Regulatory Class - Sept 26 Flashcards
Focus of FDA review of NDAs
Safe and effective, when used as labeled
Manufacturing consistency - preserve identity, strength, quality, and purity
Must contain substantial evidence from adequate and well-controlled investigations
“Adequate and well-controlled” Studies
Clear statement of objectives
Summary of methods of analysis
Study design that permits valid comparison with control
Selection assures subjects have disease/condition
Methods of assignment to minimize bias
Using only foreign clinical data
Population must be applicable to US
Done by qualified clinical investigators
FDA is able to validate data
Proprietary name
Name used to market the product
Includes: Primary and secondary choices, pronunciation, where it was derived, and pharmacological meaning
Reviewed to minimize risk, and prevent overstate of efficacy or superiority claims
Reviewed as early as end of Phase II; Reviewed 90 days prior to action date (FDA gets 180 days if submitted with IND)
Establishment registration
Information used to prepare inspections
Includes listing of all drugs in commercial distribution (if company already produces drugs, just add it to the listing)
Must be done prior to the production of final drug product
Labeler code assignment
National drug code (11-digit) provided to US drugs
First 4-5 digits are assigned by FDA - identify the labeler
Remaining digits assigned by manufacturer - identify product codes
Pre-NDA meeting
Type B meeting
4-6 months prior to anticipated submission date
Submit request 60 days prior to desired meeting date
Briefing package at least 4 weeks prior to meeting
Present clinical data to be submitted
Discuss format submission
NDA Patent Information
Submit information to verify that the sponsor has all the rights necessary to legally manufacture and sell the drug
Includes drug substance, drug product, and method-of-use
Debarment certification
Sponsor did not use services of anyone debarred by FDA
Debarred investigators may not receive investigational product
NDA Index
First document that should be made in creating the NDA
Use as an outline for the final submission
FDA Form 3454
Financial Certification
FDA Form 3455
Financial Disclosure
Labeling contents
Container / carton labels
Proposed package insert, includes an annotated version (links to special info in the submission) and a final ‘clean’ draft version
Package insert includes highlights of prescribing info:
Product names Boxed warning Recent major changes Indication and usage Dosage and administration Dosage forms and strengths Contraindications Warnings and precautions Adverse reactions Drug Interactions Use in specific population
Package insert - full prescribing info:
Includes all topics in the highlights and: Drug abuse and dependence Overdosage Clinical pharmacology Nonclinical toxicology Clinical studies References How supplied/ storage and handling Patient counseling info
Boxed Warnings
put on products that have a special risk
mainly used to inform physicians
NDA: Clinical Data: Other studies and information section
Any clinical info relevant to safety and effectiveness
List of countries where drug is approved
List of countries where drug has been disapproved or withdrawn from marketing
Integrated summary of effectiveness
included for each indication
Supports dosage and dose interval recommended in product labeling
Compare and analyze all results from controlled trials; address drug-demographic, drug-drug, and drug-disease interactions; describe any evidence of longterm effectiveness, tolerance, and withdrawal effects
Integrated summary of safety
safety data from all sources - including animal data, clinical studies, and foreign marketing experience
Adverse events from all studies
Analysis of clinical lab data, evaluating abnormalities; discussion of drug-drug interactions
Safety update reports
New safety data that could affect labeling, contraindications, warnings, precautions, AEs
Submitted 4 months after the initial submission if requested by the FDA
Pediatric use information
Requires: Safety and efficacy info; for proposed indications for use; all relevant pediatric populations, dosing and administration info
May be deferred if drug ready for approval before completing pediatric studies or they are delayed until additional safety or effectiveness data are collected
Pediatric use Exceptions for requirement
No meaningful therapeutic benefit over existing treatments
Not likely to be used in a substantial number of pediatric patients
Necessary studies are impossible or highly impractical
Evidence suggests drug would be ineffective or unsafe in all pediatric age groups
Orphan drugs
Or is reasonable attempts to produce a pediatric formulation have failed
NDA: Case report form tabulations
Must be provided for each patients from all Phase 2 and Phase 3 studies; For each patient from all Phase 1 pharmacology studies, Safety data from all clinical studies
NDA: Case report forms (CRFs)
For each patient that died
For any patients that withdrew due to an AE
Biosimilars
generic version of biologics
Not allowed now as the processes are unlikely to be identical, differing in safety, efficacy, and purity.
