Empirical Analysis of Drug Approval-Drug Patenting Linkage ...
New Drug Development and Approval
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New Drug Development and
Approval Process
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Stages of Drug Development and Review
• Sponsors–companies, research institutions, and other organizations develop a new drug.
• Pre-clinical testing and Proposal for human testing.
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• Schedule of tests and procedures, • Medications and dosages to be studied• Length of the study• Study’s objectives, and other details
INTERNATIONAL REVIEW BOARD
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Phase 1 studies are usually conducted in healthyvolunteers. Determine what the drug’s most frequent side effects
are and, often, how the drug is metabolized and excreted.
The number of subjects typically ranges from 20 to 80.
Stages of Drug Development and Review
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• Phase 2 emphasis is on effectiveness. • This phase aims to obtain preliminary data on
whether the drug works in people who have a certain disease or condition.
Stages of Drug Development and Review
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• For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment–usually an inactive substance (placebo), or a different drug.
• Safety continues to be evaluated, and short-term side effects are studied.
• Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300.
Stages of Drug Development and Review
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• Phase 3 studies begin if evidence of effectiveness is shown in Phase 2.
• These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs.
• The number of subjects usually ranges from several hundred to about 3,000 people.
Stages of Drug Development and Review
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• Post-market requirement and commitment studies must be done after FDA has approved the drug for marketing.
• Additional information about a product’s safety, efficacy, or optimal use.
Stages of Drug Development and Review
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• New Drug Application (NDA)–This is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States.
• An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured
Stages of Drug Development and Review
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Drug Candidatesafety testing
Animal Studies- relevant species
- transgenic KO/KI mice- conditional KOs
- agonists/antagonists- antibodies- antisense
- RNAi
Studies ofDisease Mechanisms
Human Studies Phases I,II, III
Target-receptor; -ion channel; -transporter;
-enzyme; - signalling molecule
Lead Search-Develop assays (use of automation) -Chemical diversity-Highly iterative processMolecular Studies
The Drug Discovery Process
Lead optimization-selectivity -efficacy in animal models-tolerability: AEs mechanism- based or structure-based?-pharmacokinetics-highly iterative process
Drug Approvaland Registration
Target selection & validation
Discovery Development
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Target Selection & Validation• Define the unmet medical need (disease)
• Understand the molecular mechanism of the disease
• Identify a therapeutic target in that pathway (e.g gene, key enzyme, receptor, ion-channel, nuclear receptor)
• Demonstrate that target is relevant to disease mechanism using genetics, animal models, lead compounds, antibodies, RNAi, etc.
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Discovery• Develop an assay to evaluate activity of compounds on the target
- in vitro (e.g. enzyme assay)- in vivo (animal model or pharmacodynamic assay)
• Identify a lead compound
– screen collection of compounds (“compound library”)
– compound from published literature
– screen Natural Products
– structure-based design (“rational drug design”)
• Optimize to give a “proof-of-concept” molecule—one that shows efficacy in an animal disease model
• Optimize to give drug-like properties—pharmacokinetics, metabolism, off-target activities
• Safety assessment, Preclinical Candidate!!!
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Development
Pharmaceutical R&DFormulation
Clinical Investigator& patientClinical PharmacologyClinical Research
Statistics & EpidemiologyData CoordinationResearch Information SystemsInformation Services
Regulatory AffairsProject Planning & ManagementMarketing
Process R&DChem Eng. R&DManufacturing
Bio Process R&D
Safety AssessmentToxicology
Drug Metabolism(ADME)
PharmacologyPre-Clinical
Clinical
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Clinical Trials
Product Profile Marketing SOIProduct Profile Marketing SOI
Information Learned1. Absorption and metabolism
2. Effects on organs and tissue
3. Side effects as dosage is increased
Information Learned1. Effectiveness in treating disease2. Short-term side effects in health -impaired patients3. Dose range
Information Learned1. Benefit/risk relationship of drug
2. Less common and longer term side effects
3. Labeling information
Compassionate Use
Phase IISeveral hundred health-impaired patients
Treatment Group Control Group
Phase IIIHundreds or thousands of health-impaired patients
InvestigationalNew Drug application
IND
Phase I20 - 100 healthy volunteers take drug for about one month
Remote data entry
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Clinical Trials
Continued
Clinical Trials
ContinuedAPPROVALPROCESS
(Ex. FDA)
Reviews,comments, and
discussions
Drug Co./Regulatoryliaison activities
APPROVAL
Submit toRegulatory Agencies
AdvisoryCommittee Regulatory
Review Team
New DrugApplication
(NDA)
Worldwide Marketing Authorization (WMA) in other countries
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Drug Discovery—Convergence of DisciplinesPatent LawCombinatorial
Chemistry
SyntheticChemistry
PhysicalChemistry
Physiology
Biochemistry
DMPK
Enzymology
Immunology
Pharmacology
InformationTechnology
Modelling
Physiology
SafetyAssessment
Metabolism
PharmacologyPathology
Behavior
NovelMolecule
Intellectual Property
StructuralActivity
PharmacokineticProperties
In Vivo activity
Safety
Design
Pharmaco-
dynamics
Physiology
Physiology
Physiology
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Sources of New DrugsPlant Materials
1. Reserpine ( Tranquilizer and a hypotensive agent)
2. Periwinkle (anti-tumor)
Vincristine
Vinblastine
3. Pacific yew tree (ovarian cancer)
Paclitaxel
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Sources of New Drugs2. Semi-synthetic drugs
Ex Dioscorrea (Mexican yams)
Cortisone and Estrogen
3. Animals
Hormonal substances
Ex Thyroid extract (Insulin, Pituitary hormone)
Urine of pregnant mares (estrogen)
Biologicals (serum, antitoxins, vaccines)
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Sources of New Drugs4. Genetic Engineering
Recombinant DNA production (produce any protein)
--“Gene Splicing” lower organisms to make protein
-- human growth hormone, human insulin, hepatitis B vaccine Epoetin Alpha, and interferon
Monoclonal antibody production
--dx home pregnancy products
-- combat disease such as LE, juvenile onset diabetes, MG
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Sources of New Drugs5.Human Gene Therapy
used to prevent, treat, cure, diagnose, or mitigate human diseases caused by genetic disorders.
ADA (adenosene deaminase deficiency)
Sicke cell anemia
Malignant melanoma
Renal cell cancer
Heart disease
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GOAL DRUGProduced the specified desired effect
Administered at the most desired route
Have optimal onset and duration of activity
Exhibits no side effect
Eliminated from the body completely
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http://www.slideshare.net/rahul_pharma/drug-discovery-and-development-10698574
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