Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials: Guidance for Sponsors, Clinical Investigators, and IRBs

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Sponsors,
Clinical Investigators, and
IRBs
Data Retention When Subjects
Withdraw from FDA-Regulated
Clinical Trials
Additional copies are available from:
Good Clinical Practice Program, HF-34
Office of Science & Health Coordination, Office of the Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) (301)-827-3340
http://www.fda.gov/oc/gcp/draft.html
U.S. Department of Health and Human Services
Food and Drug Administration
Office of the Commissioner (OC)
Good Clinical Practice Program (GCPP)
October 2008

Contains Nonbinding Recommendations
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TABLE OF CONTENTS
I. INTRODUCTION .................................................................................................................... 1
II. BACKGROUND ..................................................................................................................... 1
III. DISCUSSION ........................................................................................................................
IV. FDA POLICY ........................................................................................................................

Contains Nonbinding Recommendations
Guidance for Sponsors, Clinical Investigators, and IRBs1
Data Retention When Subjects Withdraw from FDA-
Regulated Clinical Trials
This guidance represents 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 appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate
telephone number listed on the title page of this guidance.
I. INTRODUCTION
This guidance is intended for sponsors, clinical investigators and institutional
review boards (IRBs). It describes the Food and Drug Administration’s (FDA)
longstanding policy that already-accrued data, relating to individuals who cease
participating in a study, are to be maintained as part of the study data. This pertains to
data from individuals who decide to discontinue participation in a study, who are
withdrawn by their legally authorized representative, as applicable, or who are
discontinued from participation by the clinical investigator. This policy is supported by
the statutes and regulations administered by FDA as well as ethical and quality standards
applicable to clinical research. Maintenance of these records includes, as with all study
records, safeguarding the privacy and confidentiality of the subject’s information.
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
The Federal Food, Drug, and Cosmetic Act (the act) authorizes the study of an
investigational product to develop safety and effectiveness data about the product. The
act also requires the maintenance of records documenting these data and the submission
of certain reports regarding this use to FDA.2, 3 FDA (by delegation from the Secretary)
1 This guidance document was developed by the Good Clinical Practice Program and the
Office of the Chief Counsel (OCC), both in the Office of the Commissioner (OC), FDA.
2 The investigational new drug provisions of the act condition use of such drugs upon, for
example, "the establishment and maintenance of such records, and the making of such
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Contains Nonbinding Recommendations
implemented these provisions by issuing regulations relating to investigational drugs, the
Investigational New Drug (IND) regulations at 21 CFR Part 312, and investigational
devices, the Investigational Device Exemptions (IDE) regulations at 21 CFR Part 812.
These regulations specify that data collection and maintenance are indispensable
requirements when conducting a clinical investigation of an unapproved product.
For example, the IND regulations require investigators “… to prepare and
maintain adequate and accurate case histories that record all observations and other data
pertinent to the investigation on each individual administered the investigational drug or
employed as a control in the investigation" (21 CFR 312.62(b)). Similarly, the IDE
regulations require an investigator to maintain "Records of each subject's case history and
exposure to the device" (21 CFR 812.140(a)(3)).
Additionally, the regulations relating to the submission of marketing applications
require the submission of all relevant data in order for FDA to determine whether a
product meets the standard for approval. A new drug application (NDA) must include a
description and analysis of each clinical pharmacology study and controlled clinical
study, a description of each uncontrolled trial, and an integrated summary of all available
information about the safety of the drug product (21 CFR 314.50(d)(5)) and “copies of
individual case report forms for each patient who died during a clinical study or who did
not complete the study because of an adverse event, whether believed to be drug related
or not, including patients receiving reference drugs or placebo” (21 CFR 314.50(f)(2)).
Similarly, an application for premarket approval (PMA) for a device must include “safety
and effectiveness data, adverse reactions and complications, patient discontinuation,
patient complaints, device failures and replacements, tabulations of data from all
individual subject report forms and copies of such forms for each subject who died during
a clinical investigation or who did not complete the investigation” (21 CFR
814.20(b)(6)(ii)). Likewise , an application for a biologics license application (BLA)
must include data derived from nonclinical laboratory and clinical studies which
demonstrate that the manufactured product is safe, pure, and potent (21 CFR 601.2(a)).
reports to the Secretary, by the manufacturer or the sponsor of the investigation of such
drug, of data (including but not limited to analytical reports by investigators) obtained as
the result of such investigational use of such drug, as the Secretary finds will enable him
to evaluate the safety and effectiveness of such drug in the event of the filing of an
application pursuant to subsection (b)." 21 USC 355(i)(1)(C).
