Regulatory Class - Nov 14

Question 1

Reasons for FDA inspections

Answer 1

 Directed inspections for specific reason (received notice of complaint about a product)
 Routine audit to ensure company compliance with GLPs, GCPs, cGMPs or QSRs
 Reinspection following warning letter
 Recall effectiveness check
 Preapproval inspection (PAI)

Question 2

What does FDA inspect?

Answer 2

 Any product or activity required to comply with specific FDA regulations
 Factory, warehouse, establishment in which regulated products are manufactured, processed, packed or stored
 Nonclinical studies
 Clinical trials
 Safety reporting

FDA also inspects foreign manufacturers and clinical investigators if the products are distributed in the US; usually need their governmental approval first; if not inspected, product can be held at the border

Question 3

What may FDA not inspect?

Answer 3

 Financial data – except for Financial Disclosure related documents
 Personnel data – other than information regarding qualifications of personnel performing FDA-related functions
 Sales data – other than shipment information
 Research data – other than information subject to reporting to and inspection by FDA
 Quality Assurance audit reports

Unclear the rules about taking pictures

Question 4

FDA Inspection Procedure

Answer 4

 Primary contact reviews inspector’s credentials and FDA Form 482 – Notice of Inspection
 Notify everyone that FDA is inspecting
 Escort inspector to conference room and Always accompany inspector
 Assemble inspection team (based on scope of inspection)
 All questions should be directed to primary contact
 FDA inspector may request documentation for review (only give specific documents)
 Inspector may request copies (mark confidential and make copy for sponsor)
 FDA inspector may request product samples (sponsor can charge for that sample)

Question 5

End of FDA Inspection

Answer 5

 At conclusion of inspection inspector holds exit interview
 Inspector reviews and explains observations
 Documented on Form 483
 Cites appropriate regulation for each deficiency
 Company can respond and identify perceived errors
 Once Form 483 issued and inspector leaves facility, no changes can be made

Question 6

Response to FDA Form 483

Answer 6

Should respond within 15 days of inspection and effective response can prevent warning letter

Contents:
 An evaluation of the extent of the problem (how often does it happen)
 Assessment of the root cause of the problem (insufficient training)
 Corrective actions (want to see actions happen)
 Preventive actions
 Timeframe for training
 Supporting documentation

Question 7

Establishment Inspection Report (EIR)

Answer 7

 Narrative report prepared by inspector after inspection
 Describes inspectional findings – each observation included on Form 483 plus other lesser observations

Includes:
 Reason for inspection
 Dates
 Classification and findings of previous inspection
 Scope of inspection
 Type of inspection
 Brief description of products, processes or systems included

Would mention not follow guidance documents, because those can’t be written in the Form 483

Question 8

cGMP Inspections

Answer 8

 Comprehensive – covers all aspects of facility’s FDA- regulated products and processes (All major areas of quality system - every 2 years)
 Abbreviated – performed on a specific area (May include one product or one specific aspect of company’s operations - due to new product or change)
 Directed – in response to product failure or contamination (Focuses on conditions that led to violation, or complaint; comes from the FDA center)

Two classifications of inspections:
 Routine Inspections (Scheduled biannually; Verify general compliance with GMPs)
 Preapproval Inspections (PAI) - Prior to approval of NDA or PMA

Question 9

PAI Inspections

Answer 9

 Cover all facilities associated with a submission, including drug component manufacturing (drug substances), finished drug product manufacturing, device manufacturing, and control testing laboratories
 Risk-based decision criteria to determine which facilities to inspect and scope of inspection

Must do it at a reasonable time - which means during normal business hours

 Scheduled to ensure no delay in meeting approval timelines

Question 10

PAI Inspections Objectives

Answer 10

 Ensure information contained in the submission (e.g. CMC information) is consistent with on-site information (can the company do what they say they will do)
 Ensure company can manufacture the product in accordance with information submitted
 Readiness for commercial marketing
 Quality system is designed to achieve sufficient control over
the facility and commercial manufacturing operations
 Ensure data integrity
 Audit raw data and verify all relevant data was submitted

Question 11

PAI Inspections:Typical Form 483 observations

Answer 11

 Lack of an adequate proposed commercial batch record to provide for a reproducible manufacturing operation
 Missing data related to the data filed in the CMC section
 Insufficiency, discrepancy, or failing of an analytical method validation program
 Lack of suitability of the facility, equipment or manufacturing operations intended for making the commercial API or finished product

Question 12

Bioresearch Monitoring (BIMO)

Answer 12

 Protect the rights, safety and welfare of subjects involved in FDA-regulated clinical trials
 Verify accuracy and reliability of clinical trial data
 Assess compliance with statutory requirements and FDA’s regulations

