NIRI BioPharma Industry Roundtable January 10, 2007

1. NIRI BioPharma Industry RoundtableJanuary 10, 2007 Daniel E. Troy

2. The Situation at FDA Before 2004 • Healthy appreciation for risk/benefit • All drugs have risks • FDA as a risk management agency • Lessons of the AIDS experience • Bayesian statistics discussion • Focus on post-marketing systems • Role of PDUFA

3. 2004 • Preemption • Importation • Flu Vaccine • SSRIs • Vioxx

4. Consequences of Drug Safety Controversy • Pendulum has swung • bureaucratic incentives • Slow-down in approvals • Increased requests for pre-market studies • Routine use of black box warnings • Routine use of RiskMAPs • Tysabri “pause” • Palladone withdrawal • Whistleblower culture

5. A (Scary) Vision of the Future • RiskMAP Tools • Targeted Education • Reminder Systems • Performance-Linked Access Systems • Real-World Examples • Forteo • Humatrope • Crestor • Symalin

6. RiskMAP Tools • Targeted Education and Outreach Healthcare practitioner letters Training programs for healthcare practitioners or patients Continuing education for healthcare practitioners Prominent professional or product notifications Patient labeling such as Medguides and PPIs Promotional techniques such as DTC ads highlighting appropriate use Patient-sponsor interaction and education systems such as disease management and patient access programs

7. RiskMAP Tools 2. Reminder systems Consent forms Training programs including testing or other documentation Enrollment of physicians, pharmacists, or patients in registries Limited number of doses in any prescription or refill limits Specialized patient packaging Stickers, attestations

8. RiskMAP Tools • Performance-Linked Access Systems Sponsor’s use of compulsory access systems Prescription only by specially certified healthcare practitioners Product dispensing limited to specially certified pharmacies or practitioners Product dispensing only with evidence or other documentation of safe-use conditions (e.g., lab test results)

9. Real-World Examples • Forteo (12/02) • Limited initial detailing as quantified by target population and number of sales reps • Physician education program • Sampling – doctors must receive education on drug and sign form acknowledging they have been informed about drug’s risk and the approved patient population • No DTC advertising

10. Real-World Examples • Humatrope (8/03) • Restricted labeling • Physician education • Marketing limited to pediatric endocrinologists • Limited sales force • No DTC • Controlled distribution process

11. Real-World Examples • Crestor (8/03) • 5 mg professional samples to be made available • Retailers must go through wholesalers to get 40 mg dose • Symalin (3/05) • No DTC • No journal ads for 1 year • Promotion limited to physicians specializing in diabetes management • Gradual introduction of Symalin into marketplace • Education and outreach programs • And all this is without explicit legal authority!

12. Further Raising the Ante:Kennedy-Enzi Bill • Train wreck ahead? -- Most of these language and proposals will become a part of the PDUFA reauthorization debate in the next Congress • Would required Risk Evaluation & Mitigation Strategy (REMS) for all NDAs, BLAs, ANDAs, and supplements for a new indication • Required elements • professional labeling • adverse event reporting • pharmacovigilance statement & justification • REMS assessments

13. Kennedy-Enzi Bill:REMS: Additional Potential Elements • MedGuide • Patient package insert • Communication plan to HCPs • Post-approval study • Post-approval clinical trial • Preclearance of advertising • Specific disclosures in advertising • Ban on DTC advertising

14. Kennedy-Enzi Bill:Restrictions on Distribution and Use • The Secretary could impose restrictions on distribution and use: • specially trained HCPs • special certifications for pharmacies, health care centers, etc. • evidence or documentation of safe-use conditions, patient monitoring, registries • Sponsor is responsible for enforcing compliance with the restrictions, including limiting the participation of HCPs who have failed to comply • The Secretary has wide discretion in deciding whether to impose a REMS requirement on a marketed drug

15. Kennedy-Enzi Bill:Review, Action, and Dispute Resolution • Secretary must review, approve, and describe the REMS • No earlier than 15 days and no later than 35 days after “discussions” have begun, the applicant may request “dispute resolution” • Dispute resolution mechanism is DSB • Secretary can meet action deadline by initiating discussions and complying with timing deadlines of the dispute resolution process

16. Follow-On Proteins • Two Different Regimes • Pathways to approval • 505(b)(2) • PHS Act • Omnitrope decision • Waxman legislation

17. Two Different Regimes • Food Drug and Cosmetic Act (section 505) • mostly small molecules • for historical reasons, some proteins, e.g., • insulin • some hormones, including human growth hormone • Public Health Service Act • most biotechnology drugs

18. FDCA – Pathways to Approval • Stand-alone NDA • ANDA (a duplicate) • showing of bioequivalence required • generally, no clinical studies • AB rated • Petitioned ANDA • differs in strength, dosage form, route of administration, or active ingredient • FDA decides, after petition, new clinical studies not needed • 505(b)(2) • used >80 times • generally for new drugs, new indications, combo products • generally not AB rated

19. FDA Reading of Section 505(b)(2) • “An application [may be] submitted under [section 505(b)(1)] for which [safety and effectiveness] investigations . . . relied upon by the applicant [to support] approvals of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted [and] shall also include [patent certifications for patents on the drug for which investigations were conducted or a method of use statement].”

