Clinical Trials Monitoring

K. Bodeker CRA209 1 of 10

Clinical Trials Monitoring by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA) began under the Food and Drugs
Act of 1906 (U.S. Food and Drug Administration, 2009a). The Federal Food, Drug, and
Cosmetic Act was enacted in 1938, initiating significant change for the drug and food industry
(U.S. Food and Drug Administration, 2009a, 2009i). Currently, the FDA regulated over $1
trillion in products, overseeing the vast drug and device industry (U.S. Food and Drug
Administration, 2009i). Clinical trials designed to evaluate drugs and/or devices fall within this
supervision under multiple federal codes within Title 21 (Applications for FDA Approval of a
Biologic License, 2008; Applications for FDA Approval to Market a New Drug, 2008;
Bioavailability and Bioequivalence Requirements, 2008; Electronic Records; Electronic
Signatures, 2008; Federal Food Drug and Cosmetic Act, 2008; Financial Disclosure by Clinical
Investigators, 2008; Institutional Review Boards, 2008; Investigational Device Exemptions,
2008; Investigational New Drug Application, 2008; Premarket Approval of Medical Devices,
2008; Protection of Human Subjects, 2008). Within this tangle of oversight, three simple sections
significantly stand out, the first two targeting drug trials:
(a)FDA inspection. A sponsor shall upon request from any properly authorized officer
or employee of the Food and Drug Administration, at reasonable times, permit such
officer or employee to have access to and copy and verify any records and reports
relating to a clinical investigation conducted under this part. Upon written request by
FDA, the sponsor shall submit the records or reports (or copies of them) to FDA. The
sponsor shall discontinue shipments of the drug to any investigator who has failed to
maintain or make available records or reports of the investigation as required by this
part (Inspection of Sponsor's Records and Reports, 2008, 21 C.F.R. § 312.58).
and:
An investigator shall upon request from any properly authorized officer or employee
of FDA, at reasonable times, permit such officer or employee to have access to, and
copy and verify any records or reports made by the investigator pursuant to 312.62.
The investigator is not required to divulge subject names unless the records of
particular individuals require a more detailed study of the cases, or unless there is
reason to believe that the records do not represent actual case studies, or do not
represent actual results obtained (Inspection of Investigator's Records and Reports,
2008, 21 C.F.R. § 312.368).
The third section focuses on device trials:
(a) Entry and inspection. A sponsor or an investigator who has authority to grant
access shall permit authorized FDA employees, at reasonable times and in a
reasonable manner, to enter and inspect any establishment where devices are held
(including any establishment where devices are manufactured, processed, packed,
installed, used, or implanted or where records of results from use of devices are kept).


(b) Records inspection. A sponsor, IRB, or investigator, or any other person
acting on behalf of such a person with respect to an investigation, shall permit
authorized FDA employees, at reasonable times and in a reasonable manner, to
inspect and copy all records relating to an investigation.
(c)Records identifying subjects. An investigator shall permit authorized FDA
employees to inspect and copy records that identify subjects, upon notice that FDA
has reason to suspect that adequate informed consent was not obtained, or that reports
required to be submitted by the investigator to the sponsor or IRB have not been
submitted or are incomplete, inaccurate, false, or misleading. (Inspections, 2008, 21
C.F.R. § 812.145).
With this codification, the FDA has clearly delineated authority to inspect clinical trials,
including associated medical records. It is interesting to note, however, the sections differ in the
inclusion of the investigational review board (IRB) (21 C.F.R. § 312.58 and .368 v. 21 C.F.R. §
812.145). Differences such as these highlight the need to review the source Federal Regulation
Code (CFR) or U.S. Code (U.S.C.) rather than secondary documentation. Thus herein, the Code
of Federal Regulations will be reviewed, analyzing clinical trials monitoring and the FDA. Both
direct and indirect actions and influences will be considered.

Monitoring, Inspections, and Audits

The current thinking at the FDA has been documented within the E6:Good Clinical Practice
guideline issued by the International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH) (ICH, 1996) and published in the
Federal Register (International Conference on Harmonisation; Good Clinical Practice:
Consolidated Guideline; Availability, 1997). While the Federal Register states E6 is a guideline
representing the FDA’s current thinking and is not binding for the FDA or the public, it also
states, “The guideline should be followed when generating clinical data that are intended to be
submitted to regulatory authorities” (International Conference on Harmonisation; Good Clinical
Practice: Consolidated Guideline; Availability, 1997). In keeping with this statement, the
definitions of three words commonly associated with clinical trials monitoring were reviewed in
the E6 glossary.