3 The investigational device provisions similarly require "that the person applying for an
exemption for a device assure the establishment and maintenance of such records, and the
making of such reports to the Secretary of data obtained as a result of the investigational
use of the device during the exemption, as the Secretary determines will enable him to
assure compliance with such conditions, review the progress of the investigation, and
evaluate the safety and effectiveness of the device." 21 USC 360j(g)(2)(B)(ii).
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Contains Nonbinding Recommendations
FDA law and regulations require the collection and maintenance of complete
clinical study data. This includes information on subjects who withdraw from a clinical
investigation, whether the subject decides to discontinue participation in the clinical trial
(21 CFR 50.25(a)(8)) or is discontinued by the investigator because the subject no longer
qualifies under the protocol (for example, due to a significant adverse event or due to
failure to cooperate with study requirements). FDA recognizes that a subject may
withdraw from a study; however, the withdrawal does not extend to the data already
obtained during the time the subject was enrolled. FDA’s longstanding policy has been
that all data collected up to the point of withdrawal must be maintained in the database
and included in subsequent analyses, as appropriate.4
III. DISCUSSION
FDA law and regulations recognize that a complete and accurate risk/benefit
profile of an investigational product depends upon the data from every subject’s
experience in the clinical trial. For example, if a subject’s data could be withdrawn from
a study, a sponsor would not have access to data on adverse events experienced by the
subject and would be unable to evaluate whether changes to the protocol or the informed
consent documents are needed to ensure the rights, safety, and welfare of other trial
subjects.5
4 FDA previously addressed the topic of data withdrawal in the preamble to the 1996
final rule providing an exception from informed consent requirements for emergency
research, 21 CFR 50.24. In response to a comment that a subject’s legally authorized
representative should be allowed to prevent the review of the subject’s data, FDA stated:
“FDA regulations (see, for example, Sec. 312.62 and Sec. 812.140(a)(3)) require
investigators to prepare and maintain adequate case histories recording all observations
and other data pertinent to the investigation on each individual treated with the drug or
exposed to the device. The agency needs all such data in order to be able to determine the
safety and effectiveness of the drug or device. The fact of having been in an investigation
cannot be taken back. Also, if a subject were able to control the use (inclusion and
exclusion) of his or her data, and particularly if the clinical investigation were not
blinded, the bias potential would be immense. Thus, the agency rejects this comment
because it could prevent FDA from learning of an important effect of the product and
significantly bias the results of the investigation” (”see comment 95, 61 Federal Register
51498, 51519, October 2, 1996). It should be appreciated that FDA’s response applies to
the most potentially difficult situation, that is, studies involving an exception from the
informed consent requirements in which subjects, due to a life threatening medical
condition, are unable to provide informed consent to participate in the study. Subjects
may subsequently withdraw from such studies, but the data collected up to withdrawal
may not be removed.
5 Such review of safety data by sponsors is required by 21 CFR 312.56 and 21 CFR
812.46.
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Contains Nonbinding Recommendations
The validity of a clinical study would also be compromised by the exclusion of
data collected during the study. There is long-standing concern with the removal of data,
particularly when removal is non-random, a situation called “informative censoring.”
FDA has long advised “intent-to-treat” analyses (analyzing data related to all subjects the
investigator intended to treat), and a variety of approaches for interpretation and
imputation of missing data have been developed to maintain study validity.6 Complete
removal of data, possibly in a non-random or informative way, raises great concerns
about the validity of the study.
There is particular concern with a study’s reliability when subjects withdraw their
data in a non-random way because they are unhappy with their experience, either because
they failed to obtain a desired effect or suffered an adverse event. Loss of these subjects’
data could greatly distort effectiveness results and could hide important safety
information (for example, toxicity) of a poorly tolerated treatment. Allowing subjects to
withdraw data could even provide an opportunity for unscrupulous parties to “improve”
study results by selectively encouraging certain subjects to withdraw from a study.
The importance of ensuring the scientific validity of clinical research is reflected
not only in FDA’s regulations but in international documents and published literature as
well. The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH), in which FDA participates,
identifies as a principle of good clinical practice that “clinical trials should be
scientifically sound."7 Other international guidance documents include similar
statements, such as the International Ethical Guidelines for Biomedical Research
Involving Human Subjects, Guideline 1, which states “scientifically invalid research is
unethical in that it exposes research subjects to risks without possible benefit …”8
Published literature on medical research ethics, dating back to the Nuremburg
Code of 1947,9 also emphasizes the importance of scientific validity. As maintained by
6 For a discussion of problems presented by missing data in the analysis of clinical trials,
please see “Points to Consider on Missing Data” from the Committee for Proprietary
Medicinal Products of the European Medicines Agency (EMEA),
http://www.emea.europa.eu/pdfs/human/ewp/177699EN.pdf.
