ANDAs – Key Regulatory and Legislative Issues

ANDAs – Key Regulatory and Legislative Issues September 19, 2002 PLI Biotechnology Law ConferenceSan Francisco, California

PART I – Power Protecting and PreservingA Drug Franchise Under Waxman-Hatch – Exclusivity and the 30-month Stay

Market Protections Available • Patents (and extensions) • Traditional enforcement • Listing patents in FDA's "Orange Book" • Statutory exclusivities/extensions under Waxman-Hatch • Other strategies

Listing Patents in FDA's "Orange Book" • Requires patent certification by generic competitors • If approval sought pre-expiration, generic must notify sponsor of bases for alleged invalidity or non-infringement. • Sponsor may sue for infringement and impose 30-month stay of generic approval.

Statutory Exclusivities Under Waxman-Hatch • New Chemical Entity (NCE) Exclusivity • Prohibits the filing of an ANDA (or 505(b)(2) NDA) for a product that contains the NCE for 5 years after approval of the first NDA. • (4 years if ANDA includes a Paragraph IV challenge to listed patent) • NCE: "a drug that contains no active moiety that has been approved by FDA in any other [NDA]."

Statutory Exclusivities … • 3-Year Exclusivity • Available for NDAs which contain: • Reports of "new" "clinical trials" • That were "essential to approval" of the NDA • Conducted or sponsored by the applicant • FDA may not approve an ANDA or 505(b)(2) NDA for 3 years after approval • Applies for new indications, Rx  OTC switch, new dosing regimen, and some other labeling changes. Carve out for pediatric labeling.

Statutory Exclusivities -- Other • Orphan Drug Exclusivity • 7 year exclusivity • Drugs for rare conditions (<200,000 people in U.S.) • Pediatric Exclusivity • 6-month extension of existing patent or Waxman-Hatch exclusivity • 180-day generic (ANDA) exclusivity

Generic Drug Strategies • Generic industry -- diverse in sizes and approaches of companies • Business factors influencing drug selection • Market size, pricing of innovator product • Patent landscape • Strategic "fit" with production capabilities, therapeutic or technical areas of focus (if any) • Chance of 180-day exclusivity; other generic entry • Ease of marketing • Other – some firms are dosage form oriented

Generic Defense Strategies • Patent listing, litigation • Development of follow-on/ancillary patents • Strategy may be impacted by pending legislation • Amendments seeking 3-year exclusivity • New indication for original product (limited utility) • Changed dosage form • New dosing regimen • New strength(s)

PART II – Problems with Power Federal Trade Commission Oversight of Patent Litigation Settlements Between Big Pharma and the Generic Industry and Other Alleged Nefarious Activity

Abbott – Geneva – 2000 • Drug: Hytrin® (terazosin HCl) • Alleged antitrust violation – Abbott paid Geneva • to not sell an approved capsule version while the companies litigated patent issues on the tablet version • not transfer or relinquish Geneva’s 180-Day “ANDA Exclusivity” rights – thus, keeping other generics off the market • Resolution: consent order

Abbott – Geneva • Consent order … • bars agreements that: • restrict ANDA applicant from giving up 180-day exclusivity; or • restrict ANDA applicant from entering the market with a non-infringing product • agreements to pay to stay off market done to settle patent litigation need court OK and FTC chance to comment • required Geneva to waive its 180-day exclusivity rights on a Hytrin tablet so other generics could enter market

Schering – AHP/ESI & Upshur-Smith • Drug – K-Dur® (potassium chloride) • Alleged antitrust violation – agreements to settle patent litigation • Upshur-Smith: for $$, agreed to stay off market; as first to file a Para. IV patent cert., had 180-day Exclusivity; its delay in marketing meant subsequent ANDA filers could not go to market • Resolution – July 2002 – an FTC administrative law judge threw out the FTC action; saying deal was really procompetitive

Hoechst-Marion-Rousell & Andrx • Drug– Cardizem CD • Alleged antitrust violation – agreements to settle patent litigation by which, for $$: • Andrx agreed to stay off the market • Andrx agreed to not relinquish its 180-day Exclusivity rights • Resolution – consent order --

Hoechst-Marion-Rousell & Andrx … • Consent order … (similar to Hytrin®) • barred from agreeing to NOT relinquish 180-day exclusivity rights (which, if kept, can preclude subsequent generic filers from marketing even if approved and even if patent expired) • barred from agreeing to restrictions on entering market with a non-infringing generic • Interim patent litigation settlements involving payments to generics require Court OK and notice to FTC

Other Alleged Nefarious Activity – Biovail Patent Listing Case • Drug – Tiazac® (diltiazem) • Alleged violative activity: • filing a patent in Orange Book (O.B.) that did not claim marketed drug – effectively kept generic off due to need to certify to new patent • illegal exclusive marketing license with patent holder (differed from Biovail)

Other Alleged Nefarious Activity – Biovail Patent Listing Case … • Resolution – consent order: • Biovail to divest part of exclusive patent license • Biovail to not enforce any rights that would trigger a 30-month Waxman-Hatch • barred from wrongfully listing patents in O.B.