Audit
The ICH definition lists that trial activities should be evaluated to determine they were
conducted in accordance with protocol, the sponsor’s standard operating procedures (SOPs),
Good Clinical Practice (GCP), and local, state, federal, and international regulations (ICH, 1996,
p. 2). Audits also determine if the data were recorded properly and analyzed appropriately.
A specific auditor is not named, other than the audit should be “independent.”


Monitor
This more connotative-friendly term is defined by ICH as the act of oversight, presumably
while the clinical trial is still progressing. The protocol is to be used as a reference as are the
same regulations as those for an audit (ICH, 1996, p. 6).

Inspection
The ICH specifically states an inspection is undertaken by “regulatory authority(ies)” to
officially review a clinical trial, its physical environment, data, and operation. Investigative sites,
the contracted research organization (CRO) and the sponsor are all open for an inspection when
deemed appropriate by the FDA (ICH, 1996, p. 5).

Use within the C.F.R.
Reviewing applicable code, audit is not used within 21 C.F.R. § 312 or 21 C.F.R. § 812. In
the setting of a clinical drug trial, monitor is used to designate multiple responsibilities of the
trial sponsor. A CRO is defined to be a person or contractor who accepts the responsibility for
“…selection or monitoring of investigations…” (21 C.F.R. § 312.3(b)). In addition to selecting
qualified investigators, section 312.50 of the same code states sponsors are responsible for
“…ensuring proper monitoring of the investigation(s)…” The selection of the monitor is
mandated by 21 C.F.R. § 312.53(d), designating the sponsor (or CRO) of the clinical trial to find
an individual who is qualified by both experience and education. Monitoring is required
specifically from the sponsor, however, if the investigational new drug is used in absence of
consent for emergent use (21 C.F.R. § 312.54). The documentation of oversight performed by
the sponsor (and CRO, if applicable) would be used for an FDA inspection (21 C.F.R. § 312.58)
Additionally, results from investigative site monitoring will be provided in annual IND reports to
the FDA (21 C.F.R. § 312.56(b)).
Monitoring of a drug trial by the FDA is listed only once within 21 C.F.R. § 312. Subpart E
focuses on drugs intended to treat life-threatening or severely debilitating illnesses. Within this
section, the FDA assumes responsibility to monitor the trial to evaluate the conduct and evaluation
of the clinical trial (Active Monitoring of Conduct and Evaluation of Clinical Trials, 2008).
Monitor, as both a noun and a verb, is defined within the C.F.R. for device trials (21 C.F.R. §
812.3(j)). A monitoring procedure is to be defined as a part of the investigational plan (21 C.F.R.
§ 812.25) and include the name and address of the assigned monitor. The sponsor is charged to
ensure proper monitoring (21 C.F.R. 812.40; 21 C.F.R. 812.46), selecting adequate monitors (21
C.F.R. § 812.43(d)), and like the drug trial, monitoring all progress when under emergency use
(21 C.F.R. § 812.47). And also like a drug trial, detailed correspondence and records from the
monitor should be included in investigator records for review by the FDA (21 C.F.R. § 812.140).
Direct oversight of a clinical trial is provided by the FDA through inspection, as outlined in
21 C.F.R. § 312.58, 21 C.F.R. §312.368, and 21 C.F.R. § 812.145. and is quoted previously
(p. 1-2). Through these three sections of the C.F.R., the FDA is given the authority to inspect all
records and documents related to the clinical trial from both the sponsor and investigator.
Authority is also given to inspect related records of subjects to verify truthfulness and accuracy


of documentation. FDA inspections are carried out under the Bioresearch Monitoring Program
(BIMO) (U.S. Food and Drug Administration, 2009d) with the Office of Criminal Investigations
(OCI) conducting investigations on clinical investigator fraud (U.S. Food and Drug
Administration, 2009j)

Bioresearch Monitoring Program

The FDA’s Bioresearch Monitoring Program utilizes five compliance program guidance
manuals (CPGM) for their inspections: (a) CPGM for clinical investigators; (b) CPGM for
sponsors, monitors, and contract research organizations; (c) CPGM for good laboratory
practice (non-clinical laboratories); (d) CPGM for in-vivo bioequivalence compliance program
7348.001; and (e) CPGM for Institutional Review Boards (U.S. Food and Drug Administration,
2009e). These documents indicate the scope and breadth of an FDA inspection, providing a
systematic backbone of a thorough inspection. While available publically from the FDA website,
these compliance guidance manuals are considered only guidance documents and are non-
binding in the opinion of the FDA.

