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US 505(b)(2) Regulatory Pathway and Strategies Industry Perspectives AAPS Regulatory Sciences Open Forum 11/16/2010 Ruth Stevens, PhD, MBA.

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Presentation on theme: "US 505(b)(2) Regulatory Pathway and Strategies Industry Perspectives AAPS Regulatory Sciences Open Forum 11/16/2010 Ruth Stevens, PhD, MBA."— Presentation transcript:

1 US 505(b)(2) Regulatory Pathway and Strategies Industry Perspectives AAPS Regulatory Sciences Open Forum 11/16/2010 Ruth Stevens, PhD, MBA

2 Lipitor Flomax Plavix 100 others Tale of Two Cliffs Big Pharma Patents 2

3 Tale of Two Cliffs Big Pharma Patents Generics Small molecules 3

4 Differentiated Products Now Essentially Drive Economics of US Generics: Mylan Percent incremental contribution to 2008 cash EPS (%) *Base EPS includes commodity generics, O-US generics, Matrix **Incremental contribution Reference: Ronny Gal, Research Analyst, Sanford C. Bernstein & Co. Presentation at GPhA 2009 Annual Meeting Differentiated products contributed** ~92% of ‘08 cash EPS 29 4

5 505(b)(2) Process Potential Regulatory Pathways for Drug Products Under Development ‘Full’ Application – Data predominantly obtained from studies conducted by the Sponsor Hybrid between an ANDA [505(j)] and a full NDA [505(b)(1)] Appropriate for drug products that are the same as approved products Studies Conducted by the Sponsor 505(j) ANDA 505(b)(2) NDA 505(b)(1) NDA 5

6 505(b)(2) Regulation Potential 505(b)(2) Candidates: Marketed, unapproved (DESI) drug* PET drugs (FDG F 18, Ammonia N 13, Sodium Fluoride F 18) Racemates Known excipients used as active drugs* New dosage form Pharmacokinetic alteration New indication New combination Pro-drug of approved drug * May or may not have an RLD 6

7 Defining the 505(b)(2) Application A 505(b)(2) application is one for which one or more of the investigations relied upon by the applicant for approval "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" (21 U.S.C. 355(b)(2)). 7

8 505(b)(2) NDA Reference Listed Drug (RLD) A drug product that has been previously approved by the FDA Listed in the Orange Book Approval documents contain some of the information needed for your 505(b)(2) 8

9 Approved Product Labeling 9 Pharmacokinetics Clinical Pharmacology Drug Substance Indication Safety DDI Reproductive

10 Highlighting the Benefits of utilizing the 505(b)(2) Regulatory Pathway 10 Industry Examples

11 Corporate Strategy 11 The company applies its KME™ development model to identify existing drugs or ‘known molecular entities’ with established safety profiles which can be developed and clinically differentiated for gastrointestinal indications. The KME™ development model allows the company to more quickly establish the efficacy profile of its candidates for the target gastrointestinal indications. 505(b)(2) provides the ability to clinically differentiate from other products Allows for market niche Not available for ANDA (505(j)) products 11

12 Corporate Strategy 12 Mr. Sims: Actually, because we start with drugs already approved by the FDA, we can file for approval using the 505b2 procedure rather than the full NDA (new drug application). Where clinical trials are required for a 505b2 application, the number of patients required and length of time needed for those clinical trials are significantly less than for a new chemical entity. For example, with ESTRASORB, our Phase 1 trial had 14 patients and our Phase 2 and Phase 3 trials required less than 400 patients. As the efficacy and safety of the active ingredients have already been established, the complexity of the studies, including the duration, is generally significantly less than for an NDA application. We believe that from the starting point of developing a drug in a micellar nanoparticle to regulatory submission, it should take no more than a three or four year time frame, which is actually quite fast for this industry. From the point of filing, we would add about another year for FDA review and approval. ©2005 The Wall Street Transcript, 67 Wall Street, NYC Tel: (212) Fax: (212) Website: Eliminate some of the studies required for a 505(b)(1) (preclinical, extensive safety and efficacy studies) Significant financial savings Significant time savings

