Review: FDA Drug Approval Process

Describe the FDA approval process for brand and generic drugs

• Application Types

  • IND = Investigational New Drug → investigational drugs

  • NDA = New Drug Application → new prescription drugs 

  • ANDA = Abbreviated New Drug Application → new generic drugs 

  • BLA = Therapeutic Biologics Application → new biologic agents 

Steps

• Preclinical test: used to determine whether product is safe for human use or if the compound exhibits pharmacological activity that justifies commercial development 

  • Does not involve human subjects

  • Study types

    • In vitro studies: cell lines, test tubes

    • In vivo studies: animal models

• IND application → sponsor submits this application

  • Involves:

    • Animal pharmacology and toxicology studies 

    • Manufacturing information

    • Clinical protocols and investigator information 

  • Sponsor submits an IND application to the FDA (Sponsor usually the manufacturer that is planning to market the drug)

  • From here FDA will consider the drug composition, preclinical testing data, manufacturing information, and plans for testing the drugs in humans

    • FDA will decide to approve IND or clinical hold 

• Phase I Clinical Trial: “dose-finding studies”

  • Testing 20-80 healthy volunteers 

  • Goals

    • Emphasis on safety of the investigational drug in humans

    • Determine most frequent side effects

    • Determine metabolism and excretion of drugs 

• Phase II Clinical Trials 

  • Testing population: Pts who drug is intended for 

  • Study population size: 1,000(s)

  • Goals

    • Emphasis on effectiveness of the investigational drug in humans

    • To obtain preliminary data on whether the drug works in patients with the disease or condition 

    • Evaluate safety (short-term side effects)

    • Remember, There is a placebo for controlled trials 

• Phase III Clinical Trials:

  • Testing population: Pts who drug is intended for 

  • Study population size: 1,000(s)

    • Goal: gather more info about safety and effectiveness 

    • Usually, two phase III trials are needed to seek FDA approval

    • Trials may be designed to study different populations, different dosages, and uses of the investigational drugs in combination with other drugs

• NDA: formal request to FDA to approve a drug for marketing in the US

• NDA includes all human and animal data/analysis 

• Prior to FDA approval, FDA:

  • Reviews submitted information in NDA

  • Reviews drug’s labeling and assures appropriate information is communicated

  • to health care professionals and consumers

  • Inspects the facilities where the drug will be manufactured

• Phase IV

  • Post-marketing surveillance 

  • Testing population: Pts who drug is intended for 

  • Study population size: > 1,000(s)

    • Goals: monitoring safety issues after drugs get on the market and detect serious unexpected adverse events and take definitive actions when needed 

IND application → sponsor submits this application

• Involves:

  • Animal pharmacology and toxicology studies 

  • Manufacturing information

  • Clinical protocols and investigator information 

• Sponsor submits an IND application to the FDA (Sponsor usually the manufacturer that is planning to market the drug)

• From here FDA will consider the drug composition, preclinical testing data, manufacturing information, and plans for testing the drugs in humans

  • FDA will decide to approve IND or clinical hold 

Phase I Clinical Trial: “dose-finding studies”

• Testing 20-80 healthy volunteers 

• Goals

  • Emphasis on safety of the investigational drug in humans

  • Determine most frequent side effects

  • Determine metabolism and excretion of drugs 

Phase II Clinical Trials 

• Testing population: Pts who drug is intended for 

• Study population size: 1,000(s)

• Goals

  • Emphasis on effectiveness of the investigational drug in humans

  • To obtain preliminary data on whether the drug works in patients with the disease or condition 

  • Evaluate safety (short-term side effects)

  • Remember, There is a placebo for controlled trials 

Phase III Clinical Trials:

• Testing population: Pts who drug is intended for 

• Study population size: 1,000(s)

  • Goal: gather more info about safety and effectiveness 

  • Usually, two phase III trials are needed to seek FDA approval

  • Trials may be designed to study different populations, different dosages, and uses of the investigational drugs in combination with other drugs

• NDA: formal request to FDA to approve a drug for marketing in the US

• NDA includes all human and animal data/analysis 

• Prior to FDA approval, FDA:

