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SAS Programming Tool to Create Statistical Outputs for Bioavailability and Bioequivalence studies

Gaurav Chauhan, Arun Kumar*Ephicacy Lifescience Analytics (ELA)

&Pankaj MishraLotus Labs Pvt. Ltd.


Introduction to BA/BE

BioAvailability (BA): Bioavailability is defined in CFR § 320.1 as

• The rate and extent to which the active ingredient is absorbed from adrug product and becomes available at the site of action

• This definition focuses on the processes by which the activeingredients are released from an oral dosage form and move to thesite of action

BioEquivalence (BE): Bioequivalence is defined in § 320.1 as

• The absence of a significant difference in the rate and extent towhich the active ingredient in pharmaceutical equivalents orpharmaceutical alternatives becomes available at the site of drugaction when administered at the same molar dose under similarconditions in an appropriately designed study


Pharmacokinetics vs. Pharmacodynamics

Pharmacokinetics (PK):

• What the body does to the drug

Absorption Distribution Metabolism Elimination

Pharmacodynamics (PD):

• What the drug does to the body Wanted effects – efficacy Unwanted effects – toxicity, No therapeutic


PK parameters


Primary PK Parameters

Cmax

• The maximum concentration of a drug observed after its administration

Tmax

• This is the time point at which the maximum drug concentration is observed in biological fluids such as plasma, serum, blood, urine etc.

AUC(0-t)

• Area under the plasma concentration – time curve from 0h to the lastquantifiable concentration to be calculated using the trapezoidal rule

AUC(0-∞)

• Area under the plasma concentration – time curve, from zero to infinityto be calculated as the sum of AUC(0-t) plus the ratio of the lastmeasurable concentration to the elimination rate constant


Secondary PK Parameters

T1/2• Terminal elimination half-life

Ke (λz)

• Apparent first-order terminal elimination rate constant calculatedfrom a semi-log plot of the plasma concentration versus time curve.The parameter is calculated by linear least-squares regression analysisusing the maximum number of points in the terminal log-linear phase.(e.g. three or more non-zero plasma concentrations)

Cpd

• Pre-dose concentrations determined immediately before a dose atsteady state


PK Parameters

AUCτ• Area under the plasma concentration-time curve during a dosage

interval (τ)

Cav,ss

• Average steady-state plasma drug concentration during multiple-doseadministration

PTF% or CTF• Peak trough fluctuation over one dosing interval at steady state

Swing• The peak-trough difference Cmax – Cmin to the trough concentration

Cmin


Steady State

• When the plasma concentration of drug at any time point duringany dosing interval should be identical to the concentration at thesame time during any other dosing interval. The steady state drugconcentrations fluctuate (oscillate) between a maximum and aminimum steady state concentration within each of the dosingintervals

• The equilibrium condition reached when the amount of drug putinto the kinetic system over time exactly equals the amount ofdrug eliminated by the system over that same period of time

• (rate in = rate out)


PK information recommended for submission

The following pharmacokinetic information is recommended for submission: • Plasma/Serum/Blood concentrations and time points

• AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2, for single dose

• Inter subject, intra subject, and/or total variability, if available

• Cmin (concentration at the end of a dosing interval), Cav (averageconcentration during a dosing interval), degree of fluctuation [(Cmax-Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] if steady-state studies are employed

• Partial AUC, requested only as an early exposure measure


PK information recommended for submission

In addition, the following statistical information be provided for AUC0-t, AUC0-∞, and Cmax:

• Geometric mean

• Arithmetic mean

• Ratio of means

• Confidence intervals

• ANOVA for AUC0-t, AUC0-∞, Cmax

• Also recommend that logarithmic transformation be provided for measuresused for BE demonstration


Regulatory Requirement (FDA)

For Non-highly variable drug:• 90% confidence interval of the ratio of the geometric means Cmax, AUC(0-t) and

AUC(0-∞) of the test and reference drug products to be within the acceptanceinterval [80%, 125%]

For highly variable drugs or drug products: PK parameter Cmax,AUC(0-t) and AUC(0-∞) that has a within-subject standard deviation of thereference product (SWR) of the log-transformed values ≥ 0.294

• 95% upper confidence bound ≤ 0

• The point estimate of the Test/Reference geometric mean ratio must within[0.80, 1.25]


Regulatory Requirement (EMEA)

For Non-highly variable drug:

• 90% CI of the ratio for AUC(0-t) and Cmax between the test and referenceproducts should be within the acceptance interval of 80-125%

• For studies to determine bioequivalence at steady state AUCτ, Cmax,ss, andCmin,ss should be analyzed using the same acceptance interval as statedabove

