efficacy claim” or are post-market trials –Data Advisory committee (if any) consideration – any summary by FDA Posted pediatric assessments or reports Public Health Advisories Drugs -- FDA Action Package required under 505(l)(2) Devices –Detailed Summary of Safety & Effectiveness info for PMAs –510k summary of safety & effectiveness data Medline citations NIH Database of structured product labels

26. 26 FDAAA & Clinical Trials Results … Phase-In of Data Results –1-Year Demographic and baseline characteristics of patients Primary and secondary outcomes Point of contact Any agreements between sponsor and investigator that “squelches” the investigator –3-Year – Rulemaking required not later than 3 years post-enactment for greater expansion of results database

27. 27 FDAAA & Clinical Trials Results … Expanded Registry and Results Database under Rulemaking –Would cover trials on both approved and unapproved products –Required Summary in lay language Summary in technical language Full study protocol Submission date – generally 1 year after completion date or estimated completion date of study Public Meeting – within 18 months of FDAAA Adverse Events – how to incorporate into databanks? –Within 18 months, rulemaking needed on how to do –If not, default provisions will go into effect

28. 28 FDAAA & Clinical Trials Results … FDA Submission Certification – NDAs, PMAs, BLAs, 510k’s and HDEs will have to include certification that all applicable requirements on trials information have been submitted –Noncompliance or false information in a certification = “Prohibited Act” under FDCA –Form 3674 – vehicle for compliance

29. 29 FDA Submission Certification -- 3674

30. 30 FDAAA & Clinical Trials Results … Civil Money Penalties – –up to $10,000 for all violations in a single adjudication –Failure to correct within 30 days, $10,000 per day Preemption – “upon the expansion,” no state may establish or continue in effect any requirement on registries or results

31. 31 Critical Path Initiative – Reagan-Udall Foundation Sec. 601 of FDAAA Not part of U.S. Government, but funded in part by FDA budget “To advance mission of FDA to modernize medical, veterinary, food, food ingredient, and cosmetic product development, accelerate innovation, and enhance product safety.” Promote research into unmet needs in those areas

32. 32 Pediatric Exclusivity & The Best Pharmaceuticals for Children Act How to Get Exclusivity: –If FDA requests a sponsor to do clinical studies on a children’s age group for a particular drug –Sponsor does studies and submits data to FDA –Get 6 months tacked on to an existing period of a patent or Waxman-Hatch Exclusivity –Get the exclusivity regardless of the results of the study as long as you did what FDA wanted

33. 33 Other Key Aspects of Pediatric Exclusivity Can Qualify for Pediatric Exclusivity up to two times Studies Done Under PREA also qualify for exclusivity, even though not specifically requested by FDA Reminder – not applicable to medical devices

34. 34 FDAAA & Pediatric Research – BPCA Reauthorization Major Changes –No pediatric extension if 9 months or less left on underlying patent or Waxman-Hatch exclusivity –Internal Committee – also reviews request for studies under BPCA –Adverse Event Reports – If relating to drugs for which labeling changes have been made, Submitted to Office of Pediatric Therapeutics –Consider handling –Shall seek recommendations from Pediatric Advisory Committee

35. 35 Pediatric Research Equity Act (“PREA”) Enacted 2003 Requires “Pediatric Assessments” on most new drug applications and supplements that are for a: –New active ingredient –New indication –New dosage form –New dosing regimen –New route of administration RESULT – applies to ANDAs and Citizen Petitions Already-marketed drugs – FDA could order studies if agency request under BPCA denied by application holder Same requirements for biologics Not applicable to medical devices

36. 36 PREA – Required Assessments Adequate Data to show: –Safety and effectiveness of the drug/biologic for the claimed indication in all relevant pediatric subpopulations; and –To support dosing and administration for each pediatric subpopulation for which the drug/ biologic is safe and effective

37. 37 FDAAA & Pediatric Research – PREA Reauthorization Major Changes and Additions: –Reviews by FDA “Internal Committee” – established by Section 403 of FDAAA “shall” be used to consult with reviewing divisions relative to pediatric plans and requests for deferrals and waivers Will recommend if pediatric supplements shall get priority review –Deferrals – have to include a timeline for completion of the studies –If waiver sought because pediatric formulation not possible, your submission will be posted on FDA’s website –Labeling disputes – to be referred to Pediatric Advisory Committee

38. 38 FDAAA & Pediatric Research – PREA Reauthorization … Disseminating “Pediatric Assessments” –210 days after submission – FDA posts on its website: Medical, statistical and clinical pharmacology reviews of those assessments –Sec’y shall require sponsors of assessments that result in labeling change to distribute information on labeling changes reported to FDA in the form of an annual summary to physicians & other health care providers

39. 39 FDAAA & Pediatric Research – Medical Devices Title III – Pediatric Medical Device Safety & Improvement Act of 2007 Sec. 302 – Tracking Pediatric Device Approvals –Applies to PMAs, Product Development Protocols and Humanitarian Device Exemptions (HDE) –Application must: describe “any pediatric subpopulations that suffer from the disease…” Identify # of patients

40. 40 FDAAA & Pediatric Research – Medical Devices …. Section 303 – Modification of HDE –Can make a profit if for pediatric population –Must restrict number of devices distributed to an amount specified in the HDE –Pediatric population defined as 21 or less (PREA is 18) Section 304 – Encouraging Medical Device Research – HHS to come up with a plan within 180 days of enactment Section 305 – Grants to Improve Pediatric Device Availability -- $6,000,000 authorized

41. 41 FDAAA & Pediatric Research – Medical Devices …. Section 307 – Postmarket Surveillance – Amends Sec. 522(a) of FDCA: –Sec’y may order manufacturer to do postmarket surveillance of any Class II or III device The failure of which would be reasonably likely to have serious adverse health consequences; or Expected to have “significant use” in pediatric patients; or –Can be ordered for more than 36 months if needed [previously, Sec. 522 only applied if intended to be (a) implanted for > 1 year or (b) life-sustaining/ life-supporting and used outside a device user facility]

42. 42 Citizen Petitions Section 914 of FDAAA -- Adds a new Section 505(q) to the FFDCA FDA cannot delay approval based on a citizen petition unless FDA determines that a delay in necessary to protect the public health If FDA so determines, must, within 30 days of the determination: –Notify the affected applicant(s) either via a meeting or document Petition decisions must be made in 180 days and can not be extended for any reason

43. 43 Biosimilars – “Sense of Senate” Endorsement Had been in Senate Version; not in FDAAA –to give FDA authority and flexibility to approve biopharmaceuticals subject to an abbreviated approval pathway –ensure patient safety remains paramount –establish a pathway that is “efficient, effective and scientifically-grounded and includes measures to ensure timely resolution of patent disputes –provides appropriate incentives for R&D of biopharmaceuticals Current Generic “conventional wisdom” – not this year; But, BIO -- pushing -- to avoid 2009

44. 44 Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President THE WEINBERG GROUP INC. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.454.2979 Cell 760.815.4762 michael.swit@weinberggroup.com www.weinberggroup.com Questions?

45. 45 About your speaker… Michael A. Swit, Esq., is a Vice President at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to drug, biologics and medical device/diagnostic clients seeking to market products in the United States. His expertise includes product development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts. Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA. A magna cum laude graduate of Bowdoin College, he received his law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.

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