Joint UNICEF, UNFPA & WHO meeting with manufacturers and suppliers of diagnostic products, vaccines, finished pharmaceutical products and active

Transcription

1 Joint UNICEF, UNFPA & WHO meeting with manufacturers and suppliers of diagnostic products, vaccines, finished pharmaceutical products and active pharmaceutical ingredients Copenhagen, Denmark November

2 TECHNICAL UPDATE REGARDING THE INSPECTION OF BIOEQUIVALENCE STUDIES Presentation given by Stephanie Croft Inspection Services Prequalification Team Medicines HIS/EMP/RHT World Health Organization Copenhagen, Denmark November

3 1. Introduction OUTLINE 2. Current guideline requirements 3. Steps of the revision process 4. Main revisions to the guidelines applying to BE studies 5. For more information Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

4 1. Introduction Most products submitted for WHO prequalification are generics and are therefore supported by clinical bioequivalence studies (some by biowaivers). Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

5 1. Introduction In 2014, 6 inspections of CROs: > 1 Notice of concern (issued in 2015) for non compliance > 3 Non-compliant (but no NOC) > 2 Compliant In 2015, 7 inspections of CROs: 4 Compliant 2 Pending 1 inspection performed as a GAP analysis and capacity building exercise in Ethiopia )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

6 2. Current guideline requirements Both industry (CROs) and inspectors make reference to the following guidelines for WHO PQ: )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

7 2. Current guideline requirements For Bioanalysis, CROs and WHO inspectors also make reference to: + articles and otherguidelines as appropriate )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

8 EMA Bioanalytical validation guidelines Analysis of recurring deficiencies found in the field Expert committee/ working group discussions/reports Comments from regulatory authorities of member states WHO Good data management practices EU Annex 11 computerized systems GAMP 5 guidelines Comments from industry stakeholders CFR 21 Part 11 Copenhagen, Denmark November

9 3. Steps of the guideline revision process > Principle agreed during the Oct meeting > Public consultation: May 2015 > Numerous comments (~270 comments) > Discussion during informal consultation meeting: 1 st July 2015 > New public consultation: August 2015 > Still a few comments (90 comments) > Presentation to fiftieth meeting of the WHO Expert Committee meeting in October 2015 > Adopted after minor amendments > Next step: Executive board meeting in May 2016 Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

10 3. Main revisions to the guideline > Structure of the document General section Clinical section Bioanalytical section Pharmacokinetics, statistics, reporting section Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

11 3. Why revise? )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

12 3. Main revisions to the guideline > Updated based on experience from inspections Investigational products packaging and labelling Bioanalytical activities More details on method development, validation Study sample analysis Focus on data integrity Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

13 3. Main revisions to the guideline: Investigational products packaging and labelling This has been raised as one of the most frequently occuring issues since the last 10 years of inspections. New section 14 now gives a detailed description of the necessary steps: )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

14 3. Investigational products packaging and labelling (cont'd) )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

15 3. Main revisions to the guideline: bioanalytical activities > Significantly more detail has been added (section now covers approximately 4 pages), including: Integration settings (smoothing should be kept low enough not to mask interferences or changes in geometry) The different iterations on calibration curves should be saved Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

16 3. Bioanalytical activities (cont'd) > If the first or last calibration sample is rejected, the range should be truncated > Details on audit trail requirements (full, and activated at all times) > Internal standard variation should be trended and used to demonstrate result validity > Incurred sample reanalysis (should be done) > Preparation of calibration curve and quality control samples (should be done simultaneously with subject samples) Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

17 3. Data Integrity: a problem worldwide! Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

18 3. Data Integrity: a problem worldwide! Cetero Research 2011, USA "Widespread falsification and manipulation of equilibration samples to meet predetermined acceptance criteria" Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

19 3. Data Integrity: a problem worldwide! Cetero Research 2011, USA "Widespread falsification and manipulation of equilibration samples to meet predetermined acceptance criteria" MDS Pharma, 2004 & 2006, Canada "biased manipulation of study data resulting in the acceptance of failed runs" GVK, India, 2015 "widespread falsification of ECGs" Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

20 3. Main revisions to the guideline: Increased focus on data integrity In 2015, a Notice of concern was issued by the WHO to a CRO further to the detection of falsification issues by inspectors. Generally, findings of data manipulation in one part of a study will cast doubt on the reliability of the data submitted in other parts of the study! Every CROs objective should be to obtain the true results and not simply passing results )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

21 3. Increased focus on data integrity New: ALL DATA IS IMPORTANT (for instance, blood work, X-rays and ECGs) because they are part of the verification and demonstration that the subject was fit to participate in a BE trial prior to his enrollment and that the drug did not have a negative impact on health during or after the study. )Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

22 5. FOR MORE INFORMATION > Latest draft to be published online when all comments have been analysed and forwarded to subgroup plus Members of the ECSPP for final endorsement. > August 2015 draft (not the most recent draft!) is currently publicly available online at: > quality_assurance/guidance_invivobestudiesqas15622sk pdf Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers Copenhagen, Denmark November

23 THANK YOU FOR YOUR ATTENTION! Please your questions to: and Copenhagen, Denmark November