Guidance for
Industry
Computerized Systems Used in
Clinical Investigations
U.S.
Department of Health and Human Services Food and Drug
Administration (FDA)
Office of the Commissioner (OC)
May 2007
(download the PDF)
Guidance
for Industry
Computerized Systems Used in
Clinical Investigations
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Good Clinical Practice Programs Office of the Commissioner
U.S. Department of Health and Human
Services Food and Drug Administration Office of the
Commissioner (OC) May 2007 TABLE OF CONTENTS
I. INTRODUCTION
II. BACKGROUND
III. SCOPE
IV. RECOMMENDATIONS
A. Study Protocols .
B. Standard Operating Procedures
C. Source Documentation
and Retention
D. Internal Security Safeguards
1. Limited Access
2. Audit Trails
3. Date/Time Stamps
E. External Security
Safeguards
F. Other System Features
1. Direct Entry of Data
2. Retrieving Data
3. Dependability System Documentation
4. System Controls
5. Change Controls
G.
Training of Personnel
DEFINITIONS
REFERENCES
APPENDIX A
Guidance for Industry1
Computerized
Systems Used in Clinical Investigations
I. INTRODUCTION
This document provides
to sponsors, contract research organizations (CROs), data
management centers, clinical investigators, and
institutional review boards (IRBs), recommendations
regarding the use of computerized systems in clinical
investigations. The computerized system applies to records
in electronic form that are used to create, modify,
maintain, archive, retrieve, or transmit clinical data
required to be maintained, or submitted to the FDA. Because
the source data2 are
necessary for the reconstruction and evaluation of the study
to determine the safety of food and color additives and
safety and effectiveness of new human and animal drugs,3 and
medical devices, this guidance is intended to assist in
ensuring confidence in the reliability, quality, and
integrity of electronic source data and source documentation
(i.e., electronic records).
This guidance
supersedes the guidance of the same name dated April 1999;
and supplements the guidance for industry on Part 11,
Electronic Records; Electronic Signatures — Scope and
Application and the Agency's international harmonization
efforts4 when
applying these guidances to source data generated at
clinical study sites.
1
This guidance has been
prepared by the Office of Critical Path Programs, the Good
Clinical Practice Program, and the Office of Regulatory
Affairs in cooperation with Bioresearch Monitoring Program
Managers for each Center within the Food and Drug
Administration.
2 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.” For the purpose of this guidance, these
terms describe the same information and have been used
interchangeably.
3 Human
drugs include biological drugs.
4 In
August 2003, FDA issued the guidance for industry entitled
Part 11, Electronic Records; Electronic Signatures-Scope
and Application clarifying that the Agency intends 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.
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
There is an increasing
use of computerized systems in clinical trials to generate
and maintain source data and source documentation on each
clinical trial subject. Such electronic source data and
source documentation must meet the same fundamental elements
of data quality (e.g., attributable, legible,
contemporaneous, original,5 and
accurate) that are expected of paper records and must comply
with all applicable statutory and regulatory requirements.
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. (21 CFR 312, 511.1(b), and 812).
In March 1997, FDA issued 21
CFR part 11, which provides criteria for acceptance by FDA,
under certain circumstances, of electronic records,
electronic signatures, and handwritten signatures executed
to electronic records as equivalent to paper records and
handwritten signatures executed on paper. After the
effective date of 21 CFR part 11, significant concerns
regarding the interpretation and implementation of part 11
were raised by both FDA and industry. As a result, we
decided to reexamine 21 CFR part 11 with the possibility of
proposing additional rulemaking, and exercising enforcement
discretion regarding enforcement of certain part 11
requirements in the interim.
This guidance finalizes the
draft guidance for industry entitled Computerized Systems
Used in Clinical Trials, dated September 2004 and
supplements the guidance for industry entitled Part 11,
Electronic Records; Electronic Signatures – Scope and
Application (Scope and Application Guidance), dated
August 2003. The Scope and Application Guidance clarified
that the Agency intends 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. However, other Part 11
provisions remain in effect.
The approach outlined in the
Scope and Application Guidance, which applies to electronic
records generated as part of a clinical trial, should be
followed until such time as Part 11 is amended.
5 FDA
is allowing original documents to be replaced by copies
provided the copies are identical and have been verified as
such (See, e.g., FDA Compliance Policy Guide # 7150.13). See
Definitions section for a definition of original data.
III. SCOPE
The principles outlined in
this guidance should be used for computerized systems that
contain any data that are relied on by an applicant in
support of a marketing application, including computerized
laboratory information management systems that capture
analytical results of tests conducted during a clinical
trial. For example, the recommendations in this guidance
would apply to computerized systems that create source
documents (electronic records) that satisfy the requirements
in 21 CFR 312.62(b) and 812.140(b), such as case histories.
