DEBATING THE OPERATING CURVES FOR DDU TESTS ON MARKETED INHALERS

Transcription

1 DEBATING THE OPERATING CURVES FOR DDU TESTS ON MARKETED INHALERS Industry s problem with the current FDA DDU requirements Presented by Bo Olsson, AstraZeneca R&D Lund on behalf of IPAC-RS DDU Working Group 27 April

2 IPAC-RS developed and submitted PTI test proposal (Nov. 2001) Brief History FDA asked for clarifications, especially for situations with offtarget batch means (Nov 2002) Industry comments indicate DDU specifications too tight FDA Draft CMC Guidances ( ) FDA proposed standards equal to the guidance test as resolution? (Oct 03) Form Working Group under ACPS to resolve remaining issues and finalize test (Jan 2004) IPAC-RS submitted modified procedure (March 2003) FDA asked for theoretical results on other quality standards (April 2003) FDA statisticians discussed additional details (Aug 2003) IPAC-RS submitted requested information and generalized code (June 2003) 2

3 Joint FDA & IPAC-RS Working Group Established in 2004 under FDA Advisory Committee for Pharmaceutical Science (ACPS) Populated by senior representatives from FDA and technical experts from OINDP industry Robert O Neill (Director, Office of Biostatistics, CDER), Chair Moheb Nasr (Director, New Drug Chemistry, CDER) Badrul Chowdhury (Director, Pulmonary Division, CDER) Lawrence Yu (Director, Office of Generic Drugs, CDER) Overall objective: to develop a mutually acceptable, standard DDU specification (test and acceptance criteria) for OINDP, and make a formal recommendation to the ACPS in

4 Consensus Reached to Date Parametric tolerance interval (PTI) approach is an improvement on current DDU test Concept requires refinement and further development to address regulatory requirements It is time to move forward and come to closure Working Group is formed to devote necessary resources and time to resolve issues (through data review and analysis, and development of appropriate statistical procedures) 4

5 Issues where Consensus is Needed Evaluation of simulated performance and actual performance Zero tolerance criterion Statistical details of the test design Applicability to non-normal distributions Better understanding the difference between operating characteristic (OC) curves of draft Guidances and IPAC-RS proposal 5

6 Focus of Today s Presentation FDA is currently not convinced that industry has a problem Show data to demonstrate that Draft Guidance: does not reflect range of OINDP capabilities is overly restrictive compared to non-us public standards does not reflect range of US regulatory practice

7 Data 1. IPAC-RS DDU database (2001) 2. Non-FDA public standards (2004) 3. FDA approved specifications ( ) 7

8 IPAC-RS DDU DATABASE (2001) 80 products*, observations release and real-time stability data * Multiple strengths counted as different products 8

9 Product Status US commercial, approved before % US commercial, approved after % US, phase IIb-application 31% Non-US, commercial 20% Non-US, phase IIb-application 11% Undisclosed 4% US commercial and development products are typically also available on or developed for non-us markets 9

10 Product Types CFC MDI 22% HFA suspension MDI 29% HFA solution MDI 1% Pre-metered DPI 21% Device metered DPI 24% Non-pressurized nasal spray 2% 10

11 observations CFC susp Device met. DPI HFA susp. HFA soln. Pre-met. DPI Product mean Nasal Delivered Dose, %LC Products/batches/tests 11

12 Comparison of Variability grouped by Product Type RSD (%) median RSD CFC HFA HFA Pre-metered Device metered Nasal suspension suspension soln. DPI DPI spray US marketed<1990 US marketed>1990 Non-US marketed US development Non-US development Not disclosed <6% RSD needed to consistently comply with FDA draft specification 12

13 Comparison of Variability grouped by Product Status RSD (%) median RSD US commercial US Development non-us non-us? <1990 >1990 commercial developm. CFC susp HFA susp HFA solution Premetered DPI Device metered DPI Non-pressur. nasal <6% RSD needed to consistently comply with FDA draft specification 13

14 What the Range of Variability Means Practically Majority of products (mostly HFA suspension MDIs and device metered DPIs) would have high failure rate if tested against requirements in Draft Guidance High failure rates are unacceptable from the business perspective Substantially increases cost Stability failures and recalls Process is deemed out of control by the compliance division 14

15 Key Message 1 The DDU requirements in the FDA Guidances are overly restrictive and are not reflective of the range of technological capability of OINDP on the market and in development 15

16 NON-FDA PUBLIC STANDARDS (2004) 16

17 DDU multidose DPI/pMDI Standards in US, Canada, Europe, Australia US CAN EU/AUS Probability to Accept, % Standard Deviation, σ (% of LC) Products in database 22% have RSD<6% 66% have RSD<10% OC curves assuming normal distributed data with batch mean at 100% of label claim and batch standard deviation (σ) made up from equal parts of between-and within-container variation. 17

