Regulatory Class - Oct 24 Flashcards
Making changes to an NDA
Change to any condition of an approved application must be described fully and submitted in an NDA supplement or annual report
Submitted in the least burdensome notification
Must describe the changes in enough detail so the FDA can determine that the change was reported in the correct category
NDA Supplements with Clinical Data require a user fee.
Assessing the effects of the change
Need to do additional testing to assess whether identity, strength, quality, purity, or potency of drug product will be affected - with regard to safety and effectiveness
Chemical, physical, microbiological, biological bioavailability and/or stability profiles
Compare test results from pre- and post-change to determine if results are equivalent (not identical but within predetermined acceptable range)
NDA Supplement: Major Change
Substantial potential to have an adverse effect on identity, strength, quality, purity or potency of a drug product - relate to safety and effectiveness
Requires a prior approval supplement
Examples of Major Changes
Change in qualitative or quantitative formulation of drug product
Change requiring completion of studies to demonstrate equivalence
Change that may affect sterility
Change in manufacturing that may affect physical, chemical or biological properties of the drug substance
Contents of NDA Supplements
Detailed description of proposed change Drug product involved Manufacturing site affected Methods used and studies performed to assess the effects of the change Data from studies
Prior Approval Supplement - Expedited Review
Will happen in the interest of public health (ex. drug shortage)
Or if a delay in making change would present undue hardship to applicant (ex. changes due to catastrophic events)
NDA Supplement: Moderate Changes
Changes being Effected (CBE) supplement or
CBE 30 days supplement
Changes Being Effected in 30 Days
Must submit supplement more than 30 days prior to distribution of product with the change
Explain the basis for the change and identify date change will be made
(ex. change in container closure system that affect drug quality)
FDA can require approval before distribution or as sponsor to require more info
If FDA disapproves, the manufacturer must stop distribution
NDA Supplement - Changes Being Effected
Distribution can begin when FDA receives the supplement
If FDA disapproves, the manufacturer must stop distribution
NDA Supplement - Changes Being Effected - Examples
Changes in size or shape of container, change to add or strengthen contraindication or statement of drug abuse, changes in instructions to increase safe use
Minor Change
Minimal potential to have an adverse effect - relate to safety and effectiveness
Description of changes may be included in next Annual Report
Examples of Minor Changes
Deletion or reduction in an ingredient that effects color
Replacement of equipment with same design and operating principles
Change in size or shape of container - same number of dosage units
Extension of expiration dating based on data obtained from protocol approved in the NDA
Editorial or minor change in labeling
Change Info in Annual Report
Statement that the effects of the change have been assessed
Full description of the manufacturing and controls changes
Date each change was implemented
Data from studies/tests performed to assess effects of change
Labeling Changes
Need to make sure advertising and promo materials comply with new label
Comparability Protocol
Describes tests, studies, and acceptance criteria to demonstrate the absence of an adverse effect from a specified change or type of change
May reduce the supplement reporting category for those changes
If the proposed comparability protocol was not approved with the original application, it must be submitted as a Prior Approval Supplement
NDA Annual Report
Submitted within 60 days of the anniversary date of FDA’s approval - Use form FDA 2252
Summary of significant new info that might affect safety, effectiveness, or labeling
Quantity of drug product distributed in and outside the US
Labeling - changes since last report
CMC Changes
Nonclinical and Clinical Info (published and unpublished reports)
Status of postmarketing study commitments
PMA Supplement
Required for review and approval by FDA before making any change affecting the safety or effectiveness
Changes that don’t affect safety or effectiveness must be reported in Annual Report
Only info supporting the change is required to be included in the PMA supplement
Needs a section identifying each change and explaining the reason for the change
All require User Fees
Examples of Changes requiring PMA supplements
New indications for use Labeling or packaging changes Manufacturing facility or process changes Changes in sterilization procedures Changes to performance specification Changes to components Changes to principles of operation Extension of expiration date
Types of PMA Supplements
Panel-Track 180-Day Real-Time Special PMA 30-Day Notice
Panel Track Supplement
Most burdensome supplement
Significant change in design or performance or new indication for use and substantial clinical data are necessary
Changes in the device that may raise different types of safety and effectiveness questions
Changes in which there may be no accepted test methods for evaluating the issues of safety or effectiveness
These changes usually require significant changes in the labeling
Ex. different patient populations, different duration, remaining contraindications
180-day Supplement
Significant changes that affect safety and effectiveness
Changes in components, materials, design, specification, software, labeling
Change to different manufacturing facility
Usually require only new preclinical testing (and possibly limited confirmatory clinical data)
Ex. change to principles of operation; control mechanism; device design or performance; labeling; acceptance criteria
Real-Time Supplement
Minor changes that affect safety and effectiveness
Ex: change in design, software, labeling; changes that were expected with that device type and validated
The sponsor and FDA agree to interaction to jointly review the supplement and the FDA provides feedback immediately.
