Drug discovery and development overview

Description Clinical

Pharmacology Indications and

Usage Contraindications Warnings Precautions Adverse Reactions

Drug Abuse and Dependence

Overdosage Dosage and

Administration How Supplied Clinical Studies References

Immunologist Tissue staining 1908 Nobel Prize

for Medicine “Magic Bullet” Salvarsan

Paul Ehrlich: All who are about to embark on developing a new drug must bring to the task four essentials:› brains› persistence› capital› luck

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12

Discovery The Screen The Lead Development R R Safety Assess Cand Patents Dosage Form Dev IND/IDE Clinical Trials Phase 1 Review Safety Data Phase 2 End Phase 2 Clin Rev Phase 3NDA/BLA/PMA FDA ReviewApproval Product Launch

The term includes basic and applied research as well as development activities carried on or supported in the pharmaceutical, biological, chemical, medical, and related sciences, including psychology and psychiatry, if the purpose of such activities is concerned ultimately with the utilization of scientific principles in understanding diseases or in improving health.

The term “Discovery” is used to describe the early phases of the overall biomedical discovery process, that is, the synthesis of or the search for compounds and the screening processes developed to identify “lead” compounds.

Uncured Diseases Approximate

Annual PrevalenceApproximate

Economic Cost(billions)

Cardiovascular 56,000,000 $128

Cancer 10,000,000 $104

Alzheimer’s 4,000,000 $100

Diabetes 16,000,000 $ 92

Arthritis 40,000,000 $ 65

Depression 17,400,000 $ 44

Stroke 3,000,000 $ 30

Osteoporosis 28,000,000 $ 10

National Cancer Institute National Heart, Lung and Blood

Institute National Institute on Aging National Institute of Arthritis and

Musculoskeletal and Skin Diseases National Institute of Diabetes and

Digestive and Kidney Diseases

American Cancer Society American Heart Association Howard Hughes Medical Institute Salk Institute for Biological Studies

Select area of therapeutic or diagnostic interest

Establish long term (5 to 10 year) goals for program

Commit needed resources

Short term plans, 1 to 3 years Identifies areas for discovery research Allocates resources to carry out the

plan› people› space› equipment› money

Discovery research Marketing Clinical research

Product Market Proprietary Aspects Technologies used Mechanism of action Regulatory agencies involved Clinical trials

Diagnostic Therapeutic Device Combination

Who will use the product? What special needs does that group

have? Who will pay for the product?

Basic Research Feasibility Explore research/design options Lead candidate

Cloning Protein purification Monoclonal antibodies Carbohydrate technology In vivo genetic modification Transgenic manipulation Cell culture

Tool to identify new drug candidates Usually a subcellular component

(enzyme, receptor, etc.) removed from a living system and studied in vitro

ACTIVES: agents that stimulate or inhibit normal function

Receptor: any biological macromolecule which can be activated by a drug to cause a biological response or effect.

Agonist: a drug which binds to a receptor and elicits a biological response

Antagonist: occupies (or blocks) a receptor but does not elicit a response

Intrinsic activity: the measure of a drug’s ability to elicit a response

Synthetic program High through-put screening program Compound libraries

Fermentation/microbial sources Plant/herbal sources Arachnid and amphibian sources Marine sources

Tool to identify new drug candidates Usually a subcellular component

(enzyme, receptor, etc.) removed from a living system and studied in vitro

An active is a substance that causes inhibition or stimulation in a screening model, thereby indicating the substance may have pharmacological effect.

A compound that exhibits pharmacological properties which suggest its value as a starting point for drug development.

The process of synthesizing chemical variations, or analogs, of a lead compound, with the goal of creating those compounds with improved pharmacological properties.

From WSJ Jan 27, 2000: Three teams of researchers have

discovered a gene for a protein that appears to prevent nerves in the brain and spinal cord from growing back after being damaged by injury or disease.

By studying the protein, researchers hope they can design drugs that might help regenerate damaged nerves

Scientist are looking for the receptor for the protein. Once it is found, drug companies may be able to design antagonists to block the effect of the protein, allowing damaged nerves to regenerate.

Ames TestIn vitro metabolism

microsomes hepatocytes liver slices

Compound from synthetic program,combinatorial library, chemical library,

natural product source, etc.

