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!