Warning! Warning! Warning! Letters

Learning Tools

(for Investigators and others)

“Public” Learning Tools

Warning Letters– By Erich Jensen

Project Manager Center for the

Advancement of Clinical Research [CACR]

Determination Letters– By Judy Nowack

Associate Vice President Office of the Vice

President of Research [OVPR]

Presentation Outline

FDA Warning Letters– Process– Location– Case Studies

OHRP Determination Letters– Process– Location– Case Studies

FDA Warning Letters

Process

Location

Cases

“Read the SMALL PRINT of the 1572” [Investigator Commitments: Box 9]

I agree…to make those records available for inspection

“Read the SMALL PRINT of the 1572” [Investigator Commitments: Box 9]

S _______ M ______ ______ A _____ to _______ L ____ __________ ________ L et FDA Inspect

__P__ _______ _______ R etain Records I _____ _______ N ____ _ _ _ T ____ ______

upervise

aintain Recordsdhere Protocolearn Investigator’s Brochure

Re ort Adverse Events

nform Subjects

otify I R Brain Staff

The Essential GCP Document

1. Select Site

2. Contact Site

3. Schedule Site

4. Arrive (482)

5. Review Records

6. Interview Staff

7. Present Findings

8. Depart (483)

9. Write Report (EIR)

10. Classify Inspection

FDA Office Site Location

“FDA Inspector Cometh” Process

Step 10. FDA classifies Inspection

• When evaluation is completed, FDA classifies inspection and sends a letter to site

Classification Type of Letter

NAI (No Action Indicated) Notice of no significant deviations

VAI (Voluntary Action Indicated)

Informational

OAI (Official Action Indicated)

Warning

FDA Warning Letters (WL)

A post FDA inspection document– An informal advisory to a firm communicating FDA's

position on a matter but does not commit FDA to taking enforcement action

– http://www.fda.gov/oc/gcp/clinenforce.html

Warning Letter Case: “1572”

Academic Investigator:

Dr. Yu

[U of C, San Diego]

WL (17 Apr 02): Yu, MD, PhD

“You failed to obtain a signed investigator statement, Form FDA 1572.”– from all investigators prior to permitting them to

begin participation in the investigation.”

“You failed to provide a complete list of the sub-investigators.” – who assisted you in the conduct of the

investigation.”

Warning Letter Case: “S upervise” and “T rain Staff”

Academic Investigator:

Dr. Bear

[Virginia Commonwealth University]

1572 Commitments: Box 9

S _______ M ______ ______ A _____ to _______ L ____ __________ ________ L et FDA Inspect

__P__ _______ _______ R etain Records I _____ _______ N ____ _ _ _ T ____ ______

upervise

aintain Recordsdhere Protocolearn Investigator’s Brochure

Re ort Adverse Events

nform Subjects

otify I R Brain Staff

PeopleIssues

WL (27 Sep 02): Bear, MD, PhD

How many times are the following “people issues” mentioned?– “Not qualified,” “inexperienced,” “unauthorized” – Need to “retrain,” “monitor,” “supervise”

http://www.fda.gov/foi/warning_letters/g3537d.htm

WL (27 Sep 02): Bear, MD, PhD

S upervise– “It is your responsibility to

monitor all personnel…”– “There are several examples

of…reports that were not signed or dated by you or a subinvestigator responsible to you.”

– “…please explain how you will supervise study staff to ensure…”

– “Your response is therefore inadequate to explain how a different person was granted the authority to…”

T rain staff– “…individuals who have

prepared study drugs have not been registered pharmacists qualified by training and experience…”

– “…visits were conducted by personnel not medically qualified to evaluate the subject’ disease status,…”

– “…attributes these errors to the “initial inexperience” of the person who…”

WL (27 Sep 02): Bear, MD, PhD

“These errors reflect a pattern of insufficient training and experience that may impact the safety and welfare of subjects, and the ability to determine the safety and efficacy of the study drug.”

Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that

the Data and Reported Results are Credible, and Accurate,

and that

the Rights, Integrity, and Confidentiality of Trial Subjects are Protected.

= the safety and efficacy of the study drug

= the safety and welfare of subjects

Warning Letter Cases:SMALL PRINT Issues

Academic Investigators Dr Mitchell Creinin Dr Michael Gruber Dr Alkis Togias

Academic Investigator Cases

Investigator School FDA Inspectors

Mitchell

Creinin

University of Pittsburgh School of Medicine

Center for Devices and Radiologic Health [CDER]

Michael

Gruber

New York University Medical Center

Center for Biologics Evaluation and Research [CBER]

Alkis

Togias

John Hopkins Asthma & Allergy Center

Center for Drug Evaluation and Research [CDRH]

What are the 1572 issues in each case?

S upervise M aintain Records A dhere to Protocol L earn Investigator’s Brochure L et FDA Inspect

Re P ort Adverse Events R etain Records I nform Subjects N otify IRB T rain Staff

The Essential GCP Document

Mitchell Creinin: Pittsburgh [Device]

Inform Subject– “…informed consent document…does not identify foreseeable risks…”

Notify IRB– “…failed to submit the sponsor’s model consent form … to the Magee-

Womens Hospital IRB…” Adhere to Protocol

– “…log forms were not completed…in specific dates.” Report Adverse Events

– “irritation or discomfort…was not recorded on …case report forms.” Maintain Records

– “You did not maintain complete records related to each…case history.”

