Food and Drug Administration Reporting Standards for Investigational Drugs and Biological Products
FOOD AND DRUG ADMINISTRATION
REPORTING STANDARDS FOR INVESTIGATIONAL DRUGS AND BIOLOGICAL PRODUCTS
FDA
regulations require the sponsor of an Inves-tigational New Drug (IND) to
‘promptly review all information relevant to the safety of [a] drug obtained or
otherwise received by the sponsor from any source, foreign or domestic,
including informa-tion derived from any clinical or epidemiological
investigations ’ (21 C.F.R. § 312.32(b)). The safety information that sponsors
receive from clinical inves-tigations often is in the form of reports relating
to experiences of the clinical study subjects.
An
investigator has no obligation to report adverse events to the FDA and is only
required to report adverse events to the sponsor. Under FDA regulations,
investi-gators evaluate adverse experiences based on two crite-ria: whether the
event is serious and whether it was caused by the drug. Investigators are
required by the FDA’s regulations to ‘promptly report to the sponsor any
adverse effect that may reasonably be regarded as caused by, or probably caused
by, the drug. If the adverse effect is alarming, the investigator shall report
the adverse effect immediately’ (Id.
at § 312.64(b)).
Depending
on several criteria discussed below, FDA regulations provide two mechanisms for
spon-sors to report adverse event and other safety information about
investigational drugs to the agency. Sponsors report adverse experiences to the
FDA either as an expedited report or as part of an IND annual report (21 C.F.R.
§§ 312.32–33). Adverse experi-ences that are not reported to the FDA under one
of these two mechanisms are usually included in listings submitted to FDA as
part of a final study report.
The
goal of expedited safety reporting is to ensure timely communication to the FDA
of the most impor-tant new information about the safety of investigational
drugs (52 Fed. Reg. 8798, 8815 (1987)). Expedited reports are required for adverse
events experienced by subjects taking investigational drugs if the event is (1)
‘serious’, (2) ‘associated with the use of the drug’ and (3) ‘unexpected’. The
regulatory standards for these three criteria are discussed below. Expedited
safety reports also are required when the sponsor receives reports of
pre-clinical findings that suggest significant risk to human subjects
including reports of mutagenicity, teratogenicity or carcino-genicity (21
C.F.R. § 312.32(c)(1)(i)(B)).
There
are two types of expedited reports: written IND safety reports and telephone
IND safety reports (21 C.F.R. § 312.32(c)). The type of expedited safety report
that is required depends upon the seriousness of the event. A written IND
safety report informs the FDA of an event associated with the study drug that
is serious and unexpected (Id. at §
312.32.(c)(1)). IND sponsors must submit written IND safety reports within 15
calendar days after the sponsor’s initial receipt of the reportable information
(Id.). A telephone IND safety report
is required when an adverse event is fatal or life threatening (Id. at § 312.32(c)(2)). IND sponsors
must make such a report to the agency as soon as possible but in no event later
than 7 calendar days after the sponsor’s initial receipt of the reportable
information (Id.).
FDA
regulations define a ‘serious adverse event’ for subjects receiving
investigational drugs as one that results in any of the following outcomes:
death, a life-threatening adverse drug experience, inpatient hospi-talization
or prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important medical
events that may not result in death, be life-threatening or require hospitalization
may be considered to be serious adverse drug experiences when, based upon
appropriate medical judgment, they may jeopardize the patient and may require
medical or surgical inter-vention to prevent one of the outcomes listed in this
definition (21 C.F.R. § 312.32(a)).
Because
adverse events that are fatal or life threat-ening are included in the
definition of a ‘serious’ event, they must be submitted to the FDA as a written
report in addition to a telephone report.
Telephone
and/or written IND safety reports are req-uired only for adverse events that
are ‘unexpected’. FDA regulations define an unexpected adverse drug experience
with an investigational drug as one for which
the specificity or
severity is not consistent with the current investigators’ drug brochure or, if
an investigator brochure is not required or available, the specificity or
severity of which is not consistent with the risk information described in the
general investi-gational plan or elsewhere in the current application, as
amended (Id.).
An
expedited IND safety report is not
required for an adverse event unless the event is associated with the use of
the drug. For purposes of IND safety reporting, an event is ‘associated’ with
the use of a drug if ‘there is a reasonable possibility that the experience may
have been caused by the drug’ (Id. at
§ 312.32(a)).
In addition to promptly reviewing adverse safety information
that it receives, an IND sponsor must also ‘promptly investigate’ all safety information, regardless of
whether the information meets the crite-ria for submitting an expedited safety
report (Id. At 312.32(d)). If the
investigation reveals additional ‘relevant’ follow-up information, then the
information must be submitted to the FDA as soon as it is available (Id.). The preamble to FDA’s final rule
sheds light on whether additional information must be submitted:
Determining the
relevance of information is invari-ably a matter of judgment. In this case,
relevant information is information that explains or clarifies the
circumstances of the reported adverse experience. For example, each follow-up
might include reports of autopsy findings or reports of their results of
addi-tional blood tests (52 Fed. Reg. 8798, 8818 (1987)).
If
a sponsor initially determines that safety informa-tion does not meet the
criteria for expedited report-ing, but a subsequent investigation reveals that
the information should be reported to the FDA, then the sponsor must report the
information as soon as possi-ble ‘and in no event later than 15 calendar days
after the determination is made’ (21 C.F.R. § 312.32(d)).
As
part of the IND annual reports, sponsors report all adverse experiences with investigational drugs and preclinical findings suggesting a
significant risk for human subjects to the FDA. Food and Drug Admin-istration
regulations require IND sponsors to submit a summary of the status and progress
of investiga-tions each year, within 60 days of the anniversary date on which
the IND went into effect (Id. at §
312.33). One purpose of the requirement for submitting annual reports is to
provide both sponsors and the FDA with insight into the status and progress of
the studies conducted under an IND (52 Fed. Reg. at 8819). In furtherance of
this purpose,
FDA believes it is
important periodically to aggregate all [adverse] experiences, whether or not
the individ-ual events are thought to be drug related, for review and analysis.
Such groupings may show an increased incidence of an adverse experience or
other problem that would not be readily ascertainable in a review of single,
discrete adverse events (Id.).
The
regulations require that annual reports include a brief summary of the status
of each clinical study that is in progress or completed (21 C.F.R. §
312.33(a)).
The
information must include, at a minimum, the total number of subjects initially
planned for inclusion in the study, the number of subjects entered into the
study as of the report’s date, the number who have completed the study as
planned and the number who have dropped out of the study for any reason (Id.).
Annual
reports must also include a narrative or tabular summary of the most frequent
and most seri-ous adverse experiences by body system and a list of preclinical
studies completed or in progress during the previous year (Id. at § 312.33(b)). Food and Drug Administration regulations and
the preamble to those regulations do not specify what the agency expects
sponsors to include among the most frequent and most serious events. The FDA
has, however, issued guidance on good risk-assessment practices, includ-ing the
generation, acquisition, analysis and presenta-tion of pre-marketing safety
data [FDA CDER/CBER Guidance for Industry, Premarketing Risk Assessment (March
2005)]. Sponsors also must list in the annual report all patients who died
during participation in the investigation and all who discontinued the study in
association with any adverse experience, regard-less of any conclusions about
whether the event was related to the drug (Id.
at §§ 312.33(b)(3)–(4)). Annual reports must also include a summary of all IND
safety reports submitted during the preceding year (Id. at § 312.33(b)(2)).
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