Drug Development

Drug Development - An Overview Swapna.G M.Pharm(Pharmacology)

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 1960’s : 70-100 1970’s : 60-70 1980’s : 50 1990’s :40

AIMS of Drug Development To develop drugs with : Less toxicity Increased potency & efficacy Increased palatibility/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

Protein-Ligand Docking GAPDH D- Glyceraldehyde 3-phosphate dehydrogenase Active site Procedure : • using the structure of the enzyme • docking molecules from chemical library • retrieving the “best 100 ligands“ • vizualizing the 100 complexes • eliminating duplicates • propose 25 inhibitor structures • biological testing

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 • 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 5→4

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 centres  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: 100’s - 1000’s 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 labelling • 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 centres,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

35%

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

Drugs in Developmental phases & Expected Approval Dates

2005 Moxifloxacin II Gatifloxacin II Diarylquinoline R207910 I/II Otsuka Compound I Pyrrole LL3858 I Synthase Inhibitor FAS 20013 I Nitroimidazole PA-824 Diamine SQ-109 Translocase I Inhibitors

2006

2007

2008

III III

2009

2010

2011

2012

2013 2014 2015

NDA NDA

II II II

III II/III II/III II/III

I I

II II

II/III II/III

I

II

II/III

NDA NDA NDA NDA NDA NDA NDA