FDA and EMA GCP Pre-Market Inspections

19 JANUARY 2021, XXX

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AGENDA

 INSPECTION PROCESS
 TRENDS IN INSPECTION FINDINGS
 INSPECTOR INTERACTIONS
 INSPECTION READINESS/PREPARATION

glQMS, January 2021

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End to End Inspection Process

Inspection Inspection
Pre-Inspection
Conduct Response
Follow-up
Inspection Submission of
Pre Inspection Arrival of Facilities Inspection Response
Notification requested
Requests inspector Tour report received issued
Received information
Confirmation of Implementation
Inspection Opening CAPAs
Authority Interviews of agreed
Preparation Meeting agreed
Request actions

Inspection
Document
Close
Review
Meeting
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FDA versus EMA GCP Inspections

Topic FDA EMA

Announcement Written (6 weeks) or Not !, no agenda Written (6-8 weeks), with agenda

Number of Inspectors Often 1 Usually 2 for Sponsor and 1 for

Investigator Site
Experience of Inspectors GXP Experts GCP Experts
Inspection Focus Data Process
Scope Investigator Site, CRO, Speciality Lab, Investigator Site, CRO, Sponsor
Sponsor (sequential, parallel) (sequential)
Close Out meeting Written Summary (483) Verbal Summary
Potential Outcomes 483, Report, Warning Letter Report
Guidelines FDA inspection guidance EMA inspection guidance
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Inspection Focus and Findings

 Inspection Topics are predictable !

 For FDA desribed in their Inspection Manuals.
 For EMA described in their SOPs.

 Findings should be predictable !

 Use the above as inspection readiness tool.
 Known internal quality issues trends (e.g., CSR amendments are flag for Quality issues).

 Findings can be prevented !

 Pro active detection and closure via strong CAPAs (including impact assessment on data where needed), and if not (completely)
feasible: via strong storyboards.
 Inspection Outcome: 6

EMA Inspection Ratings

 Critical: conditions, practices or processes that adversely affect the rights, safety or well-being of the subjects and/or the
quality and integrity of data.
 Critical observations are considered totally unacceptable.

 Major: .......that might adversely affect the rights, ........

 Major observations are serious findings and are direct violations of GCP principles

 Minor: ............that would not be expected to adversely impact the rights,........

 Minor observations indicate the need for improvement of conditions, practices and processes.
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Inspection Outcome:
FDA Inspection ratings

 FDA does not rate individual findings

 An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has
observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C)
Act and related Acts. 
 483 does not include observations of questionable or unknown significance at the time of the inspection

 Note: FDA can only cite observations against CFRs, not against ICH-GCP as EMA, hence in general less findings
are raised.
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Possible Consequences following a GCP Inspection

EMA
 Inspection of new additional sites/trials in same program
 Rejection of data from selected site, re-analysis, new clinical study report
 Correction of data (e.g., re-monitoring)
 Rejection of entire trial
 Possible delay or rejection of the application
 Triggered additional inspections for other/upcoming applications
(Source: EMA presentation, 2018)

FDA: If response not adequate, warning letter is issued, can be followed by enforcement actions.
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Real Life Example

 The FDA said an investigation of Johnson & Johnson Pharmaceutical Research & Development’s role as sponsor of the antibiotic
studies had revealed “objectionable conditions” that were not adequately addressed in the company’s responses to a Form FDA
483 inspection report sent out in June 2008 and to later requests for information.

Complete response Letter: The FDA has indicated that they cannot approve the NDA for ceftobiprole at this time. They have
asked J&JPRD to conduct additional audit work of clinical investigator sites and to address specific questions related to site
monitoring

 Subsequently, the European Medicines Agency’s Committee for Medicinal Products for Human Use told J&J that full approval of
ceftobiprole in the EU (for the treatment of complicated skin and soft tissue infections) would have to be stalled pending Good
Clinical Practice inspections of trial sites run by Janssen-Cilag in the late development programme.

 http://www.circare.org/fdawls2/icon_wl_20091127.pdf
glQMS, November 2020
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TOP 3 EMA INSPECTION FINDINGS
1. GENERAL
(2020 REPORT)

 Essential documents:
 the TMF was not ready for inspection and relevant documents were either not filed, or filed late, or located outside the TMF structure;
 lack of essential documents, e.g. receipt of IMP shipment to site, records of blood samples shipment to the central laboratories;
 incomplete documentation, e.g. incomplete screening list;
 lack of contemporaneous independent copy of the CRF filed on site.
 discrepancies between source data and data reported in the CSR

 Qualification/training:
 incomplete training documentation;
 lack of training of study personnel on trial related procedures.

