ITFG and IPAC-RS

1. OVERVIEW OFITFG/IPAC-RS COLLABORATIONFOR PRESENTATION TO THEADVISORY COMMITTEE FORPHARMACEUTICAL SCIENCEPresented by: Harris Cummings, PhD15 November 2000Rockville, MD

2. ITFG and IPAC-RS The Inhalation Technology Focus Group (ITFG) of the American Association of Pharmaceutical Scientists is comprised of pharmaceutical scientists who seek to foster and advance the art and science of pharmaceutical aerosol products, aerosol technology and related processes The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) is an association of companies that develop and manufacture orally inhaled and nasal products for local and systemic treatment of asthma, chronic obstructive pulmonary disease (COPD), rhinitis, as well as new products for non-respiratory disease indications such as diabetes and migraine

3. DRAFT GUIDANCES FOR OINDP Draft Guidances for Industry: 1) Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation; 2) Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products Chemistry, Manufacturing, and ControlsDocumentation; and 3) Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action

4. PERSPECTIVES OF ITFG/IPAC-RS • ITFG and IPAC-RS: • share FDA’s goal of assuring highest levels of safety, efficacy and quality for orally inhaled and nasal drug products (OINDP) and making these products available to patients expeditiously • recognize value of having OINDP guidance documents to facilitate development and approval of new medications, but believe that differing views exist concerning CMC and BA/BE issues in draft OINDP Guidances • agree that certain sections of draft Guidance documents need to be modified to be consistent with today’s drug development technologies and capabilities • believe that additional interactive, science-based dialogues need to occur to provide full opportunity to discuss all important issues in depth in order to achieve meaningful and necessary changes in OINDP draft Guidances

5. ITFG/IPAC-RS COMMITMENT TO ADDRESS OINDP ISSUES • Following Publication of Draft Guidances, ITFG and IPAC-RS Submitted Extensive Written Comments to FDA Docket • (February 1999, August 1999, September 1999) • ITFG and IPAC-RS Organized and Implemented Extensive Data-Driven Collaboration to Address Issues in Draft Guidances • (January 2000-Present) •  Collected and Analyzed Relevant Databases •  Proposing Scientifically Justified Modifications to Draft Guidances • Collaboration Participated in first OINDP Subcommittee Meeting • (April 2000) •  Committed to Collecting Relevant Data •  Described Plans to Prepare Data-Based Technical Reports on Issues in Draft Guidances for Submission to Agency and OINDP Subcommittee • Collaboration Submitted Four Technical Reports to FDA • (July and August 2000)

6. FRAMEWORK OF ITFG/IPAC-RS COLLABORATION STEERING COMMITTEE TECHNICAL TEAMS CMCTESTS AND METHODS CMC SUPPLIER QUALITY CONTROL CMC LEACHABLES & EXTRACTABLES TOXICOLOGY WG BA/BE IN VITRO AND IN VIVO TESTS CMC SPECIFICATIONS DCU WG PSD WG

7. PARTICIPANTS IN ITFG/IPAC-RS COLLABORATION Over 100 individuals from more than 25 companies/institutions are participating in the ITFG/IPAC-RS Collaboration Aradigm AstraZeneca Aventis Bespak BI Roxane Boehringer Ingelheim Celltech-Medeva Dura Pharmaceuticals Eli Lilly Glaxo Wellcome Inhale Therapeutic Systems Inspire Pharmaceuticals IVAX Kos Pharmaceuticals Lovelace Respiratory Institute Magellan Laboratories Microdrug Pfeiffer Pfizer Presspart Primedica Schering-Plough 3M Pharmaceuticals Trudell Medical University of Rhode Island Valois

8. ITFG/IPAC-RS TECHNICAL TEAMS • Technical Teams Are at Different Stages: • Some Have Collected and Analyzed Data and Submitted Initial Assessments to Agency • Others Are Analyzing Data and Preparing to Submit Technical Reports to Agency and OINDP Subcommittee • Today Technical Team Leaders Will: • Review Work of Each Technical Team to Date • Describe Collaboration’s Data-based Conclusions • Explain Plans for Further Work • Describe Data-based Proposals to Modify Draft Guidances