CPGM for Clinical Investigators
Authorized December 8, 2008, this manual is divided into seven sections and covers
background and implementation to the headquarters’ responsibilities. Part II of the manual
(Implementation) states the objective of the inspection, first and foremost, is to protect the
“rights, safety, and welfare of subjects involved in FDA-regulated clinical trials” in addition to
assessing accuracy and reliability of data and compliance with regulations (U.S. Food and Drug
Administration, 2009g). This section also delineates the guidance manual for clinical
investigators may be used to inspect sponsor-investigators.
The true inspectional component (part III) lists in detailed order what should be undertaken
during an inspection of the site, beginning with a possible refusal by the investigator to
administrative procedures to how to conduct an international inspection. A list of all studies
undertaken by the clinical investigator must be provided to the inspector. A process to recruit
subjects should be delineated and must be provided to the FDA. The clinical site must be able to
provide documentation to the FDA investigator as to when protocols were placed to the IRB,
when safety data was submitted, and explain any deviations. Source documents, electronic
signatures and processes, and financial disclosure is also reviewed during the inspection process.
The FDA investigator will also determine monitoring as undertaken by the sponsor. Frequency
and nature are considered, as are the logs of on-site monitoring visits and follow-up activities.
The summary of findings report or, if violations are found with action indicated, an FDA
form 483 is issued to the site. Only deviations from codified regulations and not from guidance
documents are to be recorded on a 483 document (U.S. Food and Drug Administration, 2009h)
(paragraph A5).


CPGM for Sponsors, Contract Research Organizations, and Monitors
Issued in 2001, the compliance manual for sponsors, CROs, and monitors is divided into
seven parts, ranging from background to the headquarters’ responsibilities (U.S. Food and Drug
Administration, 2009f). Objectives outlined are to determine data validity from investigators and
adherence of the sponsors, CROs, and monitors to applicable regulations. The guidance manual
specifically states the inspection must occur without any prior notification (part III, paragraph A1).
The FDA inspection of a sponsor is begins with an establishment inspection, focusing on the
organization, personnel, and division of duties. Outside contractors (IRB, CROs, and monitors)
should also be provided in list form to the FDA. Job descriptions are also expected during the
establishment inspection.
Selection of investigators and monitors is reviewed under this compliance manuals, as well.
Justification for selection, including documentation of training and experience, should be
provided to the FDA at inspection. Non-compliant investigators are to be identified and
terminated. If they have not been terminated, a robust explanation of why termination has not
been carried out must be provided.
Procedures, such as monitoring activities and reporting, adverse events and their reports, and
data collection and handling are scrutinized (Part III, sections 4, 5, & 6). Case report forms must
be verified, a reasonable monitoring schedule should be in place, and original subject records
should have been reviewed to guarantee the data integrity. Review of adverse events and
reporting timeline to the FDA are examined, and information flow (from sponsor to investigator
and IRB and back again) exists and is expedient.

CPGM for Institutional Review Boards
Implemented in 1997, with this guidance manual the FDA sought to achieve IRB compliance
with the applicable regulations (U.S. Food and Drug Administration, 1997). Unlike the other
discussed compliance manuals, repeat review schedules are outlined within the text (part II, section
B) based on their classification of surveillance or directed. To verify all appropriate persons are
available for inspection, the FDA will schedule the inspection with the IRB Chairperson.
A surveillance inspection can be further categorized into initial or subsequent. An initial
inspection is, as the name suggests, the first assigned inspection once the specific FDA center has
claimed jurisdiction over the IRB. If the IRB is found to be in compliance and obtains a no action
indicated (NAI) report, re-inspection normally occurs within 5 years. If an IRB is found deficient, a
re-inspection will be performed within one year to confirm actions to ensure compliance.
As the name suggests, a directed inspection is one caused by complaint or concern. The
inspection can cover the entire compliance program for the IRB, or be focused in one
complainant area (e.g. IRB membership)
Inspectional guidelines cover review of the IRB membership (at least one physician is
required per review), written procedures (specifically called out are compliance with DHHS
regulations (45 C.F.R. § 46) versus FDA regulations (21 C.F.R. § 50 & 56), initial and


continuing review approvals, IRB reporting to the clinical investigators and the institution,
expedited reviews, emergency reviews, and informed consent.
If found significantly deficient (official action indicated; OAI), the FDA has the authority to
withhold approval of new studies, terminate ongoing studies, reject all data, disqualify the IRB,
and prosecute those involved.

