The regulations specify two mechanisms for reporting post-marketing adverse product experiences: 15-day alert reports and periodic reports.
REPORTING ADVERSE PRODUCT
EXPERIENCES FROM MARKETED PRODUCTS
The
regulations specify two mechanisms for reporting post-marketing adverse product
experiences: 15-day alert reports and periodic reports. A 15-Day Alert Report
must be submitted by an applicant or licensed manufacturer within 15 days after
receiving informa-tion regarding a domestic or foreign ‘serious’ and
‘unexpected’ adverse product experience (21 C.F.R. §§ 310.305(d),
314.80(c)(1)(i), 600.80(c)(1)(i)). A periodic report is submitted for any
adverse product experience that is not ‘serious’ and ‘unexpected’ (21 C.F.R. §§
314.80(c)(2)(i), 314.98, 600.80(c)(2)(i)).
All
domestic adverse product experience reports for both drugs and biological
products (unless treated differently as discussed above) should include a
completed FDA Form 3500A for each individual patient or attached publication.
If the adverse product experi-ence is foreign, then either a Form 3500A or a
Coun-cil for International Organizations of Medical Sciences (CIOMS) I is
acceptable (21 C.F.R. §§ 314.80(f), 600.80(f)). If the product is a vaccine,
then a VAERS form should be used (21 C.F.R. § 600.80(f)). Appli-cants or
licensed manufacturers may use computer-generated forms or an alternative
format, such as a computer-generated tape or tabular listing, if the
alternative format contains the same information as Form 3500A and if the
appropriate FDA department agrees to the alternate format in advance (Id.).
The
FDA has proposed a regulation requiring the reporting of adverse product
experiences in electronic format but has not yet taken final action on the
matter (63 Fed. Reg. 59,746 (1998)). In the interim, the agency has offered
guidance for applicants and licensed manufacturers that wish to file such
reports electronically [FDA CDER/CBER Draft Guidance on Providing Regulatory
Submissions in Electronic Format – Postmarketing Periodic Adverse Drug
Expe-rience Reports (June 2003)].
An
applicant or licensed manufacturer must submit a ‘15-Day Alert Report’ to FDA
within 15 calen-dar days of receiving information of a ‘serious’ and an
‘unexpected’ domestic or foreign adverse product experience (21 C.F.R. §§
310.305(d), 314.80(c)(1)(i), 600.80(c)(1)(i)).
The
definition of ‘serious’ for purposes of report-ing post-marketing adverse
product experiences is iden-tical to that for IND adverse product experiences
discussed above (21 C.F.R. §§ 310.305(b), 314.80(a), 314.98, 600.80(a)). The
definition of ‘unexpected’ for post-marketing adverse product experiences is
simi-lar to that for the IND adverse product experiences. An adverse product
experience is ‘unexpected’ if the experience is not listed in the current
labelling for that product (21 C.F.R. §§ 310.305(b), 314.80(a), 314.98,
600.80(a)). An adverse product experience is ‘unex-pected’ even if it could
have been anticipated from the pharmacological properties, of the product so
long as it is not listed in the labelling (Id.).
This definition includes events that are symptomatically and
patho-physiologically related to events listed in the labelling but that differ
because of greater severity or specificity (Id.).
As an example of an event that is ‘unexpected’ due to greater severity, the
regulations cite hepatic necrosis when the labelling refers only to elevated
hepatic enzymes or hepatitis and cerebral thromboem-bolism and cerebral
vasculitis when the labelling refers only to cerebral vascular accidents (Id.).
Unlike
the criteria for expedited reporting of adverse events in investigational
drugs, the regula-tions regarding reporting spontaneous post-marketing events
do not require an assessment of causality. It is the FDA’s view that when a
report regarding a drug is made spontaneously, causality is implied, because
the reporter otherwise would not have taken the time to transmit the
information to the applicant or to a regulatory authority.
Applicants
or licensed manufacturers are also required to promptly perform a ‘follow-up’
investigation into the adverse product experience and to separately report any
new information to the FDA as a ‘15-Day Alert Report Follow-Up’ within 15
calendar days receiv-ing that information (21 C.F.R. §§ 310.305(c)(2),
314.80(c)(1)(ii), 314.98, 600.80(c)(1)(ii)). If the appli-cant or licensed
manufacturer performs an inves-tigation but is unable to uncover any additional
information, then the applicant or licensed manu-facturer is expected to
maintain a record of the steps taken to seek additional information; however, a
follow-up report need not be submitted (Id.).
Fifteen-day
alert reports must be filed when ‘serious’ or ‘unexpected’ adverse product
experiences are reported in case reports or in the results of formal clinical
trials published in scientific or medical jour-nals (21 C.F.R. §§ 314.80(d),
314.98, 600.80(d)). When a 15-day alert report is based on information obtained
from an article in a scientific or medical journal, a copy of the article must
be included with the report (Id.).
A
15-day alert report is not required for informa-tion regarding an adverse
product experience that was obtained from a post-marketing study, includ-ing a
study conducted under an IND applica-tion, unless the applicant or licensed
manufacturer concludes that there is a ‘reasonable possibility’ that the
product caused the experience (21 C.F.R. §§ 310.305(c)(1)(ii), 314.80(e),
314.98, 600.80(e)). When reports of adverse product experiences obtained during
a post-marketing study are reported in any context, they should be marked to
indicate that they were so obtained (Id.).
