new drug development and approval

New Drug Development and

Approval Process

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.

• Schedule of tests and procedures, • Medications and dosages to be studied• Length of the study• Study’s objectives, and other details

INTERNATIONAL REVIEW BOARD

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

• 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

• 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

• 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

• 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

• 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

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

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.

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!!!

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

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

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

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

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

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)

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

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

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

http://www.slideshare.net/rahul_pharma/drug-discovery-and-development-10698574