FDA

What is Clinical Research?

• The essential piece to demonstrate that a new product is safe and effective

• The most costly part of development– 60% of cost spent on clinical

• The most time-consuming part of product development

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Quality Concepts in Clinical Trials

• Sponsor Responsibilities:– Ensure proper monitoring of investigations (21

CFR 312.50)– Monitor the progress of all clinical

investigations being conducted under its IND (21 CFR 312.56(a))

– Correct and/or report serious non-compliance to the FDA (812.46(a))

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• Clinical Investigator Responsibilities– Conduct study according to the protocol

(21 CFR 312.60 & 812.100)– Maintain adequate and accurate case histories

(21 CFR 312.62(b) & 812.140)

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Safety Reports• Investigator is required to report all

adverse events to Sponsor– timing depends on nature and severity– has major impact on subject safety

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21 CFR §312.64(b) & 812.150


• IRB Responsibilities– Organization and Personnel through review of

IRB membership list (21 CFR 56.107)– Functions and Operations through evidence of

written SOPs (21 CFR 56.108)– Review of Research through sufficient details

of IRB meeting minutes (21 CFR 56.109)

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FDA Viewpoint on Auditing

• FDA takes no official position on whether companies should conduct clinical audits

• FDA viewpoint on sponsor responsibilities: “Sponsors are responsible for selecting qualified investigators… ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND…” 21 CFR 312.50 & 812.40

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Some fun examples

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Reality Check• How many of you do multiple clinical trials each

year?– Investigator initiated vs. sponsor

• How many of your sites/groups have SOPs?• How many of your sites use electronic medical

records?• How many of you have experience with eCRFs?• How do you communicate with your IRB (paper

or electronic)?

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Case report form

‘The investigator should develop a plan for the supervision and oversight of the clinical trial at the site. Supervision and oversight should be provided even for individuals who are highly qualified

and experienced. A plan might include the following elements, to the extent they apply to a particular trial:’

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From Guidance Document

ICH GCP Viewpoint

• “The auditing of clinical trials is conducted in accordance with the Sponsor’s written procedures of what to audit, how to audit, the frequency of audits and the form and content of audit reports.” Section 5.19.3

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FDA Role in GCP Compliance

• Determine compliance with regulations

• Verify integrity of data

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FDA GCP Inspections

• FDA will routinely inspect some or all of the data for pivotal studies in support of an application

• FDA choice of sites are based on a variety of factors– number of sites– Number of studies at site– importance of data– type of study– Geographic location

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Role of FDA Inspection

• Essential part of PMA/510K/NDA/BLA review process

• Know your rights• Use sponsor/CRO/consultants help to

prepare• Build quality into your work

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PMA premarket approvalNDA new drug applicationBLA Biologics License ApplicationCRO contract research organization

FDA Role in Clinical Investigations

• Bioresearch Monitoring Program– An on-going audit program managed by the

Division of BIMO in each Center– To determine the adherence of sponsors, CROs,

monitors, IRBs and clinical investigators to current regulations and official guidelines

– To assess through audit procedures whether data submitted to FDA are substantiated by records

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FDA Inspection of Clinical Research

FDA Conducts Two Types of Inspections• Routine data audits (study oriented)

– Audit of key pivotal data from NDAs, BLAs, 510(k)s, PMAs, etc. to verify data and procedures

• 'For-cause' audits (investigator oriented)– Targeted audit of data or investigators as a

result of prior knowledge or suspicion or alleged violations of the regulations

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Preparing for the Inspection

Before you start, make sure you are prepared• (re)Familiarize with protocol, CRFs, other

study documents• Review Study archives• Check FOI for other inspection results

16Freedom of Information

Plan for FDA Inspection

FDA Arrival• Who is to be called• Check FDA inspector credentials• Accept Notice of Inspection (Form 482)• Confirm purpose of FDA inspection

