**Guidance for Industry**

**Computerized Systems Used in Clinical Trials**

#########  {#section .TOC-9}

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 90 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit
comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All
comments should be identified with the docket number listed in the
notice of availability that publishes in the *Federal Register*.

For questions regarding this draft document contact Patricia M. Beers
Block 301-827-3340.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**Center for Devices and Radiological Health (CDRH)**

**Center for Food Safety and Nutrition (CFSAN)**

**Center for Veterinary Medicine (CVM)**

**Office of Regulatory Affairs (ORA)**

**September 2004**

**Compliance**

**Revision 1**

**Guidance for Industry**

**Computerized Systems Used in Clinical Trials**

*Additional copies are available at:*

<http://www.fda.gov/cder/guidance/index.htm>

or

<http://www.fda.gov/cber/guidelines.htm>

or

<http://www.fda.gov/cvm/guidance/guidance.html>

or

<http://www.fda.gov/cdrh/ggpmain.html>

or

[http://www.cfsan.fda.gov/\~dms/guidance.html](http://www.cfsan.fda.gov/~dms/opa-toc.html)

or

<http://www.fda.gov/ora/compliance_ref/bimo>

or

<http://www.fda.gov/oc/gcp>

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**Center for Devices and Radiological Health (CDRH)**

**Center for Food Safety and Nutrition (CFSAN)**

**Center for Veterinary Medicine (CVM)**

**Office of Regulatory Affairs (ORA)**

**September 2004**

**Compliance**

**Revision 1**

##  {#section-1 .TOC-2}

**TABLE OF CONTENTS**

# 

# I. INTRODUCTION [2](#i.-introduction) {#i.-introduction-2 .TOC-1}

# II. Background [3](#ii.-background) {#ii.-background-3 .TOC-1}

# III. GENERAL PRINCIPLES [4](#iii.-general-principles) {#iii.-general-principles-4 .TOC-1}

# IV. Overall Approach to Meeting Part 11 Requirements [5](#iv.-overall-approach-to-meeting-part-11-requirements) {#iv.-overall-approach-to-meeting-part-11-requirements-5 .TOC-1}

# V. StanDARD OPERATING PROCEDURES [5](#v.-standard-operating-procedures) {#v.-standard-operating-procedures-5 .TOC-1}

# VI. DATA ENTRY [5](#vi.-data-entry) {#vi.-data-entry-5 .TOC-1}

## A. Computer Access Controls [5](#a.-computer-access-controls) {#a.-computer-access-controls-5 .TOC-2}

## B. Audit Trails or other Security Measures [6](#b.-audit-trails-or-other-security-measures) {#b.-audit-trails-or-other-security-measures-6 .TOC-2}

## C. Date/Time Stamps [7](#c.-datetime-stamps) {#c.-datetime-stamps-7 .TOC-2}

# VII. SYSTEM FEATURES [8](#vii.-system-features) {#vii.-system-features-8 .TOC-1}

## A. Systems Used for Direct Entry of Data [8](#a.-systems-used-for-direct-entry-of-data) {#a.-systems-used-for-direct-entry-of-data-8 .TOC-2}

## B. Retrieval of Data and Record Retention [8](#b.-retrieval-of-data-and-record-retention) {#b.-retrieval-of-data-and-record-retention-8 .TOC-2}

# VIII. System SECURITY [8](#viii.-system-security) {#viii.-system-security-8 .TOC-1}

# IX. SYSTEM DEPENDABILITY [9](#ix.-system-dependability) {#ix.-system-dependability-9 .TOC-1}

## A. Legacy Systems [10](#a.-legacy-systems) {#a.-legacy-systems-10 .TOC-2}

## B. Off-the-Shelf Software [10](#b.-off-the-shelf-software) {#b.-off-the-shelf-software-10 .TOC-2}

## C. Change Control [11](#c.-change-control) {#c.-change-control-11 .TOC-2}

# X. SYSTEM CONTROLS [12](#x.-system-controls) {#x.-system-controls-12 .TOC-1}

# XI. TRAINING OF PERSONNEL [12](#xi.-training-of-personnel) {#xi.-training-of-personnel-12 .TOC-1}

# XII. Copies of RECORDS and record INSPECTION [13](#xii.-copies-of-records-and-record-inspection) {#xii.-copies-of-records-and-record-inspection-13 .TOC-1}

# XIII. CERTIFICATION OF ELECTRONIC SIGNATURES [13](#xiii.-certification-of-electronic-signatures) {#xiii.-certification-of-electronic-signatures-13 .TOC-1}

# DEFINITIONS [15](#definitions) {#definitions-15 .TOC-1}

# REFERENCES [17](#references) {#references-17 .TOC-1}

**Guidance for Industry**[^1]

**Computerized Systems Used in Clinical Trials**

This draft guidance, when finalized, will represent the Food and Drug
Administration\'s (FDA\'s) current thinking on this topic. It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the
FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed
on the title page of this guidance.