This guidance also applies to recorded source data
transmitted from automated instruments directly to a
computerized system (e.g., data from a chemistry
autoanalyser or a Holter monitor to a laboratory information
system). This guidance also applies when source
documentation is created in hardcopy and later entered into
a computerized system, recorded by direct entry into a
computerized system, or automatically recorded by a
computerized system (e.g., an ECG reading). The guidance
does not apply to computerized medical devices that generate
such data and that are otherwise regulated by FDA.
IV. RECOMMENDATIONS
This guidance provides the
following recommendations regarding the use of computerized
systems in clinical investigations.
A. Study Protocols
Each specific study protocol
should identify each step at which a computerized system
will be used to create, modify, maintain, archive, retrieve,
or transmit source data. This information can be included
in the protocol at the time the investigational new drug
application (IND), Investigational Device Exemption (IDE),
or Notice of Claimed Investigational Exemption for a New
Animal Drug containing the protocols is submitted or at any
time after the initial submission.
The computerized systems
should be designed: (1) to satisfy the processes assigned to
these systems for use in the specific study protocol (e.g.,
record data in metric units, blind the study), and (2) to
prevent errors in data creation, modification, maintenance,
archiving, retrieval, or transmission (e.g., inadvertently
unblinding a study).
B. Standard Operating
Procedures
There should be specific
procedures and controls in place when using computerized
systems to create, modify, maintain, or transmit electronic
records, including when collecting source data at clinical
trial sites. A list of recommended standard operating
procedures (SOPs) is provided in Appendix A. Such SOPs
should be maintained either on-site or be remotely
accessible through electronic files as part of the specific
study records, and the SOPs should be made available for use
by personnel and for inspection by FDA.
C. Source Documentation
and Retention
When original observations
are entered directly into a computerized system, the
electronic record is the source document. 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 part 812, for a period of
time specified in these regulations. This requirement
applies to the retention of the original source document, or
a copy of the source document.
When source data
are transmitted from one system to another (e.g., from a
personal data assistant to a sponsor’s server), or entered
directly into a remote computerized system (e.g., data are
entered into a remote server via a computer terminal that is
located at the clinical site), or an electrocardiogram at
the clinical site is transmitted to the sponsor’s
computerized system, a copy of the data should be maintained
at another location, typically at the clinical site but
possibly at some other designated site. Copies should be
made contemporaneously with data entry and should be
preserved in an appropriate format, such as XML, PDF or
paper formats.
D. Internal
Security Safeguards
1. Limited
Access
Access must be
limited to authorized individuals (21 CFR 11.10(d). This
requirement can be accomplished by the following
recommendations. We recommend that each user of the system
have an individual account. The user should log into that
account at the beginning of a data entry session, input
information (including changes) on the electronic record,
and log out at the completion of data entry session. The
system should be designed to limit the number of log-in
attempts and to record unauthorized access log-in
attempts.
Individuals should
work only under their own password or other access key and
not share these with others. The system should not allow an
individual 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
commensurate with a documented risk assessment.
When someone
leaves a workstation, the person should log off the system.
Alternatively, an automatic log off may be appropriate for
long idle periods. For short periods of inactivity, we
recommend that a type of automatic protection be installed
against unauthorized data entry (e.g., an automatic screen
saver can prevent data entry until a password is entered).
2. Audit Trails
It is important to
keep track of all changes made to information in the
electronic records that document activities related to the
conduct of the trial (audit trails). The use of audit
trails or other security measures helps to ensure that only
authorized additions, deletions, or alterations of
information in the electronic record have occurred and
allows a means to reconstruct significant details about
study conduct and source data collection necessary to verify
the quality and integrity of data. Computer-generated,
time-stamped audit trails or other security measures can
also capture information related to the creation,
modification, or deletion of electronic records and may be
useful to ensure compliance with the appropriate
regulation.
The need for audit
trails should be determined based on a justified and
documented risk assessment that takes into consideration
circumstances surrounding system use, the likelihood that
information might be compromised, and any system
vulnerabilities. Should it be decided that audit trails or
other appropriate security measures are needed to ensure
electronic record integrity, personnel who create, modify,
or delete electronic records should not be able to modify
the documents or security measures used to track electronic
record changes. Computer-generated, time-stamped electronic
audits trails are the preferred method for tracking changes
to electronic source documentation.
Audit trails or
other security methods used to capture electronic record
activities should describe when, by whom, and the reason
changes were made to the electronic record. Original
information should not be obscured though the use of audit
trails or other security measures used to capture electronic
record activities.
