Bioequivalence of Locally Acting Gastrointestinal Drugs: An Overview

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Bioequivalence of Locally Acting Gastrointestinal
Drugs An Overview

• Lawrence X. Yu, Ph.D.
• Director for Science
• Office of Generic Drugs, OPS, CDER
• Food and Drug Administration

Advisory Committee for Pharmaceutical Science and
Clinical Pharmacology July 23, 2008
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ACPS-CP QuestionsBioequivalence Methods for
Locally Acting Drugs that Treat Gastrointestinal
(GI) Conditions

• What role should biorelevant dissolution play in
  developing BE recommendations for low solubility
  locally acting drugs that treat GI conditions?
• What role should systemic pharmacokinetics play
  in developing BE recommendation for low
  solubility locally acting drugs that treat GI
  conditions?

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Bioequivalence

• The absence of a significant difference in the
  rate and extent to which the active ingredient or
  active moiety in pharmaceutical equivalents or
  pharmaceutical alternatives becomes available at
  the site of drug action when administrated at the
  same molar dose under similar conditions in an
  appropriately designed study (21 CFR 320.1)

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Pharmaceutical Equivalence

• Same active ingredient(s)
• Ranitidine Hydrochloride
• Same dosage form
• Tablet, Capsule, Solution, Suspension...
• Same route of administration
• Oral, Parenteral, Topical...
• Identical in strength or concentration
• 100 mg, 10 mg/mL...
• May differ in characteristics such as shape,
  excipients, packaging...

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When are Bioequivalence Studies Needed?

• Development of New Drugs
• To link clinical trial material to a to-be-
  marketed product
• Change in formulation
• Change in manufacturing process
• Change in dosage form (capsule to tablet)
• Approval of Generic Drugs (ANDA)
• Post-Approval Changes

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Approaches to Determining Bioequivalence (21
CFR320.24)

• In vivo measurement of active moiety or moieties
  in biologic fluid
• Pharmacokinetic (PK) study
• In vivo pharmacodynamic (PD) comparison
• Bioequivalence study with PD endpoints
• In vivo limited clinical comparison
• Bioequivalence study with clinical endpoints
• In vitro comparison
• Any other approach deemed appropriate by the FDA

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Pharmacokinetic (PK) Study
Cmax
Concentration
Tmax - time of maximum concentration
Time
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Why Are Locally Acting GI Drugs Unique?
Systemic Circulation
Sites of Action for Systemic Drugs
Dose to Patient
GI Tract
Liver
Site of Action for GI Drugs
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Why Are Locally Acting GI Drugs Unique?
Site 1
Site 2
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Locally Acting GI Drugs Performance Factors

• Dosage Form Factors
• Immediate release, delayed release, modified
  release, etc.
• Drug substance and excipient factors
• Solubility, permeability, excipients, etc.
• Physiological Factors
• GI Motility, GI pH, etc.

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Food and Drug AdministrationAdvisory Committee
for Pharmaceutical ScienceOctober 19-20, 2004
Agenda for GI Drugs

• Bioequivalence of Locally Acting GI Drugs An
  Introduction Lawrence X. Yu, Ph.D., FDA
• Bioequivalence Testing for Locally Acting GI
  Drugs Scientific Principles Gordon L.
  Amidon, Ph.D., The University of Michigan
• Bioequivalence of Locally Acting GI
  Drugs Robert Lionberger, Ph.D., FDA
• Questions - Bioequivalence Testing for Locally
  Acting GI Drugs

http//www.fda.gov/ohrms/dockets/ac/04/slides/2004
-4078s2.htm
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Food and Drug AdministrationAdvisory Committee
for Pharmaceutical ScienceOctober 19-20, 2004
Questions for GI Drugs

• For locally acting GI drugs, is PK, if
  measurable, an in vivo test sensitive to
  formulation performance and useful as a part of a
  determination of bioequivalence?
• Are there any drug specific issues that would aid
  FDA in interpreting the results of a PK study on
  a GI acting drug with respect to a conclusion
  about bioequivalence?
• When is it possible to use dissolution testing
  alone to demonstrate bioequivalence of GI acting
  drugs?
• When should comparative clinical trial studies be
  conducted to demonstrate bioequivalence?

