The terms "protocol deviation" and "protocol violation" are not officially defined by FDA. In my experience, they are used interchangeably to mean failing to follow the protocol in any way. There is a difference between a protocol amendment and a protocol deviation/violation, again according to my own opinion, not FDA. A protocol amendment is a prospective planned change implemented in a systematic fashion. A protocol deviation/violation is generally an unplanned excursion from the protocol not implemented or intended as a systematic change. Our expectations for each are discussed below. "Protocol violation" does not appear anywhere in FDA's regulations nor does it appear in the ICH E-6 guidance.

I found only one instance in the regulations where the word "deviation" appears, and there are several references to protocol "deviations" in ICH E-6: 21 CFR 312.23(a)(6)(ii) states, "A protocol for a Phase 2 or 3 investigation should be designed in such a way that if the sponsor anticipates that some deviation from the study design may become necessary as the investigation progresses, alternatives or contingencies to provide for such deviation are built into the protocols at the outset. For example, a protocol for a controlled short-term study might include a plan for an early crossover of nonresponders to an alternative therapy."

The E-6 guidance does not define the term "protocol deviations"; the references are in the context of planned or unplanned departures from a study protocol.

* Shall both subject and investigator have to sign at the same time and day of IC administration? or can subject sign earlier day/days than the investigator, taking the form home for discussion etc.?

We don't dictate when the signatures must be affixed to the form, except that they are needed prior to entry into the study. In some cases, the subject and the person obtaining the consent may sign at the same time; in other cases, the person obtaining consent may sign later (after the subject has taken the form home to discuss the study with family members and has returned with questions that the person answers).

Number 97-01  Human Subjects Protections  Revised (p. 2)

October 31, 1996

Subject: Informed Consent Requirements in Emergency Research

Dear Colleague:

This letter advises Institutional Officials and Institutional Review Board (IRB) Chairs of responsibilities related to informed consent when research subjects are enrolled in emergent circumstances.

As in the past, the regulations for protection of human subjects of the Department of Health and Human Services (HHS) at 45 CFR Part 46 stipulate requirements for obtaining (Section 46.116) and documenting (Section 46.117) informed consent. And, the regulations give IRBs authority to alter or waive the required consent in certain circumstances (Sections 46.116(c)-(d)).1 These provisions of HHS regulations remain unchanged and in full force.

On October 2, 1996 (Federal Register, Vol. 61, pp. 51531-51533), the Secretary, HHS, announced, under Section 46.101(i), a waiver of the applicability of the 45 CFR Part 46 requirement for obtaining and documenting informed consent for a strictly limited class of research, involving research activities that may be carried out in human subjects who are in need of emergency therapy and for whom, because of the subjects' medical condition and the unavailability of legally authorized representatives of the subjects, no legally effective informed consent can be obtained. This waiver, which provides a third route through which IRBs may approve research in this class, takes effect November 1, 1996.

This waiver applies to the Basic HHS Policy for Protection of Human Research Subjects (Subpart A of 45 CFR Part 46) and to research involving children (Subpart D of 45 CFR Part 46). However, because of special regulatory limitations relating to research involving fetuses, pregnant women, and human in vitro fertilization (Subpart B of 45 CFR 46), and research involving prisoners (Subpart C of 45 CFR Part 46), this waiver is inapplicable to these categories of research.

___________________
1A previous "Dear Colleague" letter (OPRR Rep...

Last updated March 28, 2008
(2002 files added; 2003 files, 2004 files and 2005 files remain unchanged from previous postings)

This page is designed to simplify the search for copies of e-mail messages (including the original inquiry and associated reply(ies)) that have been submitted by the public to the Good Clinical Practice Program's gcp.questions@fda.hhs.gov e-mail account. The e-mail messages have been redacted to the extent permitted by the Freedom of Information Act and sorted into topic folders, which are updated on a continuing basis. The folders are prepared as self-extracting zip files that may be saved to your computer and opened, and the e-mail messages are saved in PDF format, which may be read with a free copy of Adobe Acrobat Reader.

Unless screening tests involve more than minimal risk, the IRB may decide that prospective study subjects need not sign a consent document [21 CFR 56.109(c)]. Ask your IRB to waive the need for a signed consent form.

Procedures that are to be performed as part of the practice of medicine and which would be done whether or not study entry was contemplated, such as for diagnosis or treatment of a disease or medical condition, may be performed and the results subsequently used for determining study eligibility without first obtaining consent.

71. Several comments expressed support for the provision in ß 312.30(c) that would require a sponsor to notify FDA within 30 days of adding an investigator, but asked that the final rule make clear that a sponsor may ship an investigational drug to a new investigator at the time that the investigator is added by the sponsor to the study, and that the newly added investigator may begin his or her participation in the study prior to submission of the protocol amendment, so long as the amendment is submitted within 30 days of the commencement of the investigator's participation.

FDA has revised ß 312.30(c) to make clear that, once the sponsor has added an investigator to a previously submitted study, the investigator may begin participation in the study. Notification to FDA is required within the next 30 days.

FDA will waive those requirements regarding submission and prior FDA approval of a supplemental application and receipt of certification of institutional review board (IRB) approval for the addition of investigational sites [21 CFR 812.35(b)] provided:

1. The total number of investigational sites does not exceed [##] (number is provided by the submitter).
2. You maintain current records on:

   a. the names and addresses of all investigational sites,
   b. the names and addresses of all investigators, identifying those who are currently participating,
   c. the names, addresses and chairpersons of all IRBs,
   d. the dates of IRB approvals, and
   e. the dates of first shipment or first use of investigational devices for all participating institutions.

3. Within 5 days of reachin...

Compliance Policy Guide
Sec. 130.400
Use of Microfiche and/or Microfilm for Method of Records Retention
(CPG 7150.13)
Page Updated: 11-08-2004

BACKGROUND:

The agency has received many questions concerning the use of microfiche and/or microfilm systems in lieu of the retention of original records. This Compliance Policy Guide is based on a May 11, 1979 response to a request for an Advisory Opinion on this subject. (Docket Number 77A-0270).

POLICY:

The Food and Drug Administration has ** published several regulations that permit the maintenance of certain recordkeeping systems in lieu of the retention of original records: good manufacturing practices for medical devices (43 FR 31508, July 21, 1978); good manufacturing practices for human and veterinary drugs (43 FR 45014, September 29, 1978); nonclinical laboratory studies (43 FR 59986, December 22, 1978). These regulations include the use of microfiche and/or microfilm. We therefore conclude that the utilization of a microfiche and/or microfilm reduction system in lieu of the retention of original pre-clinical, clinical, and related drug and medical device research records, and drug and medical device quality control and manufacturing records, is acceptable.

The preambles to these regulations, and the regulations, discuss the conditions applicable to the maintenance of reduction systems. These include the following:

1. All records must be readily available for review and copying by FDA investigators at any reasonable time.

2. All necessary equipment must be provided to facilitate viewing and copying of the records.

3. A reproduction must be a true and accurate copy of the original record. Thus, where the reproduction process results in a copy that does not reveal changes or additions to the original record, the original must be retained.

Also, the reproduced copy and any image shown on a viewing screen must note, in a suitable manner, that an alteration has been made and that the original record is available.

*Material between asterisks is new or revised*