Can only do this if it’s a change in a single scientific discipline and a multidisciplinary review team is not necessary
Must have FDA approval to use this type of supplement
Special PMA Supplement
Changes being effected
Labeling or manufacturing change to reflect newly acquired information that enhances safety
Can implement change immediately if the supplement includes full explanation of the basis of the changes; the receipt is acknowledge by the FDA; specify the date on which the changes are being effected
Must be based on info not available during original submission; must have new scientific data; cannot use if change affects effectiveness.
Ex. add or strengthen contraindication or warning; enhance instruction for safe use; delete false and misleading indications; add additional assurance of purity, quality, identity, strength or reliability.
30-day notice
change to manufacturing procedure or method of manufacture; device incorporating change may be distributed 30 days after FDA receives the notice unless FDA notifies you that a 135-day supplement is required
Would not qualify for physical, chemical or performance changes
PMA Annual Report
Submitted annually from date of approval of original PMA
FDA reviews within 90 days of receipt; could say the report is complete or that they want more info or that changes were not appropriate for Annual Report
list all changes made since the last annual report, but those made in a supplement you provide less detail for
Parts of a PMA Annual Report
Cover letter (PMA number, device name, company identifiers, reporting period, approval date)
Manufacturing, design, labeling changes (identify changes, rational, validation, and date of implementation) Describe changes not reported in other supplements
Summary and bibliography of reports in scientific literature
Number of devices shipped or sold
Drug Post-Approval Studies
Phase IV - to gather info about product safety, efficacy, or optimal use; evaluate CMC issues
May be required with approval or after if FDA becomes aware of new safety info (when adverse event reporting/pharmacovigilance is not enough)
Many protocols for these studies are submitted with the NDA; but they can be submitted following approval
Required for orphan drugs, or extended use drugs or if a new risk is identified
Study schedule must be developed with dates for: protocol submission, completion of patient accrual, study completion, submission of final report (schedule and rationale must be submitted to FDA)
Examples of Drug Post-Approval Studies
To demonstrate clinical benefit for drugs approved
under the accelerated approval requirements
Deferred pediatric studies
Assess a known serious risk related to use of the drug
Assess signals of serious risk related to use of the drug
Identify an unexpected serious risk when available data indicate the potential for a serious risk
Drug Postmarketing Study Status Reports
Submited in Annual Reports until the FDA notifies the company that study is completed, no longer feasibile or valid
Contents:
NDA holder information - Name, NDA number, NDA
approval date
Product information
Date of postmarketing study commitment
Study description - Purpose, patient population, drug dosage, delivery system
Study schedule
Description of current study status and explanation of status
Drug Postmarketing Study Commitment Status Categories
Pending – study not initiated but not meeting criteria for
delayed
Ongoing – study proceeding according to or ahead of schedule
Delayed – study behind original schedule
Terminated – study ended prior to completion; final
study report not yet submitted to FDA
Submitted – study completed or terminated and final study report submitted to FDA
Drug Final Study Report
Describe the study results
Explain how the study did or did not meet the requirements
FDA Review of Status Reports
Annual Status Reports - within 3 months of receipt
Final Status Reports - within 1 year of receipt unless it’s part of a supplement
FDA could consider the study satisfied, want to set up a new study if this one was not fulfilled, or could release the committment and end reporting requirement
PMA Post Approval Studies
intended to help assure continued safety and effectiveness of an approved device
Usually protocols are negotiated during PMA review or they must be submitted as a PMA Supplement within 30 days of approval
Changes to the protocol are also submitted as PMA supplements
Usually negotiations between FDA and Sponsor; FDA will approve less robust protocol if a robust one would impair compliance and irrelevant to standard of care
PMA PostApproval Studies: Protocol Contents
Background - regulatory history, device description,
indications for use
Study purpose, objectives and hypotheses
Study design, inclusion/exclusion criteria, comparator group
Statistical justification, primary and secondary endpoints
Statistical analysis
Study documents – case report forms, informed consent forms, IRB approvals