Any
post-market adverse product experience that is not ‘serious’ and ‘unexpected’
must be reported to the FDA in a periodic report (21 C.F.R. 314.80(c)(2)(i),
314.98, 600.80(c)(2)(i)). Periodic reports must contain a ‘narrative summary
and anal-ysis’ of the information in the report, including an analysis of all
15-day alert reports filed during that period (21 C.F.R. §§ 314.80(c)(2)(ii),
314.98, 600.80(c)(2)(ii)). Periodic reports must also include a completed FDA
Form 3500A for each adverse prod-uct experience not reported in a 15-day alert
report during the period as well as an index consisting of a line listing of
patient identification numbers and adverse reactions terms (Id.). Finally, periodic reports must
include a history of actions taken in response to adverse product experiences
during the period, such as labelling changes or the initiation of studies (Id.).
During
the first 3 years after the date of approval or licensing of a product,
periodic reports must be submitted quarterly, beginning on the date of approval
of the application (21 C.F.R. §§ 314.80(c)(2)(i), 314.98, 600.80(c)(2)(i)).
Each quarterly report must be filed within 30 days of the close of the quarter
(Id.). After 3 years, applicants or
licensed manufac-turers need only submit annual reports, which must be filed
within 60 days of the anniversary of approval or licensing (Id.). The FDA may require an applicant
or licensed manufacturer to submit quarterly reports for a period longer than 3
years (Id.).
Follow-up
investigations for adverse product expe-riences that are not ‘serious’ and
‘unexpected’ are not required. If the applicant or licensed manufac-turer
chooses to perform an investigation, then it may submit any information that it
discovers in the next periodic report rather than filing a sepa-rate
‘follow-up’ report (21 C.F.R. §§ 314.80(c)(2)(i), 314.98, 600.80(c)(2)(i)).
Periodic
reports need not contain adverse prod-uct experience information obtained from
reports in scientific literature or from foreign marketing experience or
post-marketing studies (including stud-ies conducted under IND applications)
(21 C.F.R. 314.80(c)(2)(iii), 314.98, 600.80(c)(2)(iii)). Thus, the only
adverse product experiences that must be included in periodic reports are
spontaneous reports from domestic sources that have not been included in a
15-day alert report.
In
addition to the periodic safety reports that appli-cants must submit to the
FDA, annual reports are also required for holders of drug approvals. Although
these reports primarily provide ancillary information about the product, such
as distribution data and manu-facturing changes, annual reports must also
include safety information in the form of copies of unpub-lished reports of new
clinical and preclinical findings (21 C.F.R. §§ 314.81(b)(2)).
Applicants
and licensed manufacturers are not required to report adverse product
experience infor-mation that has already been reported to the FDA. Thus, no
report should contain adverse product experiences that occurred in clinical
trials if those experiences were previously submitted as part of an approved application
(21 C.F.R. §§ 314.80(g), 314.98, 600.80(g)). Similarly, an applicant or
licensed manufacturer is not required to file a report if the FDA itself was
the source of the adverse product experience information and no additional
informa-tion was uncovered during the ‘follow-up’ investiga-tion (21 C.F.R. §§
310.305(c)(5), 314.80(b), 314.98, 600.80(b)).
Reporting
requirements apply to all entities iden-tified on the product’s label as a
manufacturer, packer or distributor (21 C.F.R. §§ 310.305(c)(1)(i), 314.80(c)(1)(iii),
314.98, 600.80(c)(1)(iii)). To avoid duplication in reporting, however, these
entities may submit any adverse product experience information to the applicant
or licensed manufacturer for inclusion in the applicant’s or licensed manufacturer’s
15-day alert report (21 C.F.R. §§ 310.305(c)(3), 314.80(c)(1)(iii), 314.98,
600.80(c)(1)(iii)). This submission must occur within 5 calendar days of the
entity’s receipt of the information (Id.).
If the entity elects this method, then it must keep a record that includes a
copy of each adverse product experience report, the date the report was
received, the date that the report was submit-ted to the applicant or licensed
manufacturer and the name and address of the applicant or licensed manufacturer
(Id.).
The
names and addresses of patients should not be included in any reports submitted
to the FDA (21 C.F.R. §§ 310.305(e), 314.80(h), 314.81(c)(2), 314.98,
600.80(h)). Instead, the applicant or licensed manufacturer should create a
unique code number of less than eight characters for each report (Id.). The applicant or licensed
manufacturer must include the name of the person who reported the adverse
product experience (Id.). The
applicant or licensed manufac-turer also must maintain sufficient patient
identifica-tion information to permit the FDA to identify the name and address
of individual patients (Id.).
PHYSICIAN/CONSUMER REPORTING:
THE FOOD AND DRUG ADMINISTRATION MEDICAL PRODUCTS REPORTING PROGRAM (MEDWATCH)
In
addition to receiving mandatory adverse event information from drug
manufacturers and distributors, the FDA also receives voluntary adverse event
reports from the medical community and consumers through its MedWatch
programme. This programme provides a system for healthcare professionals and
consumers to report adverse events to the FDA with respect to drugs, biologics,
medical devices and nutritional products such as medical foods, dietary
supplements and infant formulas. Food and Drug Administration’s website permits
healthcare professionals to voluntar-ily transmit adverse event information
electronically, and the FDA also has designed a specific MedWatch adverse event
reporting form that can be submitted by mail or fax. In addition, the FDA has a
toll-free telephone number for reporting adverse experiences.
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