IV Pan-American Conference BE PANDRH Working Group Salomon Stavchansky PhD Alcon Centennial Professor of Pharmaceutics The University of Texas at Austin.

IV Pan-American Conference BE PANDRH Working Group

Salomon Stavchansky PhDAlcon Centennial Professor of Pharmaceutics

The University of Texas at AustinCollege of PharmacyAustin, Texas 78712

[email protected]

PAHO -WHO. Dominican Republic March 2, 2005

Draft - Progress Report

Working Group• Ricardo Bolanos Argentina

• Silvia Giarcovich ALIFAR

• Silvia Storpitis Brazil

• Conrad Pereira Health Canada

• Lizzie Sanchez FDA - USA

• Justina Molzon FDA – USA

• Roger Williams USP – USA

• Regina Pezoa Chile

• *Helgi Jung Mexico

• Lidiette Fonseca Gonzalez Costa Rica

• *Ana Lucia Valle Guatemala

• Eugene Brown Jamaica

• Rosario D’Alessio PAHO

• Sabbine Kopp – Kubel WHO

• Loreta Marquez FIFARMA

• Irene Goncalves Venezuela

The II Pan American Conference (November 1999) established the Pan American Network for Drug Regulatory Harmonization (PANDRH) and rules and regulations for the Network and its working groups.

According to those regulations, harmonized proposals developed by the Working Groups are to be presented at the Conferences for their adoption or approval.

Genesis of PANDRH

Mission of BA-BE PANDRH Working Group

• to contribute to the development of harmonized bioequivalence criteria for the interchangeability of pharmaceutical products in the Americas through the promotion of technical bases to assure interchangeability of multisource products, within an international and a national context, by proposing the establishment of reference materials as comparators for bioequivalence testing.

Regulatory ConsiderationsPharmaceutical Quality

EFFICACY

MANUFACTURING

SAFETY

EFFICACY

MANUFACTURING

SAFETY

Phase 3

Pre-Clinical andClinical Studies

in Humans

PreClinicalPhase 1

Phase 2

800 Million Dollars

10 Years

Present NDA Regulatory Paradigm

CMC

Product releaseSpecifications

DISCOVERY DEVELOPMENT DELIVERY

Performance Tests• Performance tests are measures that relate to drug-

product efficacy and safety • What are the appropriate performance tests for a drug

product?

• Are performance tests necessary for control of drug product quality?

• How do performance tests, surrogate markers and specifications inter-relate?

• What value can we expect from a performance test?

(Q of the product to its expiry date)

Public Health

ACCESS

QUALITY

COST

POLICY

CLEAR RECOMMENDATIONS

REGULATION RISK TO BENEFIT

EFFICACY

MANUFACTURING

SAFETY

Present ANDA Regulatory ParadigmBioequivalence

cGMP’s CMC

in vivo in vitro

? ?

BCS

Post Approval Changes

Requires a ComparatorProduct?

SAMENESSVARIABILITY

Statistical Test

IndustryRisk

ConsumerRisk

Highly Variable DrugsFood effectsNarrow Therapeutic IndexDrugs with Long T50

Factors to Consider for Bioequivalence

Parent CompoundMetabolite(s)?P’dynamic Response

Single DoseMultiple Dose

Background Documents

• Guidelines Published by the Food and Drug Administration

• Health Canada’s Guideline on Preparation of DIN Submissions

• WHO document (1999) entitled “Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: a Manual for Drug Regulatory Authorities, Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability.”

• ICH documents

• Note for Guidance on the Investigation of Bioavailability and Bioequivalence, Committee for Proprietary Medicinal Products (CPMP), 26 July 2001 (CPMP/EWP/QWP/98)

• WHO QAS/04.093 Draft Guidance – Working Document Revision #3, September 13, 2004. Revision of the Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability

Therapeutic Equivalence can be assured when the multisource product is:

pharmaceutically equivalent and

bioequivalent.

TE = PE + BE

Therapeutic Equivalence of Multisource Product

The concept of interchangeability applies to:

1. - the dosage form and

2. - the indications and instruction for use.

Equivalence Documentation

• Comparative bioavailability (bioequivalence) studies, in which the active drug substance and/or one or more metabolites is measured in an accessible biologic fluid such as plasma, blood or urine.