# I. INTRODUCTION

This document provides guidance about computerized systems that are used
to create, modify, maintain, archive, retrieve, or transmit clinical
data required to be maintained and/or submitted to the Food and Drug
Administration (FDA) These data form the basis for the Agency\'s
decisions regarding the safety and effectiveness of new human and animal
drugs, biological products, medical devices, and certain food and color
additives. Because the data have broad public health significance, they
are expected to be of the highest quality and integrity. This guidance
document addresses long-standing FDA regulations concerning clinical
trial records. It also addresses requirements of the Electronic
Records/Electronic Signatures rule (21 CFR part 11).[^2]

Once finalized, this document will supersede the guidance of the same
name issued in April 1999. Revisions will make it consistent with Agency
policy as reflected in the guidance for industry on *Part 11, Electronic
Records; Electronic Signatures --- Scope and Application,* which issued
in August 2003, and the Agency\'s international harmonization
efforts.[^3]

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# II. Background

FDA has the authority to inspect all records relating to clinical
investigations conducted under 21 CFR 312, 511.1(b), and 812 ,
regardless of how they were created or maintained (e.g., §§ 312.58,
312.68, and 812.145). FDA established the Bioresearch Monitoring (BIMO)
Program of inspections and audits to monitor the conduct and reporting
of clinical trials to ensure that supporting data from these trials meet
the highest standards of quality and integrity, and conform to FDA\'s
regulations. FDA\'s acceptance of data from clinical trials for
decision-making purposes depends on FDA\'s ability to verify the quality
and integrity of the data during FDA on-site inspections and audits. To
be acceptable, the data should meet certain fundamental elements of
quality whether collected or recorded electronically or on paper. For
example, data should be attributable, legible, contemporaneous,
original[^4] and accurate.

This guidance addresses how Agency expectations and regulatory
requirements regarding data quality might be satisfied where
computerized systems are being used to create, modify, maintain,
archive, retrieve, or transmit clinical data. Although the primary focus
of this guidance is on computerized systems used at clinical sites to
collect data, the principles set forth may also be appropriate for
computerized systems belonging to contract research organizations, data
management centers, and sponsors. Persons using the data from
computerized systems should have confidence that the data are no less
reliable than data in paper form.

Computerized medical devices, diagnostic laboratory instruments, and
instruments in analytical laboratories that are used in clinical trials
are not the subject of this guidance. This guidance does not address
electronic submissions or methods of their transmission to the Agency,
except to the degree to which these records comply with Part 11.

The principles in this guidance may be applied where supporting data or
source documents[^5] are created (1) in hardcopy and later entered into
a computerized system, (2) by direct entry by a human into a
computerized system, and (3) automatically by a computerized system.

# 

# III. GENERAL PRINCIPLES

The Agency recommends the following general principles with regard to
computerized systems that are used to create, modify, maintain, archive,
retrieve, or transmit clinical data required to be maintained and/or
submitted to FDA.

1\. We recommend that each study protocol identify at which steps a
computerized system will be used to create, modify, maintain, archive,
retrieve, or transmit data.

2\. For each study, we recommend that documentation identify what
software and hardware are to be used in computerized systems that
create, modify, maintain, archive, retrieve, or transmit data. We also
recommend that this documentation be retained as part of the study
records.

3\. We recommend that computerized systems be designed (1) so that all
requirements assigned to these systems in a study protocol are satisfied
(e.g., data are recorded in metric units, the study blinded) and (2) to
preclude errors in data creation, modification, maintenance, archiving,
retrieval, or transmission.

4\. It is important to design a computerized system in such a manner so
that all applicable regulatory requirements for record keeping and
record retention in clinical trials are met with the same degree of
confidence as is provided with paper systems.

5\. Under 21 CFR 312.62 , 511.1(b)(7)(ii) and 812.140, the clinical
investigator must retain records required to be maintained under part
312, § 511.1(b) and § 812, respectively, for a period of time specified
in these regulations. Retaining the original source document or a
certified copy of the source document at the site where the
investigation was conducted can assist in meeting these regulatory
requirements. It can also assist in the reconstruction and evaluation of
the trial throughout and after the completion of the trial.

