6. drug design and development

April 11, 2023April 11, 2023 Sokoine University of AgricultureSokoine University of Agriculture

The Drug Discovery and The Drug Discovery and Development ProcessDevelopment Process


Lead To Proof Of ConceptLead To Proof Of Concept

• Technologies & Solutions for Selecting Best Clinical Candidate– Medicinal Chemistry– Biological Screening Assays– High Throughput Purification & Analysis– ADME-PK– Data Management

• Technologies and Solutions for Establishing POC– Process Chemistry & Development– Analytical Method Development & Validation– Bio-analytical– Regulatory & Clinical Affairs

Overview of the Drug Overview of the Drug Development ProcessDevelopment Process

• Statistics related to Research and Development

• Process of Drug Development

• Phases Involved in Drug Development

• Success vs Failures – What Accounts for Each?


What are the Characteristics of What are the Characteristics of Pharmaceutical R&D?Pharmaceutical R&D?

• Based on commercialization of biomedical research discoveries

• Innovation is critical to the process

• Specialized research is essential and development cycles are very long

• Resulting drug candidates/products must:– be treatment breakthroughs – have better profiles than existing treatments


Basic Statistics for Basic Statistics for Pharmaceutical IndustryPharmaceutical Industry

• Pharmaceutical R&D is high-risk and also very high cost

• Average cost to discover and develop one compound = $0.8-1Billion

• Takes on average 10 years to go from shelf to pharmacy shelf

• Need to screen 5,000 – 10,000 compounds to generate an approved drug

• About 3/10 drug products make profits that match or exceed R&D costs


R&D Success Rates by Development StageR&D Success Rates by Development StageDiscovery (2-10 yrs)

Preclinical TestingLab & animal testing

Phase I20-80 healthy volunteersfor safety & dosage

Phase II100-300 patient volunteers used to

for efficacy & side effects

Phase III1,000-5,000 patient volunteers used to monitor efficacy & side effects adverse

reactions to long-term use FDA Review/Approval

Additional Post-marketing testing

Compound Success Rates by Stage5,000 – 10,000 screened

250 EnterPre-clinical Testing

5 Enter Clinical Testing

1 Approved by FDA

Years

0 2 4 6 8 10 12 14 16

Source: PhRMA based on data from Center for the Study of Drug Development, Tufts University

The Drug Development ProcessThe Drug Development Process

Drug Sourcing

ScreeningLeadIdentified

Preclinical IND/CTCWorkup

FileCTC/IND

Patent process

Discovery ScreeningPreclinicalDevelopment

Registration Preparation

Post-submissionActivity

Toxicology

Metabolism

Phase I Phase II Phase III

Formulation/Stability

Process Development

FileWMA

PostFilingActivities

APROVAL

Up to 15 years

Pharmaceutical R&D PhasesPharmaceutical R&D Phases

• Basic Drug Discovery Res. (6 mths – 16 yrs)– Evidence for role of enzyme, receptor, gene or

pathway in disease– Drug target selection and validation– Compounds screening – natural & synthetics– Rational drug design/ molecular modeling– Hit-to-lead, lead optimization and selection

• Safety assessment process begins

Clinical Development: Phase IClinical Development: Phase I

• Approximately 10-40 patients – up to 1 yr

• Safety and tolerability – healthy volunteers

• Evidence of activity in some areas

• Produce a clinical pharmacology package – Bioequivalence studies– Drug interactions– Different populations (pediatrics, elderly,

kidney/liver dysfunction)

Clinical Development: Phase IIClinical Development: Phase II

• Phase IIA– 10-100 patients with target disease– Clinical/efficacy “Proof of Concept”– Normally lasts 9-12 months

• Phase IIB– 100 – 200 patients– Dose ranging studies– Set minimum effective dose– Essential to design Phase III– Normally lasts 9-12 months

Clinical Development: Phase IIIClinical Development: Phase III

• 1,000 – 4,000 patients

• Also called “Pivotal Studies”

• To Demonstrate Safety & Efficacy

• Randomized, well-controlled, blinded

• Patient outcomes included in the endpoints

• Timing: 2-4 years

Clinical Development: Phase IVClinical Development: Phase IV

• Typically specified by the regulatory agencies – safety is the usual reason

• Normally required/condition for approval• 10 – 1,000 patients• Could require outcomes/endpoint studies

• Phase V Clinical Development– New claims, new dosage forms, market

support, comparisons to competitors, etc.

New Molecular Entities (%) Entering Each New Molecular Entities (%) Entering Each Phase of Clinical TrialsPhase of Clinical Trials

The price of innovation: New estimates of drug development costs Journal of Health Economics, Vol 22 (2003), pp 151-185.

HTSActive-to-Hit (AtH)

Lead Optimization (LO)

Hit-to-Lead (HtL)

Typical Drug Discovery ProcessTypical Drug Discovery Process

“Hit” “Lead”

Screening

“Pre-clinical candidate”

Compound acquisition

Iterative design and synthesis

Data analysis and mining Mol modeling, SAR dev

In vivo efficacy screens

Physchem prop screens

ADME screens (in vitro perm, metab, safety)

In vivo DMPK

Purity, identity determ

Chronic toxAcute tox

Initial SAR,near neighbor synthesis

Hit resynthesis

Biochemical “mechanism of action” screens

Chemistry

Biology

DMPK

Some Key DefinitionsSome Key Definitions

• “Hit” = compound(s) which have demonstrated reproducible, dose-responsive activity in a primary biological assay

• “Lead” = compound(s) which have been shown to exhibit properties (activity, selectivity, ADME, etc.) perceived to optimizable through iterative cycles of medicinal chemistry and biological evaluation

• “Pre-clinical candidate” = compound which has in vivo efficacy, in vivo PK, selectivity and toxicological properties consistent with a pre-defined Target Product Profile

Failure: The Reality of Drug DiscoveryFailure: The Reality of Drug Discovery

Historically, the majority of Hit-to-Lead and Lead Optimization programs fail to deliver a pre-clinical candidate due to:– Lack of efficacy (in animal models)– Unexpected toxicity– Poor pharmacokinetics

If you must fail…

“Fail early, fail cheap”

THANK YOU


6. drug design and development

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