Drug discovery and development overview
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Transcript of 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