Study milestones/timelines (expected date of study initiation, monthly number of sites, initiation of enrollment, monthly subject enrollment, date of enrollment completion,
date of follow-up completion)
PMA Interim Post-Approval Study Status Reports
Submit every 6 months for initial 2 years
Annual reports 2 years until Final Study Report submitted
From date of PMA approval letter (unless other start date agreed to by FDA)
FDA completes review and responds within 60 calendar days
Reporting Status
“Report on Time” – received by scheduled due date
“Report Overdue” – not received by scheduled due date
“Report Overdue/Received” – received after scheduled due date
Office of Surveillance and Biometrics (OSB)
The office that reviews post-approval study reports (different from ODE which approves PMAs) may consult with ODE
Could request an interactive review process or send a deficiency letter
PMA Final Post-Approval Study Reports
Submitted within 3 months after study completion; FDA responds within 30 days and could send a letter saying the conditions have been met
If study outcome affects labeling, a PMA supplement must be submitted (no user fee for this supplement)
If conditions are not met, the FDA may withdraw the PMA; the device may be considered misbranded due to refusal to comply with approval requirement
Contents of interim and final post-approval study report
General information – PMA and PMA Supplement number, sponsor information,
sponsor contact information, device name
Submission information – date, type of data included (clinical, laboratory or animal study), Interim or Final Post-Approval Report
Study information –
purpose of study,
patient population,
dates covered by report,
summary of study progress and milestones,
rationale if milestones are not met and revised timeline, explanation for lost to follow-up,
discontinued and deceased patients,
summary of safety and/or effectiveness data
FDA Assigned Study Status
Protocol Pending – protocol not approved; < 6 months since order issued
Protocol Overdue – protocol not approved; ≥ 6 months since order issued
Study Pending – time between protocol approval and first interim report
Progress Adequate – study started; progress consistent with protocol
Progress Inadequate – study started; progress inconsistent with protocol
Completed – sponsor fulfilled condition of PMA approval and FDA closed study
Terminated – sponsor has not or cannot fulfill condition of PMA approval and FDA terminated study
Other – study does not fit into another category
FDA listing of Post-Approval Studies
Information included for 1 year following date of FDA’s letter confirming all PMA commitments fulfilled
Includes:
PMA number and approval date Applicant and device name
Medical specialty
Study name and description
Protocol approval date Study population
Study status
Adverse Drug Experience (ADE)
any adverse event associated with the use of the drug whether or not considered drug related
Life-threatening adverse drug experienced
places the patient, in the view of the reporter (e.g. medical practitioner) at immediate risk of death
Unexpected adverse drug experience (UADE)
not listed in the current labeling; has not been previously observed (in clinical trials)
Serious Adverse Drug Experience
Death
Life-threatening adverse drug experience
Inpatient hospitalization or prolongation of existing hospitalization
Persistent or significant disability/incapacity Congenital anomaly/birth defect
Postmarketing Drug Safety Reporting
Sponsor must review all adverse drug experience info received from any source
Ex, scientific literature, US and non-US, posmarketing studies
Must develop SOPs for receipt, evaluation, and reporting
Postmarketing 15-day “Alert reports”
Adverse drug experience that is serious and
unexpected (must be both)
Submitted within 15 calendar days of initial report
Postmarketing 15-day “Alert reports” – Follow-up
Follow-up report submitted within 15 calendar days of
receipt of new information
If additional information is not available, document attempts to obtain additional information
Periodic adverse drug experience reports
Submitted quarterly for first 3 years following approval of NDA (Within 30 days of the close of the quarter – beginning with the date of NDA approval) and then annually (within 60 days of anniversary of NDA approval)
Includes all ADEs not reported in 15-day reports; must describe actions taken after learning of AEs (ex. labeling, review of manufacturing methods)
Periodic adverse drug experience report contents
Narrative summary and analysis (Including an analysis of 15-day alert reports submitted during the reporting period)
FDA Form 3500A (Adverse Reaction Report)
History of actions taken due to ADEs since last report
Don’t include: postmarketing study info, reports from scientific literature; foreign marketing experience (does include 15-day reports from these studies)
Postmarketing Drug Safety Reporting Recordkeeping
Records of all ADEs, both raw data and correspondence should be kept for a minimum of 10 years
