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BE studies- Part 3 : Statistical Phase, Special Situations, Guidelines
Dr. Ammar RazaClinician, Clinical Affairs Manager, Medical Advisor
Introduction
Performance will never be identical– Two formulations– Two batches of the same formulation?– Two tablets within a batch?
Purpose of bioequivalence (BE)– Demonstrate that performance is not
“significantly” different– Same therapeutic effect– What constitutes a ‘significant’
difference?
Phases of BE studies
Clinical Phase– Screening– Selection – ICF &
Recruitment – Dosing – Sampling– Monitoring– AEs
Bioanalytical Phase
– Storage of Samples
– Method Devpt– Method Validation – Analysis of
samples – QC checks
Statistical Phase – Data analysis– Anova (SAS)– PK (WinNonlin)-
AUC, Cmax etc. – T/R ratio– 90% CI
Focus on
BE Studies: Scientific Basis
Two different formulations of a drug resulting in SIMILAR systemic
concentration-time profiles will always achieve similar concentration time
profiles at the site of efficacy or toxicity
Metrics for BE studies
Concentration vs. time profiles– Area under the curve (AUC)
Observable exposure AUC-t (zero to last detectable concn) Complete exposure AUCinf
– Maximal concentration (Cmax)– Time to Cmax (Tmax)
Statistical measures of BE metrics– Mean– Variance
Stat BE: comparing the means of two products
Overall extent
Both rate & extent
PK analysis: Approaches
BE or rate & extent of BA or exposure can be proven using– Compartmental approach - not preferred in BE – Non-compartmental approach
Based on calculation of AUC –body’s exposure Favored to prove BE- robustness Min of 15 samples- to calculate AUC
Non-compartmental approach
Determination of BE
Modern concept of BE is based on a survey of physicians carried out by Westlake in 70s - a 20% diff in dose b/n 2 formulations - no clinical significance for most drugs
– BE limits were set at 80 - 120%. Pl concn. dependent measures - Cmax or AUC are
not normally distributed– Are log normal, – BE limits became 80 - 125% (or ± 0.225 on natural log
scale)
Statistical Determination of BE
Past method– tested null hypothesis- no difference between means
Not adequate in 1980s
Current method– proves similarity between two products– BE- diff <20%
Avg rate & extent of BA of T within ±20% that of R
– Log transformed scale- limits of ratio b/n 0.8 and 1.25
The statistical procedure ..
‘two one-sided test’– introduced by Hauck
Method – defines error α- probability of concluding BE when in reality it is not true
– Usually fixed to a min- 5%– BE concluded if 90% CI of the ratio is within 80-125– Power of study (regulatory)=80%– 20% probability of not demonstrating BE even if they are
truly BE– No of sub: based on variability of metric that study must
pass on Cmax: most variable metrics
Sample size
Analysis of Variance
ANOVA– Most common technique of analysis and estimation
Lognormal distribution– Raw data must be log transformed– Comparison of means & variances of transformed data– Geometric mean (GM)– Results reported in original scale
Confidence Intervals (CI)
Inference from study to wider world Range of values within which we can have a
chosen confidence that the population value will be found
Study findings expressed in scale of original data measurement
Confidence Intervals (cont.)
Width of CI indication of (im) precision of sample estimates
Width partially dependent on:– Sample size– Variability of characteristic being
measured Between subjects Within subjects Measurement error Other error
Confidence Intervals cont.