9. NEED FOR SCIENCE-BASED DIALOGUES • We Respectfully Request that the Advisory Committee For Pharmaceutical Science: • Support the Importance and Value of Continuing Scientific Dialogue on Important CMC and BA/BE Issues for Orally Inhaled and Nasal Drug Products Before Draft Guidances Are Finalized • Endorse Our Request That Opportunities Be Identified for a Continued Dialogue Between FDA and ITFG/IPAC-RS Collaboration Regarding the Collaboration’s Technical Papers and Data-based Proposals to Modify the Draft Guidance Documents

10. RECOGNITION OF AGENCY’S COMMITMENT TO IMPROVING QUALITY OF OINDP • ITFG and IPAC-RS Recognize and Appreciate Agency’s Efforts in Issuing Draft Product Quality OINDP Guidances and Agency’s Initial Steps Towards a Scientific Dialogue • ITFG and IPAC-RS Strongly Support Agency’s Creation of the OINDP Subcommittee and Believe That the Subcommittee Should be Given an Opportunity to Deliberate Substantively on OINDP Issues • We Thank the Advisory Committee for Pharmaceutical Science and the Agency for Considering Our Comments and Proposals and Are Pleased to be Able to Participate in Today’s Meeting

11. ITFG/IPAC-RSTECHNICAL TEAMBA/BE IN VITRO AND IN VIVO TESTSPresented by: Lars Borgström, PhD15 November 2000Rockville, MD

12. BA/BE TEAM’S WORK TO DATE • Commitments made at 26 April OINDP Subcommittee Meeting • To Develop Position Statements on BA/BE Studies • To Respond to FDA’s BA/BE Questions from 26 April OINDP Subcommittee Meeting • Status • Prepared Two Technical Papers, Submitted to FDA on 30 August 2000 • Technical Paper on FDA’s Bioavailability and Bioequivalence Questions Presented at 26 April 2000 OINDP Advisory Subcommittee Meeting • Review of In Vivo and In Vitro Tests in FDA’s Draft Guidance on Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action and Anticipated Forthcoming Guidance for Orally Inhaled Drugs

13. BA/BE TEAM’S POSITION STATEMENTS BA/BE: IN VITRO TESTS BA/BE: IN VIVO TESTS In vitro testing is essential for pharmaceutical product equivalence and should be included as part of BA/BE Guidance for all nasal and oral inhalation products, but is not currently sufficient for determining BE without establishing in vivo BE. For BE approval, BA/BE Guidance documents for nasal and oral inhalation drug products for local action should require use of validated human models for in vivo testing for local and systemic exposure, efficacy and safety.

14. BA/BE TEAM’S WORKING ASSUMPTIONS • Team’s BA/BE recommendations apply to locally acting drugs only (per the current draft BA/BE Guidance) • Team’s comments apply to both orally inhaled and nasal drug products, but the dosage forms should be treated in separate Guidances • Scientific and clinical bases for developing BA/BE Guidance are evolving • Team’s BA/BE position statements reflect only the current state of knowledge

15. BA/BE TEAM’S FINDINGS: IN VITRO TESTS • In vitro tests described in the draft BA/BE Guidance are not necessarily more relevant or discriminating than clinical studies for BE assessment • The assumption that in vitro studies alone are sufficient for BE of solutions is unfounded. The draft BA/BE Guidance should not distinguish between nasal suspensions and solutions for in vivo BE • Based on the available literature, current in vitro tests may predict lung deposition, but the utility of those tests to demonstrate clinical equivalence of inhaled drug products has not been shown

16. BA/BE TEAM’S FINDINGS: IN VIVO TESTS • Systemic PK/PD estimates systemic exposure (i.e., safety) but does not estimate local delivery (i.e., efficacy and local tolerance) • Efficacy assessments alone cannot establish in vivo BE since they will not assure comparable safety (systemic exposure) • Lung deposition studies are a promising new technique, but currently cannot replace the local delivery requirement • In vitro data, regional deposition data, PK/PD studies, and clinical efficacy studies are needed to establish relationships and to characterize the formulation when a new inhaled drug is developed • Reduction of testing requirements for a new formulation of an approved drug should therefore be negotiated between the sponsor and the Agency depending on available data for each particular drug