Part III – Statutory Solutions to Power Problems An Overview of McCain-Schumer – “The Greater Access to Affordable Pharmaceuticals Act of 2001” S. 812

The 1984 Compromise • Strengthen incentives for innovative research by partially restoring patent time lost due to FDA approval delays. • Facilitate generic competition by establishing ANDA process and allowing patent challengers to receive 180-day generic exclusivity period.

Results of 1984 Compromise • Generic share of total Rx has skyrocketed (19% - 43%). • Cost of innovation has skyrocketed as new therapies become more elusive. • Legal challenges have scrambled FDA's implementing regulations, leading to costly uncertainty and allegations of abuse.

McCain-Schumer "Findings" • Drug costs rising at "alarming rate" • More generic competition will lower prices • More generic competition needed • FTC has found restraints of trade between companies • No finding re research incentives

Orange Book Listing • Patents that "claim the drug for which the application was approved," or • Patents that claim an approved method of use, • Must be submitted to FDA within 30 days of NDA approval, or 30-days of issuance (if issued post-approval)

Late Listing Penalty • Failure of NDA holder to timely list will bar patent holder (who may be different person) from enforcing the patent against any person who • has filed an ANDA or 505(b)(2) NDA, or • manufactures, uses, or sells an approved generic or 505(b)(2) drug.

Listing Challenges • ANDA applicants can bring civil lawsuit seeking correction or removal of listed patent information. • Only pending applicants may sue. • Only applies to patents listed at time of NDA approval. • No "damages" allowed.

Claim-by-Claim ¶-IV Certifications • For patents that • Include both product claim and method of use claim(s), or • Contain multiple method of use claims, • Paragraph IV Certifications, and "viii statements" must be claim-specific.

30-Month Stay Limitation • The 30-month stay of Paragraph IV ANDA approval may only be imposed with respect to patents listed at time of initial NDA approval, not post-approval patents. • For "other patents" "not described in clause (iii)"** but listed in the Orange Book, innovator must seek PI within 45 days; If PI denied, immediate approval possible. If PI granted, approval delayed until case resolved.

One-Shot Patent Enforcement • In addition to not being able to enforce late-listed patents, if no lawsuit is brought within 45 days of a Paragraph IV Notification to a listed patent, a patent owner is "barred from bringing a civil action for infringement" with respect to drug under the ANDA.

Generic Exclusivity Eligibility • Reverts to prior FDA requirement that first Paragraph IV applicant must be sued to get exclusivity. • Appears to maintain patent-by-patent exclusivity approach.

Generic Exclusivity Triggers • Reverts to "final" court decision trigger rule to start 180-day exclusivity period. • Adds settlement or consent decree as a triggering event if it contains a specific finding of invalidity/non-infringement.

Generic Exclusivity Forfeiture • Failure to market w/in 60 days of final approval or court decision (whichever is later) • Withdrawal of ANDA • Amendment from ¶IV to ¶III • Failure to obtain tentative approval w/in 30 months. • Failure to challenge newly listed patents. • FTC finds unlawful conduct by applicant

"Rolling" Generic Exclusivity • If first challenger forfeits exclusivity, all subsequent ANDAs eligible for approval. • If first subsequent ANDA to get effective approval was also the first subsequent filer (i.e., second overall filer), then it receives exclusivity. • No other subsequent ANDA eligible.

Bioequivalence Provisions • The 1992 amendments to 21 C.F.R. Part 320 "shall continue in effect as an exercise of authorities under [FDCA] sections 501, 502, 505, and 701," but may be amended by FDA. • "This section shall not be construed to alter the authority of [HHS] to regulate biological products under the [FDCA] (21 U.S.C. § 301 et seq.). Any such authority shall be exercised under that Act as in effect on the day before the date of enactment of this Act."

Part IV – the Future – Generic Biologics??? • No consensus view exists that any current legal mechanism can be used to support approval of a generic biologic • Why? • Legally, biologics licensed under Public Health Service Act, not Waxman-Hatch • Difficulty (alleged?) in characterization

“Generic” “Biologics” "One cannot completely characterize the biological product and that in itself is an issue, and quite frankly with biological products you really don’t have a homogeneous product, you have a defined range of biological components for which you find consistency in a particular clinical outcome. The challenges of analytical technology are still very great for characterizing biologics." -- Katherine Zoon, CBER

“Generic” “Biologics” Under 505(b)(2)? • For Biologics originally approved under an NDA, FDA will accept a 505(b)(2) for a “generic” version • Examples include naturally-derived active ingredients (from animal or botanical sources) or those derived from recombinant technology (e.g., insulin, HGH) • For BLA-approved products, no generic approval pathway

What is a 505(b)(2) Product ? • Not a completely new product, • Not a generic, • A product with some differences from a previously approved product. • Approval requires clinical data, but the studies may have been conducted by others.

