Bioequivalence Studies and Other Recommendations for Orally Inhaled and Nasal Drug Products: Work of the ITFG

1. Bioequivalence Studies and Other Recommendations for Orally Inhaled and Nasal Drug Products: Work of the ITFG/IPAC-RS Collaboration Presented by Cynthia Flynn, Ph. D. and Joel Sequeira, Ph. D. Rockville, MD 17 July 2001 Thank you� My name is�.Thank you� My name is�.

2. -2- 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 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. -3- ITFG and IPAC-RS formed a collaboration in 2000 to address CMC and BA/BE issues in FDA draft Guidances ITFG/IPAC-RS Technical Teams previously presented their concerns with regulatory science issues of OINDP and made commitments to gather and analyze relevant data and submit technical reports - 26 April 2000 (OINDP Subcommittee)  - 15 November 2000 (Advisory Committee) ITFG and IPAC-RS formed a collaboration in 2000 to address CMC and BA/BE issues in FDA draft Guidances ITFG/IPAC-RS Technical Teams previously presented their concerns with regulatory science issues of OINDP and made commitments to gather and analyze relevant data and submit technical reports

4. -4- The ITFG/IPAC-RS Collaboration presents two reports today: 1) Update on the work of the CMC Technical Teams of the ITFG/IPAC-RS Collaboration To inform committee members of progress made; To outline the scope of industry�s concerns with the draft OINDP Guidances; and To highlight areas where additional research has been undertaken or proposed by the industry 2) Update on Work of BA/BE Team Will include review of Team�s views on the issue of dose-response of locally acting nasal drug products, with particular application to BE studies BA/BE report will be presented by Dr. Joel Sequeria, immediately following this presentation Additional details are contained in the Written Statement submitted to the FDA and Committee members in connection with this meeting The ITFG/IPAC-RS Collaboration presents two reports today: 1) Update on the work of the CMC Technical Teams of the ITFG/IPAC-RS Collaboration To inform committee members of progress made; To outline the scope of industry�s concerns with the draft OINDP Guidances; and To highlight areas where additional research has been undertaken or proposed by the industry 2) Update on Work of BA/BE Team Will include review of Team�s views on the issue of dose-response of locally acting nasal drug products, with particular application to BE studies BA/BE report will be presented by Dr. Joel Sequeria, immediately following this presentation Additional details are contained in the Written Statement submitted to the FDA and Committee members in connection with this meeting

5. -5- Critical CMC issues, still unresolved, although some steps have been taken towards resolution Dose Content Uniformity Particle Size Distribution Tests and Methods Leachables and Extractables Critical CMC issues, still unresolved, although some steps have been taken towards resolution Dose Content Uniformity Particle Size Distribution Tests and Methods Leachables and Extractables

6. -6- Collected and analyzed DCU database Submitted report to FDA in July 2000 Met with FDA in November 2000 and May 2001 to discuss findings and plans for future work Developed improved DCU test Collected and analyzed DCU database Submitted report to FDA in July 2000 Met with FDA in November 2000 and May 2001 to discuss findings and plans for future work Developed improved DCU test

7. -7- The new test follows the parametric tolerance interval approach propounded by Dr. Walter Hauck in his numerous presentations, including last year�s subcommittee meeting on OINDP (4/26/00) The test also builds upon certain aspects of the approach put forth by the Pharmacopeial Discussion Group of ICH, published in the May-June issue of the Pharmacopeial Forum The test is grounded in general statistical considerations, quality standards set by the draft Guidances, and capabilities of modern inhalation technology. The new test follows the parametric tolerance interval approach propounded by Dr. Walter Hauck in his numerous presentations, including last year�s subcommittee meeting on OINDP (4/26/00) The test also builds upon certain aspects of the approach put forth by the Pharmacopeial Discussion Group of ICH, published in the May-June issue of the Pharmacopeial Forum The test is grounded in general statistical considerations, quality standards set by the draft Guidances, and capabilities of modern inhalation technology.

