Birth Certificate of Louis Pasteur Bioequivalence studies Regulatory Requirements on Conduct

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					                Bioequivalence studies:
        Regulatory Requirements on Conduct &
                Documentation of BE.
               Guidance & Experience.

    Meeting on WHO Prequalification Programme on Priority
               Essential Medicines, WHO/EMRO
                 6-7 June 2007, Cairo, EGYPT
                        Dr Lembit Rägo
                          Coordinator
         Quality Assurance and Safety: Medicines (QSM)
             Medicines Policy and Standards (PSM)
           WHO Headquarters, Geneva, Switzerland
                         ragol@who.int

1
                                                History. One of the medicine's
                                                most celebrated clinical trials.

                                                Wood engraving from 1885 showing a
                                                young patient receiving an anti-rabies
                                                vaccine developed by Louis Pasteur. A
                                                physician administers the vaccine while
                                                Pasteur, a chemist, looks on.




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 2
        What are the problems with BE studies (I)?

       BE studies – 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…)
       …
Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 3
        What are the problems (II)?

       CROs increasing in middle-income developing countries
           Local CROs and branches of international CROs


       Recent sever problems with CROs revealed by WHO
        inspections (in the framework of WHO prequalification
        programme) in some developing countries




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 4
        WHO Glossary
       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.
       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

Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 5
        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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 6
        Bioequivalence studies


       Products to be prequalified usually multisource
        (generic) products

       Therapeutic equivalence generally demonstrated by
        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)


Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 7
        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
       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)
       WHO Training courses (see materials of previous courses on PQ web
        site)
       … advise to manufacturers applying for prequalification

Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 8
        WHO Documents

       The Expert Committee
        documents pass wide
        international consultation
        and are finally adopted by
        the Committee composed
        of outstanding inernational
        technical experts




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 9
                                                 1
                                                1.1




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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                                                1.2




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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                                                2




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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                                                3.1




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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                                                3.2




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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                                                4




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Health Technology and Pharmaceuticals
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                                                5




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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                                                6.1




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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                                                6.2




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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        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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 19
      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



Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 20
       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



Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 21
        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



Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 22
        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



Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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       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



Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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        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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 25
        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!




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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        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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 27
         Record-keeping and handling of data (continued)

        Deliberate attempt to change subject code
        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
        CRF (IPΦ) used was not specific to the study
        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
        …

Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 28
        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!




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
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        Reporting.
        (OECD GLP 2 & 9)

       Same or different stock solution for calibration/control
        samples?
       Some zidovudine conc's were lamivudine conc's
       Discrepancy between concentration on chromatogram and
        in study report
       Composition of buffer for sample preparation not in SOP
       Errors in the bioanalytical report
       Rounding errors



Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 30
        What is WHO doing regarding 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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 31
        BSC based bio-waiver: a long way from
        concept to practice
       1995 FDA – SUPAC guidance
       1996 WHO – Interchangeability guideline - cautious and vague
        attitude
       1999 WHO – "Blue book" – cautious recognition of BCS potential,
        no change in reserved position
       2000 FDA – Guidance on BA and BE waiver based on BCS, deals
        with INDs/NDAs, ANDAs and post-approval changes
       2001 EU – Note for guidance on BA and BE – takes BCS into
        consideration
       2006 WHO – Interchangeability guideline and specific BCS
        guideline proposing the implementation of BCS approach


Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 32
      WHO Technical Report Series, No. 863, 1996


            Annex 9
            Multisource (generic) Pharmaceutical Products:
             Guidelines on Registration Requirements to Establish
             Interchangeability.




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 33
      WHO Technical Report Series, No. 863, 1996


            Annex 9, Part III – Tests for equivalence
            Section 13: In vitro dissolution
            Comparative in vitro dissolution studies may be useful in
             the documentation of equivalence between two
             multisource pharmaceutical products. However because
             of the many limitations associated with the use of in vitro
             dissolution in the documentation of equivalence it is
             recommended in these guidelines that its application for
             this purpose should be kept to a minimum.