How is 505(b)(2) Different? • The applicant and FDA may rely on prior FDA safety and efficacy determinations, based on studies conducted by someone else even though the applicant does not have a right of reference to the data. 21 U.S.C. § 355(b)(2) • Safety and efficacy can also be supported by published reports

Types of 505(b)(2) NDAs • New Chemical Entity (rarely) • Changes to a Previously Approved Drug • New dosage form, dosing regimen, strength, or route of administration • New indication • New active ingredient • New inactive ingredient that requires studies beyond limited confirmatory studies • Rx  OTC switch (Claritin) • Duplicates of approved drugs that cannot be approved under an ANDA

Patent and Exclusivity Issues • 505(b)(2) NDA must include patent certification(s). • 505(b)(2) NDA must also list any relevant patent(s). • Same Paragraph IV challenge system as ANDAs, EXCEPT, no 180-day exclusivity period.

Patent and Exclusivity Issues • A 505(b)(2) product may itself qualify for 3 or 5 years of new drug exclusivity • 3-year exclusivity requires: • New clinical studies (other than BE studies) • Conducted by the applicant • Essential to the approval of the application • 5-year exclusivity for "New Chemical Entities" • NCEs can be old drugs (i.e., ingredient never approved under an NDA)

Patent and Exclusivity Issues • Waxman-Hatch Exclusivities block ANDAs and 505(b)(2) NDAs, but cannot block a "full" NDA. • 3-year exclusivity blocks other pending 505(b)(2)s, regardless of filing date; creates race to approval. • Only the first 505(b)(2) for a change can receive exclusivity. Studies for later applications deemed not essential for approval. • 5-year exclusivity does not block other 505(b)(2)s that were filed before first approval.

Legal Challenges andOpportunities Under 505(b)(2) • Has FDA Expanded § 505(b)(2) Beyond the Scope Intended by Congress? • What Opportunities and Pitfalls Await the 505(b)(2) Applicant? • Is 505(b)(2) A Viable Pathway for "Generic Biologics?"

Pfizer/Pharmacia's Challenge To FDA's 505(b)(2) Approach • Requests amendment of 505(b)(2) Guidance and 21 C.F.R. 314.54 • Requests FDA not to approve any 505(b)(2) NDA based on proprietary data • Requests FDA to not assign “A” rating to any approved 505(b)(2) Drug

Pfizer/Pharmacia Petition Statement of Grounds • Reliance on proprietary data not authorized by FDCA for 505(b)(2) NDAs • Published Studies vs. • Proprietary Data vs. • FDA Findings of Safety/Efficacy • Reliance on proprietary data would be an unconstitutional “taking” • “A” ratings not permitted for 505(b)(2) drugs

Which Way is the Generic Biologics Wind Blowing ?? • No 505(b)(2) approved yet for a biotech product • FDA Guidance on “Well-Characterized Biologics” – a manifesto for action? • Transfer of CBER therapeutics review divisions to CDER – a harbinger of a bureaucracy being repositioned to handle generic biologics?

A Few Predictions and Questions • FDA will not do it on its own; will require statutory authorization • McCain-Schumer will not be the vehicle, but may be regarded by some as necessary itself to be enacted before tackling generic biologics • Is the generic industry ready to challenge technologically?

A Few Predictions and Questions … • Where does the science of characterization and replication stand on large molecules? • How will bioequivalence be judged? • Are the “drug” models relevant? • If not, will generic biologics always require comparative clinical studies?

Questions? Call, e-mail, fax or write:Michael A. Swit, Esq. Law Offices of Michael A. Swit 539 Samuel Ct., Suite 229 Encinitas, California 92024 760-815-4762 ♦ 760-454-2979 (fax) mswit@fdacounsel.com http://www.fdacounsel.com

About the speaker ... Michael A. Swit has extensive experience in all aspects of FDA regulation with a particular emphasis on drugs and medical device regulation. In addition to his regulatory law experience, Mr. Swit also served for three and a half years as vice president and general counsel of Pharmaceutical Resources, Inc. (PRI) a prominent generic drug company and, thus, brings an industry and commercial perspective to his representation of FDA-regulated companies. While at PRI from 1990 to late 1993, Mr. Swit spearheaded the company’s defense of multiple grand jury investigations, other federal and state proceedings, and securities litigation stemming from the acts of prior management. Mr. Swit then served from 1994 to 1998 as CEO of Washington Business Information, Inc. (WBII) a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA publishing company. Before starting FDACounsel.com, he was with Heller Ehrman from May 2001 to May 2003, and also twice in private practice with McKenna & Cuneo, from 1988 to 1990 and, most recently, from 1999 to 2001, first in that firm’s D.C. office and most recently, in its San Diego office. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius from 1984 to 1988. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law including, since 1989, co-directing a three-day intensive course on the generic drug approval process, serving on the Editorial Board of the Food & Drug Law Journal, and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved, published by WBII. Mr. Swit holds an A.B., magna cum laude, with high honors in history, in 1979, from Bowdoin College, and earned his law degree from Emory University in 1982. He is a member of the California, Virginia and District of Columbia bars.

ANDAs – Key Regulatory and Legislative Issues