Transcript
Page 1: FDA Guidelines for Drug Development & Approval

FDA Guidelines for Drug Development & Approval

Raheem Bahadar PhD Scholar

Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad.

Page 2: FDA Guidelines for Drug Development & Approval

Food and Drug Administration (FDA), a federal agency of United States Department of Health and Human Services was formed in June 1906.

FDA is responsible for protecting and promoting public health through the regulation and supervision of◦ Food safety◦ Dietary Supplements ◦ Prescription and OTC pharmaceutical drugs◦ Biopharmaceuticals &◦ Medical Devices

Background

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Active Pharmaceutical Ingredient (API)◦ A drug substance is the API or component that

produces pharmacological activity.◦ API may be produced by chemical synthesis,

recovery from a natural product, recombinant DNA technology, fermentation or combination of these processes

New Chemical Entity (NCE)◦ A drug substance with unknown clinical,

toxicological, physical and chemical properties.

Introduction

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Drug Product◦ A drug product is the finished dosage form (e.g.

capsule, tablet, injectable etc) that contains API, general in association with other excepient, or inert ingredients.

Introduction

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New Drug Development “FDA Guidelines“

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Preclinical

TestingPhase I Phase II Phase III Phase IV Phase IV

New Drug Development FDA Guidelines

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Preclinical Testing◦ Animal pharmacology & toxicology data are

obtained to determine the safety and efficacy of the drug.

◦ No attempt is made to develop a final formulation during this stage.

New Drug Development FDA Guidelines

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Phase I◦ An Investigational New Drug (IND) application is

submitted to the FDA. Clinical testing takes place once the IND application is submitted and approved.

◦ Healthy volunteers in phase I clinical studies to determine drug tolerance and toxicity.

◦ Dually signed consents from investigator and volunteers are pre requisite at this phase.

◦ Toxicological studies- including acute, chronic in various animal species are planned during this phase

New Drug Development FDA Guidelines

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Phase II◦ Limited number of diseased volunteers (patients) are

treated for the ailment or condition for which drug was developed under closed supervision.

◦ Dose-response studies, bioavailability, Pharmacokinetics are performed to determine the optimum dosage regimen for treating the disease.

◦ Safety is measured to determine Therapeutic Index.◦ A drug formulation having good physico-chemical

stability is developed.◦ Chronic Toxicity studies are started in two species;

such studies normally last more than 2 years duration.

New Drug Development FDA Guidelines

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Phase III◦ A large scale, multicenter clinical studies are

performed with the final dosage form developed in phase II.

◦ Objective of these studies are to determine safety and efficacy of the drug product in large diseased human sample.

◦ Side effects are monitored.

New Drug Development FDA Guidelines

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Submission of New Drug Application (NDA)◦ An NDA is submitted to FDA for review and

approval after the completion of clinical trials that show to the satisfaction of the medical community that the drug is satisfactory by all parameters and is safe as demonstrated by animal and human studies.

New Drug Development FDA Guidelines

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Phase IV◦ After NDA submission and approval large scale

manufacturing of product starts and is marketed◦ Improvement in product formulation in terms of

manufacturing, packing carries on◦ Additional clinical studies in special population is

conducted such as in elderly, pediatric and renal impaired patients etc.

◦ Additional clinical studies may be performed to determine if the drug can be used for new or additional labeled indications.

New Drug Development FDA Guidelines

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Labeled indication◦ It is the disease area where drug has been tested

in Phase III trials and has exhibited profound clinical outcome compared with pre marketed standard drug and hence is approved by FDA in that particular ailment.

Off labeled Indication It is the area where drug has not been approved by

FDA may be due to limited amount of evidence, or lack of effectiveness.

Promotion of drugs in off labeled indications in not allowed in by FDA

New Drug Development FDA Guidelines

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Phase V◦ Drug formulation may be modified slightly◦ Changes in drug formulation always comply with

SUPAC guidelines.

New Drug Development FDA Guidelines

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◦ Product Line Extension Only physical form or strength is changed in the same

indication. Developing transdermal patch when only tablets have

been available, for example: Progesterone Nicotine Estradiol Ibuprofen Nitroglycerine

Additional Strength Example is Ibuprofen 200mg, 400mg As long as the new strength is in the range of total daily

dose.

New Drug Development FDA Guidelines

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Biological Products◦ Biological product according to FDA is “any virus,

serum, toxin, antitoxin, vaccine, blood, blood component or derivatives, allergenic product, or analogous product applicable to the preventions, treatment or cure of disease or injuries.

◦ Biologic License Application (BLA) is approved for marketing under the provisions of the Public Health Services (PHS) act.

New Drug Development FDA Guidelines

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Generic Drug Products◦ After patent expiry of API or Branded Drug

product, generic drug product can be marketed.◦ But the generic drug product should be

bioequivalent (I.e. having the same rate and extent of drug absorption) to the branded product.