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 34
       WHO Technical Report Series, No. 863, 1996


             Annex 9, Part III, Section 13: In vitro dissolution
             In vitro dissolution testing … should be reserved for rapidly
              dissolving drug products. When the multisource test and
              reference products both dissolve with sufficient rapidity
              (e.g. >80% in 15 minutes) their in vivo equivalence may be
              presumed. Approval of multisource formulations by the
              use of comparative in vitro dissolution studies should be
              based on the generation of comparative dissolution
              profiles rather than single-point dissolution tests …
              Multiple dissolution test conditions and physiologically
              relevant media are recommended.




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 35
      Chronology of BCS implementation

    1995 FDA – SUPAC guidance
    1996 WHO – Interchangeability guideline - cautious and vague attitude
    1999 WHO – "Blue book" – cautious recognition of BCS potential, no
     change in reserved position
    2000 FDA – Guidance on BA and BE waiver based on BCS, deals with
     INDs/NDAs, ANDAs and post-approval changes
    2001 EU – Note for guidance on BA and BE – takes BCS into
     consideration
    2006 WHO – Interchangeability guideline and specific BCS guideline
     proposing the implementation of BCS approach




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 36
      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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 37
      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 characterising 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.




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 38
      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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 39
       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




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 40
     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_9
            37.pdf




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 41
       WHO Technical Report Series, No. 937, 2006
       Annex 8


           WHO revisions to the criteria for BCS classification
            High solubility: max 250ml at 37C over pH 1.2-6.8
                  FDA - pH 1-7.5
                  EMEA - pH 1-8, preferably 1, 4.6 and 6.8
              Highest strength (dose): according to Essential Medicines
               List (14th EML 2005)
              Permeability: absorbed at least from 85%
                  FDA - 90% or more
                  EMEA – linear and complete absorption




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 42
      WHO Technical Report Series, No. 937, 2006
      Annex 8


  WHO extensions to the scope of application of biowaiver
   Class I APIs classification criteria relaxed - both solubility and
    permeability
   Class II weak acidic APIs eligible for biowaiver, if
          soluble in 250 ml or less at pH 6.8
          rapid dissolution at pH 6.8
          similar dissolution profiles (f2) to comparator at pH 1.2, 4.5 and 6.8
     Class III APIs eligible for biowaiver, if very rapid dissolution




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 43
         BCS according to WHO

                                 Solubility at pH 1-6.8

                         CLASS I                   CLASS II
                         Highly permeable          Highly permeable
                         Highly soluble            Poorly soluble
                         (very rapid dissolution   Eligible only if the
                         or profile comparison)    D:S at pH 6.8 is 250ml or
                         Eligible                  lower*
  Absorbed
    >85%                                           CLASS IV
                         CLASS III
                         Poorly permeable          Poorly permeable
                         Highly soluble            Poorly soluble
                         Eligible if very
                         rapidly dissolving        Not eligible
Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 44
     WHO Technical Report Series, No. 937, 2006
     Annex 8


            3 Tables of APIs
                 non-complementary orally administered EML APIs
                 complementary EML APIs
                 newly /2005/ classified APIs
            In case of incomplete data APIs classified conservatively
             ("worst case" approach)
            Potential risks, indications (EML) and comments included
             to support risk assessment and decision making




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 45
      WHO Technical Report Series, No. 937, 2006
      Annex 8




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 46
        Conclusions


       QUALITY first, only then BE
       For many developing country manufacturers BE studies a
        "bottleneck"
       Need to start implementing BSC based biowaiver in PQ
        Programme step-by-step
       Need for additional guidance and training re BE and
        BSC/dissolution based biowaiver




Department of Medicines Policy and Standards,
Health Technology and Pharmaceuticals
 47

				
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