The FDA s 505(b)(2) Drug Approval Process And Implications For Managed Care Pharmacy. AMCP 2004 Educational Conference Baltimore, MD October 15, 2004

Transcription

1 The FDA s 505(b)(2) Drug Approval Process And Implications For Managed Care Pharmacy AMCP 2004 Educational Conference Baltimore, MD October 15, 2004

2 Paul J. O Connor, RPh, MBA Aon Consulting Rebecca L. Dandeker, J.D. Kirkpatrick & Lockhart, LLP

3 What Is a 505 (b)(2) Drug? Not a generic Not totally new Similar, but with limited differences, to previously approved drug Often an innovative variation of previously approved drug(s) containing the same active moiety

4 Statutory Origins The Federal Food, Drug, And Cosmetic Act of 1938 Proof of safety and manufacturing information Required for New Drugs Copycat Drugs go directly to market Not Required: Proof of effectiveness Affirmative FDA approval- Effective if no objection

5 Kefauver-Harris Drug Amendments, 1962 Revision of NDA requirements Proof of Effectiveness Affirmative FDA approval Retrospective review (DESI) for compliance to new standards of all NDA s from previous 24 years FDA s published rulings on effectiveness applied to pioneer and copycat (me-too) drugs

6 Kefauver-Harris (Con t) Early version of ANDA Only for products subject to a DESI notice Submitted manufacturing data & labeling Relied on safety & effectiveness (S&E) of pioneer Paper NDA Approval of duplicate drug Based solely on publicly available medical literature

7 The Hatch-Waxman Amendments, 1984 Patent extension and market exclusivity for pioneer drugs Modern ANDA created Based on Reference Listed Drug (RLD) New Bioequivalence testing requirement Manufacturing & labeling requirements continue

8 Hatch-Waxman: 505(b)(2) Pathway 505(b)(1) - Traditional NDA for pioneer products 505(b)(2) - Streamlined approval process for new products with same active moiety as previously approved drug (RLD)

9 Hatch-Waxman: 505(b)(2) Pathway Requires full reports of investigations of S&E But allows Sponsor to rely on investigations not conducted by the Sponsor and with no right of reference Public scientific data from RLD Published medical literature Non-public data on file with FDA/Prior FDA S&E decision Differences from RLD must be supported with Sponsor s clinical data of safety and effectiveness

10 Summary of Differences 505(b)(1) 505(b)(2) ANDA User Fees / No No Review Schedule 12 mo. 12 mo. 21 mo. Scientific Studies Full Partial Bioequiv alence New Active Moiety No No New Chemical Entity (Ingredient) / No No New Indication No New Formulation * New Dosage form or Strength No* Patented No Market Exclusivity No** * Limited changes ** Except against other generics

11 Legal Controversy 2001 Pfizer Petition against FDA Policy 2002 Pfizer Petition against Dr. Reddy s Labs (b)(2) NDA for amlodipine maleate tablets (RLD was besylate salt) 2003 Torpharm Petition against Synthon s (b)(2) NDA for paroxetine mesylate tablets (RLD was hydrochloride salt) All denied by FDA, Oct. 14, 2003

12 Legal Arguments Opponents Codifies paper NDA policy Reference to NDA investigations can be only published parts, not proprietary parts Undermines patent Inadequate Studies on (b)(2) drug Can t support AB rating Proponents Step beyond paper NDA policy FDC Act expressly says no right of reference and doesn t say limit to published Not permitted to infringe, must design around Needless treatment with placebo avoided AB rating is appropriate if bioequivalent to RLD

13 Legal Controversy Continues 2003 Bio Petition on subset of biologicallyderived products Pending FDA says unique scientific issues 2004 Abbott Petition on differences in active ingredient only Pending Depakote (divalproex) vs. Andrx valproate sodium FDA says these (b)(2) NDA s may not offer a therapeutic benefit and may lead to marketplace confusion due to pharmaceutical alternatives

14 Really, What Are 505(b)(2) s? What Are The Practical Implications?

15 How Does a 505 (b)(2) Differ From the Innovator Drug? Dosage form Strength Delivery mechanism Different formulation (e.g., different salt, complex, enantiomer, new combination of previously approved drugs)

16 Examples of 505(b)(2) Approvals New Delivery Mechanism Canasa (mesalamine) suppositories Axcan Clobex TM (clobetasol proprionate) lotion Galderma Luxiq TM (betamethasone valerate) foam - Connetics Testim TM (testosterone) gel - Auxilium New Dosage Form Altoprev TM (lovastatin) extended release tablets - Andrx DepoDur TM (morphine Sulfate) liposomal injection Skye Pharma Doxil (doxorubacin HCl) liposomal injection New Formulation Pexeva TM (paroxetine mesylate) tablets Synthon Stalevo (carbidopa/levodopa/entacapone) tablets Orion Xopenex (levabuterol HCl) inhalation Sepracor New Indication Avodart (dutasteride) capsules - GlaxoSmithKline Thalomid (thalidomide) capsules - Celgene

17 Sponsor s Benefits of the 505 (b)(2) Pathway Vs. traditional NDA Simplified approval process Use of previously published studies Quicker to market Lower cost Lower risk proven commodity

18 Benefits (Cont d) Vs. ANDA (Generic) Branded generics to market sooner 505 (b)(2) s may qualify for patent or additional marketing exclusivity 3 to 5 years vs. 180 days for first ANDA Length depends on amount of additional data required to support the application 180 day exclusivity not available

19 Practical Implications for Managed Care Pharmacy

20 Formulary & Benefit Issues Likely simplified P&T review Pricing less than innovator Possibly more expensive than generic Formulary positioning Tier 1 or Tier 2? 505 (b)(2) may not be substitutable under state pharmacy law Will the innovator drug be covered?

21 Management Issues Timing When will generic equivalents reach market? Do you invest in an intervention to move market share that has only short-term value? Alternatively, if 505 (b)(2) represents opportunity for significant savings, can you wait?

22 Other Considerations Provider and/or patient education Need for pull-through Unlike generic manufacturers, some assistance may be available from 505(b)(2) supplier Off-Label use for generics Potential for confusion

23 Potential for Substitution Avita (tretinoin cream) AB rated AmVaz (amlodipine maleate tablets) not AB rated, but approved labeling says the bioavailability of amlodipine is not altered by salt form GA, LA, MI pharmacist s judgment CT, OR, TX dosage form switch FL, IL, VA state formulary

24 Future Possible pathway for Biologic generics FDA moving toward using 505(b)(2) as generic biologic pathway But denied (b)(2) approval for Sandoz Omnitrope (DNA human growth hormone) FDA: Unable to reach a decision due to uncertainty regarding scientific and legal issues. Statutory changes needed?

25 Future (cont d) Most likely an increase in use of 505(b)(2) pathway Medicare Modernization Act, 2003 limited the number of 30-Month Stays that can be granted by the FDA to innovator company Reduced barrier to entry for 505(b)(2) s In practice, it increases window of opportunity to gain return on investment A more rigorous patenting of similar compounds by Pharmaceutical Manufacturers possible