8. -8- Parametric tolerance interval approach uses information contained in a sample more efficiently than the DCU tests in the FDA draft Guidances. This increased efficiency allows the test to provide an improved level of consumer protection (in the statistical sense), while at the same time mitigating the producer risk compared to the FDA draft Guidance tests. Quality is defined in terms of the proportion of doses in the batch that fall within a specified target interval. To ensure the pre-defined batch quality, the new test uses three acceptance criteria: for the sample mean, sample standard deviation, and the so-called acceptance value. These acceptance criteria ensure that the mean dose is close to the label claim, that dose variability is controlled and that the frequency of outliers is limited. Control of through-life trends is achieved through a stratified sampling plan that allows simultaneous evaluation of both between-container and through-container-life uniformity of multi-dose products using a single test. The test establishes a uniform minimal quality standard regardless of the dosage form (e.g., MDI, DPI, multi-dose, unit-dose, sprays), yet allows the producer to select the testing schedule most appropriate for their product. The improvements accomplished by this test are due to the use of a parametric approach (rather than the non-parametric approach of the draft Guidances) and an increased sample size (price producers have to pay). Parametric tolerance interval approach uses information contained in a sample more efficiently than the DCU tests in the FDA draft Guidances. This increased efficiency allows the test to provide an improved level of consumer protection (in the statistical sense), while at the same time mitigating the producer risk compared to the FDA draft Guidance tests. Quality is defined in terms of the proportion of doses in the batch that fall within a specified target interval. To ensure the pre-defined batch quality, the new test uses three acceptance criteria: for the sample mean, sample standard deviation, and the so-called acceptance value. These acceptance criteria ensure that the mean dose is close to the label claim, that dose variability is controlled and that the frequency of outliers is limited. Control of through-life trends is achieved through a stratified sampling plan that allows simultaneous evaluation of both between-container and through-container-life uniformity of multi-dose products using a single test. The test establishes a uniform minimal quality standard regardless of the dosage form (e.g., MDI, DPI, multi-dose, unit-dose, sprays), yet allows the producer to select the testing schedule most appropriate for their product. The improvements accomplished by this test are due to the use of a parametric approach (rather than the non-parametric approach of the draft Guidances) and an increased sample size (price producers have to pay).

9. -9- The IPAC-RS companies and the DCU Working Group under the leadership of prominent industry experts have undertaken an unprecedented effort to develop a test that could replace the DCU tests in the draft CMC Guidances. In this process, the DCU Working Group has consulted with ITFG scientists, academicians and representatives of the Agency. The Working Group expects to submit a written proposal on the alternative DCU test to the Agency in the fall of 2001. the proposed test will benefit the Agency, the industry and patients by establishing a long-term solution to the control of DCU in OINDP, by ensuring consistent quality standards for such products, and by facilitating the development and CMC approval of new orally inhaled and nasal medicines. The IPAC-RS companies and the DCU Working Group under the leadership of prominent industry experts have undertaken an unprecedented effort to develop a test that could replace the DCU tests in the draft CMC Guidances. In this process, the DCU Working Group has consulted with ITFG scientists, academicians and representatives of the Agency. The Working Group expects to submit a written proposal on the alternative DCU test to the Agency in the fall of 2001. the proposed test will benefit the Agency, the industry and patients by establishing a long-term solution to the control of DCU in OINDP, by ensuring consistent quality standards for such products, and by facilitating the development and CMC approval of new orally inhaled and nasal medicines.