17. BA/BE TEAM’S CONCLUSIONS • Team’s Review Paper Was Intended to Highlight Areas in Draft BA/BE Guidance Where Scientific Basis Is Uncertain and Where More Scientific Discussion and Debate Are Needed • Agency's Questions to OINDP Subcommittee on 26 April Underscore the Agency's Concerns With Some of the Positions in the Draft BA/BE Guidance • We Encourage the Agency to Solicit Further Scientific Discussion on These Positions Before Finalizing Current Draft or Issuing Further Guidance Documents

18. BA/BE TEAM’S NEXT STEPS • Requesting Opportunity to Meet with Agency to Discuss Team’s Findings • Willing to Address Further Questions Raised by Agency

19. ITFG/IPAC-RSBA/BETECHNICAL TEAMRESPONSES TO AGENCY’S BA/BE QUESTIONS RAISED AT OINDP SUBCOMMITTEE MEETINGPresented by: Les Harrison, PhD15 November 2000Rockville, MD

20. ITFG/IPAC-RS COLLABORATION FDA QUESTION EVALUATION • Small Working Groups Formed to Research Each Question • Scientific Data (Literature and Company Experience) Used to Prepare Answers • Answers Reviewed by Entire BA/BE Technical Team • Consensus Required for All Answers

21. OVERVIEW OF COLLABORATION RESPONSES • FDA Raised Difficult Technical Issues at April 26 Meeting • Most Issues Are Still Open • Collaboration Committed to Address Questions in Order to Complement OINDP Subcommittee's Discussion • Collaboration Collected and Analyzed Scientific Data to Help Resolve Uncertainties • Collaboration has Provided Additional Scientific Substantiation to Subcommittee’s Answers • Collaboration has Provided Responses Where Subcommittee’s Answers Were Limited • Need More Opportunities to Consider these Difficult Questions • Agency Should Continue to Dialogue with Public

22. IN VITRO BA/BE TESTING A. Profile Analysis (1) • QUESTION: • 1. Should all stages, including the inlet (throat) of the cascade impactor (CI) be considered in a comparison of test and reference products? • SUMMARY OF ANSWER: • Yes, All Stages Should Be Considered for Products With Polydisperse Particle Size Distributions

23. IN VITRO BA/BE TESTING A. Profile Analysis (2) • QUESTION: • 2. Should a statistical approach rather than a qualitative comparison be used for profile comparisons? If yes, does the chi-square comparative profile approach seem appropriate? • SUMMARY OF ANSWER: • Yes, a statistical approach should be used • The chi-square approach may be appropriate for particle size comparisons; further assessment is needed • Guidance should define “equivalence limits” (extent to which two profiles can differ and still be considered equivalent)

24. IN VITRO BA/BE TESTING B. In Vitro Tests for DPIs: Comparability (1a) • QUESTION: • 1. Prior to doing in vivo studies to establish equivalence of a test DPI product, a firm would need to design its product to have the best likelihood of being found equivalent in these in vivo studies. • a. What design features of the device and formulation and what parameters should be considered in determining pharmaceutical equivalence? • SUMMARY OFANSWER: • Equivalence in all of the following categories should maximize the likelihood of being equivalent in vivo studies: • formulation • device elements • chemical, physical and in-vitro characteristics that demonstrate the performance of the assembled system

25. IN VITRO BA/BE TESTING B. In Vitro Tests for DPIs: Comparability (1b) • QUESTION: • b. What comparative in vitro tests should be conducted to help support bioequivalence? • SUMMARY OFANSWER: • delivered dose amount and delivered dose uniformity • aerodynamic particle size distribution of delivered dose, and of carrier or excipient materials; characteristics of dispersing the formulated powder to desired particle size distribution across a physiologically relevant range of airflows and environmentally realistic range of temperatures and humidities; • microbiological burden in the powder formulation • chemical, physical and microbiological stability of contained formulation • chemical and physical composition of device, including extractive materials • reliability of device throughout the defined use period

