Bioavailability and Bioequivalence General concepts and overview

WHAT IS IT??? WHY IS IT??? HOW IS IT??? REGULATION VERSUS PHARMACEUTICAL COMP.

Generic Drug product: Definition Same active ingredient (s) Same strength Same dosage form Same route of administration Same indications

NDA vs. ANDA Review Process Generic Drug ANDA Requirements Chemistry Manufacturing Controls Labeling Testing Bioequivalence Study (In Vivo, In vitro) Original Drug NDA Requirements Chemistry Manufacturing Controls Labeling Testing Animal Studies Clinical Studies (Bioavailability) Note: Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.  Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the origina; drug).

FDA Definitions Used in Bioequivalence Determinations 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 FDA Definitions Used in Bioequivalence Determinations

FDA Determinations of Bioequivalence Main Terms 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 FDA Determinations of Bioequivalence Main Terms Pharmaceutical equivalents Pharmaceutical alternatives Therapeutic equivalents Bioavailability Bioequivalence FDA Determinations of Bioequivalence. Main Terms. The Orange Book defines 5 terms that describe the most important concepts for discussing product substitution.1 These terms are: Pharmaceutical equivalents Pharmaceutical alternatives Therapeutic equivalents Bioequivalence Bioavailability Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

Pharmaceutical Equivalents 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 Pharmaceutical Equivalents Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration Equivalent products contain the same amount of ingredient in the same dosage form but may differ in characteristics, such as shape, release mechanisms, and packaging Pharmaceutical Equivalents. The FDA considers 2 drug products pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration.1 Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or other applicable standards (eg, strength, quality, purity, and identity). However, these drug products may differ in characteristics, such as shape, release mechanisms, and packaging. Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm. Accessed September 29, 2003. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm. Accessed September 29, 2003.

Pharmaceutical Alternatives 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 Pharmaceutical Alternatives Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, are different salts, esters, or complexes of the same moiety, are different dosage forms, or are different strengths Other pharmaceutical alternatives Different dosage forms and strengths within a single product line by a single manufacturer Extended-release formulations when compared with immediate- or standard-release formulations Pharmaceutical Alternatives. The FDA considers 2 products to be pharmaceutical alternatives if they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or if they have different dosages or strengths, such as quinidine sulfate 200-mg tablets versus quinidine sulfate 200-mg capsules. Other products considered to be pharmaceutical alternatives include different dosage forms and strengths within a product line by a single manufacturer, and extended-release (ER) products when compared with immediate- or standard-release formulations of the same active ingredient.1 Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

Therapeutic Equivalents 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 Therapeutic Equivalents Drug products are considered therapeutic equivalents if they are all of the following Pharmaceutical equivalents Bioequivalent Approved as safe and effective Adequately labeled Manufactured in compliance with current Good Manufacturing Practice regulations Therapeutic equivalents are expected to have the same clinical effect and safety profile Therapeutic Equivalents. Drug products are considered therapeutic equivalents if they meet the following criteria:1 They are approved as safe and effective and are pharmaceutical equivalents; They are bioequivalent in that They do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or If they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard They are adequately labeled and are manufactured in compliance with Current Good Manufacturing Practice regulations Drugs marketed before 1938 and drugs marketed between 1938 and 1962 that are safe but not approved are excluded from FDA evaluations. When administered under conditions specified in the product label, therapeutic equivalents are expected to have the same clinical effect and safety profile. Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

Bioavailability (quantifies ABSORPTION = ?, Reasons for poor F) The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation Pharmacokinetics conc. vs time Conc.(mg/L) Time (h) 25 0.0

Why do we care about BIOAVAILABILITY? The “true dose” is not the drug swallowed; BUT is the drug available to exert its effect. 􀂄 Dissolution 􀂄 Absorption 􀂄 Survive metabolism May have a drug with very low bioavailability 􀂄 Dosage form or drug may not dissolve readily 􀂄 Drug may not be readily pass across biological membranes (i.e. be absorbed) 􀂄 Drug may be extensively metabolized during absorption process (first-pass, gut wall, liver) Important component of overall variability 􀂄 Variable bioavailability may produce variable exposure