• Comparative pharmacodynamic studies in humans.

• Comparative clinical trials.

• Comparative in vitro tests

• In vitro dissolution tests in combination with the Biopharmaceutics Classification System

COST

Oral Drug Products for which in vivo documentation of equivalence is considered especially important

• (a) Oral immediate release pharmaceutical products with systemic action when one or more of the following criteria apply:

• (i) Indicated for serious conditions requiring assured therapeutic response;

• (ii) Narrow therapeutic window/safety margin, steep dose-response curve;

• (iii) Pharmacokinetics complicated by variable or incomplete absorption or absorption window, nonlinear pharmacokinetics, presystemic elimination/high first-pass metabolism >70%;

• (iv) Unfavorable physicochemical properties, e.g., low solubility, instability, metastable modifications, poor permeability, etc.,

• (v) Documented evidence for bioavailability problems related to the drug or drugs of similar chemical structure or formulations;

• (vi) Where a high ratio of excipients to active ingredients exists.

Oral Drug Products for which in vivo documentation of equivalence is considered especially important

• (b) Non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (such as transdermal patches, suppositories, etc.).

• (c) Sustained or otherwise modified release pharmaceutical products designed to act by systemic absorption.

• (d) Fixed combination products

• (e) Non-solution pharmaceutical products which are for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc. application) and are intended to act without systemic absorption. In these cases, the bioequivalence concept is not suitable and comparative clinical or pharmacodynamic studies are required to prove equivalence. This does not, however, exclude the potential need for drug concentration measurements in order to assess unintended partial absorption.

USA Present Statistical Criteria

• Comparison between test and reference product

• Use natural log transformation of Cmax and AUC

• Criterion: 90% confidence intervals about geometric mean test/reference ratios for both Cmax and AUC must fall within 80 – 125%

• Applies to all systemically acting drugs (i.e., not locally acting) with measurable blood or urine levels without regard to the drug’s inherent variability

• Same criteria used by pioneer firms to support formulation changes

Some International Criteria

Country/Region AUC 90% CI

Criteria

Cmax 90% CI

Criteria

Canada (most drugs) 80 – 125% none (point estimate only)

Europe (some drugs) 80 – 125% 75 – 133%

South Africa (most drugs) 80 – 125% 75 – 133% (or broader if justified)

Japan (some drugs) 80 – 125% Some drugs wider than 80 – 125%

Worldwide (WHO) 80 – 125% “acceptance range for Cmax may be wider

than for AUC”

Comparator Product• The innovator product is usually the most logical comparator product.

Quality, safety and efficacy have been well assessed.

• If an innovator product cannot be identified or is not available in the market. – What to do?

• The selection of the comparator product is usually made at the national level by the drug regulatory authority. A national drug regulatory authority has in principle three options:

– choose the innovator product which has been established for quality, safety and efficacy (international comparator), or to

– choose the market leader for which the pharmaceutical quality, safety and efficacy has been established (national comparator), or

– in the case the above are not available, the drug regulatory authority is encouraged to consider a product available on another market, that has been assessed for quality, safety and efficacy, and/or was chosen by another national or a regional regulatory authority (regional specific comparator).

• It should be noted that a possibility exists for significant differences to emerge between comparator products used in different countries.

Criteria recommended for waiver of evidence of in vivo

bioavailability or bioequivalence • When multisource pharmaceutical are to be administered

parenterally (e.g., intravenous, intramuscular, subcutaneous, intrathecal administration) as aqueous solutions and contain the same active substance(s) in the same concentration and the same excipients in comparable concentrations;

• (b) When multisource pharmaceutical products are solutions for oral use, contain the active substance in the same concentration, and do not contain an excipient that is known or suspected to affect gastro-intestinal transit or absorption of the active substance;

• (c) When multisource pharmaceutical products are a gas;

• (d) When the multisource pharmaceutical products are powders for reconstitution as a solution and the solution meets either criterion (a) or criterion (b) above;

Criteria recommended for waiver of evidence of in vivo bioavailability or bioequivalence

• When multisource pharmaceutical products are otic or ophthalmic products prepared as aqueous solutions and contain the same active substance(s) in the same concentration and essentially the same excipients in comparable concentrations;

• (f) When multisource pharmaceutical are topical products prepared as aqueous solutions and contain the same active substance(s) in the same concentration and essentially the same excipients in comparable concentrations;

• (g) When multisource pharmaceutical are inhalation products or nasal sprays, tested to be administered with or without essentially the same device, prepared as aqueous solutions, and contain the same active substance(s) in the same concentration and essentially the same excipients in comparable concentrations. Special in vitro testing should be required to document comparable device performance of the multisource inhalation product.