For highly variable drugs or drug products:

• 90% CI of the ratio Cmax between test and reference product should bewithin the [U, L] = exp [±k·SWR], where k is the regulatory constant set to0.760 and SWR is the within-subject standard deviation of the log-transformed values of Cmax of the reference product. The possibility towiden the acceptance criteria based on high intra-subject variability doesnot apply to AUC where the acceptance range should remain at 80.00 –125.00% regardless of variability


Intro to Stat-BA/BE tool

• To analyze and create BA/BE statistical report objects, Ephicacydeveloped and validated Stat-BA/BE tool

• Accommodates 8 BA/BE designs

• Reduces turn around time

• Less programmer intervention

• Validated outputs

• Ready for 6 regulatory submission• US, EMA, MHRA, TPD, MCC & ANIVSA


Designs accommodated by Stat-PK tool

Stat-PK tool generate reports for following designs: 2X2 Crossover Design ( One Test, One Reference )

3X3 Crossover Design ( One Test, Two Reference )

3X3 Crossover Design ( Two Test, One Reference )

4X4 Crossover Design ( Three Test, One Reference )

4X4 Crossover Design ( Two Test, Two Reference )

2X3 Partially Replicated Design (One Test, Two Reference)

2X4 Fully Replicated Design (One Test, One Reference)

Parallel Design


Advantages of Stat-BA/BE tool

• Turn around time Maximum of 8 hours (12 to 15 Statistical Reports)

• Report Formats RTF PDF Excel

• Page Size 8.5" X 11" 8.27" X 11.69" or 210mm X297mm

• Font Courier new Times new roman


Features available in Stat-BA/BE tool

• Report All tables in single report (RTF or PDF)

• Table Selection Option to select required single or multiple tables

• Parameter Selection PK parameter selection based on the requirements

• Parameter Ordering PK parameter order in output

• Additional Title Two additional titles for reporting object

• SAS Procedure Selection

Selection of SAS Proc: GLM or Mixed (Only for replicated designs)

• SAS log file control


Options available in Stat-BA/BE tool

• Ratio Calculation Variables ratio calculation (Maximum 3 Ratio) Example: AUC Ratio(%) = (AUC0-t/AUC0-∞)*100

• Study title Header of the report

• Rename Options to rename variables

• Parameter Ordering PK parameter order in tables and listing

• Display option Number of row per page can be controlled

• Dataset format SAS – XPT


Dataset format required for Stat-BA/BE tool

• Dataset format

XPT

• Dataset type Longitudinal

• Required Variables in SDTM domain (PP domain) STUDYID (Study ID), SUBJID (Subject ID), SEQ (Sequence), PER (Period),

PKTESTCD (PK parameters), PKRESN (Numeric PK value), UNIT (Unit), ANALYTE (Name of Analyte), TRT (Treatment)


SDLC Approach for Stat-BA/BE Tool Development


Documents generated during SDLC

1. User Requirement Specification2. Tool Requirement Specification3. TL Mock Shell4. Master Validation Plan5. Test Plan6. Expected Results7. User Manual


Tool Structure

Utility.sas

datacheck.sas

xls2csv.sas

ltstemp.sas

fmt.sas

rmcall.sas

audit.sas

report.sas

pgm01.sas

pgm02.sas

pgm0n.sas

pgm03.sas

Editing and Connecting all

individual macros

Convert xpt to SAS dataset and check all required variables its

label and format

Convert xls to csv format

Set report’s format, i.e. font size, font type.

Set variables formats

Check Condition for individual table and reports macros

Audit for SAS dataset, track user ID, date and what

update.

Report TL using PROC REPORT with required conditions

Individual Table Macros. It create final dataset for

report.


Flow chart of Stat-BA/BE tool functionality

(Data Check)Error

YES NO

Identify Study Design

Design Utility Program Selection

Fill required information in the utility

Library allocation

Excel sheet conversion into .sas7bdat

Fill design excel sheet

Report template call

Report format call

Report Macro call

Table i = YES,i= 1 to n, where n number of tables

in design

Call ith table macro

Call report macro

Generate final reports in respective folders

Skip ith table

YES

NO

EndEnd

Inpu

ts b

y us

er


Utility for Stat-BA/BE tool (Cont’d …)


Table Selection Excel Sheet


Utility for Stat-BA/BE tool (Cont’d …)


Table of Contents for 2X2 Crossover BA/BE Design


Table of Contents for 3X3 Crossover BA/BE Design (2 Test, 1 Reference)


BA/BE Report Example

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