In vitro evaluation - human/mammalreceptor/ enzyme assay; reporter

system

Active

Biochemical, tissue or animal model offunction

Active

Animal model of theraputic target

Pharmacokinetics, formulation, acutetoxicology

Approval for clinical development

Yes

Yes

No

No

For every experiment the researcher should record:› each item, source, lot number and

quantity used › experimental conditions, e.g., times,

temperatures, pressures, etc.› all calculations› sampling schedule, results

Safety and Efficacy Chemistry/Pharmacy Clinical/Regulatory Marketing/Legal Potential Ups and Downs

Process not well controlled; nonreproducible results

Insufficient experience to adequately predict critical parameters

Process not scaleable “as is” Documentation incomplete, poorly

recorded, poorly organized, or does not support claims

Introduction and Summary

Assays Chemistry Pharmacy Patents Clinical Plan

Regulatory Affairs Potential Liabilities Competition Candidate Potential Safety Recommendation

Research Development

Overallobjective

Select adevelopment

candidate

Submit an NDA

CorporateMandate

Broad, Looselydefined

Narrow, focused

Compoundstested

Many, diverse One

Types ofstudies

Few Many

Research v. Development

Research Development

Regulatory Little or none Extensive

Timetable Loose, flexible Strict,constrained

Recognition Innovation Speed

Culture Chaotic Structured

Workstyle Entrepeneurial Interdependent

Research Development

Quantity µg mg g g kg

Safety Ames, P450 1 w 105 w

Formulation Capsule Tablet, inject.

Metabolism Radiolabeled Assay

Budget Departmental Proj. Acct. No.

Costs <$100,000 >$1,000,000

1. Establish raw material specifications2. Scale-up production processes3. Establish critical process control

parameters4. Establish final product specifications5. Validate analytical methods6. GLP preclinical studies7. Prepare clinical trial material8. Initiate stability/reliability studies9. Establish document systems

New Chemical Entities (NCE) or New Molecular Entities (NME) -

active ingredients never before used as drugs

The active ingredient intended to diagnose, treat, cure, or prevent disease or affect the structure or function of the body, excluding other inactive substances used in the drug product.

Identity: normally two identity tests required

Strength/potency Sensitivity Specificity Purity: normally 98+% for NCE’s Stability Safety and efficacy

The finished dosage form (tablet, capsule, etc.) that contains a drug substance--generally, but not necessarily, in association with other active or inactive ingredients.

Establish specifications and specification testing requirements for:

• identity•potency/strength•purity•stability

United States Pharmacopoeia and National Formulary - designated as the official compendia pursuant to federal and some state statutes, and containing enforceable standards and specifications for strength, quality, purity, packaging, labeling, and where applicable, bioavailability of drugs

Nonclinical laboratory study - in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety.

Regulations established in the U.S. in 1976 to ensure the quality and integrity of bioresearch and animal test data submitted to the FDA

Regulations on facilities and equipment Regulations involved in tests and

controls Regulations on personnel and

organization

Verify the quality and integrity of data submitted to FDA

Inspect nonclinical laboratories engaging in safety studies for regulated products

Audit ongoing and completed lab safety studies

Determine degree of compliance with GLP regulations

Toxicology› Acute toxicity› Subacute and chronic toxicity› Reproductive and developmental studies› Mutagenicity

Metabolism Pharmacology Tissue residue Environmental

Study of how the drug is absorbed, distributed throughout the body, metabolized and excreted (ADME)

Determination of the rate constants (kinetics) for ADME

Engineering: Determine pilot plant requirements for preparation of clinical trial material

Clinical Affairs: Begin the design of clinical studies to establish efficacy and tolerance of the new drug candidates in human beings

Regulatory Affairs› Prepare IND/IDE› Pre-IND/IDE meeting with the FDA to

discuss plans for Phase I clinical trials

Drug/Biologic/Component Characteristics

Description of actives, excipients, components, and solvents required for formulation or assembly

Analytical test methods Process or assembly instructions Processing equipment incompatibilities

Regulatory Affairs Regulatory status of drug substance

and finished product History or status of communications

with FDA World wide regulatory strategy

Engineering Equipment/environmental/facility

requirements for manufacture Special handling requirements

The scaled-up version of the product is ineffective or uncharacteristic when compared to the research version

Facilities are inadequate for aseptic handling of product, microbiological testing and/or quality control

Quality specifications for raw materials, drug substance and processing intermediates

Stability of raw materials Preliminary product specifications Storage requirements

Marketing and Medical Product name Initial dose levels Packaging configurations Projected initial market demand (units

per month)

Regulatory Affairs Regulatory status of drug substance

and finished product History or status of communications

with FDA World wide regulatory strategy

Engineering Equipment/environmental/facility

requirements for manufacture Special handling requirements

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12

Discovery The Screen The Lead Development R R Safety Assess Cand Patents Dosage Form Dev IND/IDE Clinical Trials Phase 1 Review Safety Data Phase 2 End Phase 2 Clin Rev Phase 3NDA/PLA/PMA FDA ReviewApproval Product Launch