6.  When original observations are entered directly into a computerized
    system, the electronic record is the source document.

7.  Records relating to an investigation must be adequate and accurate
    in the case of investigational new drug applications (INDs) (see §
    312.57 and § 312.62), complete in the case of new animal drugs for
    investigational use (INADs) (see §511.1(b)(7)(ii)), and accurate,
    complete and current in the case of investigational device
    exemptions (IDEs) (see § 812.140(a) and § 812.140(b)). An audit
    trail that is electronic or consists of other physical, logical, or
    procedural security measures to ensure that only authorized
    additions, deletions, or alterations of information in the
    electronic record have occurred may be needed to facilitate
    compliance with applicable records regulations. Firms should
    determine and document the need for audit trails based on a risk
    assessment that takes into consideration circumstances surrounding
    system use, the likelihood that information might be compromised,
    and any system vulnerabilities. We recommend that audit trials or
    other security methods used to capture electronic record activities
    document who made the changes, when, and why changes were made to
    the electronic record.

8.  We recommend that data be retrievable in such a fashion that all
    information regarding each individual subject in a study is
    attributable to that subject.

9\. To ensure the authenticity and integrity of electronic records, it
is important that security measures be in place to prevent unauthorized
access to the data in the electronic record and to the computerized
system.

# IV. Overall Approach to Meeting Part 11 Requirements

As described in the FDA guidance entitled *Part 11, Electronic Records;
Electronic Signatures- Scope and Application* (August 2003), while the
re-examination of part 11 is underway, FDA intends to exercise
enforcement discretion with respect to part 11 requirements for
validation, audit trail, record retention, and record copying. That is,
FDA does not intend to take enforcement action to enforce compliance
with these requirements of part 11 while the agency re-examines part 11.
Note that part 11 remains in effect and that the exercise of enforcement
discretion applies only to the extent identified in the FDA guidance on
part 11. Also, records must still be maintained or submitted in
accordance with the underlying requirements set forth in the Federal
Food, Drug, and Cosmetic Act (Act), the Public Health Service Act (PHS
Act), and FDA regulations (other than part 11), which are referred to in
this guidance document as *predicate* *rules*, and FDA can take
regulatory action for noncompliance with such predicate rules.[^6]

Specific details about the Agency's approach to enforcing part 11 can be
found in the *Part 11 Scope and Application* guidance.

# V. StanDARD OPERATING PROCEDURES

We recommend that standard operating procedures (SOPs) pertinent to the
use of the computerized system be available on site. We recommend that
SOPs be established for the following:

-   System Setup/Installation

-   Data Collection and Handling

-   System Maintenance

-   Data Backup, Recovery, and Contingency Plans

-   Security

-   Change Control

-   Alternative Recording Methods (in the case of system unavailability)

# VI. DATA ENTRY

## A. Computer Access Controls

To ensure that individuals have the authority to proceed with data
entry, data entry systems must be designed to limit access so that only
authorized individuals are able to input data

(§ 11.10(d)).[^7] Examples of methods for controlling access include
using combined identification codes/passwords or biometric-based
identification at the start of a data entry session. Controls and
procedures must be in place that are designed to ensure the authenticity
and integrity of electronic records created, modified, maintained, or
transmitted using the data entry system

(§ 11.10). Therefore, we recommend that each user of the system have an
individual account into which the user logs-in at the beginning of a
data entry session, inputs information (including changes) on the
electronic record, and logs out at the completion of data entry session.

We recommend that individuals work only under their own password or
other access key and not share these with others. We recommend that
individuals not be allowed to log onto the system to provide another
person access to the system. We also recommend that passwords or other
access keys be changed at established intervals.

When someone leaves a workstation, we recommend that the SOP require
that person to log off the system. Alternatively, an automatic log off
may be appropriate for long idle periods. For short periods of
inactivity, we recommend that some kind of automatic protection be
installed against unauthorized data entry. An example could be an
automatic screen saver that prevents data entry until a password is
entered.

## B. Audit Trails or other Security Measures

Section 11.10(e) requires persons who use electronic record systems to
maintain an audit trail as one of the procedures to protect the
authenticity, integrity, and, when appropriate, the confidentiality of
electronic records. As clarified in the *Part 11 Scope and Application*
guidance, however, the Agency intends to exercise enforcement discretion
regarding specific part 11 requirements related to computer-generated,
time-stamped audit trails (§ 11.10(e), (k)(2) and any corresponding
requirement in § 11.30). Persons must still comply with all applicable
predicate rule requirements for clinical trials, including, for example,
that records related to the conduct of the study must be adequate and
accurate (§§ 312.57, 312.62, and 812.140). It is therefore important to
keep track of all changes made to information in the electronic records
that document activities related to the conduct of the trial.
Computer-generated, time-stamped audit trails or information related to
the creation, modification, or deletion of electronic records may be
useful to ensure compliance with the appropriate predicate rule.