26. IN VIVO BA/BE TESTING A. Clinical Studies for Local Delivery of Nasal Aerosols and Sprays(1) • QUESTION: • 1. Three study designs have been proposed in the draft guidance for drugs intended to have local action; traditional treatment study; day(s) in the park study, and environmental exposure unit study. These study designs are based on seasonal allergic rhinitis (SAR). Is it feasible to demonstrate a dose-response for locally acting nasal drugs? If not, what other approaches can be relied upon to establish equivalent local delivery? • SUMMARY OFANSWER: • Studies proposed in draft Guidance are useful for determining comparability • Their value for establishing clinical equivalence and substitutability is unproven • Traditional treatment study is most appropriate study design for assessing nasal drug products intended for local delivery • Statistical requirements must be proposed if clinical studies are to be used for equivalence testing • Current study designs are not adequate to confidently establish dose-response relationships nor is there an alternative method available

27. IN VIVO BA/BE TESTING A. Clinical Studies for Local Delivery of Nasal Aerosols and Sprays(2) • QUESTION: • 2. Can bioequivalence be established based on SAR assure bioequivalence for other indications such as recurrence of nasal polyps, or other non-SAR conditions? • SUMMARY OFANSWER: • A pre-existing indication for nasal polyps or other non-SAR condition at same dose should be transferable from Reference to Test product if all BE requirements for SAR met • To transfer a pre-existing indication for use in children, it should be shown that the studies conducted to assess systemic safety are predictive of this subgroup.

28. IN VIVO BA/BE TESTING B. Clinical Studies for Local Delivery of Orally Inhaled Corticosteroids (ICS) • QUESTIONS: • 1. A number of approaches have been proposed to assess bioequivalence of ICS (e.g., clinical trials, bronchoprovocation tests, steroid reduction model, trials with surrogate measures such as exhaled nitric oxide (eNO), etc. • Are any of these study designs proven to offer better discrimination in terms of dose-response sensitivity? • 2. What other in vivo approaches (e.g., surrogate markers) might be sufficiently sensitive and validated to establish in vivo BA and BE for inhaled corticosteroids?

29. IN VIVO BA/BE TESTING B. Clinical Studies for Local Delivery of Orally Inhaled Corticosteroids (ICS) • SUMMARY OFANSWER: • Comparative dose-response trial with pulmonary function measurements as the primary analysis parameters remains the method of choice. • However, variability is large, and metrics sensitive enough for BE with trial designs that are practical from subject number and length of study are not yet available. • No alternative design has been sufficiently validated.

30. IN VIVO BA/BE TESTING c. PK or PD Studies for Systemic Exposure of Locally Acting Drugs • QUESTION: • Are there situations where in vitro data plus systemic PK and systemic PD data can be relied on to assure local drug delivery for either nasal or inhaled drugs? • SUMMARY OFANSWER: • Yes, there could be situations where in vitro data plus systemic PK and systemic PD data may be relied upon for BE. • If a predictive in vitro/in vivo correlation can be documented, the sponsor should have the opportunity to discuss the possibility of waiving clinical studies. • Post-approval changes to manufacture of approved Reference or approved Test products may not require extensive testing, but such changes are outside the scope of this draft Guidance.

31. BA/BE TEAM’S CONCLUSIONS • Questions Posed by FDA on the Draft BA/BE Guidance have Underscored a Number of Open Issues • BA/BE Team Collected a Substantial Body of Information that Merits Examination by the Agency and OINDP Subcommittee • BA/BE Team Encourages Further Scientific Collaboration and Consideration of Key BA/BE Issues by Agency Utilizing Existing Avenues: • OINDP Subcommittee • PQRI • AAPS/FDA/USP Workshop • Dialogue with ITFG/IPAC-RS Collaboration • Federal Research Grants • We Hope the Agency is Receptive to Our Comments and Continues to Dialogue With Public Before Finalizing Current Draft or Issuing Further Guidances