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FDA Form 482

Site Policy

Main Contact• Identify who is to be notified at the time

inspection commences and how• Identify who is authorized to receive and

accompany FDA inspector• Plan how oral inquiries and requests for

documents are processed

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General Do’s and Don’ts

DO !• Greet FDA and ask for identification and FDA Form 482• Provide work area that affords privacy• Make available phone/internet/power• Offer coffee, tea, water, bathroom• Provide visitor pass or parking pass• Keep conversation polite and professional• Extend common courtesy

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General Do’s and Don’ts

Don’t even think about: !• Pay for meals• Offer any monetary compensation• Offer gifts (even at holiday time)• Photograph, record or tape things• Socialize with FDA after work hours• Ask personal questions• Look over the inspector’s shoulder• Complain about government, taxes, FDA

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Company/Site Policy

• Document Production

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Company/Site Policy

Document Marking and Duplication• Do not permit marking of documents by FDA

Inspector– Make copies for FDA and retain a copy of each

document provided to FDA• Mark documents containing trade secret or

confidential information before providing– If confidential information is conveyed orally,

establish these facts to FDA; use witness

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Company/Site Policy

Affidavits• Establish policy on whether to review FDA

prepared affidavits• Circumstances under which an affidavit could be signed• Do not sign affidavit or volunteer any

information unless such disclosure is consistent with company policy

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During Inspection• Company/site representative should

accompany FDA Inspector at all times, to ensure access only to information and those parts of the premises under the FD&C Act

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Keep an accurate written record of:• Areas of the site visited and to whom he/she spoke• Accurate and complete record of all comments and

suggestions made by inspector, unanswered questions and site commitments– Any commitments made to FDA should have concurrence

of top management

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• A daily summation with FDA, and separately with site staff is helpful

• If additional inspection days are required, prepare an agenda for next day with FDA

• Prepare daily report to management

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Company/Site Policy

Corrections during Inspection• If a change is made during the inspection,

decide whether the change/correction will be conveyed to the FDA inspector and, if so, in what manner

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Correction to 483

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The Inspection Process

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“What will the Inspectors ask me to produce for the audit”

Source Documentation

• All of the source documents should cover the entire period of the study and be present at the time of the audit to allow the auditor(s) to properly conduct the audit

• A ‘standard’ GCP site inspection will include a tour of the facility and a thorough review of the documentation

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• Documents in the project notebook filed during the course of the trial

• List of the study subjects and their corresponding study numbers– Should the FDA investigator ask for the identities

and demographics of your study subjects because of some concern, you are required to comply with the request

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Warning Letter07-HFD-45-0601


• Two-way correspondence with the IRB, sponsor/monitor

• Original signed consent forms for all the patients

• Case Report Forms (CRFs) for all the patients

• Source Documentation (Patient medical records, clinic and hospital charts)

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• Records of patients who were study drop outs

• Product storage facilities and accountability records

• Serious Adverse Event Reports and documentation

• Monitor visit log

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Data Inspection ProcessSubject Records• Did the Investigator maintain records that are

supportive of each entry in CRFs for each subject

• Were all CRFs completed in a timely fashion

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Could you recreate CRF from source?

Data Inspection ProcessFor eCRF situations• Were all regulations and requirements

followed relative to 21 CFR §11• Do source documents support any

changes/corrections to the e-CRF

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Data Inspection Process

Reporting of Study Progress• Did investigator terminate or discontinue the

study before completion• Incidence and reports of SAEs to Sponsor and

IRB handled properly• Did Investigator maintain copies of all reports

submitted to sponsor and IRB

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Records Retention• Who maintains custody of required records• Data storage media• Record storage conditions• Investigator aware of FDA record retention

regulations

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Data Audit Procedures• Subject study data• Number and type of subjects• Existence and availability of subjects• Documentation of prior conditions• Subject inclusion/exclusion criteria• Screen log/failures

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Protocol Adherence

– Enrollment of subjects who did not meet the inclusion/exclusion criteria

– Changes in the protocol in dosage, frequency, time of dosing, or method of dosing of the ‘test article’

– Failure to report serious adverse events promptly to the IRB and the sponsor

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Protocol Adherence

– Failure to document illnesses, hospitalizations, and other significant problems concurrent with the study