20. Different Interpretations of 505(b)(2) • Paper NDA only (literature based) • Parkman letter – bypass “phantom ANDA” • FDA can rely on prior finding of safety and effectiveness and require only “bridging” studies • FDA can use material in NDAs

21. FDA View of (b)(2)(from 10/14 Citizen Petition Response) • Plain language of (b)(2) is broad, or at least ambiguous • 1987 Parkman Letter announced broad view • 1989 NPRM sought notice and comment • 1994 Final Rule embodied this view in the regulation • 1999 guidance articulated what FDA has been doing, with industry knowledge and participation

22. Public Health Service Act • Covers biologics – “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product . . . applicable to prevention, treatment, or cure of a disease or condition in human beings” • Are also drugs • No express abbreviated pathway • Raw data made public

23. Differing views of FDA’s Authority to Create Abbreviated Pathway Under PHS Act • None • Can do so prospectively, after notice and comment rulemaking • Can even affect existing product, but after notice-and-comment rulemaking • Can make policy by approval by making ad hoc shortcuts (with some use of guidance as well)

24. OmnitropeTM Decision • OmnitropeTM (somatropin [rDNA origin]) • Recombinant human growth hormone • Relatively simple protein with a known mechanism of action • Well characterized single active ingredient • Regulated under the Federal Food, Drug, and Cosmetic Act (FDCA) • Not the Public Health Service Act (PHSA) like most biologics • Sandoz submitted a 505(b)(2) application under the FDCA • Included original clinical trials involving OmnitropeTM • Referenced Pfizer’s somatropin product, Genotropin® • OmnitropeTM received FDA approval on May 30, 2006 • FDA determined that OmnitropeTM is “highly similar” to Genotropin® • Relied on the finding that Genotropin® is safe and effective • Did not rely on manufacturing or trade secret data related to Genotropin® • To the extent the products differ, the clinical trials supported the conclusion that OmnitropeTM is safe and effective • Not rated therapeutically equivalent to Genotropin® (insufficient data)

25. OmnitropeTM Analysis • Not a new pathway for follow-on proteins • Previous approvals include GlucaGen®, HydaseTM, and Fortical® • FDA confirmed its historical interpretation of 505(b)(2) • May rely on FDA’s finding of safety and efficacy for a previously approved drug product • Not the data or trade secrets in the approved product’s application • May rely on publications for which the 505(b)(2) applicant does not have a right of reference • Fact specific determination • OmnitropeTM is a relatively simple protein (well characterized, single active ingredient, known mechanism of action) • Based on the specific facts, FDA concluded that OmnitropeTM is highly similar to Genotropin® and approved OmnitropeTM under a 505(b)(2) application that included new clinical data • There is no abbreviated approval process under the PHSA

26. Access to Life-Saving Medicine Act Background • Introduced last year to establish an abbreviated approval process for biologics under the Public Health Service Act (PHSA) (H.R. 6257, S. 4016) • Will likely be reintroduced this year • Biologics are different than small molecule drugs • Small molecule drugs are chemically synthesized and are easy to duplicate • Biologics are complex protein products made from living organisms that are inherently variable

27. Access to Life-Saving Medicine Act Abbreviated Approval • A follow-on biologic that is “comparable” to a reference product may rely on the reference product’s finding of safety, purity, and potency • Requirements for a comparable biological product • No clinically meaningful differences from the reference product • Comparable molecular structure to the reference product • FDA is required to find that certain products have comparable structures (e.g., minor differences in amino acid sequence) • Same mechanism of action as the reference product • Same conditions of use as the reference product • Same route of administration, dosage form, and strength as the reference product

28. Access to Life-Saving Medicine Act Abbreviated Approval (cont.) • A comparable biologic may differ from the reference product if there is sufficient data to establish safety, purity, and efficacy • An application for a comparable biologic will likely require clinical data • FDA must take final action on an application for a comparable biological product within the earlier of 180 days from when FDA accepts the application for filing or eight months from its submission date, unless the applicant agrees to an extension • Postmarketing studies may not be required for approval • An applicant for a comparable biological product may request that FDA make a determination about interchangeability • Interchangeability means that the comparable product can be expected to produce the same clinical result as the reference product