Degree of confidence required– More confidence = wider interval
Width of equivalence limits represents allowable boundary for ratio (or difference) of means b/n products in comparison
In other words, width of CI dependent on:– Standard error (SE)
Standard deviation, sample size– Degree of confidence required
Statistical Analysis (Two One-sided Tests Procedure)
Statistical analysis of pharmacokinetic measures– Confidence intervals– Two one-sided tests
AUC and Cmax– 90% Confidence Intervals (CI) must fit between
80%-125%
Typical BEAssessment Criteria
90% confidence interval Ratio of geometric means Acceptance criteria: 80 – 125% Log transformed AUCT & Cmax
Statistical Approaches for BE
Average bioequivalence Population bioequivalence Individual bioequivalence
Average BE Conventional method Compares only population averages Does not compare products variances Does not assess subject x formulation interaction
Statistical Approaches for BE
Population and individual BE– Include comparisons of means and variances
Population BE– Assesses total variability of the measure in the
population
Individual BE– Assesses within subject variability– Assesses subject x formulation interaction
Statistical effects in model
Sequence effect Subject (SEQ) effect Formulation effect Period effect Carryover effect Residual
Statistical Analysis Bioequivalence criteria
– Two one-sided tests procedure Test (T) is not significantly less than reference Reference (R) is not significantly less than testSignificant difference is 20% ( = 0.05 significance
level)– T/R = 80/100 = 80%– R/T = 80% (all data expressed as T/R so this
becomes 100/80 = 125%)
Special Situations
Highly variable drugs Endogenous substances Parent/ metabolite issues Long half-life drugs
Highly Variable Drugs (HVDs)
Intrasubject variability (CV%) ≥30%– Significant first pass metab or to a poor or erratic
absorption process Sample size in BE studies is determined -by
BA parameter with highest variability– most cases, Cmax has higher variability than
AUC May not pass even when the reference
product is tested against itself
Factors Contributing to the Variability
Related to Formulation– Disintegration– Dissolution– Permeability
NON-related to Formulation
Absorption:– Rate of GI transit: Stomach to the colon– Transport through GI mucosa
Pancreatic or bile acid secretion
Drug metabolism– induction– inhibition– Liver blood flow
Excretion– Renal blood flow
HVDP
highly variable drug product (HVDP) - formulation of poor pharmaceutical quality - drug itself is not highly variable- big component of within formulation variability (WFV)
– cannot be detected in traditional 2-treatment, 2-period, 2-sequence cross-over design studies
– Replicate designs- facilitate their detection - within-subject variabilities of test & reference formulations can be estimated separately
When they are v. different - one of the formulations is a HVDP
Approaches
Evaluate bioequivalence at steady-state– Variability expected at steady-state is < that after single dose– Always true?– Can not be applied to all HVD/HVDP
Assessment of BE on the metabolite– When parent undetectable- metabolite is less variable– smaller sample size - BE studies for HVD if based on the
metabolite Add-on Individual BE- may help overcome existing problems ABE Average BE with scaling approach & widen CI
IBE Vs. ABE
Study periods are duplicated 4 vs. 2– Bad: duration & cost x 2– Good: may reduce pool size of volunteers - HVD
Has not found unanimous consensus in the scientific community – Remains under investigation– Subject of discussion in future
Wider CI
Major regulatory agencies have provisions - can accommodate effect of higher variability associated with Cmax on design of BE studies
EMEA -expanded limits (e.g., 75-133%) for Cmax in certain cases -NO safety or efficacy concerns
MCC, SA - allow for expanded limits for Cmax in certain cases
Example
2 BE studies on formulations of drugs A & B– same no. of sub in each study – GMR is the same in both– Two One-Sided Test - only difference b/n 2 studies is
magnitude of CV Drug A - low within-subject variability (ANOVACV
15%) - 90% CI falls comfortably within BE limits Drug B is highly variable - ANOVA-CV of 35%
– Study on drug B was underpowered- simple remedy - repeat study with a greater no. of sub
ProgesteroneThe Poster Drug for High Variability
A repeat measures study of Prometrium® 2x200 mg caps in 12 healthy PM females yielded:
Intrasubject CV for AUC of 61%
Intrasubject CV for Cmax of 98%
Generic company calculated that a 2 period crossover BE study - require dosing in 300 PM women to achieve adequate statistical power
Endogenous substances
Pose a major problem Baseline levels present
– Administration of drug can alter levels / feedback mechanism
– Oral admin- frequently produces only a negligible inc in baseline; wide variability
– Baseline should be measured throughout the day before dosing
Endogenous substances