10. -10- Key Concerns �15% label claim mass balance requirement in draft Guidances is is not justified as a drug product specification: Mass balance attempts to measure emitted dose, which is controlled by a separate spec (DCU) Could be appropriate as part of system suitability control, but not as a release specification for finished drug product Limits should be determined from validation studies and not set arbitrarily Label claim is not necessarily defined by the total mass of drug collected on all stages and accessories Compliance in general is not feasible (database analysis) Update Collected and analyzed industry data. Only 11% of products (4of 35) have no results outside 85-115% LC submitted report to FDA in August 2000 Next Steps Need to receive clarification from the Agency on intention of the mass balance requirement and explore alternate ways to address Agency�s concerns. For instance, mass balance may be valuable as a control of system suitability. Working Group prepared proposal for PQRI to investigate this issue and make a data-based recommendation for the CMC Guidances Additional details in PSD paperKey Concerns �15% label claim mass balance requirement in draft Guidances is is not justified as a drug product specification: Mass balance attempts to measure emitted dose, which is controlled by a separate spec (DCU) Could be appropriate as part of system suitability control, but not as a release specification for finished drug product Limits should be determined from validation studies and not set arbitrarily Label claim is not necessarily defined by the total mass of drug collected on all stages and accessories Compliance in general is not feasible (database analysis) Update Collected and analyzed industry data. Only 11% of products (4of 35) have no results outside 85-115% LC submitted report to FDA in August 2000 Next Steps Need to receive clarification from the Agency on intention of the mass balance requirement and explore alternate ways to address Agency�s concerns. For instance, mass balance may be valuable as a control of system suitability. Working Group prepared proposal for PQRI to investigate this issue and make a data-based recommendation for the CMC Guidances Additional details in PSD paper

11. -11- Key Concerns Draft BA/BE Guidance recommends that to establish BE, the Test and Reference products have to demonstrate equivalent PSD profiles, based on chi-square differences between T and R. This method has limitations: developed for one particular product type and specific particle sizing equipment - applicability to other products and PSD methods may be limited critical equivalence limit is set arbitrarily . �Update Carried out initial investigation of alternate analytical techniques, such as that based on bootstrapping, that may improve the discriminating ability of profile comparisons, and provide consistency in the approach used for various products and measuring devices. Next Steps Recommend further investigation of profile comparison methods to: identify appropriate means to compare Reference and Test products evaluate what test metrics have clinical relevance. PSD Working Group prepared a proposal for PQRI to investigate whether a method for comparing particle size distributions of the Test and Reference product may be developed such that it does not depend on particular product type or particle sizing equipment, and may include metrics that relate to clinical relevance of various particle sizes. Key Concerns Draft BA/BE Guidance recommends that to establish BE, the Test and Reference products have to demonstrate equivalent PSD profiles, based on chi-square differences between T and R. This method has limitations: developed for one particular product type and specific particle sizing equipment - applicability to other products and PSD methods may be limited critical equivalence limit is set arbitrarily . �Update Carried out initial investigation of alternate analytical techniques, such as that based on bootstrapping, that may improve the discriminating ability of profile comparisons, and provide consistency in the approach used for various products and measuring devices. Next Steps Recommend further investigation of profile comparison methods to: identify appropriate means to compare Reference and Test products evaluate what test metrics have clinical relevance. PSD Working Group prepared a proposal for PQRI to investigate whether a method for comparing particle size distributions of the Test and Reference product may be developed such that it does not depend on particular product type or particle sizing equipment, and may include metrics that relate to clinical relevance of various particle sizes.

12. -12- Key Concerns CMC draft Guidances require a large number of tests on the finished drug product, some of which are redundant or add little value to the assurance of product quality Update Collected industry data on a number of tests Developed data-based consensus recommendations Proposed alternate language for draft MDI/DPI guidance regarding eight MDI tests The overall goal of the investigation and recommendations is to: maximize the value of characterization and control testing minimize redundant testing and testing that does not provide meaningful information about product quality. Submitted findings to FDA in May 2001 Paper: Recommendations for Tests and Methods Key Concerns CMC draft Guidances require a large number of tests on the finished drug product, some of which are redundant or add little value to the assurance of product quality Update Collected industry data on a number of tests Developed data-based consensus recommendations Proposed alternate language for draft MDI/DPI guidance regarding eight MDI tests The overall goal of the investigation and recommendations is to: maximize the value of characterization and control testing minimize redundant testing and testing that does not provide meaningful information about product quality. Submitted findings to FDA in May 2001 Paper: Recommendations for Tests and Methods