In addition, clinical investigators must, upon request by FDA, at
reasonable times, permit agency employees to have access to, and copy
and verify any required records or reports made by the investigator (§§
312.68, 511.1(b)(7)(ii) and 812.145). In order for the Agency to review
and copy this information, FDA personnel should be able to review audit
trails or other documents that track electronic record activities both
at the study site and at any other location where associated electronic
study records are maintained. To enable FDA\'s review, information about
the creation, modification, or deletion of electronic records should be
created incrementally, and in chronological order. To facilitate FDA's
inspection of this information, we recommend that clinical investigators
retain either the original or a certified copy of any documentation
created to track electronic records activities.

Even if there are no applicable predicate rule requirements, it may be
important to have computer-generated, time-stamped audit trails or other
physical, logical, or procedural security measures to ensure the
trustworthiness and reliability of electronic records. We recommend that
any decision on whether to apply computer-generated audit trails or
other appropriate security measures be based on the need to comply with
predicate rule requirements, a justified and documented risk assessment,
and a determination of the potential effect on data quality and record
integrity. Firms should determine and document the need for audit trails
based on a risk assessment that takes into consideration circumstances
surrounding system use, the likelihood that information might be
compromised, and any system vulnerabilities.

If you determine that audit trails or other appropriate security
measures are needed to ensure electronic record integrity, we recommend
that personnel who create, modify, or delete electronic records not be
able to modify the documents or security measures used to track
electronic record changes. We recommend that audit trials or other
security methods used to capture electronic record activities document
who made the changes, when, and why changes were made to the electronic
record.

Some examples of methods for tracking changes to electronic records
include:

-   Computer-generated, time-stamped electronic audit trails.

-   Signed and dated printed versions of electronic records that
    identify what, when, and by whom changes were made to the electronic
    record. When using this method, it is important that appropriate
    controls be utilized that ensure the accuracy of these records
    (e.g., sight verification that the printed version accurately
    captures all of the changes made to the electronic record).

-   Signed and dated printed standard electronic file formatted versions
    (e.g., pdf, xml or sgml) of electronic records that identify what,
    when, and by whom changes were made to the electronic record.

-   Procedural controls that preclude unauthorized personnel from
    creating, modifying, or deleting electronic records or the data
    contained therein.

## C. Date/Time Stamps

We recommend that controls be put in place to ensure that the system\'s
date and time are correct. The ability to change the date or time should
be limited to authorized personnel and such personnel should be notified
if a system date or time discrepancy is detected. We recommend that
someone always document changes to date or time. We do not expect
documentation of time changes that systems make automatically to adjust
to daylight savings time conventions.

We also recommend that dates and times include the year, month, day,
hour, and minute. The Agency encourages establishments to synchronize
systems to the date and time provided by trusted third parties.

Clinical study computerized systems are likely be used in multi-center
trials and may be located in different time zones. For systems that span
different time zones, it is better to implement time stamps with a clear
understanding of the time zone reference used. We recommend that system
documentation explain time zone references as well as zone acronyms or
other naming conventions.

# 

# VII. SYSTEM FEATURES

The Agency recommends that a number of computerized system features be
available to facilitate the collection, inspection, review, and
retrieval of quality clinical data. Key features are described here.

## A. Systems Used for Direct Entry of Data 

We recommend that prompts, flags, or other help features be incorporated
into the computerized system to encourage consistent use of clinical
terminology and to alert the user to data that are out of acceptable
range. We recommend against the use of features that automatically enter
data into a field when the field is bypassed.

## B. Retrieval of Data and Record Retention 

FDA expects to be able to reconstruct a clinical study submitted to the
agency. This means that documentation, such as that described in the
General Principles, Sections III.1, III.2 and III.5, should fully
describe and explain how data were obtained and managed and how
electronic records were used to capture data. We suggest that your
decision on how to maintain records be based on predicate rule
requirements and that this documented decision be based on a justified
risk assessment and a determination of the value of the records over
time. As explained in the Part 11 Scope and Application guidance, FDA
does not intend to object to required records that are archived in
electronic format; nonelectronic media such as microfilm, microfiche,
and paper; or to a standard electronic file format (such as PDF, XML, or
SGML). Persons must still comply with all predicate rule requirements,
and the records themselves and any copies of required records should
preserve their original content and meaning. Paper and electronic record
and signature components can co-exist (i.e., as a hybrid system) as long
as the predicate requirements (21 CFR parts 50, 56, 312, 511, and 812)
are met, and the content and meaning of those records are preserved.