BA-BE may be demonstrated by evidence obtained in vitro in lieu of in vivo data. ( Waiver of in vivo Data)

• 1.- The drug product is in:– the same dosage form– in a different strength, – is proportionally similar in its active and inactive

ingredients – manufactured at the same site

• 2. Both drug products meet an appropriate in vitro test approved by a Drug Regulatory Authority and/or accepted reference pharmacopeias, or has demonstrated in vivo – in vitro correlation ( e.g., correlation level A, etc)

BA-BE may be demonstrated by evidence obtained in vitro in lieu of in vivo data. ( Waiver of in vivo Data)

• 3. Both drug products are proportionally similar in their active and inactive ingredients.

• 4. The drug product is a reformulated product that is identical, except for a different color, flavor, or preservative that could not affect the bioavailability of the reformulated product

• 5. Regulatory Authorities, for good cause, may require evidence of in vivo bioavailability or bioequivalence for any drug product

In Vitro Dissolution Profile Comparison.Similarity Factor.

f2 between 50 and 100 suggests similarityalso the average difference at any dissolution time point should not be greater than 15% between products

f2 less than 50 doesn't necessarily mean lack of similarity.You may use a different method: -- statistical analysis should be provided, e.g., 90% confidence intervals.

N = NUMBER OF SAMPLING TIME POINTSRt = REFERENCE VALUE (PRE CHANGE)Rt = TEST VALUE ( POST CHANGE)T = IS THE DISSOLUTION VALUE AT TIME t

}100])(1

1{[50 5.02

12 xTR

nLogf

n

ttt

Special Consideration for Antiretroviral Products

• At the present time, the BA-BE working group strongly recommends that in the case of anti-retroviral drug products, proof of pharmaceutical equivalence and bioequivalence be required to infer therapeutic equivalence. However, further discussion is warranted.

• BCS is a scientific framework for classifying drug substances (API’s) based on their aqueous solubility and intestinal permeability.

• Class 1: High Permeability - High Solubility• Class 2: High Permeability - Low Solubility • Class 3: Low Permeability - High Solubility • Class 4: Low Permeability - Low Solubility

• In addition, immediate release solid oral dosage forms are

categorized as having rapid or slow dissolution.

Biopharmaceutics Classification System (BCS)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSOPRTION

SIMILAR SYSTEMIC AVAILABILITY

Basis of BCS

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Drug Permeability Class

Antipyrine High (Potential IS candidate)

Caffeine High

Carbamazepine High

Fluvastatin High

Ketoprofen High

Metoprolol High (Potential IS candidate)

Naproxen High

Propranolol High

Theophylline High

Verapamil High (Potential ES candidate)

Amoxicillin Low

Atenolol Low

Furosemide Low

Hydrochlorthiazide Low

Mannitol Low (Potential IS candidate)

Methyldopa Low

WHO Essential Drugs: Oral

Kasim, N. A., et.al. Molecular Pharmaceutics, 1, 85, (2004)

WHO US DRUGS

325 Medicines 200 Drugs Products260 Drugs 141 Oral123 Oral IR 43 On WHO List

Maximum StrengthSolubility mg/mlDose NumberclogPLogPpKaTherapeutic Class

Solubility Classification

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

Dose number ≤ 1.0 Solubility ≤ 0.1 mg/ml Solubility ≤ 0.01 mg/ml No solubilityinformation

Per

cen

tage

of

imm

edia

te-r

elea

se o

ral d

rugs

WHO

US

High Solubility Drugs

Source: Amidon, G.L Personal Communication

Solubility Conclusions

• Majority of Drugs (67%) are High Solubility (Do<1)

• Similar on WHO and FDA lists

• A Dissolution BE test is the best test

Is it advisable to grant bio-waivers based on BCS and in vitro

Dissolution? If it is advisable, when to grant the bio-waiver?