13. -13- Recommendations for Tests and Methods Paper: Eight MDI tests investigated are: - Water Content - Pressure - Shot Weight - Particle Size Distribution - Spray Pattern - Dose Content Uniformity - Plume Geometry - Impurities and Degradants Provides a critical assessment of the value that these individual tests add to the development and control of a new product. Concludes that a fixed list of control tests may not be appropriate for all products. Concludes that the draft CMC MDI/DPI Guidance: should support the concept of characterizing a new product in development and applying that information to select appropriate control tests for the commercial product; and should support minimization of redundant control tests which do not add meaningful information about product quality. Next Steps Team considering development of proposals that could be submitted to PQRI based on the concepts and the findings in Recommendations for Tests and MethodsRecommendations for Tests and Methods Paper: Eight MDI tests investigated are: - Water Content - Pressure - Shot Weight - Particle Size Distribution - Spray Pattern - Dose Content Uniformity - Plume Geometry - Impurities and Degradants Provides a critical assessment of the value that these individual tests add to the development and control of a new product. Concludes that a fixed list of control tests may not be appropriate for all products. Concludes that the draft CMC MDI/DPI Guidance: should support the concept of characterizing a new product in development and applying that information to select appropriate control tests for the commercial product; and should support minimization of redundant control tests which do not add meaningful information about product quality. Next Steps Team considering development of proposals that could be submitted to PQRI based on the concepts and the findings in Recommendations for Tests and Methods

14. -14- Key Concerns What are appropriate reporting/identification/qualification thresholds for leachables & extractables? How is a correlation between leachables and extractables established? Which critical components should be subject to routine extractables testing? What are appropriate practices for establishing safety of leachables? Is extractables profiling appropriate for control of component composition? Update Collected drug product specific leachables and extractables data in order to investigate the concept of correlation Formed Toxicology WG to address toxicology issues for leachables Investigated current supplier practices for control of component composition and extractables profiles Submitted to FDA technical paper, Points to Consider (March 2001) Key Concerns What are appropriate reporting/identification/qualification thresholds for leachables & extractables? How is a correlation between leachables and extractables established? Which critical components should be subject to routine extractables testing? What are appropriate practices for establishing safety of leachables? Is extractables profiling appropriate for control of component composition? Update Collected drug product specific leachables and extractables data in order to investigate the concept of correlation Formed Toxicology WG to address toxicology issues for leachables Investigated current supplier practices for control of component composition and extractables profiles Submitted to FDA technical paper, Points to Consider (March 2001)

15. -15- Points to Consider (March 2001) proposes: Toxicological qualification should be performed only on leachables Reporting and qualification thresholds for leachables A leachables qualification process Alternate language for the draft Guidances, which clarifies the requirements for leachables and extractables studies That a Correlation is established when each leachable in the drug product can be assigned qualitatively, directly or indirectly, to an extractable. Critical components include only those device components that are in contact with the formulation or the patient�s mouth or nasal mucosa. Next Steps Team will submit to PQRI a proposal that: reporting and toxicological qualification thresholds for leachables should be developed, and the thresholds proposed by the Team be considered.Points to Consider (March 2001) proposes: Toxicological qualification should be performed only on leachables Reporting and qualification thresholds for leachables A leachables qualification process Alternate language for the draft Guidances, which clarifies the requirements for leachables and extractables studies That a Correlation is established when each leachable in the drug product can be assigned qualitatively, directly or indirectly, to an extractable. Critical components include only those device components that are in contact with the formulation or the patient�s mouth or nasal mucosa. Next Steps Team will submit to PQRI a proposal that: reporting and toxicological qualification thresholds for leachables should be developed, and the thresholds proposed by the Team be considered.

