Labeling as a route map for drug development Mike Page Senior Director, Regulatory Affairs

1. 27 March 2009 Labeling as a route map for drug development Mike Page Senior Director, Regulatory Affairs

2. Definitions • What is labeling? • Why use the label as the guide? • When to start? • How to manage label development? • Some examples

3. PLEASE ASK QUESTIONS

4. What is labeling?

5. What is an approval? “FDA will approve an application after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls and labeling…” 21 CFR 314.105(c)

6. What gets approved?

7. What is labeling? The term "labeling" means all labels and other written, printed, or graphic matters (1) upon any article or any of its containers or wrappers, or (2) accompanying such article [intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease]. Section 201(m) of the FD&C Act “Brochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogs, house organs, letters, motion picture films, film strips, lantern slides, sound recordings, exhibits, literature, and reprints and similar pieces of printed, audio, or visual matter descriptive of a drug and references published (for example, the ‘‘Physicians Desk Reference’’) for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor are hereby determined to be labeling…” 21CFR 202.1(l)(2)

8. What is labeling for? • Basis for all communication on product • Describes effectiveness • First line risk management tool • Physicians labeling rule emphasizes information component • “The labeling shall contain a summary of the essential scientific information needed for the safe and effective use of the drug.” 21 CFR 201.56 (a)

9. Boxed Warning Indications & Usage Dosage & Administration Dosage Forms & Strengths Contraindications Warnings & Precautions Adverse Reactions Drug Interactions Use in Specific Populations Drug Abuse & Dependence Overdosage Description Clinical Pharmacology Nonclinical Toxicology Clinical Studies References How Supplied/Storage & Handling Patient Counseling Information US labeling format

10. Highlights Source: www.FDA.gov/cder/guidance/5669high.pdf

11. Using the label for mapping development

12. Generating target product profile What are the critical attributes for the success of the product? Efficacy Indication? Unmet medical need? Patient population? Novel mechanism of action? Dosing Formulation Compliance/convenience? Considerations for special populations? Drug interactions? Safety Improved tolerability? Managing risk?

13. Example draft label template Document desired label and update as data become available

14. External factors • Competitive landscape – present and future • Class labeling • Evolving regulatory environment • Prescriber experience of other products

15. Defining the program • Align desired state with data requirements • Clinical pharmacology studies • Drug interactions • Clinical studies • Patient population • Endpoints • Add regulatory requirements • Bioequivalence/comparability • Thorough QT study? • Abuse potential? “Is this study really necessary?”

16. Early decision points – PK and dosing • Case study: • NCE nearing Phase 1 start. Most prescribed competitor product dosed twice a day with food. Anticipated high value enhanced compliance based on convenience of single daily dosing with no food effect. • Target label: The recommended dose is xx mg taken once a day with or without food • What studies? • What claims?

17. Dosing and administration • Target – once daily dosing with or without food • Initial PK studies • Assess intrinsic PK factors and suitability for once daily dosing • Assess food effect in early studies • Decision points • Pivotal studies will define dosing recommendations for label • Reformulate? • Compliance?

18. Updated target label OR

19. Drug interactions • In vitro P450 data can render in vivo studies unnecessary • Dosage adjustment recommendations can impact approvability and form key component of labeling • Which DDI studies should be considered ? • Based on therapy area, likely concomitant medications • Drug interactions seen for competitor products • Early DDI studies can inform later clinical program • Population PK • Con meds to include/exclude

20. Optimizing data presentation

21. Aligning label with efficacy messages • Limited rep calls, limited time • Educating physicians on efficacy outcomes can take a lot of time • Simplifying efficacy messages is highly advantageous • Focus on clinically relevant endpoints • Aim for effective presentation in label itself • Consider presentation of the clinical efficacy message in selecting endpoints

22. Simplicity of clinical message

23. Superiority - some regs… An advertisement for a prescription drug may not, either directly or by implication, e.g., by use of comparative test data or reference to published reports, represent that the drug is safer or more effective than another drug, nor may an advertisement contain a quantitative statement of safety or effectiveness…unless the representation has been approved as part of the labeling in a new drug application 21 CFR 202.1 (e)(6) (ii)

24. Careful, now…

25. Maximizing chance of superiority labeling • Demonstrate superiority separately in two studies • Comparator use closely scrutinized for fair representation • Dose • Population • Blinding • Show consistent effect across multiple study endpoints • Show acceptable toleration/safety • Consider labeling possibilities • “ X is superior to…” • data tabulations, p-values, confidence intervals.

26. Comparative safety claims • Comparator safety statements not generally included • Comparative safety labeling must be based on “adequate and well controlled studies” • Avoid inclusion of data which might be misleading

27. Value of pharmacology “Product X achieves its therapeutic effect by means of a novel mechanism of action. “Novel mechanism provides similar level of efficacy to established medicinal products but reduces the likelihood of adverse effects” • Highly valuable branding message, especially in precedented indication • What studies to perform? • What claims can be made?

