CHAPTER § 1.04 Postmarketing Adverse Events
| Jurisdiction | United States |
§ 1.04 Postmarketing Adverse Events
[1] Introduction
After a drug has been approved and is marketed, it is frequently used by a substantially more diverse group of patients than the subjects of the drug's clinical trials. As a result, adverse events not previously seen can occur. Adverse events, or "adverse drug experiences," are undesirable effects that occur in conjunction with use of the drug, but may not necessarily be causally related to the drug.325 Adverse reactions, on the other hand, which are required to be listed in the PI, are "undesirable effect[s] . . . for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the . . . event."326 Post-marketing adverse events are reported to the sponsor or FDA (through FDA's MedWatch Adverse Event Reporting Program327), and sometimes these reports are sufficiently serious to warrant a change in the drug's labeling to warn physicians and patients of these events.
[2] Sponsors' Adverse Event Reporting Requirements
FDA requires sponsors of approved drugs (as well as other persons or corporations that are identified on the drug's label "as a manufacturer, packer, or distributor")328 to submit reports to the Agency regarding adverse events.329 The sponsor must review adverse event information from a variety of sources: spontaneous reports (from patients and physicians); postmarketing studies (clinical as well as epidemiological and surveillance studies); and scientific literature.330 Furthermore, sponsors must create and maintain procedures for receiving and reporting adverse events.331 Adverse drug experiences are generally reported using FDA Form 3500A (MedWatch form for industry).332
[a] Fifteen-Day "Alert Reports"
Sponsors must file 15-day "Alert reports" with FDA for adverse events that are both serious and unexpected.333 As the name of the report indicates, these reports must be filed within 15 days of "initial receipt of the information by the [sponsor]."334 "Serious" adverse events are events that result in one or more of the following: death, immediate risk of death, hospitalization (or prolongation of an existing hospitalization), significant disability or incapacity, or birth defects.335 "Unexpected" adverse events constitute events that are not included in the drug's current labeling.336
Fifteen-day Alert reports should include four basic elements: (1) an identifiable patient; (2) an identifiable reporter; (3) a suspect drug; and (4) a serious, unexpected adverse experience.337 Additionally, the date on which the sponsor became aware of the relevant adverse event should be included in the Alert report.338
The sponsor must investigate each adverse event that prompts a 15-day Alert report.339 A follow-up report must be submitted to FDA within 15 days of receiving new information regarding the adverse event that underlies the original Alert report.340 If no additional information is obtainable, the sponsor shall maintain records relating to the steps it did take in investigating the adverse event.341
A notable qualification to the 15-day reporting requirement exists with respect to postmarketing studies. Serious, unexpected adverse events that occur during a post-marketing clinical trial or surveillance study must be submitted as a 15-day Alert report, but only if there is a reasonable possibility that the drug caused the adverse experience.342
[b] Periodic Reports
Adverse events that do not require 15-day Alert reports (those that are not both serious and unexpected) must be filed with FDA in periodic reports.343 Such reports must be filed on a quarterly basis for 3 years following approval of the application (or following marketing of the drug if marketing did not directly follow approval), and on an annual basis thereafter.344 Periodic reports should contain: (1) a summary and analysis of the adverse events included in the periodic report as well as all 15-day Alert reports submitted to FDA during the relevant period; (2) an individual case safety report (ICSR) (e.g., FDA Form 3500A) for each adverse event during the relevant period that did not require a 15-day Alert report; and (3) a listing of actions taken since the last report because of adverse events (e.g., labeling changes that were implemented or clinical studies that were initiated in response to an adverse event).345
Unlike 15-day Alert reports, periodic reports are not required for adverse events that the sponsor discovers from postmarketing studies, scientific literature, or foreign markets.346 Additionally, sponsors can request waivers from FDA exempting them from filing Form 3500As for non-serious, expected adverse events.347
[c] Warning Letters Issued for Noncompliance with Adverse Event Reporting Requirements
If an FDA inspection reveals a failure to report adverse events or maintain an adequate adverse event reporting system, FDA may communicate the violations to the sponsor through either an "Untitled Letter" or a "Warning Letter." Untitled Letters are most often used to inform the sponsor of non-serious violations. Warning Letters, on the other hand, are generally used to address what FDA considers "significant deviations or violations."348 Such violations could include the failure to file 15-day Alert reports, inaccurate 15-day Alerts, untimely or delinquent 15-day Alerts, the repeated failure to submit periodic reports, the failure to investigate serious and unexpected adverse events, and the failure to create procedures for adverse event reporting.349
After the receipt of a Warning Letter, sponsors have 15 working days to respond to FDA and describe the specific steps taken to correct the alleged violations and procedural changes developed to prevent future violations. The Agency warns that failure to correct violations of FDA adverse event reporting requirements can result in "seizure, injunction, and/or civil money penalties."350
[3] FDA Requirements for Updating Labeling Due to New or More Frequent Adverse Events
[a] Differentiating Older from Newer Drugs
In January 2006, FDA updated the labeling requirements for pharmaceut icals.351 Drugs that were approved before June 30, 2001 ("older" drugs) are exempt from the new labeling format.352 Drugs with New Drug Applications ("NDA") or efficacy supplements that were approved after June 30, 2001 ("newer" drugs) are subject to the new labeling regulations.353
[b] When Labeling Changes Are Required
In general, the labeling of both newer and older drugs "must be updated when new information becomes available that causes the labeling to become inaccurate, false, or misleading."354 Additionally, as part of FDAAA,355 Congress requires the Secretary of HHS to notify sponsors, or other responsible parties, if she or he is aware of new safety information that the Secretary believes should be included in a drug's labeling.356 Following that notification, the sponsor has 30 days to either: (1) submit proposed changes to the labeling that would address the expressed concern; or (2) submit a notice stating that no labeling change should be required along with an explanation for that conclusion.357 If the Secretary disagrees with the sponsor's proposed labeling changes or conclusion that no such changes should be required, the Secretary must initiate discussions to reach agreement on whether the labeling should be modified and, if so, how.358 Within 15 days of the conclusion of these discussions, the Secretary may issue an order requiring the sponsor to make the labeling changes the Secretary deems appropriate.359 The sponsor must then submit a supplement for these labeling changes within 15 days of the Secretary's order; however, the sponsor may choose to appeal the order if done so within 5 days.360
Adverse events primarily fit into four sections of the drug's labeling: the Boxed Warning, Contraindications, Warnings and Precautions, and Adverse Reactions.361 Not all adverse events will require updates to all, or even any, of these sections of the labeling; what must be changed will depend on the nature and severity of the event, as well as the sponsor's and FDA's judgment.
[i] Boxed Warning—Newer Drugs Only
FDA regulations state that "[c]ertain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required by the FDA to be presented in a box."362 To keep labeling from being "inaccurate, false, or misleading," boxed warnings may need to be included or updated in a sponsor's labeling when postmarketing reports reveal events requiring such serious warnings or contraindications. FDA Guidance on the requirements of the 2006 revisions to the labeling regulations identifies three typical situations in which the boxed warning section is appropriate,363 and postmarketing adverse events could require changes with respect to a boxed warning in the following two of those situations:
(1) "There is an adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using a drug;"364 or
(2) "There is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation)."365
Should either of these situations arise in light of data obtained in the postmarket context, the relevant drug's labeling may require the addition of a boxed warning or the modification of an existing boxed warning.
[ii] Contraindications
The "Contraindications" section is another area of a drug's labeling which should be updated when needed in order to ensure that the labeling is not inaccurate, false, or misleading. Manufacturers of both older and newer drugs should update...
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