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WHO Prequalification Programme June 2007
Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutical Classification System.
Hotel Bratislava
1 Malyshko Street
Kyiv, Ukraine
Date: 25 to 27 June 2007
Multisource (generic) products Multisource (generic) products
WHO Prequalification Programme June 2007
Multisource (generic) products Multisource (generic) products
WHO Guidelines for Registration Requirements to Establish Interchangeability
Presenter: Dr Lembit Rägo
Director and Coordinator, Quality Assurance and Safety: Medicines (QSM)
Medicines Policy and Standards (PSM)
World Health Organization
Geneva, Switzerland
E-mail: [email protected]
WHO Prequalification Programme June 2007
What are the problems with BE studies (I)?
BE studies in vivo – small scale clinical trials!
Lack of appropriate regulations
Lack of ethical review/ review capacity
Local industries may not have the experience and resources
Lack of regulatory capacity– Lack of financial resources – Lack of adequately trained human resources
Copying ICH GCP and other relevant documents from ICH regions alone does not solve the problems (regulations do not stand in vacuum…)
…
WHO Prequalification Programme June 2007
What are the problems (II)?
Complaints that no organizations that can carry out BE studies in vivo
– Historically in Europe it was done by universities
CROs increasing in middle-income countries– Local CROs and branches of international CROs
Sever problems with CROs revealed by WHO inspections (in the framework of WHO prequalification programme) in some developing countries
WHO Prequalification Programme June 2007
WHO Definitions Related to in vivo BE Studies (I)
Contract Research organization (CRO): A scientific organization (commercial, academic or other) to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be defined in writing.
Good Clinical Practice (GCP): A standard for clinical studies which encompasses the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies and which ensures that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are properly documented.
WHO Prequalification Programme June 2007
WHO Definitions Related to in vivo BE Studies (II)
Good Laboratory Practice (GLP)*: A quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported (OECD/WHO) *as applied to human bioanalysis studies
WHO Prequalification Programme June 2007
Handbook for Good Clinical Research Practice (GCP), World Health Organization 2005
Structured as 14 principles, 115 pages
Serves as and adjunct to WHO's GCP from 1995, and subsequent ICH GCP
Contains CD version with all major reference documents as hyperlinks
WHO Prequalification Programme June 2007
Bioequivalence studies
Products to be prequalified usually multisource (generic) products
Therapeutic equivalence generally demonstrated by a bioequivalence study in CROs
Findings of deficient and discrepant bioequivalence data and non-compliance with norms and standards for GCP (WHO) and GLP (WHO GPNPCL, and OECD/WHO as appropriate)
WHO Prequalification Programme June 2007
What resources are available to assist proper conduct of BE studies from WHO (I)?
Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (1)
Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (2)
Additional guidance for organizations performing in vivo bioequivalence studies (3)
Guidance on the selection of comparator pharmaceutical products for equivalence
WHO Prequalification Programme June 2007
What resources are available to assist proper conduct of BE studies from WHO (II)?
Assessment of interchangeable multisource (generic) products (4)
"Note to applicants on the choice of comparator products for the prequalification project” (see WHO PQ web site - 5)
WHO Public Inspection reports of CROs (see PQ web site - 6)
Guidance for Ethics Committees (7)
WHO Training courses (see materials of previous courses on PQ web site)
… advise to manufacturers applying for prequalification
WHO Prequalification Programme June 2007
WHO Documents
The Expert Committee documents pass wide international consultation and are finally adopted by the Committee composed of outstanding inernational technical experts
WHO Prequalification Programme June 2007
WHO Technical Report Series, No. 937, 2006 Annex 7
WHO Technical Report Series, No. 937, 2006 Annex 7
Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.
Intended to provide recommendations to sponsors and national regulatory authorities on in vivo and vitro requirements to assure interchangeability of multisource medicinal products without compromising quality, safety and efficacy.
http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf
WHO Prequalification Programme June 2007
WHO Technical Report Series, No. 937, 2006, Annex 7
WHO Technical Report Series, No. 937, 2006, Annex 7
Section 9: In vitro testing
Over the past three decades, dissolution testing has evolved into a powerful tool for characterizing the quality of oral pharmaceutical products.
The dissolution test … is now emerging as a surrogate equivalence test for certain categories of orally administered pharmaceutical products.
For these products (typically solid oral dosage forms containing APIs with suitable properties) a comparative in vitro dissolution profile similarity can be used to document equivalence of a multisource with a comparator product.
WHO Prequalification Programme June 2007
WHO Technical Report Series, No. 937, 2006 Annex 7
WHO Technical Report Series, No. 937, 2006 Annex 7
Section 9: In vitro testing
9.1 In vitro testing and the Biopharmaceutical Classification System
9.1.1 Biopharmaceutics classification system– High solubility– High permeability
9.1.2 Determination of dissolution characteristics of multisource products in consideration of a biowaiver based on BCS
– Very rapidly dissolving – Rapidly dissolving
WHO Prequalification Programme June 2007
WHO Technical Report Series, No. 937, 2006 Annex 7
WHO Technical Report Series, No. 937, 2006 Annex 7
Section 9: In vitro testing
9.2 Qualification for a biowaiver based on BCS
9.2.1 Dissolution criteria for biowaivers based on the BCS according to the properties of active pharmaceutical ingredients
WHO Prequalification Programme June 2007
WHO Technical Report Series, No. 937, 2006 Annex 8
WHO Technical Report Series, No. 937, 2006 Annex 8
Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms".