32. ITFG/IPAC-RSTECHNICAL TEAMCMC SPECIFICATIONSPresented by: Bo Olsson, PhD15 November 2000Rockville, MD

33. DOSE CONTENT UNIFORMITY (DCU) • Team’s Hypothesis: • The current state of OINDP technology may not allow general compliance with the dose content uniformity specifications in the draft FDA CMC Guidances. • Questions Raised by the Agency at OINDP Subcommittee Meeting: • Should there be a single content uniformity standard for all orally inhaled and nasal drug products (OINDPs)? • Should the FDA continue development of the proposed statistical approach to evaluating content uniformity? • Team’s Approach: • Collect Worldwide Database to Investigate Actual DCU Capabilities and Appropriate Statistical Approaches

34. DCU WORKING GROUP STATUS REPORT • Collected Worldwide DCU Database Containing Data From 10 Companies on 77 Orally Inhaled and Intranasal Drug Products (Currently on the Market and Under Development) With a Total of 46,016 Individual Observations • Analyzed Collected Data, Prepared and Submitted Initial Assessment of DCU Database to FDA on 31 July 2000 • Developed Proposed Plan for Stage 2 Analysis of DCU Database and Submitted it to FDA on 22 September • Meeting With Agency on 20 November to Discuss Initial Assessment of DCU Database and Proposed Plan for Stage 2 Analysis of DCU Database

35. DCU WORKING GROUP FINDINGS • Key Requirement of Draft Guidance Specification for DCU • Reject a batch if a DCU determination outside 75-125% of the Label Claim (LC) is obtained • Findings From DCU Database • Main analysis showed that: • Grand Mean Dose Content is100% LC • 68% of all products show results outside 75-125% LC

36. CONCLUSIONS FROM INITIAL ASSESSMENT OF DCU DATABASE • The Initial Assessment of the DCU Database Supports the Hypothesis That Orally Inhaled Products Do Not in General Comply With the DCU Specification in the FDA Draft CMC Guidances. • The Relatively Large Difference Between Products and Between Product Types Suggest That a Single Content Uniformity Specification for All Orally Inhaled Products Is Not Suitable.

37. PLAN FOR FURTHER ANALYSIS OF DCU DATABASE • In consultation with FDA, DCU Working Group will continue analysis of DCU database to investigate • Compliance with FDA Draft Guidances’ Complex Criteria • ICH Approach • Dr. Hauck’s Approach of Statistical Hypothesis Testing • Other Approaches

38. PARTICLE SIZE DISTRIBUTION (PSD) • Team’s Commitment Made at OINDP Subcommittee Meeting: • Examine the relevancy of the mass balance requirement as a product specification versus system suitability requirement. • Investigate if fewer than 3-4 stage groupings can provide equivalent control. • Team’s Approach: • Collect worldwide database to investigate actual PSD capabilities and appropriate statistical approaches for control of PSD in OINDP • Question Investigated in the Initial Assessment: • Can the current state of OINDP technology generally comply with the mass balance criterion in the draft FDA CMC Guidances?

39. PSD WORKING GROUP STATUS REPORT • Collected Worldwide PSD Database Containing Data From 7 Companies on 35 Orally Inhaled and Intranasal Drug Products (Currently on the Market or Under Development) With a Total of 3,606 Individual PSD Determinations • Analyzed Collected Data, Prepared and Submitted Initial Assessment of PSD Database to FDA on 29 August • Developing Plan for Further Analysis of PSD Database • Willing to Meet With Agency to Discuss Initial Assessment of PSD Database and Plan for Further Analysis

40. PSD WORKING GROUP FINDINGS • Draft Guidance Mass Balance Specification • Total mass of drug collected on all stages and accessories during particle size testing should be within 85-115% LC on a per actuation basis • Main Finding from PSD Database • Only 4 of 35 products showed no results outside 85%-115% LC