 SOPS
 lack of evidence that sponsor SOPs have been followed and used;
 SOPs not updated as required;

 sponsor failure to implement an efficient quality management system.

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TOP 3 EMA INSPECTION FINDINGS
2. TRIAL MANAGEMENT

 Monitoring:
 monitor has not identified number of deficiencies on site;
 inadequate monitoring activities performed at site; monitor not following monitoring plan.
 lack of escalation process to resolve issues identified by monitor;

 Data management:
 inappropriate system for reporting protocol violations;
 data management activities were only undertaken after the clinical conduct of the trial was completed;

 Clinical study report (CSR):

 inconsistencies between source data and data reported in the CSR;
 inaccurate information reported in CSR; relevant information missing in the CSR.

 Protocol/CRF
 insufficient design of the study protocol, e.g. no instructions related to concomitant medication or unscheduled visits;
 the design of the CRF is not suitable to accurately collect the data specified within the protocol
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TOP 3 EMA INSPECTION FINDINGS
3. IMP
 Supplying/Storage/Retrieving/Destruction:
 insufficient amount of IMP supplied to site by sponsor;
 lack of temperature monitoring of IMP during transport or storage.

 Prescription/Administration/Compliance:
 IMP not administered in the required timeframe after its preparation;
 lack of evidence of IMP compliance calculation
 incomplete certificates of compliance signed by the qualified person;
 lack of traceability in records for IMP kits
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Actual recent EMA Finding at Sponsor Inspection

XXX system was used as an investigator site portal including the receipt and confirmation of essential
documents. Grading: critical
 Sponsor must provide a system that allows full investigator control over essential documents. This is an issue
regarding the completeness, availability, content and structure of the TMF:
 The sponsor had full control of the XXX e-system and secured its right (via signed contract) to terminate service at any
time with their investigators, although XXX was issued by the investigators as electronic part of the investigator file.
 Each workflow for uploading needs to be initiated by sponsor staff and documents can be refused by sponsor staff.
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TOP 5 SPONSOR FDA Inspection findings

(2020 REPORT)

 No split between sponsors and investigators.

 Number 4: General responsibilities sponsors. Failure to:

 [1. select qualified investigators]
 [2. provide investigators with the information needed to conduct the study properly]
 [3. ensure proper monitoring of the study]
 [4. ensure the study is conducted in accordance with the protocol and/or investigational plan]
 [5. ensure that FDA and all investigators are promptly informed of significant new adverse effects or risks].
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Actual recent FDA 483s/warning letters

 sponsor 483_2019
 Investigator483_2019

 warningletter_investigator_2019
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Recent inspection trends
1: Inadequate Trial Master File

Trigger for trend: start of using eTMFs instead of paper TMFs. Examples of recent critical/major findings:

 The TMF was presented as a paper TMF for inspection. However, the TMF did not contain all the essential documents required to
enable the reconstruction of trial events and demonstrate compliance with the regulations and the organisation’s own quality system.

 Several essential documents were retained within different electronic systems which were not defined to be part of the TMF and to
which inspectors were not provided direct access.

 The TMF had not been fully defined to include all the ancillary systems and the documents located within them.

 Where the TMF maintenance had been contracted out to a third-party contractor, there was limited information available in the
organisation’s own files to demonstrate effective oversight of clinical trial activities to fulfil its obligations as a sponsor.
 Recent inspection trends 17

2: Lack of Control by Investigator on Essential documents

and on eCRF
 Trigger for trend: use of eCRF instead of paper eCRF, use of eTMF and of electronic essential document uploading systems/shared
investigator/sponsor TMF.