What is the question?

Waiver of in vivo studies…

Not waiver of bioequivalence

Immediate Release Products. Solubility Considerations

• highest dose strength of an IR product

• 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

• The volume estimate of 250 ml is derived from typical BE study protocols that prescribe administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water.

PROPOSED DRUG CLASSIFICATION BYG. AMIDON, et-al Pharm. Res. 12,3(1995)

HIGH PERMEABILITY I HIGH SOLUBILITYHIGH PERMEABILITY II LOW SOLUBILITY

LOW PERMEABILITY III HIGH SOLUBILITYLOW PERMEABILITY IV LOW SOLUBILITY

HIGH PERMEABILITYEXTENT OF ABSORPTION

>>90%

HIGH SOLUBILITYDOSE mg/ml/250 ml

SOLUBILITY mg/ml

Do <1 HS

Do= pH = 1 – 6.8 ?

Immediate Release Products. Solubility Considerations

• The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans

• 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.

Permeability Methods

• (1) in vivo intestinal perfusion studies in humans;

• (2) in vivo or in situ intestinal perfusion studies using suitable animal models;

• (3) in vitro permeation studies using excised human or animal intestinal tissues; or

• (4) in vitro permeation studies across a monolayer of cultured epithelial cells.

Where are we going?

– Waiver of In Vivo Bioequivalence Study Requirements

• Waiver Based on the Pharmaceutical Dosage Form (Solutions)

• Waiver Based on the Biopharmaceutics Classification System

• Waiver Based on the Dose. (Highest Strength should be tested)

Waiver of in vivo BA and BE for IR products based on BCS

• BCS Class 1: - Highly Soluble (Highest dose soluble in 250 ml in water over pH range of 1.2 - 6.8 - Highly Permeable (Extent of absorption greater than 85%)

- Rapidly dissolving (Basket at 100 rpm, paddle at 50 rpm in 900 ml of pH 1.2, and 6.8 buffer)

• For a waiver of BE, the test and the reference product should exhibit similar dissolution

profile, f2 criteria

BCS Class

Drug Solubility

pH 1.2

Drug Solubility

pH 6.8

Drug Permeability

Preferred Procedure

I High High High>85% Dissolution in 15

min., pH = 6.8.

II-A High Low High>85% Dissolution in 15

min., pH = 1.2

II-B Low High High

>15 min at pH=1.2, then 85% Dissolution in 30

min., pH = 6.8; F2>50; 5 points minimum; not more than one point >

85%.

II-C Low Low High

>15 min at pH=1.2; then 85% Dissolution in 30

min., pH = 6.8 plus surfactant*; F2>50; 5 points minimum, not more than one point >

85%.

Proposal Discussed with Professor Amidon

BCS Class

Drug SolubilitypH 1.2 and pH 6.8

Drug PermeabilityPreferred Procedure

IHigh High

>85% Dissolution in 45 min., pH = 6.5

II Low High

>85% Dissolution in 45 min., pH = 6.5

4 pt dissolution profile, F2 > 50. If

needed, add surfactant and

justify, use lowest amount

III

andIV

I am not ready to endorse in vitro dissolution in lieu of in

vivo studies

No Food-BE studies, IR.

Forms, Class I 

Stavchansky’s Proposal

Intestinal Transporters

• Mrp2 Multidrug resistance associated protein 2• Pept 1 Oligopeptide transporter• Oatp 3 Intestinal organic anion transporting

polypeptide 3• OCT 1 Organic cation transporter• CNT Nucleoside transporter N1 (purine) N2

(Pyrimidine)• MDR1 Multidrug resistance protein 1• BCRP Breast cancer resistance protein

Metabolites and Bioequivalence• The Concentration-time profile of the parent drug is more sensitive to

changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution, and elimination.

• When may Metabolite concentrations be necessary:

– The measurement of concentrations of therapeutically active biotransformation product is essential if the substance studied is a pro-drug.

