Regulatory Class - Oct 24

Question 1

Making changes to an NDA

Answer 1

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.

Question 2

Assessing the effects of the change

Answer 2

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)

Question 3

NDA Supplement: Major Change

Answer 3

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

Question 4

Examples of Major Changes

Answer 4

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

Question 5

Contents of NDA Supplements

Answer 5

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

Question 6

Prior Approval Supplement - Expedited Review

Answer 6

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)

Question 7

NDA Supplement: Moderate Changes

Answer 7

Changes being Effected (CBE) supplement or

CBE 30 days supplement

Question 8

Changes Being Effected in 30 Days

Answer 8

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

Question 9

NDA Supplement - Changes Being Effected

Answer 9

Distribution can begin when FDA receives the supplement

If FDA disapproves, the manufacturer must stop distribution

Question 10

NDA Supplement - Changes Being Effected - Examples

Answer 10

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

Question 11

Minor Change

Answer 11

Minimal potential to have an adverse effect - relate to safety and effectiveness
Description of changes may be included in next Annual Report

Question 12

Examples of Minor Changes

Answer 12

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

Question 13

Change Info in Annual Report

Answer 13

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

Question 14

Labeling Changes

Answer 14

Need to make sure advertising and promo materials comply with new label

Question 15

Comparability Protocol

Answer 15

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

Question 16

NDA Annual Report

Answer 16

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

Question 17

PMA Supplement

Answer 17

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

Question 18

Examples of Changes requiring PMA supplements

Answer 18

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

Question 19

Types of PMA Supplements

Answer 19

Panel-Track
180-Day
Real-Time
Special PMA
30-Day Notice

Question 20

Panel Track Supplement

Answer 20

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

Question 21

180-day Supplement

Answer 21

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

Question 22

Real-Time Supplement

Answer 22

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

Question 23

Special PMA Supplement

Answer 23

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.

Question 24

30-day notice

Answer 24

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

Question 25

PMA Annual Report

Answer 25

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

Question 26

Parts of a PMA Annual Report

Answer 26

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

Question 27

Drug Post-Approval Studies

Answer 27

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)

Question 28

Examples of Drug Post-Approval Studies

Answer 28

 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

Question 29

Drug Postmarketing Study Status Reports

Answer 29

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

Question 30

Drug Postmarketing Study Commitment Status Categories

Answer 30

 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

Question 31

Drug Final Study Report

Answer 31

Describe the study results

Explain how the study did or did not meet the requirements

Question 32

FDA Review of Status Reports

Answer 32

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

Question 33

PMA Post Approval Studies

Answer 33

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

Question 34

PMA PostApproval Studies: Protocol Contents

Answer 34

 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)

Question 35

PMA Interim Post-Approval Study Status Reports

Answer 35

 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

Question 36

Reporting Status

Answer 36

 “Report on Time” – received by scheduled due date
 “Report Overdue” – not received by scheduled due date
 “Report Overdue/Received” – received after scheduled due date

Question 37

Office of Surveillance and Biometrics (OSB)

Answer 37

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

Question 38

PMA Final Post-Approval Study Reports

Answer 38

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

Question 39

Contents of interim and final post-approval study report

Answer 39

 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

Question 40

FDA Assigned Study Status

Answer 40

 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

Question 41

FDA listing of Post-Approval Studies

Answer 41

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

Question 42

Adverse Drug Experience (ADE)

Answer 42

any adverse event associated with the use of the drug whether or not considered drug related

Question 43

Life-threatening adverse drug experienced

Answer 43

places the patient, in the view of the reporter (e.g. medical practitioner) at immediate risk of death

Question 44

Unexpected adverse drug experience (UADE)

Answer 44

not listed in the current labeling; has not been previously observed (in clinical trials)

Question 45

Serious Adverse Drug Experience

Answer 45

 Death
 Life-threatening adverse drug experience
 Inpatient hospitalization or prolongation of existing hospitalization
 Persistent or significant disability/incapacity  Congenital anomaly/birth defect

Question 46

Postmarketing Drug Safety Reporting

Answer 46

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

Question 47

Postmarketing 15-day “Alert reports”

Answer 47

 Adverse drug experience that is serious and
unexpected (must be both)
 Submitted within 15 calendar days of initial report

Question 48

Postmarketing 15-day “Alert reports” – Follow-up

Answer 48

 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

Question 49

Periodic adverse drug experience reports

Answer 49

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)

Question 50

Periodic adverse drug experience report contents

Answer 50

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)

Question 51

Postmarketing Drug Safety Reporting Recordkeeping

Answer 51

Records of all ADEs, both raw data and correspondence should be kept for a minimum of 10 years

Question 52

NDA – Field Alert Report

Answer 52

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)

Question 53

Medical Device Reporting (MDR)

Answer 53

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

Question 54

SOPs for Medical Device Reporting

Answer 54

 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

Question 55

Requirements for Medical Device Reporting

Answer 55

 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

Question 56

Contents of MDR

Answer 56

 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

Question 57

Medical Device Tracking

Answer 57

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

Question 58

For what is Medical Device Tracking required?

Answer 58

 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

Question 59

Medical Device Tracking: Manufacturer’s Responsibility

Answer 59

 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

Question 60

Information required to be tracked prior to distribution to patient

Answer 60

 Distributor’s name,
 Distributor’s address,
 Distributor’s telephone number  Device’s location

Question 61

Information required to be tracked following distribution to patient

Answer 61

 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

Question 62

Medical Device Tracking Audits

Answer 62

 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

Question 63

Medical Device Tracking: Going out of business

Answer 63

 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

Question 64

Remedial action

Answer 64

any non-routine action, that is necessary to prevent recurrence of a reportable event

Question 65

Post market surveillance

Answer 65

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