Bioavailability and  Bioequivalence Studies

Introduction

  • It is essential to ensure uniformity in standards of quality, efficacy & safety of Pharmaceutical products
  • Reasonable assurance is to be provided that various products containing the same active ingredient, marketed by different licensees are clinically equivalent & interchangeable
  • Release of an active substance should be known & reproducible
  • Both Bioavailability & Bioequivalence focus on the release of the drug substance from its dosage form & subsequent absorption in circulation
  • Similar approaches to measure Bioavailability should be followed in demonstrating Bioequivalence 

Bioavailability

  • Measurement of the relative amount & rate at which, the drug from the administered dosage form, reaches the systemic circulation & becomes available at the site of action
  • Bioavailable fraction (F), refers to the fraction of administered dose that enters the systemic circulation

F   =  Bioavailable dose/Administered dose

OBJECTIVES OF BIOAVAILABILITY STUDIES

  • Primary stages of development of a suitable dosage for a new drug entity.
  • Development of a new formulation of the existing drugs.
  • Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage and stability on drug absorption.
  • Useful in determining the safety and efficacy of the drug product.

 Concept of Equivalents

  • Bioequivalence
  • Pharmaceutical equivalent/alternative of the test product,
  • when administered at the same molar dose,
  • has the rate and extent of absorption
  • not statistically significantly  different from that of the reference product
  • Pharmaceutical equivalents
  • Pharmaceutical alternatives
  • Therapeutic equivalence – FDA classifies those products as therapeutically equivalent which
  • Same active substance or therapeutic moiety
  • Clinically show the same efficacy & safety profile

Reference Product

  • Identified by the Regulatory Authorities as “Designated Reference Product”
  • Usually the Global Innovator’s Product
  • Protected by a patent
  • Marketed under manufacturers brand name
  • Clinical efficacy & safety profile is well documented in extensive trials
  • All generics must be Bioequivalent to it
  • In India, CDSCO may approve another product as a Reference product

Generic Drug

  • Drug product which is identical or bioequivalent to Brand/ Reference drug in: Active ingredient (s), Route of administration, Dosage form, Strength, Indications, Safety
  • May have different:
  • Inactive ingredients,  Colour, Shape
  • Almost half of the drugs in the market have Generics
  • An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic drug approval for an existing licensed medication or approved drug

Fundamental Bioequivalence Assumption

When a generic drug is claimed bioequivalent to a Reference drug, it is assumed that they are therapeutically equivalent

Bioequivalence Background

  •  Using bioequivalence as the basis for approving generic copies in the US

“Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Waxman-Hatch Act

  •  Created Generic Industry & ↑ their availability
  •  Most successful legislation
  •  Benefited Brand & Generic firms
  •  Generic firms→ Rely  on findings of safety & efficacy of Innovator drug after Patent expiration
  •  Innovator firms→ Patent extensions of 5yrs to make up for time lost while their products were going through FDA’s approval process

Indian Legislation

  •  In India, CDSCO provides “Guidelines for Bioavailability & 

    Bioequivalence Studies”  mentioned in Schedule Y

  •  As per the Drugs & Cosmetics Rules (IInd Amendment) 2005, all bioavailability and bioequivalence studies should be conducted in accordance with these Guidelines

The requirement of BA & BE Studies

  •  For IND/NDAs:

    To establish equivalence between:

  • Early & late clinical trial formulations
  • Formulations used in clinical trial & stability studies
  • Clinical trial formulations & to-be-marketed drug product
  • Any other comparisons, if appropriate
  • ANDA for a generic drug product
  • Change in components, composition, &/or  manufacturing process
  • Change in dosage form (capsules to tablet)

Objectives of BA & BE Studies

  •  Development of suitable dosage form for a New Drug Entity
  •  Determination of the influence of excipients, patient-related factors & possible interactions with other drugs
  •  Development of new drug formulations of existing drugs
  •  Control of quality of drug products, the influence of → processing factors, storage & stability
  •  Comparison of availability of a drug substance from a different form or same dosage form produced by different manufacturers

When is Bioequivalence not necessary (Biowaivers)?

  1. Aqueous parental Solution; a same active substance with the same concentration, same excipient
  2. Oral Solution; a same active substance with the same concentration, excipient not affecting GI transit or absorption
  3. Gas
  4. Powder for reconstitution as a solution; meets criterion (a) or (b)
  5. Otic/Ophthalmic/Topical Solution; a same active substance with the same concentration, same excipient
  6. Inhalational Product/ Nasal Spray; administered with or w/o same device as reference product; prepared as an aqueous solution; a same active substance with the same concentration, same excipient

Orange Book

  •  All FDA approved drugs listed (NDA’s, ANDA’s & OTC’s)
  •  Expiration of patent dates
  •  Drug, Price and Competition Act (1984) – FDA required to publish Approved Drug Products with Therapeutic Equivalence & Evaluations

Methods used to assess Equivalence

  1. Pharmacokinetic Studies
  2. Pharmacodynamic Studies
  3. Comparative Clinical Studies
  4. Dissolution Studies

Pharmacokinetic Studies

Subject selection

  • Healthy adult volunteers
  • Age: 18-45 yrs
  • Age/Sex representation corresponding to a therapeutic & safety profile
  • Weight within normal limits→ BMI
  • Women: Pregnancy test prior to 1st & last dose of study; OC pills C/I
  • Drug use intended in Elders  (Age >60yrs)
  • Teratogenic Drugs→ Male volunteers
  • Highly toxic drugs: Patients with the concerned disease (stable) eg. Cancer