7 http://www.fda.gov/cder/guidance/959fnl.pdf. ICH E6 Guidance for Industry, “Good
Clinical Practice: Consolidated Guidance,” adopted as official guidance by FDA, Section
2.5.
8 http://www.cioms.ch/frame_guidelines_nov_2002.htm. These guidelines are published
by the Counsel of International Organizations for Medical Sciences (CIOMS). Guideline
11 reiterates this principle.
9 The Nuremberg Code: http://ohsr.od.nih.gov/guidelines/nuremberg.html
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Emanuel, et. al., “For a clinical research protocol to be ethical, the methods must be valid
and practically feasible: the research must have a clear scientific objective; be designed
using accepted principles, methods, and reliable practices; have sufficient power to
definitively test the objective; and offer a plausible data analysis plan.”10 The importance
of scientific validity to ethical research is also underscored in modern ethical documents,
such as the Declaration of Helsinki11 and the Belmont Report, issued in 1979 by the
National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research.12
In summary, data collected on study subjects up to the time of withdrawal must
remain in the trial database in order for the study to be scientifically valid. If a subject
withdraws from a study, removal of already collected data would undermine the
scientific, and therefore the ethical, integrity of the research. Such removal of data could
also put enrolled subjects, future subjects, and eventual users of marketed products at an
unreasonable risk. Finally, removal of data would fundamentally compromise FDA’s
ability to perform its mission, to protect public health and safety by ensuring the safety
and effectiveness of regulated products.
IV. FDA POLICY
Following are key points regarding FDA’s policy on the withdrawal of subjects
from a clinical investigation, whether the subject elects to discontinue further
interventions or the clinical investigator terminates the subject’s participation in further
interventions:
10 Emanuel, EJ, Wendler, D, and Grady, C., “What Makes Clinical Research Ethical?”
JAMA 283:20 (May 24/31, 2000 2701-11).
11 "Medical research involving human subjects must conform to generally accepted
scientific principles, be based on a thorough knowledge of the scientific literature, other
relevant sources of information, and on adequate laboratory and, where appropriate,
animal experimentation." The Declaration of Helsinki (2000) (as amended 2002, 2004)
http://www.wma.net/e/policy/b3.htm.
12 The Belmont Report addresses the connection between scientific validity and ethics
through the Principle of Beneficence. Beneficence has two complementary aspects:
maximizing possible benefits and minimizing possible harms. The Report recognizes as
one of the components of maximizing benefits, "In the case of scientific research in
general, members of the larger society are obliged to recognize the longer term benefits
and risks that may result from the improvement of knowledge and from the development
of novel medical, psychotherapeutic, and social procedures."
http://ohsr.od.nih.gov/guidelines/belmont.html
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Contains Nonbinding Recommendations
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• 	According to FDA regulations, when a subject withdraws from a study, the data
collected on the subject to the point of withdrawal remains part of the study database
and may not be removed.
• 	An investigator may ask a subject who is withdrawing whether the subject wishes to
provide continued follow-up and further data collection subsequent to their
withdrawal from the interventional portion of the study. Under this circumstance, the
discussion with the subject would distinguish between study-related interventions and
continued follow-up of associated clinical outcome information, such as medical
course or laboratory results obtained through non-invasive chart review, and address
the maintenance of privacy and confidentiality of the subject’s information.
• 	If a subject withdraws from the interventional portion of the study, but agrees to
continued follow-up of associated clinical outcome information as described in the
previous bullet, the investigator must obtain the subject’s informed consent for this
limited participation in the study (assuming such a situation was not described in the
original informed consent form). In accordance with FDA regulations, IRB approval
of informed consent documents would be required (21 CFR 50.25, 56.109(b), 312.60,
312.66, 812.100).
• 	If a subject withdraws from the interventional portion of a study and does not consent
to continued follow-up of associated clinical outcome information, the investigator
must not access for purposes related to the study the subject’s medical record or other
confidential records requiring the subject’s consent. However, an investigator may
review study data related to the subject collected prior to the subject’s withdrawal
from the study, and may consult public records, such as those establishing survival
status.