– Failure to perform critical tests, examinations, or assessments at the protocol-specific time or visit

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Protocol Adherence

– Administration of concomitant therapy that could compromise the study results

– Failure to report concomitant therapy

– Entering more subjects into the study than originally approved by the IRB or the sponsor

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Product Accountability– Did the sponsor maintain accounting

procedures for the test article– Were all unused supplies returned to

sponsor or disposed of properly– Limitations of test article access and

distribution– Route of administration and proper use

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Medical/Clinical Laboratory Facilities• Are the facilities adequate, and proper diagnostic equipment

available, to fulfill protocol requirements?

• Is the equipment in good working order?

• Does the equipment require calibration and are there records documenting the required equipment calibration?

• Is the laboratory accreditation/license documentation current?

• Is there proper documentation and storage of trial samples?

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Safety Information• How does sponsor assure that the

Investigator notifies promptly of SAEs• Is monitor involved in reporting• Is timeframe consistent with regulations• Does source data support SAEs• Any deaths or dropouts due to SAEs

46(SAE)serious adverse event


IRB Communication• Proper approval and documentation for

protocol and informed consent• Documentation of IRB qualifications• Communication/correspondence between

Investigator and IRB• Continuing review performed

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It’s Over – Now What??

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FDA Inspection Follow-up

At the end of the inspection a discussion is scheduled with key personnel to discuss the findings (exit interview)

• May issue Form 483• May note observations (annotate)• Will record any verbal responses and

promised corrections

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What is a 483 Observation?

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Exit Interview• Report of FDA inspector findings with appropriate

site management• Opportunity for site to correct any

misunderstandings; incorrect deficiencies• If Form 483 is issued, each observation should be

reviewed with the Inspector and understood• Commitment to FDA

– Plans to correct deficiencies– Timetable for future actions (answer will be recorded

by FDA)51


After Inspection• All items on FDA 483 should be responded

to in a letter to appropriate FDA Office• Follow-up report to appropriate

company/site employees

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After Inspection• Form 483 items should be reviewed by

company/CRO regulatory, technical, or legal personnel– work with Sponsor to address issues

• State how and when you expect to make corrections to FDA

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Warning Letter

g4841d

Some items can appear in a letter that were not on the 483

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What Happens to Inspection Findings?

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FDA Follow-up• Investigator reviews notes, observations,

documents collected, etc. • All records collected during inspection are

attached as exhibits

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FDA Inspection Process

Completion of Inspection• Inspector returns to office and prepares

written report of findings [an Establishment Inspection Report (EIR)]

• Audit classification is determined and submitted to FDA Headquarters for concurrence

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FDA Follow-up• A recommendations for classification is

made– Headquarters agrees with Field most of the

time

• EIR and exhibits are forwarded to assigning office at HQ (BIMO) for final review and classification

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FDA Inspection Process

Completion of Inspection• Based on Classification of Inspection

follow-up letter usually sent• Additional Courses of Action

– as needed or required

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Top ten ways to tell your FDA inspection is going badly

10. FDA sets up temporary housing in your parking lot 9. The FDA inspector mutters “uh-oh” each time he

enters a different department, or opens a different folder

8. A “60 Minutes” crew asks to film the inspection 7. The FDA inspector won’t even enter the room where

the test article is stored 6. The Congressman you called for help won’t return

your call, but returns your campaign contribution

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Top ten ways to tell your FDA inspection is going badly

5. Instead of a Form 482, the FDA Inspector begins with, “You have the right to remain silent….”

4. The FDA inspector comes to audit a specific study, but its not one you completed

3. The FDA inspector knows all of your employees by their first names

2. The FDA inspector is a former employee; that you fired

1. The FDA Commissioner conducts the exit interview

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FDA’s Purpose for Inspections

• Remember, the FDA is both a Public Health & Consumer Protection Agency and must assure the people that the products it approves meet the required standards

• For the government, that means they and you) need to AUDIT!

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