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 Good Morning. Mr. Chair and members of advisory committee for pharmaceutical science and clinical pharmacology, FDA colleagues, and distinguished guests. I am Lawrence X. Yu, Director for Science, Office of Generic Drugs, FDA. It gives a great pleasure and privilege to introduce this morning’s topic: Bioequivalence of locally acting gastrointestinal (GI) drugs. I want to emphasize that today’s discussion will be focusing on bioequivalence of locally acting GI drugs in general. We will not discuss any specific drug or drug products. Again… Advisory Committee for Pharmaceutical Science and Clinical Pharmacology July 23, 2008

ACPS-CP Questions Bioequivalence 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?

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) Bioequivalence is defined as the absence of a significant difference in the rate and extent of drug absorption. Bioequivalence concentrates on the release of a drug substance from a drug product and subsequent absorption into the systemic circulation or sites of absorption. Bioequivalence is about drug release, dissolution, and absorption; the characteristics of drug product quality.

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...

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 Bioequivalence is used in drug development to link clinical trial and to be marketed drug products for the purpose of changes in formulation, manufacturing process, and dosage forms. Equally significant is to the approval of generic drugs. Bioequivalence along with pharmaceutical equivalence assure therapeutic equivalence. Therapeutically equivalent products are expected to have the same safety and efficacy profiles, which are the basis for the approval and use of generic drug products. Bioequivalence is also used in post approval changes for both new and generic drugs.

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

Pharmacokinetic (PK) Study ln Concentration AUC Time Cmax Concentration Among all these approaches, the PK study is the most commonly used approach, particularly for most systemically acting drugs. PK study measures the drug and metabolites if any in the plasma over time. It generally uses two PK parameters: AUC and Cmax to determine whether the test product is bioequivalent to the reference listed drug product or not. AUC is the surrogate for the extent of drug absorption while Cmax is the surrogate for the rate of drug absorption. Tmax - time of maximum concentration Time

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 For the systemic drugs, the pharmacokinetics is an excellent surrogate for the safety and efficacy. Bioequivalence is the most commonly used biomarker because the drug produces its effect after it reaches the systemic circulation. However, this is not the case for locally acting GI drugs. For GI drugs, the site action is before the drug reaches the systemic circulation. Therefore, the plasma concentration may not reflect the drug concentration at the site of action.

Why Are Locally Acting GI Drugs Unique? Site 1 For the systemic drugs, the pharmacokinetics is an excellent surrogate for the safety and efficacy. Bioequivalence is the most commonly used biomarker because the drug produces its effect after it reaches the systemic circulation. However, this is not the case for locally acting GI drugs. For GI drugs, the site action is before the drug reaches the systemic circulation. Therefore, the plasma concentration may not reflect the drug concentration at the site of action. Site 2

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.

Questions - Bioequivalence Testing for Locally Acting GI Drugs Food and Drug Administration Advisory Committee for Pharmaceutical Science October 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

Food and Drug Administration Advisory Committee for Pharmaceutical Science October 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

Food and Drug Administration Advisory Committee for Pharmaceutical Science October 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/2004-4078M1.htm

Food and Drug Administration Advisory Committee for Pharmaceutical Science October 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/2004-4078M1.htm

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/reports/generic.html

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.

Example Drug X; Highly soluble, IR tablet The test and reference list drug products have the same formulations, qualitatively and quantitatively

Example Drug Y; Highly soluble, IR tablet The test and reference list drug products do not have the same formulations, qualitatively and quantitatively

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

Food and Drug Administration Advisory Committee for Pharmaceutical Science and Clinical Pharmacology July 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