Good Laboratory Practice (Nonclinical Laboratories)
If used for the generation of clinical trial data, a nonclinical laboratory is to be inspected by
the FDA approximately every 2 years (U.S. Food and Drug Administration, 2001) (Part II,
objective 2). The principle objective for the inspection is to verify the integrity of data generated
within the lab. Again, surveillance or directed inspections can be implemented. Areas inspected
are: (a) physical-chemical testing, (b) toxicity studies, (c) mutagenicity studies, (d) tissue residue
depletion studies, (e) analytical and clinical chemistry testing, and, (f) other studies (to be
specified). In addition to personnel and the lab’s organization, equipment is also to be assessed.
A data audit is also to be conducted when performing an inspection in nonclinical
laboratories. This audit is to ensure the data are: (a) attributable, signatures or initials indicate the
appropriate personnel who observed or recorded the data; (b) legible, data are easily readable and
recorded in permanent medium; (c) contemporaneous, the data were recorded as they were
generated; (d) original, the first recording of the data; and (e) accurate, true to the observations.
A form 483 will be issued for any noted deficiencies. If the laboratory receives an OAI,
administrative actions range from a warning letter and re-inspection to rejecting data and
disqualifying the facility. Lastly, the FDA may implement the Application Integrity Policy,
which is designed to stop fraud and untrue statements, so decisions are based upon reliable and
robust data (U.S. Food and Drug Administration, 2001, 2009b).

Bioresearch Monitoring Human Drugs In Vivo Bioequivalence
Implemented in 1999, this guidance document covers trials designed to establish
bioequivalence. These trials require both clinical and analytical components and have come to
the forefront due to the debate over the ethics of placebo-controlled clinical trials (U.S. Food and
Drug Administration, 2009c). The primary objective of an inspection is to verify quality of data
submitted to the Center for Drug Evaluation and Research (CDER) as a bioequivalence study.
Secondarily, the protection of human welfare and rights is to be verified and compliance with
regulations assured (specifically named 21 C.F.R. § 312, 320, 50, & 56).
The inspection is a merge between those done for a clinical investigator and those at a
nonclinical laboratory. A data audit (as described previously) is also undertaken. A directed audit
is performed for rapid evaluation and resolution when problems are suspected. A routine data
audit is performed for a pivotal study or approval of a generic product.


Electronic Records and Signatures

Each of the inspection manuals described briefly above list electronics inspections.
Regulations outline scope, implementation, and definitions needed for this inspection (Electronic
Records; Electronic Signatures, 2008). This section of the C.F.R. specifically denotes electronic
signatures as equal to paper records and handwritten signatures (21 C.F.R. § 11.1(a)). With this,
the FDA also states that the computers and computer systems must be available to inspection by
the FDA. The FDA acknowledges there are two types of systems that maybe utilized in clinical
trials, open systems and closed systems. An open system is not controlled by the persons
responsible for the electronic data and records. A closed system is controlled by those persons.
To be valid, the electronic signature must have the printed name of the signer, the date and
time the document was signed, and the interpretation of the signature (reviewed, approved,
rejected). These signatures must remain linked to the documents they sign and must not be able
to be copied or removed. Each electronic signature must be unique, password protected, and not
reused by other persons.
Controls and passwords are also reviewed in subpart B of 21 C.F.R. § 11. Additionally, the
computer should have time stamp capacity so that an audit trail can be maintained. Individuals
must be assigned to determine responsibilities, levels of access, and assign electronic signatures.
Perhaps most importantly, the systems must have the capacity to print off legible data for
inspection and review by the FDA.