Inspect everything related to clinical trials

Question 13

Nonclinical Laboratory Inspections

Answer 13

 Verify quality and integrity of data submitted in research or marketing application
 Inspect nonclinical laboratories conducting safety studies intended to support research or marketing applications (Approximately every 2 years and usually without prior notification)

Two classifications of inspections:
 Surveillance Inspections
 Directed Inspections

Question 14

Nonclinical Laboratory Inspections: Surveillance Inspections

Answer 14

 Periodic, routine determination of compliance with GLP regulations
 Facility inspections
 Audits of ongoing or recently completed studies

Inspector will probably look at multiple studies

Question 15

Nonclinical Laboratory Inspections: Directed Inspections

Answer 15

 Verifying the reliability, integrity, and compliance of critical safety studies supporting pending submissions
 Investigating issues brought to FDA’s attention
 Reinspecting laboratories previously classified OAI (Generally within 6 months after firm responds to warning letter)
 Verifying results from third-party or sponsor audits submitted to FDA

Question 16

Nonclinical Laboratory Inspections Procedures

Answer 16

 Interview personnel
 Tour facility
 Review SOPs
 Review at least one completed study

Question 17

Nonclinical Laboratory Inspections: Criteria for determining studies to inspect

Answer 17

 Safety studies conducted on FDA-regulated products that have been initiated or completed since the last GLP inspection
 Safety studies that encompass the full scope of laboratory operations
 Studies that are significant to safety assessment, e.g. carcinogenicity, reproductive toxicity, chronic toxicity studies
 Studies in several species of animals

Question 18

Clinical Investigator Inspections

Answer 18

 Protect the rights, safety and welfare of subjects
 Assess compliance
 Verify accuracy and reliability of clinical data submitted to FDA

 Investigator is responsible for the overall conduct of the clinical study
 Inspections may be announced or unannounced

Usually investigating sites contributing the most data for a marketing application (or high-enrolling)
Will do real-time clinical site inspections but cannot do data verifications

Question 19

Types of Clinical Investigator Inspections

Answer 19

 Study-oriented inspections
 Investigator-oriented inspections
 Bioequivalence study inspections

Question 20

Clinical Investigator Inspections: Study-oriented inspections

Answer 20

 Conducted by field office personnel
 Typically 2-4 days
 Assigned by FDA headquarters based on pending marketing submission
 Sites generally selected based on amount of data contributed (e.g. highest enrolling sites)

Majority of inspections

Question 21

Clinical Investigator Inspections: Investigator-oriented inspections

Answer 21

 Verify accuracy and reliability of submitted data
 Investigator’s data is crucial to product’s approval
 Unusual findings or trends in submitted data
 Investigator has participated in many studies
 Investigator conducted study outside their specialty
 Targeted “for-cause” based on complaint
 Sponsor concerns
 Termination of clinical site
 During on-going study for real-time assessment
 Request of FDA review division
 Class of products identified by FDA as products of special interest (i.e. targeted based on public health concerns)

Question 22

Clinical Investigator Inspections: Bioequivalence study inspections

Answer 22

Conducted for pending NDA or ANDA including bioequivalence data that is critical to product approval

Common for ANDA submissions

Question 23

Clinical Investigator Inspections Procedure

Answer 23

 Field office contacts investigator to schedule inspection (wants it in 10 days of initial contact)
 FDA inspector presents credentials and FDA Form 482 (Notice of Inspection)
 Interviews investigator, study coordinator, or responsible person at site

Inspection process includes review of: 
 Delegation of authority
 IRB approval of study documents
 Protocol compliance
 Informed consent
 Financial disclosure
 Drug/device accountability 
 Monitoring oversight
 Study data

Question 24

Conclusion of Clinical Investigator Inspections

Answer 24

Exit interview with investigator
 Findings discussed and clarified
 Issue Form 483 “Inspectional Observations” to clinical investigator

Common Form 483 observations:
 Failure to follow protocol
 Failure to conduct or supervise study 
 Protocol deviations
 Inadequate recordkeeping
 Investigational product accountability 
 Informed consent issues

Question 25

Sponsor Inspections

Answer 25

Inspection of sponsor and/or CRO:
 Generally unannounced but not always
 Assess how sponsor assures the validity of data submitted to them by clinical investigators
 Verify compliance with applicable regulations

2 types of inspections:  Routine/Surveillance  For cause

Question 26

What FDA inspects during Sponsor Inspections

Answer 26

 Protocol (original & revisions)
 Investigator agreements & financial disclosures
 Organizational charts
 Correspondence
 CRO or vendor agreements
 Product accountability records
 Monitoring plan & reports
 Qualification records for Monitors and Clinical Investigators
 Training records
 Study subject records (CRFs, diaries, etc.)
 Adverse event reports
 Clinical Databases/Data line listings
 SOPs for conduct of study