13 Case Study: Colcrys TM - DESI Colchicine Tablets for treatment of acute gout and familial Mediterranean fever (Mutual Pharmaceuticals, NDAs and , July 2009) Colchicine injection removed from the market in February, 2008 because of often-fatal toxicity –Mutual showed that this toxicity was due to excessive dose and/or concomitant medications Approved based only on literature for efficacy for the treatment of familial Mediterranean fever (FMF) and a single Phase 3 study for the treatment of acute gout 13

14 Case Study: Ulesfia TM - Excipient 5% benzyl alcohol lotion for treatment of head lice (Sciele Pharma, NDA , April 9, 2009) Widely-used chemical in cosmetic industry –Never approved as active ingredient so FDA classified it as NME Development program: –Nonclinical Literature for repeat dose and genetic toxicology Literature for in vitro studies demonstrating mechanism of action 2-year toxicology and carcinogenesis studies from the National Toxicology Program –Clinical Pharmacology/Biopharmaceutics 2 PK studies (2nd was done because presence of API in the catheter wash was confounded results of the 1st study) –Efficacy 2 Phase 3 trials, 615 subjects total (240 on treatment) –Safety Relied on its database of 8 studies (2 Phase 3, 3 Phase 2, 2 Phase 1, 1 special safety study) Extensive publication review Received 5 years data exclusivity 14

15 Case Study: Cafcit  Caffeine citrate for treatment of apnea of prematurity (Mead Johnson, NDA , September 21, 1999) Development Program: –Submitted 1 double-blind trial in 58 preterm infants and 90 literature articles Human PK studies from literature (19 articles) Drug-drug interactions from literature (71 articles) –No human PK studies conducted in premature infants Used plasma caffeine levels from subjects in the study and used special software to do population PK analysis Received orphan drug status (7 years data exclusivity) and expedited review 15

16 Pro-Drugs Fundamental: –Where does the pro-drug become the RLD? 16

17 Case Study: Valacyclovir Oral tablet for treatment of herpes –Pro-drug of acyclovir –Pro-drug in systemic circulation for about 30 min – Hepatic esterases convert pro-drug to acyclovir –Similar plasma metabolic profile to acyclovir after conversion 17

18 Valacyclovir Regulatory Path 505(b)(2) NDA as a new molecular entity –Acyclovir is RLD Can rely on some acyclovir nonclinical & clinical data –Nonclinical studies for NME –Full Phase 1 PK program –Phase 2 dose-ranging –1 adequate and well-controlled Phase 3 study 5 Years marketing exclusivity 18

19 505(b)(2) Benefits Able to earn exclusivity –3 years: clinical studies essential for approval – 5 years: NCE – old drugs never approved under an NDA – 7 years: Orphan Drug 19

20 Benefits of 505(b)(2) Get out of competitive environment of Generics Regulatory Review Period (10 months) May be attractive for investors –505(b)(2) allows for clinical differentiation –Market potential may be greater than generics 20

21 505(b)(2) Risks Imprecise development costs and timelines –ANDA’s have few re-do’s of BE –Recruitment of patients not naive –Uncertain dose (Phase 2) Unknown competition –Other companies can target the same opportunity 21

22 505(b)(2) Risks Uncertain market acceptance –Formulary –Sales Force –Doctors –Patients 22

23 505(b)(2) Risks May not be attractive for investors –“Generics have less risks and better returns” VC’s don’t understand 505(b)(2) ROI may be lower than 505(b)(1), or a total payoff may be lower (double $50MM or $500MM) 23

24 505(b)(2) Risks Like Generics (505(j)): –must include patent certification(s) –include all relevant patent(s) –subject to the same Paragraph IV challenge and litigation including a 30-month stay, but it is not granted a 180-day exclusivity 24

25 25 Considerations: Willingness to take educated risks In-house Expertise Company Culture Historical Precedence Decision to Pursue the 505(b)(2) Regulatory Pathway

26 Thank You Regulatory Sciences Co-Moderators –Michael Bornstein, PhD –Annette Bak, PhD, MBA Rajneesh Taneja, PhD, RPh 26


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