 Lack of contamporenous independent copy of CRF at site.

 The EU GCP inspectors do not consider the requirement above to be met if data are captured in an electronic system and the data are stored on a
central server under the sole control of the sponsor. This is because the investigator does not hold a contemporaneous and independent copy of the data.
 No data changes to CRF allowed by sponsor (self evident checks)
 Investigator copy after closure of study needs to contain full audit trail

 The investigator/institution should have control of all essential documents and records

 Originals to be kept at investigator site
 Shared investigator/sponsor TMF and uploading systems require full access and control by investigator of documents (specific in contract, access
when study closed,…)
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Recent inspection trends

3: Electronic tools
 Use of Electronic Tools such as patient report outcome tools (Epro), econsent, apps,.. has lead to findings on lack of validation,
access controll, inadequate electronic signatures, patient privacy concerns, etc

 Example of unforeseen issue when implementing new apps:

 app that sends sms reminders to patients to ensure they adhere to visit windows. Patients responded that could not come to visit because
sick/hospitalized. This means that sms is now source of an AE/SAE and date of awareness by sponsor needs to be documented.
 Expected inspections trend in future:
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Risk Management/Risk based monitoring

 ICH-GCP revision requires risk management approach, including:

 Identification of risks both at trial and system (SOP,..) level during protocol development.
 Implementing risk reduction actions via protocol, study specific plans.
 Monitoring plan to contain justification for approach (onsite vs remote monitoring, level of SDV,..).
 Use of QTLs and description thereof in CSR.

 Risk based monitoring approaches with central monitoring has already led to findings related to patient privacy, after
sponsor collection of medical charts for remote SDV
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Inspection Interactions
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What should I do, if...

 the inspector asks a question, and I don’t know the

answer?
 the inspector is silent, after I have provided my answer to
the question?
 the inspector is aggressive ?
 ..........
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Who Can Be Interviewed?

 All employees directly involved in the activities and processes should be prepared to be
interviewed
 An inspector can also request to interview team members that were not selected as
interviewees by the Sponsor
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What Happens if You Are Interviewed?

• Prepare to explain your job and training

received
• You will be contacted should you need to
speak with the inspectors
• A time will be arranged for you to be
interviewed
− In – house....Come to the backroom....NOT
the Inspection Room
− Remote .... Do not directly call in, a TC
will be scheduled
• You will be prepped by QA to review:
− The question/issue
− Potential questions
− Supporting documentation
− Responses
• QA will be with you during any interview
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Body Language – what do you see?

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Body Language – what do you see?

glQMS, November 2020

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General Interview Approach

LISTEN REFLECT RESPOND

Rephrase the question
Let the Be concise
Collect your thoughts
Inspector finish Be honest and
the question Understand the question
BEFORE answering forthright
before answering
Formulate/structure your Avoid making excuses
response Answer only the
Reference SOPs or study question that was asked
specific procedures where Avoid making general
possible statements.
REMEMBER: IT IS OK TO SAY “I DON’T KNOW”
Refer it to the right expert
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Interview Techniques

 The “Open” Question: There are a number of possible answers & interviewee can choose a response
Example: How did you select the investigator sites
 Typically, open questions start with: who, what, where, when, why and how
 They force responses that provide more information
 Be careful to not provide too much information, request more specificity if the question is too broad, try to provide a structured answer.

 The “Closed” Question: The number of possible answers is very small and predictable
Example: Do you obtain the informed consent?
 The answer is going to be yes or no
 Not likely to yield much information, therefore least appropriate for obtaining quality information
 However, often used to confirm an inspection finding (“so, there is no documentation on this process?”)
 If intent is too cause inspection finding: add additional information into response
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Interview Techniques

 The “I Don’t Understand” Question: Looks for consistency of a response or further explanation
Example: I don’t understand, could you please that explain again?
 Seeking clarity, consistency
 If question asked again at different session or to other employee: if anticipated (if weak area) read scribe notes beforehand

 The “Hypothetical” Question: Expects the interviewee to provide likely outcomes to a hypothetical situation

Example: What would happen if you failed to obtain informed consent?