Rate versus Extent of Absorption Extent of absorption is reflected by AUC Rate of absorption, ka, is reflected by Tmax Both Rate and Extent of absorption affect Cmax Leads to 4 possible relative scenarios: 􀂄 (R) Rapid, (E) Complete Absorption yields a short Tmax, high Cmax, high AUC 􀂄 (R) Rapid, (E) incomplete absorption yields a short Tmax, low Cmax, low AUC 􀂄 (R) Slow, (E) complete absorption yields a long Tmax, high Cmax, high AUC 􀂄 (R) Slow, (E) incomplete absorption yields a long Tmax, low Cmax, low AUC

FACTORS INFLUENCING BIOAVAILABILITY: Three distinct factors are involved to influencing bioavailability. These are: 1.Pharmaceutical factors: physicochemical properties of the drug. 1. Particle size 2. Crystalline structure 3. Salt form Formulation and manufacturing variables. 1.Disintegration and dissolution time 2.Pharmaceutical ingredients 3.Special coatings 4.Nature and type of dosage form

2. Patient related factors: Physiologic factors. 1.Variations in pH of GI fluids 2.Gastric emptying rate 3. Intestinal motility 4. Presystemic and first-pass metabolism 5. Age, sex 6. Disease states Interactions with other substances. 1. Food 2. Fluid volume 3. Other drugs 3. Route of administration: 1.Parentral administration 2.Oral administration 3.Rectal administration 4.Topical administration

ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 Bioequivalence A comparison of the bioavailability of two or more drug products. Two products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption are the same Bioequivalence may be demonstrated through in vivo or in vitro test methods, comparative clinical trials, or pharmacodynamic studies Bioequivalence. The FDA considers drug products bioequivalent if they are pharmaceutical equivalents whose rate and extent of absorption are not statistically different when the products administered to patients or subjects at the same molar dose under similar experimental conditions.1 Bioequivalence may be demonstrated through in vivo or in vitro test methods. An in vitro bioequivalence standard may be used, especially when an in vitro test has been correlated with human in vivo bioavailability data. In addition, bioequivalency may also be demonstrated through comparative clinical trials or pharmacodynamic studies. Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

Bioequivalence

Regulatory Bioequivalence: An Overview “Self-evident” - Biowaivers granted Condition- excipients do not alter absorption (historical data) Solutions Suspensions Chewable, etc. Conventional Tablets Capsules MR Products Pre-1962 DESI Drugs: In Vivo evaluation for “bio-problem” drugs (TI, PK, P-Chem) Post-1962 Drugs: Generally In Vivo - some exceptions (IVIVC..) SUPAC-IR (1995) Dissolution-IR BCS (pre-/post approval) In VIVO SUPAC-MR IVIVC

Bioequivalence: IR Products Pharmaceutical Equivalent Products Reference Test Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Normal healthy subjects Crossover design Overnight fast Glass of water 90% CI within 80-125% of Ref. (Cmax & AUC) Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution spec.) Ajaz Hussain, FDA

FDA Methods to Determine Bioequivalence 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 FDA Methods to Determine Bioequivalence Generic drug manufacturers must demonstrate that a drug is bioequivalent to a reference drug product In order of FDA preference, methods used to define bioequivalence Pharmacokinetic studies Pharmacodynamic studies Comparative clinical trials In vitro studies FDA Methods to Determine Bioequivalence. Under the Drug Price Competition and Patent Term Restoration Act of 1984, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the drug product is bioequivalent to the reference (innovator) drug product.1 Methods used to define bioequivalence include PK studies, pharmacodynamic (PD) studies, comparative clinical trials, and in vitro studies. The choice of study used is based on the site of action of the drug and the ability of the study design to adequately compare the generic and reference drug products. Reference 1. Food and Drug Administration. Code of Federal Regulations. Title 21, Part 320: Bioavailability and Bioequivalence Requirements. Section 320.24. 2003. Available at: http://www.accessdata.fda.gov. Accessed September 29, 2003. Food and Drug Administration. Code of Federal Regulations. Title 21, Part 320: Bioavailability and Bioequivalence Requirements. Section 320.24. 2003. Available at: http://www.accessdata.fda.gov. Accessed September 29, 2003.