Question 27

Sponsor Inspections: Common inspection observations

Answer 27

 Inadequate monitoring
 Failure to secure investigator compliance
 Failure to submit Progress Reports
 Inadequate adverse event analysis and reporting
 Failure to notify FDA, investigators or IRBs
 Inadequate product accountability
 Failure to obtain signed Investigator Agreement/1572  Failure to obtain FDA or IRB approval

Question 28

Inspection Results Classification

Answer 28

No Action Indicated (NAI)
 No substantive noncompliances
Voluntary Action Indicated (VAI)
 Substantive noncompliances but no further regulatory action
required
 May or may not require response
Official Action Indicated (OAI)
 Serious deviations from regulations requiring prompt
correction
 Administrative and/or judicial regulatory actions required

Question 29

Adulteration

Answer 29

Adulteration – quality-related deficiencies
 Produced under unsanitary conditions or containing
filthy, putrid or decomposed substance
 Not manufactured in compliance with GMPs
 Strength, quality or purity differs from how it is represented
 Class III medical device without approved PMA (or not exempt)
 Banned device

Question 30

Misbranding

Answer 30

Misbranding – false or misleading labeling or other information
 Label fails to include the manufacturer name/address
 Label includes an inaccurate statement regarding quantity
 Label does not include established name of the drug
 Label does not contain adequate directions for use and warnings necessary to protect users
 Dangerous to health when used in dosage or manner recommended by labeling

Question 31

FDA Administrative Actions

Answer 31

 Untitled letter
 Warning letter
 Reinspection to verify corrective actions
 Regulatory meeting
 Clinical hold on study
 Withdrawal of approval
 Rejection of data
 FDA-initiated product recall
 Initiation of Disqualification Proceedings
 Deferral of substantive review of submissions

Question 32

Warning Letter

Answer 32

 Usually issued following Form 483
 Repeated noncompliances
 Company does not correct/resolve issues
 Serious noncompliances
 Issues are basic to quality control and require immediate correction
 Respond within 15 days

Question 33

Recall

Answer 33

Actions taken by manufacturer to remove from the market products that are in violation of FDA regulations
May be:  Voluntary  In response to FDA request  By FDA order

Question 34

3 classes of recall

Answer 34

 Class I recall – reasonable probability that use of or exposure to suspected product will cause serious adverse health consequences or death
 Class II recall – use of or exposure to suspected product may cause temporary or medically reversible adverse health consequences; or probability of serious adverse health consequences is remote (most are Class II)
 Class III recall – use of or exposure to suspected product is not likely to cause adverse health consequences

Question 35

Disqualification of Clinical Investigators

Answer 35

Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)
 Process to disqualify clinical investigator from receiving investigational products
 Investigator has repeatedly or deliberately failed to comply with regulatory requirements
 Investigator has deliberately or repeatedly submitted false information to sponsor or FDA

Question 36

FDA Judicial Actions

Answer 36

 Injunction
 Seizure
 Civil money penalties
 Referral to FDA’s Office of Criminal Investigations and Prosecution

Question 37

Injunction

Answer 37

Used where there is a likelihood that violations will continue or recur

FDA seeks injunctions when:
 Chronic violations and efforts by FDA to obtain voluntary compliance have been unsuccessful
 Immediate court intervention is needed to address an imminent public health hazard

Forcing an action or prohibition of an action - this is an action against the products

Question 38

Seizure

Answer 38

Civil action providing for government “arrest” of the goods

 Initiated by FDA through the Department of Justice (DOJ)
 US Attorney files Complaint for Forfeiture, judge signs order for arrest of good, US Marshalls Service executes the warrant

 Indicated when company refuses to undertake recall requested by FDA or FDA has reason to believe a recall would not be effective or discovers a violation is continuing

Response to FDA:
 Propose that goods be reconditioned to bring into compliance
 Deny FDA’s allegation of adulteration or misbranding (go to trial)
*if not claimed, they are destroyed

Question 39

Types of Seizure

Answer 39

Based on size

 Lot - One or more lots of product in one location that is adulterated or misbranded
 Multiple - More than one action to arrest goods located in different jurisdictions where goods are adulterated or lack required approval
 Mass - Warehouse full of products deemed adulterated or misbranded

Question 40

Criminal Prosecution

Answer 40

FDA Office of Criminal Investigations
 Obtains and executes search warrants and arrest warrants
 Conducts physical surveillance
 Obtains and serves grand jury subpoenas
 Obtains and reviews materials and documents to support case against an individual or company

Department of Justice (not FDA) must bring criminal case to court

FDA recommends criminal prosecution in cases where:
 There are gross violations that are evidence of management’s disregard for compliance with FD&C Act
 Obvious and continuing violations where management has not exercised appropriate care
 Life-threatening violations or where injuries have already occurred
 Deliberate attempts to circumvent the law