fda guidelines for drug development & approval

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FDA Guidelines for Drug Development & ApprovalRaheem Bahadar PhD Scholar

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

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 ofFood safetyDietary Supplements Prescription and OTC pharmaceutical drugsBiopharmaceuticals &Medical DevicesBackground

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 processesNew Chemical Entity (NCE)A drug substance with unknown clinical, toxicological, physical and chemical properties.


Drug ProductA 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.


New Drug Development FDA Guidelines

New Drug Development FDA Guidelines

Preclinical TestingAnimal 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

Phase IAn 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 phaseNew Drug Development FDA Guidelines

Phase IILimited 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

Phase IIIA 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

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

Phase IVAfter NDA submission and approval large scale manufacturing of product starts and is marketedImprovement in product formulation in terms of manufacturing, packing carries onAdditional 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

Labeled indicationIt 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 IndicationIt 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 FDANew Drug Development FDA Guidelines

Phase VDrug formulation may be modified slightlyChanges in drug formulation always comply with SUPAC guidelines. New Drug Development FDA Guidelines

Product Line ExtensionOnly physical form or strength is changed in the same indication.Developing transdermal patch when only tablets have been available, for example:ProgesteroneNicotineEstradiolIbuprofenNitroglycerineAdditional StrengthExample is Ibuprofen 200mg, 400mg As long as the new strength is in the range of total daily dose.

New Drug Development FDA Guidelines

Biological ProductsBiological 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

Generic Drug ProductsAfter 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

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

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

New Product Development FDA Guidelines

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, hygroscopicitySolubility- Dissolution, pH solubility profile.Chemical - excepient interaction, pH stability, pKa, temperature stabilityAnalytical- Method development for quantitative analysis

New Product Development FDA Guidelines

Formulation DevelopmentWhen the submission of an NDA is considered the manufacturer attempts to develop the final dosage form. InjectableFinal 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

Formulation DevelopmentTopicalIncludes 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 formulationLocal IrritationSkin SensitizationSystem Drug absorptionNew Product Development FDA Guidelines

Formulation DevelopmentOralPrototype 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

Regulatory Approvals for Product Line ExtensionAnalytical and manufacturing controlsStability InformationBioavailability and Bioequivalence studiesSafety Studies (e.g. skin irritation studies for transdermal patches) New Product Development FDA Guidelines

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

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

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 formulationChanging the manufacturing process or equipment.New Product Development FDA Guidelines

Product With drawl from marketInitiation 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

New Product Development FDA Guidelines

New Product Development FDA Guidelines

Pre Clinical TestingFILE INDPhase IPhase IIPhase