Investigational New Drug Applications, or

Notice of Claimed Exemption for a New Drug

Brief (1 - 2 hours) conference with FDA to get pre-submission feedback from FDA

Project Manager; FDA staff person that serves as liaison between sponsor and FDA; a Project Manager is assigned to each IND

Preclinical testing:Pharm/tox data including ADME, carcinogenicity and mutagenicity screening

Protection of human subjects

General Investigational plans Investigator’s Brochure Clinical Protocols Chemistry, Manufacturing and Controls Animal Pharmacology and Toxicology Previous Human Experience

FDA review time: 30 days Submission size: 4 to 10 (400 page)

volumes

Any study in humans intended to› verify effects › identify adverse reactions› determine ADME

for an investigational drug

Good Clinical Practices establish procedures to assure the

quality and integrity of data obtained during clinical testing

protect the rights and safety of clinical trial subjects

GCP Requirements

GCP Requirements

Sponsor

MonitorInvestigator IRB

Informed Consent

In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject

Biomedical research involving humans must be scientifically sound

Declaration of Helsinki Benefits justify the risks Preserve rights, safety, and well-

being of subjects Adequate information to support trial Clear, detailed protocol Prior IRB/IEC approval Medical care by qualified physician

Qualified personnel Informed consent Record keeping Confidentiality GMP investigational products Quality systems

An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.

Trial design Trial management, Data handling and

Recordkeeping› Independent Data Management Committee

Selecting Investigators Financing

selecting investigators and monitors informing investigators reviewing ongoing investigations record keeping and record retention ensuring disposition of unused drug

supplies

Quality Assurance/Quality Control› SOPs to assure compliance› access to sites and documents› data reliability› contracts with investigators

Contract Research Organization Medical Expertise

Notification/Submission to Regulatory Authorities

Confirmation of IRB Approval Investigator’s Brochure Clinical Trial Material Ensuring disposition of unused drug

supplies Monitoring

Sponsors must monitor trials to ensure the quality and integrity of the

clinical data ensure that the rights and safety of

human subjects involved in the clinical study are preserved

The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOP's), GCP, and the applicable regulatory requirement(s).

selection of a monitor written monitoring procedures preinvestigation site visits periodic site visits review of subject records record of on-site visits

A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator

control of drug record keeping and record retention investigator reports assurance of IRB review handling of controlled substances

Provide adequate resources Medical care of Trial Subjects Communication with the IRB Compliance with the protocol Control of investigational product Informed Consent Records and reports

An independent body constituted of medical, scientific, and nonscientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trials, of protocols and amendments, and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

Institutional Review Board/Independent Ethics Committee

Minimize risk to subjects Risk v. Benefit must be reasonable Subject selection must be equitable Informed consent Adequate monitoring for safety Subject Privacy

A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form.

Adverse Drug Reaction (ADR): all noxious and unintended responses to a medicinal product related to any dose

Adverse Event (AE): any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.

Unexpected, Fatal orLife Threatening and

Associated with the Useof the Drug

Serious, Unexpectedand Associated Withthe Use of the Drug

Serious, Expected andNonserious

To FDA by Telephone

Within 3 Working DaysTo FDA and allParticipating

Investigators in aWritten Report Within

10 Working Days

To FDA in Next INDAnnual Progress Report

Written Report Within10 Working Days

Written Report to allParticipatingInvestigators

Number of Subjects:

Length:

Purpose:

20 to 80

Several months

Primarily safety

FDA General Considerations for the Clinical Evaluation of Drugs• normal volunteers• generally, no concomitant drug therapy• generally excludes women of childbearing

potential and children • pretreatment physical exams and follow-up

studies

objectives of study investigator; IRB approval patient selection/exclusion study designs dosing schedules description of observations and

measurements clinical procedures and lab tests

metabolism pharmacology toxicology dose ranging side effects

Case Report Form Baseline information on patient’s

existing medical condition and personal characteristics

drug related changes e.g., blood pressure

adverse events (side effects) patient feedback

Evaluation of Phase I data for safety Prepare Phase II Protocol Update Investigator’s Brochure Recruit Phase II clinical sites

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12

Discovery The Screen The Lead Development R R Safety Assess Cand Patents Dosage Form Dev IND/IDE Clinical Trials Phase 1 Review Safety Data Phase 2 End Phase 2 Clin Rev Phase 3NDA/PLA/PMA FDA ReviewApproval Product Launch

Clinical trials Formulation development/Stability Chemical process development Metabolism/ Pharmacokinetics Toxicology