NDA – Field Alert Report
If sponsor is given:
*Information regarding any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article
or
*Information regarding any bacteriological contamination or deterioration in the drug product
Sponsor should go to the field office to determine if recalls are required; must report to the district office within 3 work days of receipt (usually via telephone with a written follow-up)
Medical Device Reporting (MDR)
Mechanism for FDA to receive significant medical device adverse events from manufacturers, importers and user facilities
To detect problems and correct them quickly
Reports use FDA Form 3500A (Medwatch) (they are publically available)
Can be used by competitors to gain info
SOPs for Medical Device Reporting
Timely and effective identification, communication and
evaluation of events
Standardize review process to determine when event must be reported
Timely transmission of completed MDRs
Documentation and recordkeeping
Records must be maintained for 2 years from event or equivalent to life of device
Requirements for Medical Device Reporting
All deaths, serious injuries, and device malfunctions
Within 30 calendar days of becoming aware of the event
Events that require remedial action to prevent an unreasonable risk of substantial harm to public health
Within 5 working days of becoming aware of the event or whenever FDA makes a written request
Follow-up or supplemental reports on previously reported events (information not known or available when initial report submitted)
Within 30 calendar days of becoming aware of the information
Contents of MDR
Patient information – name, age, gender, weight
Adverse event or product problem
Outcomes attributable to adverse event
Date of event
Device information
Initial reporter information
Contact information
Manufacturer information
If device returned, summary of evaluation or justification why device was not evaluated
Not all info will be known
Medical Device Tracking
Could be ordered by the FDA upon approval; they can also release devices from tracking requirement (manufacturer may request exempt from tracking)
FDA keeps a list of tracked devices
Trace it from manufacturer to the patient; to facilitate notification and recall is a device presents a serious risk
Tracking records maintained for the useful life of the device
After 10 years of PMA approval, reassess the need for tracking
For what is Medical Device Tracking required?
Failure of the device would be reasonably likely to
have serious adverse health consequences; or
Device is intended to be permanently implanted in the body; or
Device is life-sustaining or life-supporting used outside a device user facility
Medical Device Tracking: Manufacturer’s Responsibility
Develop tracking methods that provide information about the location of a device within a short time
3 working days for devices that have not yet been distributed to a patient
10 working days for devices that have been distributed to a patient
Information is obtained from final distributor
Written Standard Operating Procedures (SOPs)
May contract out but manufacturer remains responsible
Information required to be tracked prior to distribution to patient
Distributor’s name,
Distributor’s address,
Distributor’s telephone number Device’s location
Information required to be tracked following distribution to patient
Device identification (lot, batch, model/serial number)
Date device shipped by manufacturer
Name, address, telephone number, social security number of the patient receiving device
Date device provided to the patient
Name, address and telephone number of prescribing
physician and physician following patient
Date of explant, explanting physician contact information, date of patient’s death, date device returned to manufacturer or permanently disposed of
Patients may refuse to release info for tracking
Medical Device Tracking Audits
Manufacturer’s Audits
To confirm tracking method works and information
collected is accurate
Audit at 6 month intervals for first 3 years of device tracking; annually thereafter
Statistical sampling plan should be used
FDA may inspect tracking methods
Including review of tracking system to verify tracking method tracks a device to the end user
Medical Device Tracking: Going out of business
Manufacturer that goes out of business must notify FDA
and provide tracking records and information
If another person acquires right to manufacture or distribute tracked devices, the other person becomes responsible for tracking
If manufacturer ceases distribution of tracked device but continues to do business, manufacturer remains responsible for tracking devices previously distributed
Remedial action
any non-routine action, that is necessary to prevent recurrence of a reportable event
Post market surveillance
active, systematic, scientifically valid collection, analysis, and interpretation of data and other info about a marketed device
*prospective surveillance - patients are identified before data collection