It is not necessary to reprocess data from a study that can be fully
reconstructed from available documentation. Therefore, actual
application software, operation systems, and software development tools
involved in processing of data or records do not need to be retained.

# 

# VIII. System SECURITY

In addition to internal safeguards built into the computerized system,
external safeguards should be put in place to ensure that access to the
computerized system and to the data is restricted to authorized
personnel as required by 21 CFR 11.10(d). We recommend that staff be
kept thoroughly aware of system security measures and the importance of
limiting access to authorized personnel.

SOPs should be developed and implemented for handling and storing the
system to prevent unauthorized access. Controlling system access can be
accomplished through the following provisions of part 11 that, as
discussed in the part 11 guidance, FDA intends to continue to enforce:

-   Operational system checks (§ 11.10(f));

-   Authority checks (§ 11.10(g));

-   Device (e.g., terminal) checks (§ 11.10(h)); and

-   The establishment of and adherence to written policies that hold
    individuals accountable for actions initiated under their electronic
    signatures (§ 11.10(j)).

The Agency recommends that access to data be restricted and monitored
through the system\'s software with its required log-on, security
procedures, and audit trail (or other selected security measures to
track electronic record activities). We recommend that procedures and
controls be implemented to prevent the data from being altered, browsed,
queried, or reported via external software applications that do not
enter through the protective system software.

We recommend that a cumulative record be available that indicates, for
any point in time, the names of authorized personnel, their titles, and
a description of their access privileges. We recommend that the record
be kept in the study documentation, accessible at the site.

If a sponsor supplies computerized systems exclusively for clinical
trials, we recommend that the systems remain dedicated to the purpose
for which they were intended and validated. If a computerized system
being used for a clinical study is part of a system normally used for
other purposes, we recommend that efforts be made to ensure that the
study software be logically and physically isolated as necessary to
preclude unintended interaction with nonstudy software. If any of the
software programs are changed, we recommend that the system be evaluated
to determine the effect of the changes on logical security.

We recommend that controls be implemented to prevent, detect, and
mitigate effects of computer viruses, worms, or other potentially
harmful software code on study data and software.

# IX. SYSTEM DEPENDABILITY

The Agency recommends that sponsors ensure and document that all
computerized systems conform to their own established requirements for
completeness, accuracy, reliability, and consistent intended
performance.

We recommend that systems documentation be readily available at the site
where clinical trials are conducted and provide an overall description
of the computerized systems and the relationships among hardware,
software, and physical environment.

As noted in the *Part 11 Scope and Application* guidance, the Agency
intends to exercise enforcement discretion regarding specific part 11
requirements for validation of computerized systems. We suggest that
your decision to validate computerized systems and the extent of the
validation take into account the impact the systems have on your ability
to meet predicate rule requirements. You should also consider the impact
those systems might have on the accuracy, reliability, integrity,
availability, and authenticity of required records and signatures. Even
if there is no predicate rule requirement to validate a system, it may
still be important to validate the system, based on criticality and
risk, to ensure the accuracy, reliability, integrity, availability and
authenticity of required records and signatures.

We recommend that you base your approach on a justified and documented
risk assessment and determination of the potential of the system to
affect data quality and record integrity. For example, in the case where
data are directly entered into electronic records and the business
practice is to rely on the electronic record, validation of the
computerized system is important. However when a word processor is used
to generate SOPs for use at the clinical site, validation would not be
important.

If validation is required, FDA may ask to see the regulated company\'s
documentation that demonstrates software validation. The study sponsor
is responsible for making any such documentation available if requested
at the time of inspection at the site where software is used. Clinical
investigators are not generally responsible for validation unless they
originated or modified software.

## A. Legacy Systems

As noted in the *Part 11 Scope and Application* guidance, the Agency
intends to exercise enforcement discretion with respect to all part 11
requirements for systems that otherwise were fully operational prior to
August 20, 1997, the effective date of part 11, under the circumstances
described below. These systems are also known as legacy systems. The
Agency does not intend to take enforcement action to enforce compliance
with any part 11 requirements if all the following criteria are met for
a specific system:

-   The system was in operation before the part 11 effective date.

-   The system met all applicable predicate rule requirements prior to
    the part 11 effective date.