  • Reviews submitted information in NDA

  • Reviews drug’s labeling and assures appropriate information is communicated

  • to health care professionals and consumers

  • Inspects the facilities where the drug will be manufactured

Phase IV

• Post-marketing surveillance 

• Testing population: Pts who drug is intended for 

• Study population size: > 1,000(s)

  • Goals: monitoring safety issues after drugs get on the market and detect serious unexpected adverse events and take definitive actions when needed 

Describe the key components of prescription drug labeling

• Boxed warnings

• Indications and usage

• Dose and administration

• Dosage forms and strengths

• Contraindications 

• Warnings and precautions 

• Adverse reactions

• Drug interaction

• Use in specific populations

• Drug abuse and dependence 

• Overdose

• Description

• Clinical pharmacology 

• Nonclinical toxicology

• Clinical studies

• References

• How supplies/storage and handling

• Patient counseling information 

Prescription Drug User Fee Act (PDUFA) of 1992

• Reauthorized every 5 years (last in 2022)

• Primary purpose to provide resources (fees) to the FDA to allow them to expedite the drug review process.

• Two review timelines:

  • Standard = 10 months

  • Priority = 6 months

Orphan Drug Act (1983)

• Special designation for drug/biological product to prevent, diagnose, or treat a rare disease or condition 

  • Disease or condition that affects fewer than 200,000 persons in the US

  • Will not be profitable within 7 years following FDA approval 

• Sponsor incentives:

  • Tax credits for qualified clinical trial

  • Exemption from user fees/application costs 

  • Potential 7 years of market exclusivity = “orphan exclusivity”

Generic Drugs

• Drug Price Competition and Patent Term Restoration Act of 1984

  • Established bioequivalence as basis for approving generic drug products 

• Generic: comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use 

• Approval of generic drug is through the Abbreviated New Drug Application (ANDA)

  • Abbreviated bc it’s not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness 

  • The generic version of a drug is supposed to deliver the same amount of active ingredient into the patient’s bloodstream in the same amount of time as the “innovator” drug 

OTC drugs

• Since there is a large number of OTC drugs, FDA reviews the active ingredients and labels the therapeutic classes of drugs instead of individual drug products

• For each category, OTC drug monograph is developed and published in the Federal Register

  • Monographs serve as recipe/rule book covering acceptable ingredients, doses, formulation, and labeling 

• Once final monograph implemented, companies can make and market an OTC product without the need for FDA  pre-approval

Describe the role of the FDA Adverse Event Reporting Systems (FAERS)

• FAERS is a database that contains adverse event reports and product quality complaints resulting in adverse events that were submitted to FDA

• Designed to support the FDA’s post-marketing safety surveillance program for drug and therapeutic biological products 

• Healthcare professionals, consumers, and manufacturers can voluntarily submit reports to FARTS via MedWatch (FDA’s medical product safety reporting program for health professionals, consumers, and patients) 

  • Can also report directly to FDA or to the product’s manufacturer - who must report to FDA

Describe the role of the Vaccine Adverse Event Reporting System (VAERS)

• VAERS is a national vaccine safety surveillance program co-sponsored by the FDA and CDC

• Purpose - to detect possible signals of adverse events associated with vaccines 

• Reports come from any concerned individual: patient, parent, healthcare provider, pharmacist, vaccine manufacturer

Explain the importance of and details of the Risk Evaluation and Mitigation Strategies (REMS)

FDA Amendments Act (FDAAA) of 2007

• Authorized FDA to require sponsor to develop and comply with REMS program 

Require risk management plans

• Provide safe access to drugs with known serious risk that would otherwise be unavailable 

• Focuses on preventing, monitoring, and/or managing a specific serious risk by informing, education and/or reinforcing actions to decrease frequency and/or severity of the event 

Elements of Program 

• Medication guide or patient package insert

• Communication plan for healthcare providers

• packaging/disposal requirements for drugs with risk of abuse or overdose 

• Elements to assure safe use (training, certification)

• Implementation system

• Timetable for assessment submission 

REMS Material 

• Dear health provider letter, wallet card, prescription authorization forms, enrollment forms, patient counseling forms, training programs, informational brochures, call centers, etc