16. -16- The ITFG/IPAC-RS Collaboration plans to bring several proposals to PQRI, and continue discussions with the Agency regarding the new DCU proposal We hope that through the meetings of the OINDP Subcommittee, Advisory Committee for Pharmaceutical Science, PQRI, and other appropriate fora, the work of the ITFG/IPAC-RS Collaboration will be carefully considered We believe that FDA and industry will be better able to respond to the needs of patients by expediting the availability of new OINDP products while maintaining appropriate standards of safety, efficacy and quality We are grateful for the Agency�s consideration of BA/BE and CMC issues for OINDP, and we thank you for your attention The ITFG/IPAC-RS Collaboration plans to bring several proposals to PQRI, and continue discussions with the Agency regarding the new DCU proposal We hope that through the meetings of the OINDP Subcommittee, Advisory Committee for Pharmaceutical Science, PQRI, and other appropriate fora, the work of the ITFG/IPAC-RS Collaboration will be carefully considered We believe that FDA and industry will be better able to respond to the needs of patients by expediting the availability of new OINDP products while maintaining appropriate standards of safety, efficacy and quality We are grateful for the Agency�s consideration of BA/BE and CMC issues for OINDP, and we thank you for your attention

17. Bioequivalence Studies for Locally Acting Nasal Drugs Presented by Joel Sequeira, Ph. D. Rockville, MD July 2001 Thank you� I am speaking here as a representative of �.Thank you� I am speaking here as a representative of �.

18. -18- In its 1� year history, the BA/BE Team has been very productive and has worked constructively on these very difficult issues... ..In its 1� year history, the BA/BE Team has been very productive and has worked constructively on these very difficult issues... ..

19. -19- We do not have substantive new approaches on dose-response for efficacy, but feel that risk assessment and risk management must be done first to put this whole issue of nasal drugs into proper perspective, as discussed later in this presentation. In vitro study designs in draft BA/BE Guidance: useful for determining comparability of products, but unproven value for establishing clinical equivalence and substitutability Support inclusion of at least two doses of the Reference and Test product in the clinical dose-ranging study, and at least one of these doses should be representative of the currently approved dosage regimen for the Reference productWe do not have substantive new approaches on dose-response for efficacy, but feel that risk assessment and risk management must be done first to put this whole issue of nasal drugs into proper perspective, as discussed later in this presentation. In vitro study designs in draft BA/BE Guidance: useful for determining comparability of products, but unproven value for establishing clinical equivalence and substitutability Support inclusion of at least two doses of the Reference and Test product in the clinical dose-ranging study, and at least one of these doses should be representative of the currently approved dosage regimen for the Reference product

20. -20- The traditional treatment study offers the most appropriate study design for assessing nasal drug products intended for local delivery. There is a need for the draft BA/BE Guidance to further develop the statistical requirements for this study if it is to be used for equivalence testing and link appropriately to the guidance on Allergic Rhinitis, without confusing the issues of equivalence and comparability. Weaknesses of TTS include dependence on seasons, measurable placebo effect 2 week duration is appropriate The traditional treatment study offers the most appropriate study design for assessing nasal drug products intended for local delivery. There is a need for the draft BA/BE Guidance to further develop the statistical requirements for this study if it is to be used for equivalence testing and link appropriately to the guidance on Allergic Rhinitis, without confusing the issues of equivalence and comparability. Weaknesses of TTS include dependence on seasons, measurable placebo effect 2 week duration is appropriate

21. -21- Since the last Advisory Committee meeting, the BA/BE Team has sought additional information to answer the questions posed in connection with dose response studies, in vivo study waivers for locally acting nasal products, and test metrics for in vitro as well as in vivo comparisons. This effort continues to reinforce the earlier findings that the development of robust clinical protocols, the availability of reliable metrics, and the establishment of relevant in vitro test platforms are lagging behind present regulatory needs.Since the last Advisory Committee meeting, the BA/BE Team has sought additional information to answer the questions posed in connection with dose response studies, in vivo study waivers for locally acting nasal products, and test metrics for in vitro as well as in vivo comparisons. This effort continues to reinforce the earlier findings that the development of robust clinical protocols, the availability of reliable metrics, and the establishment of relevant in vitro test platforms are lagging behind present regulatory needs.