18 Key Message 2 Public standards for DDU quality other than the FDA Draft Guidances are less stringent, more accurately reflect the range of OINDP capabilities, and represent a better balance between process capability and assuring public safety There appears to be room for alignment of the FDA Draft Guidance standard to other public standards without compromising public safety 18

19 FDA-APPROVED SPECIFICATIONS ( ) COMPARED TO FDA DRAFT GUIDANCE 19

20 IPAC-RS 2003 Survey Requested OC curves for DDU OINDP specifications approved by FDA approved specifications received Frequent exceptions from the draft guidance specification 16 of 24 are to the right of FDA s curve at 90% acceptance and batch mean on target 8 of 24 are to the left (CFC MDIs and nasal suspensions) No chronological pattern observed e.g., more recently approved products are not necessarily all to the right or to the left 20

21 Batch Mean at 100% Label Claim 100 Probability to Accept (%) Batch mean at 100 %LC FDA multidose DPI and MDI Batch standard deviation (% LC) 21

22 Batch Mean 5% off Target 100 Probability to Accept (%) Batch mean at 105 %LC FDA multidose DPI and MDI Batch standard deviation (% LC) 22

23 Batch Mean 10% off Target 100 Probability to Accept (%) Batch mean at 110 %LC FDA multidose DPI and MDI Batch standard deviation (% LC) 23

24 Batch Mean 15% off Target 100 Probability to Accept (%) Batch mean at 115 %LC FDA multidose DPI and MDI Batch standard deviation (% LC) 24

25 What Exceptions? Inner/outer limits Limits on mean Through-container-life testing Life-stage means Sample size Number of actuations in a sample Outlier retesting Other 25

26 Key Message 3 The FDA Draft Guidance requirements do not represent the actual regulatory DDU specifications for many OINDP approved by the FDA since 1990 many OC curves differ substantially from that of the Draft Guidance specification many OINDP will have difficulty meeting the expectations set forth in the Draft Guidance the existence of the range of approved specifications does not negatively impact public health, rather it allows the availability of a range of products and product types to meet the medical need 26

27 EPILOGUE 27

28 Root of the Problem We speculate that Draft Guidance specification is based on historic FDA experience of CFC suspension pmdis Pre-metered DPI Nasal pump sprays Old analytical methodology and sampling plans (excessive priming, beginning only, multiple shots) Now HFA pmdis, multi-dose DPIs and other technologies More discriminating methodology and sampling plans O but same limits 28

29 An in vitro performance standard for DDU is needed such that it: does not reject good batches provides a reasonable target for developers appropriately reflects contemporary formulation and device designs and capabilities of available manufacturing processes avoids frequent exceptions from the public Guidance, coupled with uncertain delays and negotiations during the review and approval process avoids unjustified perception that process is out of compliance Current FDA Draft Guidance s specifications do not fulfil these needs 29

30 Establishing more realistic delivered dose uniformity standards will allow guidance to be both more historically based and forward looking will not change quality of approved products (actual specs approved by FDA) will be more consistent with public standards outside the US will stimulate the development and filing of new and generic products in the US will facilitate and speed up the approval process in the US 30

31 IPAC-RS PTI Test Parametric test simultaneously controls mean and standard deviation no zero tolerance Suitable for all OINDP product types, multidose and single dose Flexible Same consumer protection as FDA draft Guidance Lower producer risk, similar to non-us public standards 31

32 Comparison of OC curves Public standards and IPAC-RS PTI tests US CAN EU/AUS PTI 12/36 PTI 24/72 Probability to Accept, % Standard Deviation, σ (% of LC) 32

33 Conclusion The industry has a problem The 2001 IPAC-RS proposal addresses industry s concerns Joint FDA & IPAC-RS Working Group will work to resolve issues 33

34 Acknowledgments Jeff Blumenstein Mark Broughton Mary Devlin Capizzi David Christopher Claire D Abreu-Hayling Jennifer Gauvin Michael Golden Kristi Griffiths Niels Hartvig Jim Jamieson Paul Kovach Douglas Lee Stefan Leiner Svetlana Lyapustina Bo Olsson David Radspinner Lene Garde Rasmussen Darlene Rosario Dennis Sandell Orin Tempkin Henrik Thoning Keith Truman Ed Warner Steven White Paul Wright Bruce Wyka Jerry Zhang Aradigm AstraZeneca Aventis Boehringer Ingelheim Eli Lilly IPAC-RS Companies GlaxoSmithKline IVAX Kos Nektar Novo Nordisk Novartis Pfizer Schering-Plough 34