Well characterized drug substance Broad specifications Stability indicating assays developed Start assay validations Stability studies

Preformulation Formulation Preliminary stability Package selection Formal stability Manufacture and Packaging for clinical

supplies Technology transfer

Pharmacokinetics - ADME Duration of effect v. drug blood levels Bioequivalency/bioavailability of

alternate dose forms Biotransformation of the drug

Studies in special populations› Age› Gender› Hepatic/renal impaired› Metabolic interaction› Ethnic groups

Acute studies Rangefinding studies Subacute studies Genetic Toxicity Reproductive Toxicity Chronic Toxicity (6 months, 1 year) Carcinogenicity Studies (2 year dosing)

Number of patients:

Length:

Purpose:

100 to 300 patient volunteers

2 years

Initial trials in patients to determine efficacy

Dose ranging to determine optimal effect

Strength Frequency of administration Acceptable level of side effects Initial determination of risk-to-benefit

ratio

Pilot scale to larger scale-up batches Start process validation Assay Development

› Set or tighten specifications as needed› Continue assay development› Continue stability studies

shelf-life storage requirements primary packing materials

Determine the safety of proceeding to Phase 3

Evaluate Phase 3 plan and protocols Identify any additional information

necessary to support marketing application

Patients:

Length:Purpose:

1,000 to 3,000patient volunteers

3 yearsPIVOTALVerify safety and

effectivenessMonitor adverse

reactions from long-term use

Larger patient pool Genetic, lifestyle and physiologic

diversity Concomitant therapies and conditions

permitted Out-patient population, less rigorously

monitored

At least two pivotal (adequate and well controlled) studies are required to provide “substantial evidence” supporting claims of effectiveness for new drugs and antibiotics.

adequate size must be a controlled trial must have a blinded design (when

practical and ethical) must be randomized

Degree of response sought Desired assurance against false

positive Acceptable risk of failure to

demonstrate response

Clear statement of objectives Design that permits valid comparison

with control Method of subject selection that

provides adequate assurance that subjects have the disease or condition being studied

Adequate measures to minimize bias by subjects, observers and analysts of the data

Well-defined and reliable methods of assessment of subject’s responses

Adequate analysis of the study results to assess the effects of the drug.

Dangerous adverse effect is found Drug lacks significant effects or has an

effect less advantageous than that of an existing therapy

Drug has a significant effect, but that effect does not justify the risks associated with its use

Drug shows clear evidence of being safe and effective

Pharmacology/Toxicology Completion Prescribing Information Registration/Pricing Sales Formulation Marketing plan/support trials

70% of INDs successfully complete Phase I Clinical Trials

33% of INDs successfully complete Phase 2 Clinical Trials

27% of INDs successfully complete Phase 3 Clinical Trials and continue to NDA

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12

Discovery The Screen The Lead Development R R Safety Assess Cand Patents Dosage Form Dev IND/IDE Clinical Trials Phase 1 Review Safety Data Phase 2 End Phase 2 Clin Rev Phase 3NDA/PLA/PMA FDA ReviewApproval Product Launch

NDAPhase 2 Phase 3

Launch

Full Development Production ExperienceEarly DevelopmentProcess Optimization Process Validation

Preformulation Report Biobatch (>10% Full Scale Process Validation Batches(3)

Final Validation Report

Development Report Biobatch Qualification Validation Activities Production Acceptance ofthe Process (10 batches or

1 year)FMI, including packaging Provisional Scale-up Preliminary Release

Notification Final Transfer Report

Specifications Full Scale ProcessOptimization

Provisional TransferDocument

Pre-approval Inspection

Pilot scale stability Provisional Scale-up Report Full Scale Packaging

Preliminary processparameters

Validation Protocol Full Scale Stability

Specifications for dose form Assessment of Bio-/Validation Batch

EquivalenceEstablish Technology Transfer Team

15 -23 Months 10 - 16 Months 10 Months 15 Months

Preformulation Report Development Report FMI, including packaging Specifications Pilot Scale stability Preliminary process parameters Specifications for dose form

Biobatch (>10% Full Scale) Biobatch Qualification Provisional Scale up Full Scale Process Optimization Provisional Scale up Report Validation Protocol

Process Validation Batches (3) Validation Activities Preliminary Release Notification Provisional Transfer Document Full Scale Packaging Full Scale Stability Assessment of Bio-/Validation Batch

Equivalence

Final Validation Report Production Acceptance of the Process (10 Batches or 1 Year) Final Transfer Report Pre-Approval Inspection

The defining and testing of processes, specifications and/or equipment used, and to prove the capability and suitability of achieving required results consistently

A requirement of GMP’s for drugs and devices

“Organized, documented common sense”

A written plan stating how validation will be conducted, including test parameters, product characteristics. production equipment, and decision points on what constitutes acceptable test results.