Exclusion Criteria

  • H/o allergy to test drug
  • H/o liver or kidney dysfunction
  • H/o jaundice in the past 6 months
  • Chronic diseases eg. Asthma, arthritis
  • Psychiatric illness
  • Chronic smoker, alcohol addiction, drug abuse
  • Intake of enzyme modifying drug in the past 3 months
  • Intake of OTC/Prescription drugs past 2 weeks
  • HIV positive
  • BA & BE studies in the past 3 months
  • H/o bleeding disorder

Selection of Number of Subjects

  •  The sample size is estimated by:
  •  Pilot experiment
  •  Previous studies
  •  Published data
  •  Significance level desired, usually  0.05
  •  Power of the study, normally 80% or more
  •  Expected deviation (Δ) from the reference product, as compatible with BE
  •  If no data available, reference ratio of 0.95 (Δ = 5%) used

Study Design

  • Good experimental design enhances the power of the study
  • Depends on: question to be answered, nature of reference drug/ dosage form, the benefit-risk ratio
  • As far as possible, the study should be of crossover design & suitably randomized
  • Ideal design: Randomized two-period, two-sequence, Crossover design with an adequate washout period
  • If the half-life is long: Parallel design
  • For highly variable drugs: Replicate design
  1. Two-Period Crossover Design
  2. 2 formulations, even number of subjects, randomly divided into 2 equal groups
  3. First period, each member of one group receive a single dose of the test formulation; each member of the other group receive the standard formulation
  4. After a wash period (5 half-lives), in the second period, each member of the respective groups will receive an alternative formulation & the experiment will be repeated.

Parallel-Group Design

  • Even the number of subjects in two groups
  • Each receives a different formulation
  • No washout necessary
  • For drugs with a long half-life

Genetic Phenotyping

  • The drug is known to be subject to genetic polymorphism
  • Cross-over design→ Safety & Pharmacokinetic reasons
  • All Parallel group design
  • Indian population:
  • Captures genetic diversity of the world
  • Forms continuum of the genetic spectrum
  • >1000 medically relevant genes
  • Diverse patient/ volunteer pool for conducting BA & BE studies

Characteristics to be measured

  • Accessible biological fluids like blood, plasma &/or serum to indicate the release of the drug substance from the drug product into the systemic circulation
  • Mostly: Active drug substance
  • Active / Inactive metabolite may be measured in cases of:
  • The concentration of drug too low, Limitation of the analytical method, Unstable drug, Drug with a very short half-life, Pro-drugs
  • Excretion of drug & its metabolites in urine→ Non-linear  kinetics
  • Drugs that are not absorbed systemically from the site of application surrogate marker needed for BA & BE determination

Blood Sampling points/ Schedule

A single-dose study of an immediate release product:

  •  For at least three elimination half-lives (cover >80% of AUC)
    •  Absorption phase: 3-4 points
    •  Around Tmax: 3-4points
    •  During elimination: 4 points
  •  Intervals not longer than the half-life of the drug
  •  If urine tested, collect it for at least 7 half-lives

Parameters to be measured

  • Pharmacokinetic Parameters  measured are:
  •  Cmax
  •  Tmax
  •  AUC0-t
  •  AUC0-∞

Fasting & Fed State Conditions

Fasting Conditions:

  • Single-dose study:
  • Overnight fast (10 hrs) and subsequent fast of 4 hrs
  • Multiple-dose study:
  •  Two hours fasting before and after the dose

Fed State Studies

  • Required when:
  •  The drug recommended with food
  •  Modified release product
  •  Assessment of Cmax and Tmax difficult with fasting state study
  •  Requires consumption of high-fat food, 15 minutes before dosing
  •  Provide 950-1000 kcals
  •  Fat- 50%, Proteins 15-20%, Carbohydrate- 30-35%
  •  Ethnic & cultural variation considered
  •  Specified in protocol

  Statistical Evaluation

  • Cmax & AUC analyzed using ANOVA
  •  Tmax analyzed by non-parametric methods

To establish BE:

  •  The calculated 90% CI for Cmax & AUC, should fall within  range: 80-125%  (Range of Bioequivalence)
  •  Non-parametric data 90% CI for Tmax should lie within a clinically acceptable range

Documentation

  •  Signed detailed protocol
  •  Approval by Ethics Committee
  •  Participant Information sheet
  •  Informed Consent Form (ICF)
  •  Case Record Form (CRF)
  •  Undertaking by investigator
  •  CV of investigator
  •  Randomization chart
  •  Laboratory certification
  •  Analytical method validation details
  •  Chromatograms of all volunteers including any aberrant ones
  •  Tabulated Raw Data of volunteers

Maintenance of Records & Retention of Study Samples

  •  All Records of in vivo tests on any marketed batch of a drug product should be maintained by the Sponsor

    for at least 2 years after the expiry date of the batch

  • All Drug samples to be retained for a period of at least 3 years after the conduct of the study

                                         OR

    1year after the expiry of the batch [Stored in conditions consistent with the product labeling]

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