http//www.fda.gov/ohrms/dockets/ac/04/slides/2004
-4078S2_12_GI-Questions_files/slide0001.htm
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Food and Drug AdministrationAdvisory Committee
for Pharmaceutical ScienceOctober 19-20, 2004
Minutes for GI Drugs

• The Committee discussed the use of dissolution
  testing to establish bioequivalence for drugs
  that act in the GI tract. The members added that
  in vitro testing is good if there is control over
  the test. The members emphasized that dissolution
  tests are needed early on in the process, in
  order to narrow down the variables. Further,
  pharmacokinetics studies are useful to assure
  safety of the test product.
• In addition, the members stressed that
  dissolution tests are formulation tests, and can
  be a surrogate for clinical tests. The Committee
  discussed that dissolution tests can be very
  discriminating if the study is designed well.
  Although the committee felt that the Agency had
  all the data necessary to do dissolution testing
  for the products being discussed, dissolution
  test procedures can be simple for some drugs, but
  complicated for others. The Committee argued
  that when a lot of background information is
  available, the dissolution test could be used.
  However, the members added that when doing
  dissolution testing, careful attention needs to
  be paid to the calibrator.

http//www.fda.gov/ohrms/dockets/ac/04/minutes/200
4-4078M1.htm
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Food and Drug AdministrationAdvisory Committee
for Pharmaceutical ScienceOctober 19-20, 2004
Minutes for GI Drugs

• The members emphasized that as local acting
  products, such as GI, nasal, or topical are part
  of the Critical Path Initiative, they could
  contribute to the timely approval of generic
  drugs.
• In conclusion, the Committee agreed it was
  difficult to reach a consensus, but that in order
  to prove bioequivalence in vitro dissolution
  along with pharmacokinetics should be
  acceptable.

http//www.fda.gov/ohrms/dockets/ac/04/minutes/200
4-4078M1.htm
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FDA Critical Path May 2007

• Four Areas of Opportunity for Generic Drugs
• Improve the science underlying quality by design
  for the development and manufacture of generic
  drug products
• Improve the efficiency of current methods for
  assessment of bioequivalence of systemically
  acting drugs
• Develop methods for the assessment of
  bioequivalence of locally acting drugs
• Develop methods for characterizing complex drug
  substances and products

http//www.fda.gov/oc/initiatives/criticalpath/rep
orts/generic.html
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Bioequivalence of Locally Acting GI Drugs
General Considerations

• IR Dosage Forms
• Highly Soluble Drugs
• If test and reference list drug products have the
  same formulations, qualitatively and
  quantitatively
• Bioequivalence may be demonstrated by in vitro
  dissolution tests covering physiologically
  relevant pHs.
• If test and reference list drug products do not
  have the same formulations, qualitatively and
  quantitatively
• Studies, including in vitro, in vivo PK, PD, or
  clinical studies, may be recommended to
  demonstrate that any formulation differences
  between test and reference drug products will not
  affect the safety and effectiveness of the test
  drug product.

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Example
Drug X Highly soluble, IR tablet The test and
reference list drug products have the same
formulations, qualitatively and quantitatively
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Example
Drug Y Highly soluble, IR tablet The test and
reference list drug products do not have the same
formulations, qualitatively and quantitatively
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Bioequivalence of Locally Acting GI Drugs
General Considerations

• IR Dosage Forms
• Poorly Soluble Drugs
• Topic for discussion
• Modified Release Dosage Forms
• In vivo studies with clinical endpoint while
  exploring alternate, scientifically sound in
  vitro or in vivo approaches

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Food and Drug AdministrationAdvisory Committee
for Pharmaceutical Science and Clinical
PharmacologyJuly 22-23, 2008

• Bioequivalence of Locally Acting GI Drugs
  Scientific Considerations James E. Polli,
  University of Maryland
• Bioequivalence of Poorly Soluble Locally Acting
  GI Drugs Robert Lionberger, Ph.D., FDA