-   The system currently meets all applicable predicate rule
    requirements.

-   There is documented evidence and justification that the system is
    fit for its intended use.

If a system has changed since August 20, 1997, and if the changes would
prevent the system from meeting predicate rule requirements, part 11
controls should be applied to part 11 records and signatures pursuant to
the enforcement policy expressed in the part 11 guidance. Please refer
to the *Part 11 Scope and Application* guidance for further information.

## B. Off-the-Shelf Software

While the Agency has announced that it intends to exercise enforcement
discretion regarding specific part 11 requirements for validation of
computerized systems, persons must still comply with all predicate rule
requirements for validation. We suggested in the guidance for industry
on part 11 that the impact of computerized systems on the accuracy,
reliability, integrity, availability, and authenticity of required
records and signatures be considered when you decide whether to
validate, and noted that even absent a predicate rule requirement to
validate a system, it might still be important to validate in some
instances.

For most off-the-shelf software, the design level validation will have
already been done by the company that wrote the software. Given the
importance of ensuring valid clinical trial data, FDA suggests that the
sponsor or contract research organization (CRO) have documentation
(either original validation documents or on-site vendor audit documents)
of this design level validation by the vendor and would itself have
performed functional testing (e.g., by use of test data sets) and
researched known software limitations, problems, and defect corrections.
Detailed documentation of any additional validation efforts performed by
the sponsor or CRO will preserve the findings of these efforts.

In the special case of database and spreadsheet software that is: (1)
purchased off-the-shelf, (2) designed for and widely used for general
purposes, (3) unmodified, and (4) not being used for direct entry of
data, the sponsor or contract research organization may not have
documentation of design level validation. FDA suggests that the sponsor
or contract research organization perform functional testing (e.g., by
use of test data sets) and research known software limitations,
problems, and defect corrections.

In the case of off-the-shelf software, we recommend that the following
be available to the Agency on request:

#### A written design specification that describes what the software is intended to do and how it is intended to do it; 

#### A written test plan based on the design specification, including both structural and functional analysis; and 

#### Test results and an evaluation of how these results demonstrate that the predetermined design specification has been met.

Additional guidance on general software validation principles can be
found in FDA's guidance entitled *General Principles of Software
Validation; Final Guidance for Industry and FDA Staff*.

## C. Change Control

FDA recommends that written procedures be put in place to ensure that
changes to the computerized system, such as software upgrades, including
security and performance patches, equipment, or component replacement,
or new instrumentation, will maintain the integrity of the data and the
integrity of protocols. We recommend that the effects of any changes to
the system be evaluated and a decision made regarding whether, and if
so, what level of validation activities related to those changes would
be appropriate. We recommend that validation be performed for those
types of changes that exceed previously established operational limits
or design specifications. Finally, we recommend that all changes to the
system be documented.

# X. SYSTEM CONTROLS

The Agency recommends that appropriate system control measures be
developed and implemented.

-   Software Version Control

> We recommend that measures be put in place to ensure that versions of
> software used to generate, collect, maintain, and transmit data are
> the versions that are stated in the systems documentation.

-   Contingency Plans

> We recommend that written procedures describe contingency plans for
> continuing the study by alternate means in the event of failure of the
> computerized system.

-   Backup and Recovery of Electronic Records

> When electronic formats are the only ones used to create and preserve
> electronic records, the Agency recommends that backup and recovery
> procedures be outlined clearly in SOPs and be sufficient to protect
> against data loss. We also recommend that records be backed up
> regularly in a way that would prevent a catastrophic loss and ensure
> the quality and integrity of the data. We recommend that records be
> stored at a secure location specified in the SOPs. Storage is
> typically offsite or in a building separate from the original records.
>
> We recommend that backup and recovery logs be maintained to facilitate
> an assessment of the nature and scope of data loss resulting from a
> system failure.
>
> Firms that rely on electronic and paper systems should determine the
> extent to which backup and recovery procedures are needed based on the
> need to meet predicate rule requirements, a justified and documented
> risk assessment, and a determination of the potential effect on data
> quality and record integrity.

# 

# XI. TRAINING OF PERSONNEL

Under 21 CFR 11.10(i), firms using computerized systems must determine
that persons who develop, maintain, or use electronic systems have the
education, training, and experience to perform their assigned tasks.

The Agency recommends that training be provided to individuals in the
specific operations with regard to computerized systems that they are to
perform. We recommend that training be conducted by qualified
individuals on a continuing basis, as needed, to ensure familiarity with
the computerized system and with any changes to the system during the
course of the study.