Issues 100s or 1000s of vols to operate with net post-dose
values– Not acceptable from ethical or financial point of view
Lesser no of vols- post dose values without baseline subtraction
Steady state studies– preferred design when possible
Assay sensitivity issues
Predominating active metabolite
Parent/ metabolite issues Parent more variable Difficult to get detectable concn. (absent or
marginally present) Rate of abs- adequately evaluated only assaying
parent Measure metabolite
– Less of subs reqd– Easier to prove BE
Allopurinol, flutamide, terfenadine
Long half-life drugs
Crossover- adequate washout to avoid carryover – study lasts 4-6 m or more
Parallel design– More no. of sub (n=18 in crossover is stat equivalent to
~n=50 in parallel) Costly
Approaches: steady state or truncated AUC (stopping at 24 or 48 h)
– crossover -washout cannot be shortened, duration of study partially reduced
– Parallel design- markedly reduce duration of study
Topical application
Three classes Administered topically for absorption into sys
circulation e.g. patches– can use usual BE
Designed to exert topical activity only – absorption is negligible e.g. ointments, creams
– PD study or clinical efficacy study Designed to exert local activity – absorbed to a
certain extent only e.g. vaginal prep etc.– Considered individually
BE vs. Clinical Trial: Differences
Clinical Trial Multicentric Subjects: mostly
patients (except Ph I) Multiple doses Costly and time
consuming
BE study Single centre Subjects: Mostly
healthy vol; rarely pts. Single dose; sometimes
multiple dose Cheaper and require
less time
Focus on FDA Guidance
Two main guidances– General : “Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products — General Considerations” http://www.fda.gov/cder/guidance/5356fnl.pdf
– “Food effect bioavailability studies and fed Bioequivalence studies”
http://www.fda.gov/cder/guidance/5194fnl.pdf– Drug specific guidances
Levothyroxine Potassium hydrochloride
– Biowaiver – Retention samples
Hatch-Waxman Amendments to FFD&C Act - 1984
Considered one of the most successful pieces of legislation ever passed
Created the generic drug industry
Increased availability of generics 1984 12% prescriptions were generic
2000 44% prescriptions were generic - yet only 8% of revenue for prescription drugs
Compromise legislation to benefit both brand and generic firms
Hatch-Waxman Amendments to FFD&C Act - 1984
Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities (do not have to repeat expensive clinical and pre-clinical trials)
Allowed patent extensions and exclusivities to innovator firms
Requirements for generic drugs
• Labeling
• Chemistry/Microbiology
• Bioequivalence
• Legal
Labeling
• “Same” as brand name labeling
• May delete portions of labeling protected by patent or exclusivity
• May differ in excipients, PK data and how supplied
Chemistry
• Components and composition• Manufacturing and controls• Batch formulation and records• Description of facilities• Specs and tests• Packaging• Stability
Manufacturing Compliance Programs
Purpose - To assure quality of marketed drug products
Mechanisms - Product Testing– Surveillance– Manufacturing/Testing plant inspections– Assess firm’s compliance with good
manufacturing processes
Guidance for CROs
Scope: Guidance to organizations involved in the conduct and analysis of in vivo bioequivalence (BE) studies
Note: BE studies should be performed in compliance with:
• General regulatory requirements• Good clinical practice (GCP)• Good laboratory practices (GLP)
Guidelines
Guideline provides information on:- organization and management- study protocols- clinical phase of a study- bio-analytical phase of a study- pharmacokinetic & statistical analysis - study report
Comparison of guidelines
Importance
Understanding the generic drug approval process and the issues surrounding BE is of paramount importance to both clinicians and scientists
Welage LS, Kirking DM, Ascione FJ, Gaither CA.J Am Pharm Assoc (Wash). 2001 Nov-Dec;41(6):856-67
Resources
Text book of pharmacokinetics
http://pharmacy.creighton.edu/pha443/pdf/pkin08.pdf
Summary
Planning is important– Study design, sample size, sampling schedule, incl & excl criteria
Conduct– Clinical & ethical: Protocol approval, selection of volunteers,
housing, dosing, sampling, AE recording and reporting, ambulatory samples,
– Bioanalytical assay method, equipment (HPLC / LC MS/MS), SOPs
– PK & Statistical Software (WinNonlin, SAS etc.)
Reporting– 3 Parts, CRFs, TMF, Chromatograms
Thank [email protected]
Biowaiver
Recommended for a solid oral Test product that exhibit rapid (85% in 30 min) and similar in vitro dissolution under specified conditions to an approved Reference product when the following conditions are satisfied:– Products are pharmaceutical equivalent
– Drug substance is highly soluble and highly permeable and is not considered have a narrow therapeutic range
– Excipients used are not likely to effect drug absorption