New Drug Development and Review

Yeong-Liang Lin, MD, MS

Center for Drug Evaluation

Information

International Conference on Harmonization The US Food and Drug Administration EMEA Taiwan Department of Health Taiwan Center for Drug Evaluation

Drug Development

Discovery Development

Chemistry, manufacturing and controls

Pharmacology

Toxicology

Pharmacokinetics Clinical trial

CMC

Drug substance Drug product

Drug Substance

Nomenclature Structure General properties: appearance, color,

melting or boiling point, solubility profile, solution PH, physical form

Manufacture: manufacturer, manufacturing process and control

Manufacturing Process

Manufacturing steps: reaction, extraction, isolation, purification, processing

Chemical structure of starting material, intermediate, reagent

Solvent and auxiliary material Temperature, pH and pressure Anticipated yield

Process Controls

Controls during production to monitor the process to ensure that drug substance will conform to its specification

Operating conditions: temperature, pH, pressure

Environmental conditions In-process material test

Characterization

Elucidation of structure: chemical structure elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, crystallography

Impurity: organic, inorganic, residual solvent, heavy metal

Control of Substance

Specification Analytical procedures Validation of analytical procedures Batch analyses

Drug Product

Excipient Formulation development: proposed route of

administration, release mechanism for modified release products, changes between the proposed commercial formulation and formulations used in clinical batches

Pharmacology

Studies to examine the primary therapeutic effects of a drug candidate

Safety Pharmacology

Detect undesirable properties relevant to human safety, evaluate adverse effects and investigate the mechanism of adverse effects

- Central nervous system - Cardiovascular system - Respiratory system - Renal system - Gastrointestinal system

Toxicology Studies

Carcinogenicity studies Genotoxicity studies Reproductive toxicity studies Developmental toxicity studies Local tolerance studies

Toxicology

Acute, sub-chronic and chronic toxicity at the proposed site of exposure

At least three dose levels with high dose showing frank toxicity and low dose showing no toxicity

Final formulation and study duration equal to or longer than the proposed duration of treatment in clinical trials

Toxicology Studies

Acute toxicity studies

Characterize the spectrum of toxicity

One dose and observed for 14 days

Measurements: signs and pathology Repeated dose toxicity studies

Sub-acute or chronic studies

Observed for a period

Biopharmaceutic Studies

Background studies Bioavailability studies Pharmacokinetic studies In vitro studies

Background Studies

Absorption, distribution, metabolism and elimination studies

Carried out in a few subjects Guide early studies on humans

Bioavailability Studies

Measure the rate and extent to which an active ingredient is absorbed from a drug product

Pharmacokinetic Studies

Define the time course of drug and major metabolite concentrations in blood and other body compartments

Rate of drug absorption and delivery to systemic circulation

Changes in kinetic parameters with doses within the recommended dosing range

Influence of age, sex, race and disease states

In Vitro Studies

Define the release rate of a drug from the dosage form

Characterization of a dosage form

Drug Interaction Studies

Cytochrome P-450 superfamily Substrate for metabolic pathways Effects on other drugs Positive results suggest the need for further cl

inical evaluation

PK in Patients with Organ Impairment

Patients with impaired hepatic function Patients with impaired renal function

Clinical Trial

Phase I, II, III, IV

Phase I

Normal healthy volunteers, in general Determine toxicity, safety and early evidence

of effectiveness The number of subjects is in the range of 20-

80

Phase II

Controlled clinical trials Demonstrate effectiveness and relative safety Number of subjects: seldom beyond 100-200

Phase III

Expended controlled clinical trials Evidence of effectiveness for specific

indications and precise definition of drug-related adverse effects

Number of subjects: dependent on study hypothesis

Phase IV

Additional studies to elucidate the incidence of adverse reactions after drug approval

Large scale and long term

Ethnic Factor

International Conference on Harmonization guidance E5 Ethnic Factors in the Acceptability of Foreign Clinical Data

Waive local registration trial Utilize foreign data to predict efficacy and

safety in the new population Avoid duplication of unnecessary clinical trials

Steps

Evaluate complete clinical data package Adequate characterization of pharmacokinetic

s, pharmacodynamics, dose response, efficacy and safety in foreign populations

Characterization in a population relevant to the new region

Characterization in Foreign Populations Clinical trials conducted according to

regulatory standards in the new region

- Well controlled

- Appropriate endpoints

- Appropriate control drugs

Characterization in the New Population Influence by ethnic factors

- Extrinsic ethnic factors

- Intrinsic ethnic factors

Intrinsic Factors

Linear pharmacokinetics? Flat pharmacodynamic curve in the range of r

ecommended dosage? Wide therapeutic dose range? Metabolism through multiple pathways? High bioavailability? Low protein binding?

Extrinsic Factors

High likelihood of use with multiple medications?

High likelihood of inappropriate use?

Foreign Data Unacceptable

If foreign data not acceptable to apply directly to the new population,

- local efficacy studies

- local pharmacokinetic studies

- local pharmacodynamic studies

- local safety studies

Potential Hurdles

Inadequate efficacy Safety issues

- Hepatotoxicity

- QT prolongation

Review of Hepatotoxicity

Cases of liver failure before drug approval Clinical meaningful elevations of aminotransfe

rases Combined jaundice and ALT elevations Inadequate sample size to detect rare liver to

xicity by pre-approval clinical trials

Review of QT Prolongation

In vitro Ikr Assay: effects on ion channel

In vitro QT assay: ventricular repolarization Drug interaction Clinical trial: increase of the QT interval, incre

ases greater than 60 msec, QT intervals longer than 500 msec

Conclusion

Quality Preclinical safety information Adequate efficacy evidence Acceptable safety profile

Luck and Efforts!