Suitability of building Services Materials of construction Suitability, positioning, accuracy and

calibration of instruments

Consistent operation System failsafes Maintenance program Equipment records Equipment and system service records

Demonstrate control of process within defined limits

Demonstrate consistent performance Demonstrate consistent results

FDA reviewers must determine Whether drug is safe and effective for

intended use Whether benefits outweigh risks Whether proposed labeling is

appropriate Whether manufacturing methods and

controls are adequate

Application Form FDA-356h Index Summary Pharmacologic Class, Scientific

Rationale Proposed Label Foreign Marketing History

Chemistry, Manufacturing and Controls Human Pharmacokinetics and

Bioavailability Nonclinical, Pharmacology, Toxicology Microbiology (anti-infective)

Clinical Data Summary List of Investigators Background/Overview of Clinical

Investigators Clinical Pharmacology Controlled Clinical Trials Uncontrolled Clinical Trials

Clinical Data Summary Integrated Summary of Effectiveness Integrated Summary of Safety Drug Abuse and Overdose Benefits/Risks

Clinical Data Summary Review of Literature for Analogs Bibliography for Compound Statistical Section Case Report Forms and Tabulations

150 volumes 50,000 pages 12 to 48 months of review and

negotiations record: 42 days

Prior to NDA approval, the FDA will inspect the proposed manufacturing facility to assure that the conditions presented in the NDA do exist and have been adequately documented.

CMC Section of NDA Master Formula

› specific manufacturing instructions for full scale commercial lots

› in process specifications› product specifications

History section of NDA

Raw materials Laboratory Equipment qualification Cleaning validation SOPs

Batch record for first full scale production run

Validation protocols and reports History of production Failure investigation reports All complaints Microbiological data

Report to pilot plant detailing R&D formulation development

Report covering pilot plant experiences during scale-up

Report setting product specification

US Package Insert Sections• Description • Clinical

Pharmacology • Indications and

Usage • Contraindications• Warnings• Precautions • Adverse Reactions

• Drug Abuse and Dependence

• Overdosage • Dosage and

Administration • How Supplied • Clinical Studies • References

proprietary name and established name

dosage form and route of administration

quantitative ingredient information pharmacological or therapeutic class chemical name and structural formula

Actions of the drug in humans Pharmacokinetic data (ADME) Clinical Trial Results

Clinical Adverse Experiences Concomitant Therapy Laboratory Abnormalities Hypersensitivity Reactions

General Recommendations Dosage in Patients with Renal

Insufficiency National Drug Code

Post-marketing surveillance Prescription drug advertising and

promotional labeling Pharmaceutical industry surveillance Drug shortages Therapeutic inequivalence reporting Medication errors

Phase 4 Clinical Trials General Reporting Requirements

› Field Alert Reports › Annual Reports› Adverse Drug Reaction Reporting (ADR)› Special reports

cGMP Requirements

Satisfy pre-approval FDA request Evaluate safety and effectiveness in

general use Cost/benefit analysis Augmentation of original indication Marketing implications Expansion of claim structure

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12

Discovery The Screen The Lead Development R R Safety Assess Cand Patents Dosage Form Dev IND/IDE Clinical Trials Phase 1 Review Safety Data Phase 2 End Phase 2 Clin Rev Phase 3NDA/PLA/PMA FDA ReviewApproval Product Launch

70% of INDs successfully complete Phase I Clinical Trials

33% of INDs successfully complete Phase 2 Clinical Trials

27% of INDs successfully complete Phase 3 Clinical Trials and continue to NDA

FDA reviewers must determine Whether drug is safe and effective for

intended use Whether benefits outweigh risks Whether proposed labeling is

appropriate Whether manufacturing methods and

controls are adequate

Advisory Committee - a panel of outside experts convened periodically to advise FDA on safety and efficacy issues about drugs and other FDA-regulated products. FDA isn’t bound to take committee recommendations, but usually does.

Learn as much as possible about the committee members

Fully understand the issues the review division presents

Understand how the committee functions

Don’t over do the presentation; keep it short

Approval letter Approval letter Not approvable letter

20% of IND’s result in successful NDA’s

Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12

Discovery The Screen The Lead Development R R Safety Assess Cand Patents Dosage Form Dev IND/IDE Clinical Trials Phase 1 Review Safety Data Phase 2 End Phase 2 Clin Rev Phase 3NDA/PLA/PMA FDA ReviewApproval Product Launch