◦ These bioequivalence studies are normally conducted in healthy volunteers.

New Drug Development FDA Guidelines

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Meanwhile, generic product may differ physical appearance e.g. in color, shape, size or in the amount of excepient used.

Generic product may also differ in dosage form as well until the adequate safety studies have been established.

New Drug Development FDA Guidelines

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Before the generic product is marketed, the manufacturer must submit an Abbreviated New Drug Applications (ANDA) to the FDA for approval.

Since as NDA clinical trials have already been performed, only bioequivalence studies are required for ANDA approval.

New Drug Development FDA Guidelines

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New Product Development “FDA Guidelines “

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A New Chemical Entity (NCE)◦ Preformulation ◦ It is the characterization of the physical and chemical

properties of NCE.◦ These evaluations are started in preclinical stage and

may continue up to Phase I and Phase II.◦ Following information is usually required.

Physical- Size, Shape, crystallinity, polymorphism, Flow properties, hygroscopicity

Solubility- Dissolution, pH solubility profile. Chemical - excepient interaction, pH stability, pKa,

temperature stability Analytical- Method development for quantitative analysis

New Product Development FDA Guidelines

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Formulation Development◦ When the submission of an NDA is considered the

manufacturer attempts to develop the final dosage form.

◦ Injectable Final injectable drug product is usually developed in

the preclinical phase. Major concerns include, stability of the drug in

solution for and its sterility. Acute toxicity studies are necessary in order to

change the dosage form.

New Product Development FDA Guidelines

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Formulation Development◦ Topical

Includes antibacterial, antifungal, corticosteroids and local anesthetics.

The final dosage form for a topical drug product is usually developed in Phase I.

Release of the drug from the matrix is measured in-vitro with various diffusion cell models.

Following problems may be encountered and should be kept under checked for topical formulation Local Irritation Skin Sensitization System Drug absorption

New Product Development FDA Guidelines

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Formulation Development◦ Oral

Prototype dosage forms are often developed during the preclinical phase to ensure that drug is optimally available and dissolves in GI well.

In early stage of product development, hard gelatin capsule, are formulated for phase I clinical trials.

Final dosage form is decided to develop before the start of Phase III.

New Product Development FDA Guidelines

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Regulatory Approvals for Product Line Extension◦ Analytical and manufacturing controls◦ Stability Information◦ Bioavailability and Bioequivalence studies◦ Safety Studies (e.g. skin irritation studies for

transdermal patches)

New Product Development FDA Guidelines

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Preapproval Inspections (PAIs)◦ The manufacturing facility is inspected by FDA

after an NDA, abbreviated antibiotic drug application AADA or ANDA is submitted.

◦ Pre approval Inspection may also be initiated if a major change is reported in a supplemental application to an NDA, AADA or ADNA.

New Product Development FDA Guidelines

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Preapproval Inspections (PAIs) During PAI, the FDA investigator:

◦ Performs a GMP inspection.◦ Reviews the development report about the

validated product and rationale manufacturing directions.

◦ Consults the chemistry, manufacturing and control (CMC) section of the NDA, AADA or ANDA and determines the capability of manufacture to produce the drug product as prescribed.

◦ Recommends approval for the manufacturing of the drug product based

New Product Development FDA Guidelines

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Scale Up and Post Approval Changes (SUPAC)◦ Purpose. These guidelines are intended to

reduce the manufacturing changes that require pre-approval by FDA.

◦ Function. To review slight changes in the amount of excepient to aid in the processing of the product during scale-up.

◦ Changing the site of manufacture.◦ Scale up or Scale down the batch size of

formulation◦ Changing the manufacturing process or

equipment.

New Product Development FDA Guidelines

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Product With drawl from market◦ Initiation of recall may be voluntarily initiated

from company or it can be initiated Black box Warning for serious adverse event

reported. This box warning is even mandatory to be mentioned in leaf insert of the product pack.

New Product Development FDA Guidelines

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Pre Clinical Testing

Phase I Phase II Phase III FDA Approval

Years 3.5 1 - 2 2 - 4 4 - 6 1.5 Total = 12 - 17

Te

st P

opul

atio

n Laboratory and Animal

Studies

20 to 100 Healthy

Volunteers

100 – 300 Patient

Volunteers

1,000 to 3,000

Patient Volunteers

Review

Post Marketing

Safety Monitoring

Pu

rpos

e

Assess Safety and Biological

Activity

Determine Safety and Dosage

Evaluate Effectiveness. Look

for Side Effects.

Verify Effectiveness, Monitor Adverse

Reactions from Long-Term Use

Process Large Scale

Manufacturing -------------- Distribution -------------- Education

% o

f all

new

drug

s th

at p

ass

FILE

IND

70% of INDs

30% of INDs

27% of INDs

FILE

NDA

20% of INDs

New Product Development FDA Guidelines

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New Product Development FDA Guidelines


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