3. Date/Time
Stamps
Controls should be
established 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. Any changes to date or time should always be
documented. We do not expect documentation of time changes
that systems make automatically to adjust to daylight
savings time conventions.
We recommend that
dates and times include the year, month, day, hour, and
minute and encourage synchronization of systems to the date
and time provided by international standard-setting agencies
(e.g., U.S. National Institute of Standards and Technology
provides information about universal time, coordinated (UTC)).
Computerized
systems are likely to be used in multi-center clinical
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.
E. External
Security Safeguards
In addition to
internal safeguards built into a 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. Staff should be kept
thoroughly aware of system security measures and the
importance of limiting access to authorized personnel.
Procedures and
controls should be put in place to prevent the altering,
browsing, querying, or reporting of data via external
software applications that do not enter through the
protective system software.
You should
maintain a cumulative record that indicates, for any point
in time, the names of authorized personnel, their titles,
and a description of their access privileges. That record
should be kept in the study documentation, accessible for
use by appropriate study personnel and for inspection by FDA
investigators.
We also 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.
F. Other System
Features
1. Direct Entry
of Data
We recommend that
you incorporate prompts, flags, or other help features into
your computerized system to encourage consistent use of
clinical terminology and to alert the user to data that are
out of acceptable range. You should not use programming
features that automatically enter data into a field when the
field is bypassed (default entries). However, you can use
programming features that permit repopulation of information
specific to the subject. To avoid falsification of data,
you should perform a careful analysis in deciding whether
and when to use software programming instructions that
permit data fields to be automatically populated.
2. Retrieving
Data
The computerized
system should be designed in such a way that retrieved data
regarding each individual subject in a study is attributable
to that subject. Reconstruction of the source documentation
is essential to FDA’s review of the clinical study submitted
to the Agency. Therefore, the information provided to FDA
should fully describe and explain how source data were
obtained and managed, and how electronic records were used
to capture data.
It is not
necessary to reprocess data from a study that can be fully
reconstructed from available documentation. Therefore, the
actual application software, operating systems, and software
development tools involved in the processing of data or
records need not be retained.
3.
Dependability System Documentation
For each study,
documentation should identify what software and hardware
will be used to create, modify, maintain, archive, retrieve,
or transmit clinical data. Although it need not be
submitted to FDA, this documentation should be retained as
part of the study records and be available for inspection by
FDA (either on-site or remotely accessible).
4. System
Controls
When electronic
formats are the only ones used to create and preserve
electronic records, sufficient backup and recovery
procedures should be designed to protect against data loss.
Records should regularly be backed up in a procedure that
would prevent a catastrophic loss and ensure the quality and
integrity of the data. Records should be stored at a secure
location specified in the SOP. Storage should typically be
offsite or in a building separate from the original records.
We recommend that
you maintain backup and recovery logs to facilitate an
assessment of the nature and scope of data loss resulting
from a system failure.
5. Change
Controls
The integrity of
the data and the integrity of the protocols should be
maintained when making changes to the computerized system,
such as software upgrades, including security and
performance patches, equipment, or component replacement, or
new instrumentation. The effects of any changes to the
system should be evaluated and some should be validated
depending on risk. Changes that exceed previously
established operational limits or design specifications
should be validated. Finally, all changes to the system
should be documented.
G. Training of
Personnel
Those who use
computerized systems must determine that individuals (e.g.,
employees, contractors) who develop, maintain, or use
computerized systems have the education, training and
experience necessary to perform their assigned tasks (21 CFR
11.10(i)).
Training should be
provided to individuals in the specific operations with
regard to computerized systems that they are to perform.
Training should 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
computer education, training, and experience be documented.
DEFINITIONS
The following is a
list of definitions for terms used in, and for the purposes
of, this guidance document.
Audit Trail:
For the purpose of this guidance, an audit trail is a
process that captures details such as additions, deletions,
or alterations of information in an electronic record
without obliterating the original record. An audit trail
facilitates the reconstruction of the course of such details
relating to the electronic record.
Certified
Copy:
A certified copy is a copy of original
information that has been verified, as indicated by a 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:
Direct entry
is recording data where an electronic record is the original
means of capturing the data. Examples are the keying by an
individual of original observations into a system, or
automatic recording by the system of the output of a balance
that measures subject’s body weight.
Electronic
Record:
An electronic record is 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.
Original data:
For the purpose of this guidance, 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 copies
provided the copies are identical and have been verified as
such (see FDA Compliance Policy Guide # 7150.13).
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 a clinical trial.
Transmit:
Transmit
is to transfer data within or among clinical study sites,
contract research organizations, data management centers,
sponsors, or to FDA.
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