Pharmacokinetic Studies Key Measurements 10/6/03 ACCESS Medical Group, Ltd. S304 Bioequivalence rev08 Pharmacokinetic Studies Key Measurements Study Compound Reference Compound AUC Area under the concentration- time curve Cmax Maximum concentration A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds Tmax Time to maximum concentration Cmax Concentration Pharmacokinetic Studies. Key Measurements. To investigate the bioequivalence of 2 drug products or compounds, the FDA considers PK studies that determine the area under the concentration-time curve (AUC), maximum concentration (Cmax), and time to Cmax (Tmax) for the study compound (generic) and a reference compound (innovator).1 Each of these values for the study compound are compared with those of the reference compound. For the study and reference compounds to be considered bioequivalent, their rates and extents of absorption must not show a significant difference when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions. The red area in the diagram represents the AUC, or the extent of absorption, of the reference compound. The yellow area represents the AUC of the study compound. Cmax is an indicator of the absorption rate and Tmax is influenced by the route of compound administration. A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds. Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003. AUC Tmax Time Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

Comparative Pharmacodynamic Studies Not recommended when: active ingredient is absorbed into the systemic circulation pharmacokinetic study can be conducted Local action / no systemic absorption eg. : Topical Corticosteroid Hanoi, 2006-19-01

Comparative Clinical Studies Pharmacokinetic profile not possible Lack of suitable pharmacodynamic endpoint eg . : (Nasal suspensions) Hanoi, 2006-19-01

Study Designs Single-dose, two-way crossover design - Single-dose, parallel design Multiple-dose studies( in case of : Drugs too potent/toxic Extended/modified release products

Crossover vs. Parallel Designs Crossover design preferred Intra-subject comparison Lower variability Generally fewer subjects required Parallel design may be useful Drug with very long half-life Crossover design not practical Hanoi, 2006-19-01

Disadv. of cross over design The main problem with the cross over design is : The carry over effect………!?

Fasted vs. Fed Designs Fasted study design preferred Minimize variability not attributable to formulation Better able to detect formulation differences Hanoi, 2006-19-01

Fed Study Designs may be employed when: Significant gastrointestinal (GI) disturbance caused by fasted administration Product labeling restricts administration to fed state Hanoi, 2006-19-01

When equivalence studies are NOT necessary (Biowaivers) Aqueous parenteral solutions Solutions for oral use ( syrups, elixirs, tinctures & other soluble forms but not suspensions) Pdrs for reconstitution as a solution Otic or ophthalmic aqueous solutions Topical aqueous solutions Aqueous nebulizing inhalations or nasal sprays

B. For some products bioequivalence may be demonstrated by evidence obtained in vitro instead of in vivo data: The drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another product by the same manufacturer that was found to be bioequivalent.

For high potency drug substances, the same inactive ingredients are used for all strengths, and the change in any strength is obtained by altering the amount of the active ingredients and one or more of the inactive ingerdients are within the limits defined by the SUPAC guidances (up to level II).

Waiver of Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (B.C.S)

BCS Classifications According to the BCS, drug substances are classified as follows: Class I - High Permeability, High Solubility Class II - High Permeability, Low Solubility Class III - Low Permeability, High Solubility Class IV - Low Permeability, Low Solubility

Solubility A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 - 7.5 (WHO , pH: 1.2 – 6.8)

Permeability A drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose ( WHO, 85% ).

Conditions for BCS Bio-waivers Firms can request waivers of in vivo testing for Class 1 drug substances Drug products must meet these criteria: Immediate-release solid oral dosage forms Highly soluble, highly permeable drug substance Rapid in vitro dissolution Note: Waivers not applicable for narrow therapeutic range therapeutic range (Digoxin, Lithium, phenytoin, warfarin) drugs

A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.

BCS Class I: Dissolution USP Apparatus I (100 rpm) or II (50 rpm) Three media 0.1 N HCl or SGF USP without enzymes 0.1 N HCl or SGF USP without enzymes pH 4.5 buffer pH 4.5 buffer pH 6.8 buffer or SIF USP without enzymes NLT 85% dissolves within 30 minutes Similarity factor (f2) for test (T) v. reference (R) profile comparisons should > 50