We recommend that employee education, training, and experience be
documented.

# 

# 

# XII. Copies of RECORDS and record INSPECTION

FDA has the authority to inspect all records relating to clinical
investigations conducted under 21 CFR Parts 312 and 812, regardless of
how the records were created or maintained (21 CFR 312.58, 312.68, and
812.145). Therefore, you should provide the FDA investigator with
reasonable and useful access to records during an FDA inspection. As
noted in the *Part 11, Electronic Records; Electronic Signatures- Scope
and Application* guidance, the Agency intends to exercise enforcement
discretion with regard to specific part 11 requirements for generating
copies of records (§ 11.10(b) and any corresponding requirement in §
11.30). We recommend that you supply copies of electronic records by:

-   Producing copies of records held in common portable formats when
    records are maintained in these formats

-   Using established automated conversion or export methods, where
    available, to make copies available in a more common format (e.g.,
    pdf, xml, or sgml formats)

Regardless of the method used to produce copies of electronic records,
it is important that the copying process used produces copies that
preserve the content and meaning of the record. For example, if you have
the ability to search, sort, or trend records, copies given to FDA
should provide the same capability if it is reasonable and technically
feasible. FDA expects to inspect, review, and copy records in a human
readable form at your site, using your hardware and following your
established procedures and techniques for accessing records.

We recommend you contact the Agency if there is any doubt about what
file formats and media the Agency can read and copy.

# 

# XIII. CERTIFICATION OF ELECTRONIC SIGNATURES

As required by 21 CFR 11.100(c), persons using electronic signatures to
meet an FDA signature requirement must, prior to or at the time of such
use, certify to the Agency that the electronic signatures in their
system, used on or after August 20, 1997, are intended to be the legally
binding equivalent of traditional handwritten signatures.

As set forth in § 11.100(c)(1), the certification must be submitted in
paper, signed with a traditional handwritten signature, to the Office of
Regional Operations (HFC-100), 5600 Fishers Lane, Rockville, Maryland
20857. The certification is to be submitted prior to or at the time
electronic signatures are used. However, a single certification can be
used to cover all electronic signatures used by persons in a given
organization. This certification is created by persons to acknowledge
that their electronic signatures have the same legal significance as
their traditional handwritten signatures. See the following example of a
certification statement:

> Pursuant to Section 11.100 of Title 21 of the Code of Federal
> Regulations, this is to certify that \_\_\_[\[*name of
> organization*\]]{.underline}\_\_ intends that all electronic
> signatures executed by our employees, agents, or representatives,
> located anywhere in the world, are the legally binding equivalent of
> traditional handwritten signatures.

# DEFINITIONS

The following is a list of definitions for terms as they are used in,
and for the purposes of, this guidance document.

**Attributable Data:** Attributable data are those that can be traced to
individuals responsible for observing and recording the data. In an
automated system, attributability could be achieved by a computer system
designed to identify individuals responsible for any input.

**Audit Trail:** An *audit trail* is a secure, computer generated,
time-stamped electronic record that allows reconstruction of the course
of events relating to the creation, modification, and deletion of an
electronic record.

**Certified Copy:** A copy of original information that has been
verified, as indicated by dated signature, as an exact copy having all
of the same attributes and information as the original

**Computerized System:** A *computerized system* includes computer
hardware, software, and associated documents (e.g., user manual) that
create, modify, maintain, archive, retrieve, or transmit in digital form
information related to the conduct of a clinical trial.

**Direct Entry:** Recording data where an electronic record is the
original capture of the data. Examples are the keying by an individual
of original observations into the system, or automatic recording by the
system of the output of a balance that measures subject's body weight.

**Electronic Record:** Any combination of text, graphics, data, audio,
pictorial, or other information representation in digital form that is
created, modified, maintained, archived, retrieved, or distributed by a
computer system.

**Electronic Signature:** A computer data compilation of any symbol or
series of symbols executed, adopted, or authorized by an individual to
be the legally binding equivalent of the individual\'s handwritten
signature.

#  {#section-10 .TOC-1}

**Original data:** *Original data* are those values that represent the
first recording of study data. FDA is allowing original documents and
the original data recorded on those documents to be replaced by
certified copies provided the copies are identical and have been
verified as such. (see FDA Compliance Policy Guide \# 7130.13

**Predicate rule:** This term refers to underlying requirements set
forth in the Federal Food, Drug, and Cosmetic Act, the PHS Act, and FDA
regulations (other than 21 CFR part 11). Regulations governing good
clinical practice and human subject protection can be found at 21 CFR
parts 50, 56, 312, 511, and 812.