BLA
Essentially the same as NDA
Must submit product sample to FDA
Establishment must be inspected by the FDA; process is very significant for biologics
NDA Submission Copies
Archival copy - complete submission
Review copy - Organized by technical section - includes complete summary with each; for reviewers in each discipline
Field copy - CMC section (include complete summary); for FDA inspectors pre-approval cGMP inspections
Abbreviated New Drug Application (ANDA)
Generic drug submission
Used for drug products that are the same as a listed drug
Identical: active ingredients, dosage form, strength, route of administration, conditions of use
Does not require human safety and effectiveness information, but does require bioequivalence data
Can start 1 year before the patent expires but ANDA will not be approved until after expiration
Parts of an ANDA
Application form (FDA Form 356h) Table of Contents Reference to listed drug Conditions of USe Info to show active ingredient is the same as listed drug Info to show route of administration, dosage form and strength are the same as listed drug Bioequivalence to the listed drug Currently approved labeling for listed drug Annotated proposed labeling CMC Patent Certification Financial certification ro disclosure
Parts of an ANDA: Reference to Listed Drug section
Name, dosage form, strength
Identify whether listed drug is entitled to period of marketing exclusivity/patent (Use Orange Book)
Orange Book
Book of Approved Drug Products with Therapeutic Equivalence Evaluations
ANDA proposed labeling
Side by side comparison of labeling
Must explain any difference from approved labeling
Parts of an ANDA: CMC
Master production record (batch records) with description of equipment
Inactive ingredients - identity and characterization
-must demonstrate that inactive ingredients do not affect safety and efficacy
CTD Modules
- Region Specific (administrative and labeling documents)
- Summary Overview
- Quality (CMC)
- Nonclinical
- Clinical - Quality (CMC)
- Nonclinical Study Reports
- Clinical Study Reports
Sample eCTD
30 day review by FDA
Sample submission evaluated for technical compliance; must contain enough data to be analyzed
eCTD
Built around a master table of contents, the backbone of the submission
eCTD provides links to specific info in each section, so it’s easier to find documents, standardized
FDA Review Process for Marketing Applications
Within 60 days, FDA determines whether the NDA/BLA (in writing) may be filed or ANDA (by phone) has been received; broad look for the submission to make sure all components are there (don’t pay fee if not filed)
180-day review period starts on the date of receipt for all types of submissions: usually 10 month review period for NDA/BLA, but 6 months for priority review
90 days in, check with the FDA, start working on any deficiency; informal communications are had for changes are concerns that are not specific
End-of-review conference: held just before the approval decision and discusses any changes required or new information needed
Reasons FDA may refuse to file
Application is incomplete
Not submitted in required form
Environmental assessment not included
English translations not provided
Non-compliance with GLPs
Non-compliance with IRB or informed consent
Drug contains same active ingredient as marketed drug with exclusivity
FDA Advisory Committee Meetings
Generally required for all new molecular entities; or when drug is a topic of public interest, controversial matter or a specific expertise is needed
Provide independent, expert advice or product reviews; not FDA and not sponsor related nor participant in study; make recommendations not approvals
Public meeting, recorded and transcribed online, some nondisclosable info not included
Info provided for Advisory Committee Meetings
Sponsor: presents safety and effectiveness info, discuss postmarketing requirements, or on-going safety monitoring
Sponsor briefing package: info to understand product and its intended use, development program; potential issues or questions for discussion
FDA briefing package: summary of its opinions; concerns regarding product submission; questions for advisory committee
Committee does not have access to marketing submission
FDA Response
Complete response letter: includes all deficiencies identified in FDA’s review, and recommended actions for approval
Approval letter: approval date = date of letter
-drug cannot be shipped before effective date
Resubmission
Class 1 - 2-month review period
Class 2 - 6-month review period
Major resubmission - 6-month review period
Reasons FDA won’t approve NDA/BLA submissions
CMC inadequate to preserve identity, strength, quality, purity, stability and bioavailability
Clinical data does not demonstrate safety
Insufficient evidence of safety or effectiveness
Labeling is false or misleading
Not compliant with cGMPs or GLPs
Inadequate patent information
Sponsor does not permit inspection
Reasons FDA won’t approve ANDA submissions
CMC inadequate to preserve identity, strength, quality, purity, stability
Didn’t show proposed conditions have been previously approved
Didn’t show API is the same
Didn’t show route of administration, dosage form, or strength is the same
Insufficient info for bioequivalence
Labeling not the same
Inactive ingredients aren’t safe
Drug listed has been withdrawn
Reasons for FDA Withdrawal of Approval
Imminent hazard to public health
New data show drug is unsafe or not effective
Patent info requested by FDA was not submitted in 30 days
Failure to maintain records or make report
Manufacturing is inadequate
Labeling is false or misleading
Listed drup approval is withdrawn (for generic drug)
Grandfathered drug
those made prior to 1938
Field Copy Certification
certifies that the field copy was submitted to the field office is a true copy of the CMC section
CMC Section: Samples
must include sample to FDA labs for testing and validation of analytical methods
Toxicology Information
should include info on acute toxicology, multidose toxicology, with reproduction and mutagenicity studues
Bioavailability Studies
define the rate and extent of absorption relative to a reference dosage form
Bioequivalence studies
compares pharmaceutical alternatives to establish equivalent extents and rate of absorption
Post-Marketing Surveillance
After approval, sponsor have to review all adverse drug experiences (ADE) and if serious and unexpected must report it to the FDA within 15 days (FDA Form 3500A - MedWatch)
Periodic ADE Reports - quarterly for the first 3 years and then annually
BLA - Analytical Development
no single method will capture the full heterogeneity of the compound, so several must be used to characterize a given attribute of the protein
Rationale for method selection must be submitted
BLA - Nonclinical evaluation
Primary consideration given to the nature of the biological effect and the validity or availability of relevant model systems
Approach and rationale should be discussed
BLA - Clinical Development
For trial design, consider biological activity of the product, the limits on measurements and assessing efficacy, and the availability of suitable patients
Also consider potential for process-related isoforms to dramatically affect clinical outcomes