29. Access to Life-Saving Medicine ActOther Provisions • Market Exclusivity • Provides the first interchangeable comparable product with 180 days of exclusivity (even against authorized generics) • No market exclusivity periods for brand name products • Patents • Applicant for a comparable biological product may request a list of relevant patents from the brand name company • Applicant may provide notice of the patents that are believed to be invalid or not infringed and identify the jurisdiction where the applicant agrees to be sued • Brand name company has 45 days to bring suit on the patents • Suits brought after 45 days are limited to a reasonable royalty • No action may be brought on patents not timely disclosed • No 30-month stay period

30. Access to Life-Saving Medicine ActOther Provisions (cont.) • Citizen Petitions Relating to Comparable Biologics • May not delay approval of a comparable biologic • Prohibits FDA from considering a citizen petition submitted within 180 days of the comparable biologic’s potential approval date without good cause • Requires FDA to act on a petition within 180 days • Tax credit for clinical testing regarding the interchangeability of comparable biological products

31. Access to Life-Saving Medicine ActSummary of Issues • Scientific Issues • Comparable biological products may have different structures from the reference product, which raises safety and efficacy issues • Restricts FDA’s scientific judgment with respect to determining whether compounds contain comparable molecular structures • No clear path for interchangeability and substitution • Patent and Exclusivity Issues • Innovator companies received nothing in return for allowing comparable biological products to rely on innovator data • No market exclusivity periods for innovators • No 30-month stay period • Prohibits the enforcement of patents that are not timely disclosed • Authorizes the defendant (generic) to select the litigation jurisdiction • Miscellaneous Issues • Restricts FDA’s ability to consider issues raised in citizen petitions • Limits authorized generic products

32. Thank you!Daniel E. TroySidley Austin LLP202-736-8304Dtroy@sidley.com

33. Institute of Medicine (IOM) Report“The Future of Drug Safety: Action Steps for Congress” Recommends: • Reducing FDA’s “dependence” upon PDUFA fees. • Increasing FDA’s post-marketing safety surveillance resources. • Extending term of FDA Commissioner to six years with for-cause removal. • Requiring FDA to re-evaluate all new molecular entities no later than five years after approval. • Strengthening conflict-of-interest rules governing FDA advisory committees.

34. Institute of Medicine (IOM) Report“The Future of Drug Safety: Action Steps for Congress” Recommends: • Giving FDA unambiguous post-marketing authority to require companies to conduct risk assessment and risk management programs. • Requiring drug companies to affix new drug-designation on newly approved drugs and indications. • Amending PDUFA to include safety performance goals. • Requiring drug companies to publicize information relating to clinical trials.

35. FDA Responses Thus Far (even pre-IOM) • Enhanced Patient and Safety Information • “Drug Watch” -- will be modified; will mention different vehicles for communicating safety information (labeling, PPIs\Med Guides, public health advisories, patient information sheets, healthcare professional sheets, alerts) • Revise labeling format and new standardized electronic drug labeling through NLM • Restructured CDER -- elevating the Office of Drug Safety • Enhancing the Culture of Safety in CDER -- formal professional opinion dispute resolution process within CDER for drug safety conflicts.

36. FDA Responses Thus Far (even pre-IOM)Cont. • Drug Safety Oversight Board (DSB) -- oversees CDER drug safety work and manages communication of risk information to patients and professionals. • Enhancing Risk Communication • clinicaltrials.gov • Partnerships through the Critical Path • Develop Electronic Health Information Architecture • Dramatically Increased Use of RiskMaps

37. Additional Steps FDA is Likely to Take • Task force to address IOM report • Improve quality and effectiveness of information • Gather better post-market data through contracts with databases and working with CMS on using Part D claims data • Develop guidance on use of epidemiology data • Re-launch MedWatch portal, regular reports like MMWR • Collaborate with MIT on system to detect unanticipated problems with prescription drugs

38. Additional Steps FDA is Likely to Take – Trying to Refocus Attention on Benefits\Efficacy • Improve analytical tools (Critical Path) • collaboration with academy and private industry on databases, developing assays • Predictive Safety Testing Consortium (C-Path and companies) • five guidances on adaptive trials • Bioinformatics board • Guidance on preventative drugs • secondary and primary prevention • biomarkers • optimal trial sizes and duration

39. Additional Steps FDA is Likely to Take • Improve communication • develop a social science base • senior officer in charge of risk communication • process for drug names • collaborations with medical groups

40. Access to Life-Saving Medicine Act Background (cont.) • The Hatch-Waxman Act basically established an abbreviated approval process for small molecule drugs • It is a balance between generic and brand name interests • A generic may rely on the finding of safety and efficacy for the brand name drug • In return, brand name products received 5 and 3-year market exclusivity periods • Additionally, the first generic to challenge a patent received a 180-day market exclusivity period • There is also a 30-month stay to allow for resolution of patent litigation before the generic receives final marketing approval