Research · 6 min read
What a Company Still Owes After a Drug Is Approved
Approval is not the end of the evidence obligation. Studies promised at approval have to be reported on every year, under one of five status labels, and the agency may publish the status — including the reasons a study was not done.
Key takeaways
- Postapproval obligations run on two tracks: adverse drug experience reporting under 21 CFR 314.80 and other postmarketing reports, including study status, under 21 CFR 314.81.
- Every postmarketing study required by FDA or committed to in writing must be reported on annually until the agency concurs it is fulfilled, infeasible, or no longer useful.
- Each status report carries a defined schedule of milestones, an accrual figure, and one of five status labels: Pending, Ongoing, Delayed, Terminated or Submitted.
- FDA may publicly disclose study status information, including the reasons a promised study was not conducted, completed or reported.
- Serious and unexpected adverse drug experiences must be reported within 15 calendar days; all others quarterly for three years after approval and annually thereafter.
- FDA's own page describes real-world evidence as long used for postmarket safety monitoring and more limited in supporting effectiveness, with post-approval study requirements named as one of its framework's uses.
Answer first: two streams of obligation, running on different clocks
After approval, an applicant owes FDA two distinct things, and they are governed by two adjacent regulations.
The first is safety reporting on individual cases and in periodic summaries, at 21 CFR 314.80. The second is a set of other postmarketing reports at 21 CFR 314.81, which includes an annual status report on every postmarketing study the company was required to conduct or committed in writing to conduct.
The distinction matters because they answer different questions. Safety reporting answers what has been observed since approval. Study status reporting answers whether the research promised at approval is actually happening.
The second stream is the one that is easiest to lose track of and the one that determines whether an open question at approval ever gets closed.
The study-status report, and its five labels
Section 314.81(b)(2)(vii) requires a status report of each postmarketing study of the drug product concerning clinical safety, clinical efficacy, clinical pharmacology and nonclinical toxicology that is required by FDA — its examples are accelerated approval clinical benefit studies and pediatric studies — or that the applicant has committed in writing to conduct, either at the time of approval of an application or supplement, or afterwards.
The status of these studies must be reported annually until FDA notifies the applicant in writing that the agency concurs with the applicant's determination that the study commitment has been fulfilled, or that the study is either no longer feasible or would no longer provide useful information.
Each status report must carry defined content: the applicant's name; the product name including established and proprietary names; the application and supplement number; the date of US approval; the date of the study commitment; a description of the commitment with sufficient information to uniquely describe the study, which may include its purpose, type, patient population and the indications and dosages to be studied; and a schedule for completion and reporting.
That schedule is itself specified. It should include actual or projected dates for submission of the study protocol to FDA, completion of patient accrual or initiation of an animal study, completion of the study, submission of the final study report, and any additional milestones specified as part of the commitment. Where the schedule has been revised, both the original and the most recent previously submitted revision must be provided.
Then the current status, categorized using one of five terms describing the study's status on the anniversary date of approval or another agreed date. Pending: the study has not been initiated but does not meet the criterion for delayed. Ongoing: the study is proceeding according to or ahead of the original schedule. Delayed: the study is behind the original schedule. Terminated: the study was ended before completion but a final study report has not been submitted. Submitted: the study has been completed or terminated and a final report has been submitted to FDA.
An explanation must accompany the label, including the patient accrual rate — expressed as the number enrolled to date and the total planned enrollment — and, where the schedule has changed since the last report, a revised schedule with the reasons for the revision.
Some of that status information can be made public
Paragraph (b)(2)(vii)(b) of the same section addresses disclosure. Except for information described in that paragraph, FDA may publicly disclose information concerning a postmarketing study if the agency determines that the information is necessary to identify the applicant or to establish the status of the study — including the reasons, if any, for failure to conduct, complete and report the study.
That final clause is the one worth remembering. The reason a promised study did not happen is contemplated as disclosable information.
This is the mechanism by which a commitment made at the moment of approval can be checked years later against what was actually done. A company's description of its own evidence base and the status of its own outstanding commitments are separate records, and the second is a federal filing with a required format.
The safety stream, and what its definitions do and do not assert
Section 314.80 governs postmarketing adverse drug experience reporting, and its definitions are wider than most readers expect.
An adverse drug experience means any adverse event associated with the use of a drug in humans, whether or not considered drug related, and the definition expressly includes events occurring in the course of use in professional practice, from overdose whether accidental or intentional, from drug abuse, from drug withdrawal, and any failure of expected pharmacological action.
A serious adverse drug experience is one occurring at any dose that results in death, a life-threatening experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect — with a route back in for important medical events that may not meet those outcomes.
The reporting clocks are specific. The applicant must report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information — these are the postmarketing 15-day alert reports. The applicant must promptly investigate all experiences that are the subject of such reports and submit followup reports within 15 calendar days of receiving new information, or as requested by FDA.