Michael Gruber: NYU [Biologics]

Maintain Records– “…failed to prepare and maintain…accurate case histories…”

AND “…lack of source data…” Retain Records

– “…failed to retain investigational records.” Adhere to Protocol

– “…there were many deviations from the protocol requirements…”

Supervise– “…nurse practitioner was not listed on the Form FDA-1572 as

subinvestigator,…”

Alkis Togias: John Hopkins [Drug]

Significant Issues– “… an investigation into the death of a healthy

volunteer…”– “You failed to submit an IND…”

Alkis Togias: John Hopkins [Drug]

Learn Investigator’s Brochure– “…you also failed to submit supporting data…”

Notify IRB– “You failed to notify and obtain IRB approval…”

Report Adverse Events– “…you failed to promptly report…unanticipated problems…”

Adhere to Protocol– “You changed the dosing conditions set forth in the protocol…”

Inform Subjects– “…the following essential elements…were not included…”

Maintain AND Retain Records– “You failed to systematically record..” “No records were available…”

FDA Restricted List[http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm]

Name Address Center Type Action Date

Comments

ALKIS TOGIAS, MD BALTIMORE, MD

CDER R 02-JUN-2003

For 3 years; restrictions in part, "...will not serve as principal clinical investigator for more than one FDA regulated clinical study per year..."

More info: Dr Togias: John Hopkins

John Hopkins University: www.jhu.edu – JH Medicine Press Releases

http://www.hopkinsmedicine.org/Press_releases/archive.html

– The Gazette On-Line http://www.jhu.edu/~gazette/

– Hopkins Medical News http://www.hopkinsmedicine.org/hmn/

– JH Public Health Magazine http://www.jhsph.edu/Magazine/toc.html

Keyword search: “Ellen Roche” “OHRP”

More info: Dr Togias: John Hopkins

Office of Human Research Protection– Compliance Oversight

OHRP Compliance Activities: Determination Letters– Jul 19, 2001 (Suspends Multiple Project Assurance)– Jul 23, 2001 (Reinstates Multiple Project Assurance)– Oct 03, 2001 (First Monthly Report)– Aug 23, 2002 (Follow-up Site Inspection and Restriction

Removal)

OHRP Determination Letters

Process

Location

Cases

Office for Human Research Protections (OHRP)

Administratively located in the Office of the Assistant Secretary of HHS

Implements 45 CFR 46 (Subparts A, B, C, D) Interprets the Common Rule

Relationship of OHRP to UM

Federal Wide Assurance (FWA) UM would be subject to Federal regulation even

without FWA FWA allows multiple submissions under one

University certification FWA grants OHRP special compliance authority

OHRP looks at the Institution

OHRP holds the institution responsible for the conduct of its agents, but does not take direct action against those individual investigators who are conducting research under the university’s auspices

In this regard, it differs from FDA

OHRP Compliance Procedures

OHRP evaluates all written allegations or indications of noncompliance with HHS regulations from any source.

OHRP initiates a compliance oversight evaluation by writing to the “Institutional Official”

At UM, the Institutional Official is Fawwaz Ulaby, the Vice President for Research

Contents of a letter from OHRP initiating a compliance action

Description of the apparent or alleged noncompliance with reference to 45 CFR 46.

Except in rare instances in which there is a need to act immediately, OHRP allows the institution to conduct an investigation and report the results.

Request for ALL institutional documents associated with a protocol.

Request for an institutional response within 30 or 60 days.

Request for a “corrective action plan” if the institutional finds noncompliance anywhere in the study.

After Receiving a University Response

OHRP evaluates report– May ask for more information– May conduct site visit– May make non-compliance determinations– May require specific actions or institutional

development of a “corrective action plan”

OHRP compliance close-out letters

Are posted to the web, whether non-compliance found or not. (http://ohrp.osophs.dhhs.gov/compovr.htm)

Communications TO OHPR are available under FedFOIA, but only the communications FROM OHRP are posted

Letters may include “reminders” to institutions of interpretations OHRP has previously made

Case 1: JHU (Dr. Rolley E. Johnson)

Clean bill of health - but still damaging because the posting of a letter implies wrongdoing

Notice that complaint is not specified (Notice the list of cc’s - almost as long as the letter

itself)

Case 2: TJU and Willis Eye Hospital

Ultimate determination after several communications No federal funding source Non-compliance not itemized in this one Letter emphasizes corrective action for this research

and for the entire research compliance program– Contacting all subjects of this research– Campus-wide audit of research that might not have undergone

review– Education plan– Policies and Procedures, more support for IRB– Suspension and re-review of 268 protocols

Case 3: Mass General Hospital

Non-compliance issues specified in particular research study AND on the part of the IRB

Funded by HHS Acknowledgment of Corrective Action already

taken regarding “Additional guidance” provided

Case 4: JHU (Lead paint abatement)

Findings of IRB non-compliance– Improper use of expedited review– Improper approval of informed consent document– Inadequate expertise on the IRB

OHRP acknowledges corrective actions.

Reminder: Dr Togias: John Hopkins

Office of Human Research Protection– Compliance Oversight

OHRP Compliance Activities: Determination Letters– Jul 19, 2001 (Suspends Multiple Project Assurance)– Jul 23, 2001 (Reinstates Multiple Project Assurance)– Oct 03, 2001 (First Monthly Report)– Aug 23, 2002 (Follow-up Site Inspection and Restriction

Removal)

Summary: Determination Letters

Not always determinations of non-compliance.

Of interest in terms of current OHRP interpretations -- recognizing that you are getting only one side of the story

Actions/corrective actions taken by the institutions; although the institution may require actions by the investigator.