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Guidelines and Tools available. TRS 937 and BTIF (Bioequivalence Trial Information Form). TRS 937. Basic information including the latest scientific and technical advice in: Technical Report Series (TRS) 937, 2006. TRS 937. Table of Content: General policy

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guidelines and tools available

Guidelines and Tools available

TRS 937 and BTIF (Bioequivalence Trial Information Form)

Dr. Barbara Sterzik, BfArM, Bonn

trs 937
TRS 937

Basic information including the latest scientific and technical advice in:

Technical Report Series (TRS) 937, 2006

Dr. Barbara Sterzik, BfArM, Bonn

trs 9371
TRS 937

Table of Content:

  • General policy
  • Quality control (specification and tests, International reference materials, National laboratories)
  • Quality assurance (GMP, Inspection, Distribution, Risk analysis, Stability)

Dr. Barbara Sterzik, BfArM, Bonn

trs 9372
TRS 937

(Table of Content continue )

  • Prequalification
  • Regulatory guidance on Interchangeability
  • Donation of medicines
  • Regulatory guidance on post-approval changes
  • Nomenclature and computerized systems
  • Summary and recommendations

Dr. Barbara Sterzik, BfArM, Bonn

trs 9373
TRS 937

Dr. Barbara Sterzik, BfArM, Bonn

trs 9374
TRS 937

Annex 7 (TRS 937, 2006, p. 347 ff):

Multisource (generic) pharmaceutical products:

Guidelines on registration requirements to establish interchangeability.

Dr. Barbara Sterzik, BfArM, Bonn

trs 9375
TRS 937

TRS 937 includes revisions/updates:

  • Guidelines on registration requirements to establish interchangeability (annex 7)
  • Guidance on selection of comparator pharmaceutical drugs for equivalence assessment (revision of TRS 902, Annex 11) available on the web site

Dr. Barbara Sterzik, BfArM, Bonn

trs 9376
TRS 937
  • Proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines, immediate release, solid oral dosage forms (annex 8) available on the website
  • Additional guidelines for organizations performing in vivo bioequivalence studies (annex 9)

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 7
TRS 937 – Annex 7

Multisource (generic) pharmaceutical products:

Guidelines on registration requirements to establish interchangeability:

  • Recommendations for sponsors on the requirements for approval a generic product
  • Generic products should be used only after approval

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 71
TRS 937 – Annex 7
  • Regulatory authorities should require the documentation on: GMP quality control specifications pharmaceutical product interchangeability
  • applicable to orally administered drugs as well as to non-orally administered drugs (where systemic exposure measure are suitable e.g. certain rectal, nasal products)

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 72
TRS 937 – Annex 7
  • No need for equivalence studies:e.g.parenterally administered product in aqueous solution (same API in same molar concentration as comparator, similar excipients)orsolution for oral use

equivalent gases

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 73
TRS 937 – Annex 7
  • Bioequivalence studies in human Justification (specific aim, problems, risk) Selection of investigators Study protocol
  • Study design 2-period, single dose, cross-over study in healthy

alternative designs in special circumstances

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 74
TRS 937 – Annex 7
  • Subjects:Number:required sample size depends on variability either known through reasonable literature or by means of a pilot study

considering: drop-outs and withdrawal Selection:healthy, mainly male, 18 – 55 y,

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 75
TRS 937 – Annex 7
  • Subjects:Verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure etc.)Phenotyping of volunteers (possible side effects with “poor metabolisers” may cause drop-outs; variability reduction/explanation)

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 76
TRS 937 – Annex 7
  • Test product (identical to the projected commercial product; GMP;
  • Comparator productnormally the innovator product (quality, efficacy & safety well-assessed)

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 77
TRS 937 – Annex 7

No innovator available:

  • Nationally authorized innovators
  • WHO comparator product (see list TRS 902)
  • ICH et al. innovator

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 78
TRS 937 – Annex 7
  • Study conduct

selection of dose

sampling times (before dosing, at least 1-2 points before Cmax, 2 points around, 3-4 points during elimination)

sample fluids

pk parameter

metabolites

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 79
TRS 937 – Annex 7
  • Quantification of the API (and its metabolite/s)(GLP; methods should meet the requirements of specificity, sensitivity, accuracy, precision reproducibility)
  • Statistical analysis (should be specified in the protocol before data collection starts)

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 710
TRS 937 – Annex 7
  • Acceptance range(90% CI for AUC-ratio; Cmax-ratio of relative bioavailability should lie within the acceptance range 0.80 – 1.25)
  • Reporting of results

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 711
TRS 937 – Annex 7

In vitro Testing

For certain medicines and dosage forms , in vitro documentation of equivalencemay be appropriate (typically solid oral dosage forms)

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 7 in vitro testing
TRS 937 – Annex 7in vitro testing

Dissolution test as a surrogate equivalence test

Criteria for dissolution tests are described and are not those recommended in The International Pharmacopoeia for quality control.

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 7 in vitro testing1
TRS 937 – Annex 7in vitro testing
  • Criteria

Biopharmaceutics Classification System (BCS)

is based on aqueous solubility and intestinal permeability of the drug substance.

API is classified into four classes

Dr. Barbara Sterzik, BfArM, Bonn

trs 937 annex 7 in vitro testing2
TRS 937 – Annex 7in vitro testing

Class 1: high solubility, high permeability

Class 2: low solubility, high permeability

Class 3: high solubility, low permeability

Class 4: low solubility, low permeability

Dr. Barbara Sterzik, BfArM, Bonn

slide24
BTIF

Bioequivalence Trial Information Form (BTIF)

filled out by the applicant

Important for assessors: Reference to the study documentation (ref. to pages, sections) should be given.

Dr. Barbara Sterzik, BfArM, Bonn

slide25
BTIF

Example of the structure of BTIF is presented.

(see appendix)

Dr. Barbara Sterzik, BfArM, Bonn