Discussion

Clinical trials are continually evolving in today’s world, implementing technological
advancements to ease collation of data and verify its integrity. Electronic case report forms help
capture data more easily, removing data entry and capacity for entry errors. With the advent of
the internet and the Freedom of Information Act (Freedom of Information Act, 1966), the public
has become aware of clinical research through identified improprieties and failure of oversight.
These factors, amongst others, have spurred the U.S. Food and Drug Administration to also
adapt. Once identified, areas of deficiency were addressed through guidance and regulations.
However, legislation, regulation, and guidance documents will never be effective as a face-to-
face meeting with the FDA, such as the required inspections.
The inspections performed by the FDA are, perhaps, the strongest tool to secure investigator
compliance and robust data. A comprehensive set of manuals are provided as guidance to FDA
inspectors to ensure a systematic approach to a daunting task. The comprehensiveness of the
inspections is dictated somewhat by the type of clinical trial. A drug trial inspection requires the
sponsor, monitor, and clinical investigator to be inspected; however, a device trial also requires
the inspection of the IRB. This distinction is due to, most likely, the IRB’s ability to designate
non-significant risk devices (21 C.F.R. § 812.66). The authority conveyed to the IRB in this
instance enables an investigational device study to be undertaken without the knowledge of the
FDA through the investigational device exemption (IDE) mechanism. Thus, the FDA has a


vested interest in reviewing the IRB meeting notes, to determine the thought process behind such
a determination.
Outside of direct inspections of the investigator’s site or of the sponsor, the FDA also has
considerable influence on clinical trials. Inspecting and overseeing nonclinical laboratories
providing services for clinical trials as well as institutional review boards providing oversight for
studies directly influences clinical trials, their practices, and their productivity. Ramifications of
a poor finding spread widely throughout the research realm, with the possibility of all data being
disavowed and studies forcibly closed due to the termination of an IRB. More likely, the findings
of ‘action indicated’ will spur the IRB or nonclinical lab into diligence. This may cause
bottlenecking for a time, as new policies and procedures are put into place to comply with
regulations. During this implementation, the process will certainly be slowed and slow research.
Monitoring, as defined by ICH’s E6 guideline, is ordered to be conducted in a reasonable
interval with on-site visits. The FDA clearly states the monitor is to have adequate experience
and education. The type of experience is not clearly defined by the FDA, instead leaving it to the
sponsor to determine the adequacy of training, education, and experience. By dictating how,
when, and what to monitor in the C.F.R., the FDA has exerted considerable influence on the act
of monitoring. For this reason, the monitoring process does serve as a function of the FDA’s
authority and should be respected. It is imperative for the process of robust clinical trials for the
clinical investigators, staff, and sponsor engage in effective monitoring processes, with
systematic documentation. A viewpoint to be engaged is that, when undergoing a monitoring
process for a clinical trial, it is preparatory for an FDA inspection. Alternatively, it can be seen
that routine tasks have been delegated to an individual deemed qualified by the sponsor for
further review later. This would provide a logical basis as to why sponsor-investigators are
required to have independent monitoring of their study.

Conclusion

As expected, the FDA has significant influence on clinical trials, including monitoring and
inspection. While true monitoring is performed by the sponsor or designee, it is required by the
FDA. The FDA inspects the investigator, sponsor, contracted research organization, monitor(s),
institutional review board, and nonclinical laboratories to verify compliance with all applicable
FDA regulations (21 C.F.R. § 11, 50, 54, 56, 312, 314, 320, 601, 812, and 814).


References

Active Monitoring of Conduct and Evaluation of Clinical Trials, 21 C.F.R. § 312.87 (2008).
Applications for FDA Approval of a Biologic License, 21 C.F.R. § 601 (2008).
Applications for FDA Approval to Market a New Drug, 21 C.F.R. § 314 (2008).
Bioavailability and Bioequivalence Requirements, 21 c.F.R. § 320 (2008).
Electronic Records; Electronic Signatures, 21 C.F.R. § 11 (2008).
Federal Food Drug and Cosmetic Act, 21 U.S.C. § 301 et seq. (2008).
Financial Disclosure by Clinical Investigators, 21 C.F.R. § 54 (2008).
Freedom of Information Act, 5 U.S.C. § 552 (1966).
ICH (1996). E6(R1): Good clinical practice: Consolidated guideline. Retrieved July 7, 2009,
from http://www.ich.org/LOB/media/MEDIA482.pdf.
Inspection of Investigator's Records and Reports, 21 C.F.R. § 312.68 (2008).
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Inspections, 21 C.F.R. § 812.145 (2008).
Institutional Review Boards, 21 C.F.R. § 56 (2008).
International Conference on Harmonisation; Good Clinical Practice: Consolidated Guideline;
Availability, 62 FR 25692-25709 (1997).
Investigational Device Exemptions, 21 C.F.R. § 812 (2008).
Investigational New Drug Application, 21 C.F.R. § 312 (2008).
Premarket Approval of Medical Devices, 21 C.F.R. § 814 (2008).
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