 Trying to test knowledge of interviewee
 Demonstrates awareness of possible risks and appropriateness of follow up plans
 Stick to responses covered by SOPs or guidelines, do not provide personal opinions, refer to experts as needed
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Being Interviewed-The Do’s

 Be on time
 Bring business cards (if available), know your job description
 Have a clear understanding of the question(s) before answering
 Repeat the question(s) for clarification (if necessary)
 Be honest, direct & professional in answering
 Be aware of your body language
 Be comfortable with silence
 Be cooperative and friendly, remain calm and be non-defensive and confident
 Clarify any misunderstandings on the part of the Inspector promptly
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Being Interviewed-The Don’ts

 Go directly into the inspection room

 Try to mislead the Investigator(s)
 Engage in unconstructive arguments when responding to a question or observation
 Become defensive, confrontational, fearful or intimated
 State that something is “impossible” or couldn’t happen
 Volunteer information not specifically asked
 Say “I assume” or “I think” when you really don’t know the answer
 Ask each other questions or argue in front of the Inspector, blame others (‘it is the fault of the supplier’)
 Have ’off-line’ discussions with the Inspector
 Answer “what if” or hypothetical questions
 Read, sign or verbally affirm or deny any information in a written statement (Affidavit)-always refer to Legal!!
 Make any commitments prior to receiving QA approval (aligned with NC process)
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Specific scenarios

 What of employee left the company

 Never respond: “ I cannot help you with this, this was before my time”
 Anticipate and prepare inspection by reading all records and documents
 In case you don’t know: “ I will double check and come back to you”

 What if inspector is aggressive

 Keep calm !
 If happens with multiple employees, QA or mgmt. to provide feedback to inspector in diplomatic manner
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Specific scenarios

 Can I take documents/personal notes with me in inspection room?

 In general not recommended if not part of general strategy (See bullet below)
 Only if QCd by QA
 Remember that inspector may request to read them, even if you did not show/use them

 Can I propose to present slides ?

 Can be beneficial if for example contains story board covering weakness, or to present processes
 Ensure your presentation does not contain back up slides (Inspector may otherwise request to see them)
 Ensure your presentation is aligned with process as described in SOP(have QA review it first)
 If presentation on process: keep high level
 Ensure your presentation does not raise new concerns (information different from that in NC, commitments not covered in CAPA or project plan,… ): best practice to
have story boards reviewed by sr mgmt and by QA.
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Specific scenarios

 Inspector requests documents/records for review

 Records should be provided as is w/no modifications....EXCEPT .....
 For records containing financial or confidential personnel information the HA should be informed if removal is possible
before any action is taken (depending on local regulations)
 Audit reports should not be shared without sr mgmt. approval
 documents should be carefully reviewed (QC) before providing them, to make sure it fulfills the request
 Ideally the interviewee reviews the documents before providing to inspector to ensure awareness and to ensure
correct documents are provided
 A “tracker” is maintained for all requests, indicating the requests and their status
 Copies are kept of all records requested, noting which specific records are copied and kept by the HA
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Inspection Readiness
Start: At DataBase Lock, Stop: 1 month after DBL

Clinical Trial Team completes Inspection

Readiness Checklist, CQA supports and
provide guidance

Identification of potential issues/gaps

Transfer to Risk Log and Prepare

CAPAs/Story Boards
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Inspection Preparation (Plan):
Start: 9 months prior to submission, Stop: Submission Date

Sites Sponsor Suppliers

Target Site list Past Inspections, confirm CAPAs closed Target Supplier list

Review monitoring reports Sponsor-Supplier inspection readiness kick off

Confirm inspection readiness checklist/Risk log meeting
/Story Boards completed
Review audit reports and Non Compliances, Supplier selection, oversight documentation
confirm CAPAs closed Opening and functional presentations ready
Supplier audit and Non Compliance CAPAs closed
Pre-inspection visit and/or Inspection Training Mock inspection/interviews Agreement on Story Boards

Lessons Learned, finalize story boards Mock Inspection/interviews

Inspection Ready