28. Mechanism of action claims • Non-clinical studies must have clinical relevance • Include clinical endpoints relevant to MOA • Discuss objectives for with regulators during development

29. Anti-angiogensis labeling – follow the logic • Drug inhibits VEGF in vitro • VEGF-receptor interaction results in new blood vessel formation in vitro • Drug reduces in microvascular growth in xenotransplanted tumor • Drug inhibits metastatic disease progression from xenotransplanted tumor • Clinical increase in objective response rate • Clinical improvement in overall survival

30. Two key areas for consideration • Patient reported outcomes • Ensure outcomes are relevant to disease area • Scales must be validated • Engage Study Endpoints and Label Development group at earliest opportunity • Abuse liability assessment • Specific studies can have significant labeling impact • Engage Controlled Substances Staff early in development

31. Safety topics

32. Boxed Warning Indications & Usage Dosage & Administration Dosage Forms & Strengths Contraindications Warnings & Precautions Adverse Reactions Drug Interactions Use in Specific Populations Drug Abuse & Dependence Overdosage Description Clinical Pharmacology Nonclinical Toxicology Clinical Studies References How Supplied/Storage & Handling Patient Counseling Information US labeling topics – safety first

33. Class labeling • Consider collecting data where class labeling is in effect • Recent examples: • Suicidality – antidepressants, antiepileptics • Glycemic control – atypical antipsychotics • Dementia related psychosis – antipsychotics • Even in cases where prospective information is collected, can’t guarantee class labeling will not be implemented • Discuss approaches to class labeling at End of Phase 2

34. Suicidality assessment • Communication from Division of Psychiatry Products • Include prospective suicidality assessment for: • Every protocols • Every visit • Every phase of development • Acceptable instrument would be Columbia Suicide Severity Rating Scale (CSSRS) • Alternative to CSSRS must be justified

35. Think about REMS in Phase 3 • Labeling is first line risk management tool. • Patient package insert reviewed as labeling with NDA • More common for reviewing divisions to discuss REMS earlier in development • >150 Medication Guides listed on CDER website • Considering REMS proactively during Phase 3

36. REMS Example: Medication Guide + Communication Plan - Xenazine® Xenazine®(tetrabenazine)indicated for treatment of Huntington’s Chorea • REMS goals: • To reduce the risk of depression and suicidality • To promote informed prescribing and proper dose titration • To minimize the risk of Drug interactions with strong CYP2D6 inhibitors • REMS elements: • Medication Guide • Communication Plan with materials for • Patients • Prescribers • Pharmacists • Pharmacy management systems- materials to help prevent the risk of DDI and ensure appropriate titration • Elements to assure safe use- NONE

37. Tradename review

38. Safety topics – Invented name • Division of Medication Errors and Technical Support (DMETS) • Reviews approx 400 names per year • Rejects about 1 in 3 • Name reviewed primarily for avoidance of medication errors • Guidances in development • Name must not • overstate the efficacy • minimize the risk • broaden the indication • make unsubstantiated superiority claims • be overly “fanciful” by misleadingly implying unique effectiveness or composition • be otherwise false or misleading

39. Tradename review methodology • Failure Modes Effect Analysis (FMEA) takes into account: • Orthographic and phonetic attributes • Product characteristics • established name of the product • proposed indication • dosage form, route of administration, strength, unit of measure, dosage units • recommended dose, typical quantity or volume, frequency of administration • product packaging, storage conditions • patient population • prescriber population Draft Guidance - Contents of a Complete Submission for the Evaluation of Proprietary Names (Nov 2008) http://www.fda.gov/cder/guidance/7935dft.pdf

40. Labeling as part of tradename review • Inclusion of proposed labeling makes simpler review package • If no labeling supplied should supply: • Established name • Prescription status • Dosage forms, product strengths, route of administration • Proposed indication • Dosing information, dosing in specific populations • Instructions for use • Storage requirements • How supplied, packaging configuration

41. Timing of tradename review • Tradename reviewed as part of NDA, ANDA, BLA • Cannot be submitted earlier than End of Phase 2 • No guidance on approval times • Have back-up names available!

42. Overall conclusions • Labeling is central communication tool • Consider desired end state • Understanding label objectives will help determine development path • Update label as data emerge and alter strategy accordingly

43. Contact information Mike Page Senior Director, Regulatory Affairs United BioSource Corporation 2200 Commonwealth Bvld., Suite 100 Ann Arbor, MI 48105 Phone: +1 860 598-4677 Mobile. +1 860 501-2690 email: mike.page@unitedbiosource.com www.unitedbiosource.com