41. CONCLUSION FROM INITIAL ASSESSMENT OF PSD DATABASE • Initial Assessment of the PSD Database Indicates that: • Orally Inhaled Products Do Not in General Comply with the Proposed Mass Balance Requirement in the Draft CMC Guidances (85-115% LC) • The Proposed Requirement Is Not Suitable As a Drug Product Specification but Could Be Appropriate As a System Suitability Test Defined on a Case by Case Basis

42. PLAN FOR FURTHER ANALYSIS OF PSD DATABASE • PSD Working Group will Continue Analysis of PSD Database to • investigate further relevance of the mass balance criterion as a product specification versus system suitability requirement • compare different metrics and sets of criteria for characterizing PSD of OINDP • PSD Working Group Is Willing to Meet With Agency to Discuss Results of Initial Assessment and Plans for Further Analysis of PSD Database

43. SPECIFICATIONS TEAM CONCLUSIONS • Many Unresolved Issues Surround CMC Specifications for DCU and PSD. To Address These Issues, Team Has Collected and Is Analyzing DCU and PSD Data • Team Strongly Encourages Continued Discussion by All Interested Parties Before CMC Draft Guidances Are Finalized • Developing Statistically Sound Specifications Based on Real Data Is Essential to Creating Scientifically Credible Program of Product Quality Control

44. ITFG/IPAC-RS TECHNICAL TEAM CMC TESTS AND METHODS Presented by: Carole Evans, PhD 15 November 2000 Rockville, MD

45. TEAM’S OBJECTIVE The Team Would Like to Assist the Agency in Developing CMC Testing Requirements That Provide Valuable Information About Product Quality

46. TEAM POSITION ON DRAFT CMC GUIDANCES • To Clarify Testing Requirements for Each of the Four OINDP Dosage Forms, the Draft Guidances Should Be Edited or a Separate Guidance Should Be Developed for Each Dosage Form • In Some Instances, the Language in the Draft CMC Guidances Is Ambiguous • The Need for Certain Tests Should Be Driven by Evaluation of Data Generated During the Development Phase of Each Product

47. PRESENTATION TO OINDP SUBCOMMITTEE • Approach and Commitments: • The Team Developed Position Statements on the Following MDI Tests: • -Water • -Spray Pattern • -Plume Geometry • -Particle Size Distribution • -Shot Weight • -Impurities and Degradants • -Dose Content Uniformity • -Pressure • The Team Committed to Conducting Data-Based Investigations of these Position Statements, where Appropriate

48. TESTS & METHODS TEAM STATUS REPORT • Collected and Analyzing Data to Investigate the Team’s Position Statements for the Following MDI Tests: • -Water • -Spray Pattern • -Plume Geometry • -Temp/ Relative Humidity in Particle Size Distribution Testing • -Shot Weight • Drafted Comments on MDI Requirements for: • -Impurities and Degradants • -Dose Content Uniformity • Compiled Data from the Scientific Literature for: • Particle Size Distribution -- Investigation of Alternate Methods • Pressure testing for single propellant/co-solvent mixtures

49. TESTS & METHODS TEAM PRELIMINARY FINDINGS ON MDI TESTS • Collected Data Show That for Many Products, the Tests for Spray Pattern, Water Content, and Shot Weight Do Not Provide Meaningful Information About Product Performance • There Exists a Wide Body of Literature that Lends Support to the Use of Validated and Suitable Alternate Methods for Determining Particle Size Distribution • Literature Data Suggests That for Mixed Propellant/co-solvent Formulations, Pressure Testing During Development Is Not a Reliable Means of Measuring Propellant Mixture Ratio. Integrity of the Propellant-Alcohol Mixture Is Better Controlled by Alcohol Content Analysis

50. FURTHER WORK OF TESTS & METHODS TECHNICAL TEAM • Team Will Submit Technical Paper Containing Conclusions and Recommendations to Agency (Expected Submission - December 2000) • Team Will Collect and Analyze Data on Non-MDI Dosage Forms in Early 2001 • Team Will Request Opportunity to Meet with Agency to Discuss Team’s Findings • Willing to Address Further Questions Raised by Agency