– If an active metabolite is formed as a result of gut wall or other presystemic metabolic process(es) and the metabolite contributes meaningfully to safety and/or efficacy, it is recommended that both the metabolite and the parent drug concentrations be measured.

– Measurement of a metabolite may be preferred when parent drug levels are too low to allow reliable analytical measurement in blood, plasma, or serum for an adequate length of time or when the parent compound is unstable in the biological matrix.

• It is important to note that measurement of one analyte, drug or metabolite, allows the risk of making a Type-I error (the consumer risk) to remain at the 5% level

Drugs with Long Half-Life• A single dose cross-over pharmacokinetic bioequivalence study provided an

adequate wash-out period is used.

• If the cross-over study is problematic, a pharmacokinetic bioequivalence study with a parallel design can be used.

• sample collection time should be adequate to ensure completion of gastrointestinal transit (approximately 2 to 3 days) of the drug product and absorption of the drug substance.

• Blood sampling up to at least 72 hours should be carried out, unless

shorter periods can be justified. However, subject variability should be low

• The number of subjects should be derived from statistical calculations but generally more subjects are needed for parallel study design compared with cross-over study design.

• Powering parallel studies depends on between-subject variability, not within-subject variability

Highly Variable Drugs in the Context of Bioequivalence

• To date, there is no regulatory definition for these drugs or drug products. Any drug whose rate and extent of absorption shows large dose-to-dose variability within the same patient

• Commonly understood to include those drugs whose intrasubject coefficient of variation (Cmax and/or AUC) is approximately 30% or more

Concerns with HVD

• Resources - Cost of studies due to the large number of subjects required for a bioequivalence study to be able to pass the “goalpost”

• Ethical concerns because exposing so many healthy subject to drugs

• Potential failure of the reference product

Examples of Highly Variable Drugs

• atorvastatin, esomeprazole, pantoprazole, clarithromycin, paroxetine (CR), risedronate, metaxalone, itraconazole, balsalazide, acitretin, verapamil, atovaquone, disulfiram, erythromycin, sulfasalazine.

Why Current 80-125% Criteria Are Not Appropriate For HVDs

• dose-to-dose variability within a patient is much larger than the width of the criteria

• HVDs are “wide therapeutic index” drugs – i.e., have shallow dose response curves, and wide safety margins

• One Size Does Not Fit All !!!!!!

Recommendation for HVD

• The confidence interval reflects the degree of consumer risk (Type I error) A reduction in the level of confidence from 90% to 85%, implies a possible increase in the consumer risk

• In contrast, the width of equivalence limits represents the allowable boundary for the ratio (or difference) of the means between products in comparison. Statistically, widening the bioequivalence limits can be accomplished:– through expansion of the allowable boundary or – by scaling the criteria based on the high variability of the

reference product. – by using sequential designs

Critical dose drugs

• "Critical dose drugs" are defined as those drugs where comparatively small differences in dose or concentration lead to dose- and concentration-dependent, serious therapeutic failures and/or adverse drug reactions which may be persistent, irreversible, slowly reversible, or life threatening event

Factors to be Considered for Critical Drugs

• serious dose-dependent adverse effects exist close to the dosing range

• narrow therapeutic range or narrow tolerance range • requirement for blood level monitoring to control and

individualize treatment; this is the standard of care or normal condition of use

• dosing based on body weight, body surface area, or other highly individualized dosing requirements

• serious clinical consequences of overdosing (toxicity) or under-dosing (lack of effect)

• steep dose response relationship for efficacy and/or toxicity

When to, and not to conduct Food Effect

• When both test product and Comparator product are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permeability (BCS Class I) or

• When the Dosage and Administration section of the Comparator product states that the product should be taken only on an empty stomach, or

• When the Comparator Product label does not make any statements about the effect of food on absorption or administration.

When to, and not to conduct Food Effect

For complicated Drugs in Immediate-Release Dosage Forms (e.g., narrow therapeutic range drugs (drugs with a steep dose –response curve, critical drugs), highly toxic drugs and drugs known to have non-linear pharmacokinetics).

For Modified Release Products, Controlled Release Products Recommendation:

Bioequivalence must be demonstrated under both fasted and fed conditions.

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