Guideline for the Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application

Status: Final

Date: February 1997

Released by: Center for Drugs and Biologics, Federal Drug Administration, Department of Health and Human Services

Target Audience: Developers of drugs/biologics

Laws and Regulations:

·CFR 21 Part 320 – Bioavailability and Bioequivalence Requirements – defines biopharmaceutic vocabulary and lays out the appropriate steps for establishing the bioavailability of drugs

·Waxman-Hatch Act (aka Drug Price Competition and Patent Term Restoration Act of 1984) – established the Abbreviated New Drug Application (ANDA) process for generics, providing a faster review track for applications to market generic versions of brand-name drugs without running costly and duplicative clinical trials; instead this Act requires that generic drugs demonstrate bioequivalence to the already approved dosage form

·Federal Food, Drug, and Cosmetic Act – the series of laws empowering the FDA to oversee the safety of drugs, food, and cosmetics in the United States

·21 CFR 10.90 (Food and Drug Administration regulations, recommendations, and agreements) – description of the types of documents issued by the FDA in the form of regulations, recommendations, and agreements

Definitions:

Abbreviated New Drug Application (ANDA): application used for a generic drug seeking approval from the FDA for sale and marketing

Analysis of variance: a statistical test that examines the role of selected factors in the variance of response for a particular variable

AUC: area under the curve; pharmacology term describing the concentration of a drug in the blood over time; used to estimate the bioavailability and total clearance of drugs

Bioavailability: the amount of drug that actually reaches the target area in the body after it has been administered

Bioequivalence: state in which two different formulations of the same drug in the same dose amount have comparable bioavailability, with the same amount of each drug reaching the same target tissue and having similar effects

Biopharmaceutics: area of pharmaceutical science focusing on what happens to a drug once it enters the body and travels to the target area, including metabolism, elimination

Cmax: maximum or peak plasma concentration (after administration and before a second dose is administered); state in which the rate of drug absorption equals the rate of elimination

Confidence interval: the measure of confidence that a result will fall within a limited range of numbers; the smaller the confidence interval, the more likely the result is not due to chance

Kel: elimination rate constant that represents the amount of drug eliminated from the body per unit of time

Pharmacokinetic linearity: state in which the dose concentration is proportional to that dose and the rate of elimination of the drug is proportional to the concentration; dose-independent

New drug application (NDA): application a drug company gives to the FDA when seeking approval to sell and market a new drug for which there is no already approved equivalent

Pharmacokinetics: area of pharmacology focusing on the effect of body processes on drugs, including absorption, distribution, metabolism, and elimination

Sensitivity: used to assess the results of diagnostic and screening tests; indicates the proportion of diseased persons in a screened population, measuring the probability of correctly diagnosing a condition

Specificity: used to assess the results of diagnostic and screening tests; indicates the proportion of nondiseased persons, measuring the probability of correctly identifying a nondiseased person

Tmax: the amount of time it takes a drug to reach maximum plasma concentration (Cmax) following administration

Vd: volume of distribution; in pharmacology, the ratio of the total amount of drug in the body to the concentration of the drug in the blood

Background:

The New Drug Application (NDA) and abbreviated new drug application (ANDA) for the FDA include a Human Pharmacokinetics (PK) and Bioavailability section. Here a drug company will detail what tests and procedures they conducted to demonstrate what a drug does once it enters the body, and how certain processes in the body affect the drug and, ultimately, determine the effect of the drug.

Specifically, this section of the application must describe the bioavailability of the drug, particularly how much of a drug reaches the target area for a given dosage form. If the drug being tested is a generic form of an already approved drug, this section must demonstrate the generic’s bioequivalence to the already approved drug. The PK tests must show that the same amount of the generic drug in a given dosage form reaches the target tissue as the currently approved drug.

Summary:

This guideline suggests how to prepare the section of the NDA and ANDA that deal with the pharmacokinetics and bioavailability of the drug seeking approval for sale and marketing.

Rationale:

Drug developers conduct various tests on a drug at different stages of drug development. Deciding what tests are necessary and useful can be difficult. Knowing exactly what data the FDA will be looking for in an NDA or ANDA would help drug companies choose appropriate tests to conduct. An FDA guidance that delineates the types of tests that will reveal these data and outlines a format to follow when writing up the NDA or ANDA will help streamline the drug review and approval process, avoiding unnecessary, wasteful steps.

Resulting Recommendations:

The guideline recommends including data collected from the following studies. Drug developers should choose those studies that are appropriate for their particular drug.

·Pilot/background studies – use small patient pool; assess absorption, distribution, metabolism, and elimination of study drug to help in design of preliminary clinical trials and kinetic studies; suggest using radioisotope techniques

·Bioavailability/bioequivalence studies – determine how quickly and how much of the active ingredient of a drug is absorbed by the body and reaches the target area of the body

·PK studies – demonstrate how long the drug is active in the body and what are the resulting concentrations of related metabolites; studies showing how quickly the drug is absorbed into blood and then eliminated are of special importance, particularly regarding changes in kinetic parameters with dose (ie, dose-dependent kinetics) within the recommended clinical dosing range, and influences of demographics, disease states, other drugs, drug binding, and the effect of the drug on special populations (eg, patients with impaired hepatic or renal function)

·Other in vivo studies – test bioavailability in animals or humans using pharmacological or clinical endpoints

·In vitro studies – dissolution studies used to determine how quickly the active ingredient of a drug releases from the dosage form and, thereby, portrays dosage form and ensures consistent performance of drug

The guideline also recommends that applicants follow a particular format in presenting the data for the NDA and ANDA. The suggested format includes:

·Summary of studies – summary of all in vivo biopharmaceutic studies presented in table format, with most important studies listed up front

·Summary of data and overall conclusions – provided in table format, including data on PK parameters (ie, peak concentration [Cmax], area under the curve (AUC), time to reach peak concentration (Tmax), elimination constant (Kel), distribution volume (Vd), plasma and renal clearance, and urinary excretion

·Drug formulation – all formulations of drug used during drug development should be described and related studies identified, as well as any changes in manufacturing or formulation

·Analytical methods – description of methods used in in vivo biopharmaceutic study

·Dissolution – information regarding dissolution of each strength and dosage form of formulation seeking approval, including comparison dissolution study of drug lot used in in vivo biopharmaceutic study; includes dissolution performance and summary of dissolution method and suggested specification

·Individual study reports format – should include objective, dosage form(s) investigated, name of principal investigator, premises where clinical trials and assays of collected sample took place, all individual data needed for conclusions (eg, info on patient demographics, medication taken during trial, adverse reactions, etc), analysis of data, and conclusion. Analytical method(s) should also be described, including information on sensitivity, linearity, specificity, and reproducibility of method. Appropriate statistical methods should be used in the data analysis, including such tests as Analysis of Variance (ANOVA), calculations of power analysis and PK parameters, confidence intervals, and ratio analysis. Report should end with a paragraph summing up the main conclusions of the study.

Impact:

This guidance will help guide drug developers when they plan what tests to conduct during preclinical and clinical drug development in order to ensure that the data they collect are the actual data the FDA is interested in seeing in the NDA and ANDA. It will also help streamline the application process and save time for both the drug developer and FDA employees who review the applications.