Drug Development - An Overview

Drug Development
The average time it takes to bring a drug to market is ~15 yrs 6 years : Drug Discovery & Pre-clinical phase 6-7 years: Clinical Trials 2 years : Approval phase The average cost to bring a drug to market is ~$800million 70-90% of new chemical entities (NCEs) fail >60% of terminations: Phases II & III Steady decline in no. of drugs introduced into the market 1960s : 70-100 1970s : 60-70 1980s : 50 1990s :40

AIMS of Drug Development

To develop drugs with :
Less toxicity Increased potency & efficacy Increased palatability /acceptability

Drug Development Phases

Discovery of NCE (New Chemical Entity) Preclinical Development Investigational New Drug Application (IND) Phase I clinical trials Phase II clinical trials

Phase III clinical trials

New Drug Application (NDA) Phase IV clinical trials

DRUG DISCOVERY

Natural products
Analog Design Peptidomimetics Targeted discovery Random Screening Serendipity

Target Identification
The key to rational mechanism-based drug discovery is identifying a good target for drug development. A target may be already known from the mechanism of action of existing drugs or natural ligands.

A target may be identified from an understanding of basic cellular and physiological processes and/or the disease mechanism.
A target may be identified from mutations or alterations in specific disease-related genes. A target may be identified by sequence or structural homology to known targets. A target may be identified serendipitously.

Lead Identification
After an appropriate molecular target is identified, the next major task in the drug discovery process is generation and optimization of lead compounds
Identification of lead compounds requires: Developing appropriate screening assays

Screening molecular libraries containing potential lead compounds

Pre-Clinical Development
Objectives: Pharmacological profile Toxicity profile
Acute toxicity (LD50)

Subacute toxicity(<3 months)

Chronic toxicity (6-18 months) Teratogenicity, Mutagenicity, carcinogenicity

Pharmacokinetic profile i.e.ADME studies Chemical & Pharmaceutical development survival: of 5000 pre-clinical 5 INDs

SPONSOR/FDA Meetings (Pre-IND)

Open discussion
Testing phases Data requirements Any scientific issues that may need to be resolved

Submission of IND application

IND application contents: Descriptive name of the drug, including the chemical name & structure of NCE Complete list of components of the drug Quantitative composition of the drug Name & address of supplier of any new drug substance and a description of synthesis of any new drug substance Statement of the methods, facilities & controls used for the manufacture, processing & packaging of the new drug

Submission of IND application

Statement covering all information from preclinical investigations and any clinical studies &experience with the drug Copies of labels for the drugs A description of scientific training & experience considered appropriate by the sponsor to qualify an investigator as a suitable expert to investigate the drug Names and curriculum vitae of all investigators An outline of planned methodology to be adopted in clinical trials

Clinical Trials
PHASE I
Objective: Safety, pk/pd in normals study size: 20-80

time: 2-3 years

open study 80% proceed to Phase 2 54

Phase I Failures
Pre-clinical animal models behavior in humans
Inadequate preclinical data Change in drug formulation between time of preclinical and clinical testing

pk/pd relationships
Poorly designed clinical studies

Drug too toxic in humans

Phase II Clinical Studies

objectives: to assess therapeutic efficacy & safety and to find appropriate dosage schedule of drug in patients Types of studies: small controlled trials in patients limited centers study size: 100-300 time: months - 2 years survival: 2 go on to Phase 3

SPONSOR/FDA Meetings (End of Phase II)

Plan protocols for phase III

Discuss & identify any additional information that may be required to support the submission of NDA

Phase III Clinical Studies

objectives:

Long term toxicity data

Benefit-risk relationship Dose-response relationships Assessment of adverse drug reactions targeted patients multi-centered placebo-controlled double blinded cross over design size: 100s - 1000s time: 1-4 years survival: 1

Phase II & III Failures

Infrequent adverse reactions observed Drug-drug interactions Drug-disease interactions in ill patients Genetic Effectiveness insufficient (20%) Economic (24%)

SPONSOR/FDA Meetings (Pre-NDA)

Discussion of presentation of data (both paper & electronic) in support of the application Uncover any major unresolved problems or issues

Identify studies the sponsor is relying on as adequate in establishing the effectiveness of the drug
Help reviewers to become acquainted with general information to be submitted Discuss presentation of data in NDA to facilitate its review

Submission of NDA
NDA application contents: Detailed reports of preclinical studies Detailed reports of clinical studies Information on composition & manufacture of drug and on controls & facilities used in manufacture Samples of drug and its labeling Full case reports of each person who received drug needed only in limited circumstances Patent information Material previously submitted to FDA in the IND or in periodic reports must be included by reference in the NDA

Responses of FDA
1. Not approvable letter 2. Approvable letter 3. Approval letter

Phase IV Clinical Trials (Post Marketing Surveillance)

Drug marketed in limited centers, closely monitored for unexpected effects which were never foreseen If significant toxic effect-withdrawn from market If safe-marketed overall

Primary Causes of Failure in 348 Terminated NCEs

13%
21%

Safety Efficacy Economics

31%

Others

Ref: DiMasi, J. Clin Pharmacol Ther (2001) 69;297-307.

Drugs in Developmental phases & Expected Approval Dates

2005 Moxifloxacin II

2006

2007 III

2008

2009

2010 NDA

2011

2012

2013 2014 2015

Diarylquinoline R207910 I/II Otsuka Compound I Pyrrole LL3858 I Synthase Inhibitor FAS 20013 I Nitroimidazole PA-824 Diamine SQ-109 Translocase I Inhibitors I I I

II II II II II II

III II/III II/III II/III II/III II/III II/III

NDA NDA NDA NDA NDA NDA NDA