22. -22- Casale TB., Azzam SM., Miller RE etal., Demonstration of therapeutic equivalence of generic and innovator beclomethasone in seasonal allergic rhinitis. Ann. Allergy Asthma Immunol 1999; 82:435-41 Design Issues with Casale et al 1999 as a model BE traditional treatment study: Primary objective = Test BDP AQ dose X vs Dose Y vs. placebo Secondary objective = Reference BDP AQ vs. Test BDP AQ add doses Reversed hierarchy more appropriate Designed as difference study, not equivalence Sample size adequate to distinguish between active and placebo but INADEQUATE to distinguish between differing doses of either type of BDP or between the two types of BDP had there actually been a difference Type II design error Detected differences between active and placebo but fail to statistically differentiate between the different actives or different doses of either active. Failure to differentiate does not mean that a difference does not exist, had the design been more robust in order to detect one Order of administration of active then placebo (double dummy) not randomized Danger of bias through wash-out/off effects Casale TB., Azzam SM., Miller RE etal., Demonstration of therapeutic equivalence of generic and innovator beclomethasone in seasonal allergic rhinitis. Ann. Allergy Asthma Immunol 1999; 82:435-41 Design Issues with Casale et al 1999 as a model BE traditional treatment study: Primary objective = Test BDP AQ dose X vs Dose Y vs. placebo Secondary objective = Reference BDP AQ vs. Test BDP AQ add doses Reversed hierarchy more appropriate Designed as difference study, not equivalence Sample size adequate to distinguish between active and placebo but INADEQUATE to distinguish between differing doses of either type of BDP or between the two types of BDP had there actually been a difference Type II design error Detected differences between active and placebo but fail to statistically differentiate between the different actives or different doses of either active. Failure to differentiate does not mean that a difference does not exist, had the design been more robust in order to detect one Order of administration of active then placebo (double dummy) not randomized Danger of bias through wash-out/off effects

23. -23- Steps to Confirming Correct Study Design The recommended study design should address the issue of substitutability and not confuse this with comparability Need to develop statistical requirements for this study design for use in equivalence testing Steps to confirming a correct study design: Draft Guidance must address the issue of substitutability and not confuse this with comparability Need to develop statistical requirements for this study design for use in equivalence testingSteps to confirming a correct study design: Draft Guidance must address the issue of substitutability and not confuse this with comparability Need to develop statistical requirements for this study design for use in equivalence testing

24. -24- One way to deal with open questions in BE study design is to use risk management to focus scientific investigation on those critical elements whose uncertainty should be given priority as the development of guidances progresses Three risk areas that are present with locally acting nasal sprays in the context of dose response and clinical equivalence: primary local effect local side effects systemic side effects from absorption of a fraction of a locally applied preparation While the first two risk areas can possibly be grouped together and dealt with in a single trial, the third must be treated independently. In fact, the types of clinical trials needed to address each risk area may be very different in nature and construction. It cannot, therefore, be presumed that an in vitro test that correctly correlates with the local actions will also be predictive of the systemic outcome. One way to deal with open questions in BE study design is to use risk management to focus scientific investigation on those critical elements whose uncertainty should be given priority as the development of guidances progresses Three risk areas that are present with locally acting nasal sprays in the context of dose response and clinical equivalence: primary local effect local side effects systemic side effects from absorption of a fraction of a locally applied preparation While the first two risk areas can possibly be grouped together and dealt with in a single trial, the third must be treated independently. In fact, the types of clinical trials needed to address each risk area may be very different in nature and construction. It cannot, therefore, be presumed that an in vitro test that correctly correlates with the local actions will also be predictive of the systemic outcome.

25. -25- Although the Team agrees that development and validation of an appropriate model for assessing dose-response as a model of in vivo equivalence (in terms of local efficacy and local side effects) is an important element in development of equivalence standards for this group of products, the BA/BE Team believes that a high risk area in the establishment of product equivalence is the systemic absorption component. We suggest that the design of studies to assess systemic availability and equivalence between nasal solutions for local action deserves appropriate attention. Although the Team agrees that development and validation of an appropriate model for assessing dose-response as a model of in vivo equivalence (in terms of local efficacy and local side effects) is an important element in development of equivalence standards for this group of products, the BA/BE Team believes that a high risk area in the establishment of product equivalence is the systemic absorption component. We suggest that the design of studies to assess systemic availability and equivalence between nasal solutions for local action deserves appropriate attention.