**Software Validation:** Confirmation by examination and provision of
objective evidence that software specifications conform to user needs
and intended uses and that the particular requirements implemented
through the software can be consistently fulfilled. *Design level
validation* is that portion of the software validation that takes place
in parts of the software life cycle before the software is delivered to
the end user.

**Source Documents:** Original documents and records including, but not
limited to, hospital records, clinical and office charts, laboratory
notes, memoranda, subjects\' diaries or evaluation checklists, pharmacy
dispensing records, recorded data from automated instruments, copies or
transcriptions certified after verification as being accurate and
complete, microfiches, photographic negatives, microfilm or magnetic
media, x-rays, subject files, and records kept at the pharmacy, at the
laboratories, and at medico-technical departments involved in the
clinical trial.

**Transmit:** *Transmit* is to transfer data within or among clinical
study sites, contract research organizations, data management centers,
or sponsors. Other Agency guidance covers transmission from sponsors to
the Agency.

# REFERENCES

FDA, *21 CFR Part 11, \"*Electronic Records; Electronic Signatures;
Final Rule*.\"* *Federal Register* Vol. 62, No. 54, 13429, March 20,
1997.

FDA, *Compliance Program Guidance Manual,* \"Compliance Program
7348.810 - Sponsors, Contract Research Organizations and Monitors,\"
October 30, 1998.

FDA, *Compliance Program Guidance Manual*, \"Compliance Program
7348.811 - Bioresearch Monitoring - Clinical Investigators,\" September
2, 1998.

FDA, *Glossary of Computerized System and Software Development
Terminology*, 1995.

FDA, *Good Clinical Practice VICH GL9,* 2001.

FDA, *Guideline for the Monitoring of Clinical Investigations*, 1988.

FDA, *Information Sheets for Institutional Review Boards and Clinical
Investigators*, 1998.

FDA, *Software Development Activities*, 1987.

International Conference on Harmonisation, \"E6 Good Clinical Practice:
Consolidated Guideline,\" *Federal Register*, Vol. 62, No. 90, 25711,
May 9, 1997.

FDA, *Part 11, Electronic Records; Electronic Signatures --- Scope and
Application*, 2003.

FDA, *General Principles of Software Validation; Guidance for Industry
and FDA Staff,* 2002.

[^1]: This guidance has been prepared by an Agency working group
    representing the Bioresearch Monitoring Program Managers for each
    Center within the Food and Drug Administration, the Office of
    Regulatory Affairs, and the Office of the Commissioner.

[^2]: Part 11 applies to records in electronic form that are created,
    modified, maintained, archived, retrieved, or transmitted under any
    records requirements set forth in Agency regulations. Part 11 also
    applies to electronic records submitted to the Agency under the
    requirements of Federal Food, Drug, and Cosmetic Act and the Public
    Health Service Act, even if such records are not specifically
    identified in Agency regulations.

[^3]: In August 2003, FDA issued the guidance for industry entitled
    *Part 11, Electronic Records; Electronic Signatures- Scope and
    Application* clarifying that the Agency intended to interpret the
    scope of part 11 narrowly and to exercise enforcement discretion
    with regard to part 11 requirements for validation, audit trails,
    record retention, and record copying. In 1996, the International
    Conference on Harmonisation of Technical Requirements for
    Registration of Pharmaceuticals for Human Use (ICH) issued *E6 Good
    Clinical Practice: Consolidated Guidance*.

[^4]: FDA is allowing original documents to be replaced by certified
    copies provided the copies are identical and have been verified as
    such. (see FDA Compliance Policy Guide \# 7130.13). See
    "Definitions" section for a definition of original data.

[^5]: Under 21 CFR 312.62 (b) reference is made to records that are part
    of case histories as "supporting data;" the ICH *E6 Good Clinical
    Practice* consolidated guidance uses the term \"source documents.\"
    These terms describe the same information and have been used
    interchangeably in this guidance.

[^6]: This term refers to underlying requirements set forth in the
    Federal Food, Drug, and Cosmetic Act, the PHS Act, and FDA
    regulations (other than 21 CFR Part 11). Regulations governing good
    clinical practice and human subject protection can be found at 21
    CFR parts 50, 56, 312, 511, and 812. See Definitions section at the
    end of this document listing definitions of this and other terms
    used in this guidance.

[^7]: As FDA announced in the *Part 11 Scope and Application* guidance,
    we intend to enforce certain controls for closed systems in § 11.10,
    including §11.10(d).