Intended to give national regulatory authorities information on orally administered APIs on WHO Model List of Essential Medicines whether biovaiwer can be granted for generic formulations.
http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf
WHO Prequalification Programme June 2007
What is WHO doing re ETHICS?
Operational Guidelines for Ethics Committees that Review Biomedical Research (TDR/PRD/ETHICS/2000.1)
http://www.who.int/tdr/publications/publications/pdf/ethics.pdf
Surveying and Evaluating Ethical Review Practices: a complementary guideline to the Operational Guidelines for Ethics Committees that Review Biomedical Research (PUB: TDR/PRD/ETHICS/2002.1)
http://www.who.int/tdr/publications/publications/pdf/ethics2.pdf
7
WHO Prequalification Programme June 2007
CRO inspections - areas covered
Clinical: General organization, the protocol, protection of trial subjects, responsibilities of the investigator, responsibilities of the sponsor/monitor, record-keeping and handling of data, handling and accountability for pharmaceutical products, quality assurance for the conduct of a clinical trial
Bio-analytical: Apparatuses/material/reagents, SOPs, performance of the study, test and reference items, storage and retention of records and materials, quality assurance
PK analysis and statistics
Reporting
WHO Prequalification Programme June 2007
Examples of findings
Based on CRO inspections performed by WHO
Inspections study-specific
Team of 3 inspectors (2 WHO team + national inspector as observer)
Based on 6 CROs inspected
WHO Prequalification Programme June 2007
Findings. General organization.
Transfer of responsibilities from sponsor to CRO not documented
Unclear procedure for assigning Subject ID (two subjects assigned the same ID on the Attendance Sheet Form!)
No SOP for drug dispensing
No SOP for assigning study numbers
No trial site staff sample signature log for the study
Organization chart not readily available, no version date
No QC system to ensure accuracy and consistency in recording and document control
WHO Prequalification Programme June 2007
Findings. The protocol (II)
Validity of screening tests?
No CRFs designed for the study (raw data not transferred to CRFs)
Not included:
Name and address of sponsor
Description of trial site and information on investigators
Method and procedure of randomisation, randomisation schedule and how it was established
Method and timing of subject allocation to investigational groups
WHO Prequalification Programme June 2007
Findings. The Protocol, cont. (III)
Not included:
Information to volunteers (informed consent)
Procedures for maintaining subject identification code list
Statistical justification for the number of subjects
Method for measuring blood pressure - sitting or supine? And if both, which value to use…
Type of test tubes for blood sampling
PK analysis; Method of calculating PK pararmeters, e.g. AUC, how to deal with deviations from planned sampling times
How to evaluate the results, including statistics and how to handle withdrawals
WHO Prequalification Programme June 2007
Responsibilities of the Sponsor/Monitor
No monitors appointed by the sponsor. No monitoring/audit reports available.
No evidence of assessment of the trial site (labs, equipment, staff, facilities)
Audits performed by the sponsor, but scheduled after the report was issued and no audits' reports available
Issues with certificate of insurance subscribed by the CRO
WHO Prequalification Programme June 2007
Record-keeping and handling of data
No study or protocol number on ECGs to link them to the study.
Of 95 ECGs copied by inspectors, 43 appeared to have been recorded from one subject, 21 from a second subject and 11 from a third subject (i.e. in total 75 ECGs from 3 persons!).
For several subjects the "screening" and "follow up" ECGs appeared to have been recorded from different subjects
No mention on ECG print outs of the identity of the equipment used
Some ECGs had no date of birth of subject
Doubts as to the authenticity of ECG documentation!
WHO Prequalification Programme June 2007
Record-keeping and handling of data (continued)
No mention of name, batch no or expiry date of the in vitro diagnostic serology test kit in source doc's or lab data
Discrepancies between Attendance Sheet Forms and CRF Screening pages (screening visit dates)
Discrepancies between Volunteer Card and CRF (smoking/alcohol)
Unclear dosing time
Identical (actual) blood sampling times for two subjects!
Recordings of actual sampling times - same handwriting, however initials of phlebotomists different at different sampling times!
Deviations from planned blood sampling times not reported
Inconsistencies in screening dates
WHO Prequalification Programme June 2007
Record-keeping and handling of data (continued)
Discrepancies between source documents and study report
Method/procedure of randomization not documented
No record of subjects screened
Source documents not kept
Original entry erased!
Type of tubes and anticoagulant used not documented
Errors on the CRFs
Expiry date of medications not recorded on CRFs
Appearance of tablets incorrectly described
Missing: Lab data, ECG…
Final study report not signed by the monitor
…
WHO Prequalification Programme June 2007
Bioanalytical. Test and reference items
Batch numbers of reference substances used not documented – were the batches used, those for which CAs were available?
Not possible to verify purity of reference substances used!
WHO Prequalification Programme June 2007
Reporting.(OECD GLP 2 & 9)
Some zidovudine conc's were lamivudine conc's
Discrepancy between concentration on chromatogram and in study report
Same or different stock solution for calibration/control samples?
Composition of buffer for sample preparation not in SOP
Errors in the bioanalytical report
Rounding errors
WHO Prequalification Programme June 2007
Conclusions
QUALITY first, only then BE has any meaning
If consistent quality can not be assured this has to be achieved first!
For many developing country manufacturers in vivo BE studies are a "bottleneck"
Need for additional guidance and training regarding BE and BSC/dissolution based biowaiver implementation