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

2. Tale of Two Cliffs Big Pharma Patents Lipitor Flomax Plavix 100 others2

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

4. Differentiated products contributed** ~92% of ‘08 cash EPS
Differentiated Products Now Essentially Drive Economics of US Generics: Mylan
Percent incremental contribution to 2008 cash EPS (%)
Differentiated products contributed** ~92% of ‘08 cash EPS 29
In recognition of this fact, Mylan, Teva and Watson have started 505b2 development programs and for Mylan it is already a substantial source of revenues.
*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 4

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

6. Potential 505(b)(2) Candidates:
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. Reference Listed Drug (RLD)
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)

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

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

11. Corporate Strategy
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

12. Corporate Strategy
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.
Eliminate some of the studies required for a 505(b)(1) (preclinical, extensive safety and efficacy studies)
Significant financial savings
Significant time savings
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13. Case Study: ColcrysTM - 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, 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: UlesfiaTM - 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
Population PK software: NONMEM (UCSF)
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

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

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

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

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)

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

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

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