Everything else is reported periodically. The applicant must report each adverse drug experience not covered by a 15-day alert report at quarterly intervals for three years from the date of approval, and then at annual intervals — each quarterly report within 30 days of the close of the quarter and each annual report within 60 days of the anniversary of approval. FDA may extend or reestablish the quarterly requirement in writing, for example following approval of a major supplement.
There is one more piece of plumbing in this section that explains why counts can differ between sources. Where a person other than the applicant appears on the label as a manufacturer, packer or distributor, that nonapplicant may meet its obligations by submitting all reports of serious adverse drug experiences to the applicant instead of to FDA — within five calendar days of initial receipt — after which the applicant complies with the section. The nonapplicant must keep a record of that action.
Where real-world evidence fits, and what the term means
FDA maintains a page devoted to this, and it defines both halves of the phrase. Real-world data is defined there as data relating to patient health status and the delivery of health care routinely collected from a variety of sources. Real-world evidence is defined as the clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of that data.
The distinction is between raw records and an analysis of them. The first is collected in the ordinary course of care. The second is something a person or organization produces from the first, and the analysis is where the reasoning lives.
The page describes the agency's own history with these terms in modest language. FDA states that it has a long history of using what it currently calls real-world data and real-world evidence to monitor and evaluate the postmarket safety of approved drugs, and that real-world evidence has also been used historically to support effectiveness, but on a more limited basis.
It also names two uses its framework addresses: helping to support the approval of a new indication for a drug already approved, and helping to support or satisfy drug post-approval study requirements. That second use links this section directly back to the status reports above — a post-approval obligation is one of the places real-world evidence has a defined role.
For a reader assessing a commercial claim, the practical consequences are narrow and checkable. Postmarket safety monitoring is the long-established use, and the page says effectiveness support has been more limited. A page citing real-world evidence for an effectiveness claim is therefore describing the less established of the two uses, and the honest version of such a claim names the data source and the analysis rather than the phrase alone.
Sources
- 21 CFR 314.81 — Other postmarketing reportsThe requirement for annual status reports on postmarketing studies required by FDA or committed to in writing, with accelerated approval clinical benefit studies and pediatric studies given as examples; the condition on which annual reporting ends; the required content of each status report including applicant and product names, application numbers, approval and commitment dates, the study description and the milestone schedule with original and revised versions; the five status categories and their definitions; the explanation requirement including patient accrual expressed as enrolled to date against total planned; and FDA's ability to disclose status information publicly including the reasons for failure to conduct, complete and report a study.
- 21 CFR 314.80 — Postmarketing reporting of adverse drug experiencesThe definition of adverse drug experience including events in professional practice, overdose, abuse, withdrawal and failure of expected pharmacological action; the definition of a serious adverse drug experience and its outcome list; the 15-calendar-day alert reporting requirement for serious and unexpected experiences and the followup requirement; the periodic reporting schedule of quarterly reports for three years after approval and annual reports thereafter with their 30-day and 60-day deadlines; and the nonapplicant route permitting submission of serious adverse drug experience reports to the applicant within five calendar days with a record kept.
- Real-World EvidenceThe definitions of real-world data and real-world evidence quoted here; the statement that FDA has a long history of using them to monitor and evaluate the postmarket safety of approved drugs; the statement that real-world evidence has also been used historically to support effectiveness but on a more limited basis; and the two framework uses named on the page — helping to support approval of a new indication for a drug already approved, and helping to support or satisfy drug post-approval study requirements.
Frequently asked questions
Does a company still owe FDA anything once a drug is approved?
Yes, on two tracks. Under 21 CFR 314.80 it must report adverse drug experiences on 15-day and periodic schedules. Under 21 CFR 314.81 it must file other postmarketing reports, including an annual status report on each postmarketing study required by FDA or committed to in writing.
What are the five status labels for a postmarketing study?
Pending, meaning not initiated but not meeting the criterion for delayed; Ongoing, proceeding according to or ahead of the original schedule; Delayed, behind the original schedule; Terminated, ended before completion with no final report submitted; and Submitted, completed or terminated with a final report submitted to FDA.
How long does the annual status reporting go on?
Until FDA notifies the applicant in writing that it concurs with the applicant's determination that the commitment has been fulfilled, or that the study is no longer feasible or would no longer provide useful information.
Can the public find out why a promised study was not done?
The regulation contemplates it. FDA may publicly disclose information concerning a postmarketing study where the agency determines the information is necessary to identify the applicant or establish the study's status, including the reasons, if any, for failure to conduct, complete and report the study.
How fast must a serious postmarketing adverse event be reported?
An adverse drug experience that is both serious and unexpected, whether foreign or domestic, must be reported as soon as possible but no later than 15 calendar days from initial receipt of the information, with followup reports within 15 calendar days of new information. Other experiences are reported quarterly for three years after approval, then annually.
What does real-world evidence mean?
FDA's page defines real-world data as data relating to patient health status and the delivery of health care routinely collected from a variety of sources, and real-world evidence as the clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of that data. The page says the agency has a long history of using both to monitor postmarket safety, and that such evidence has supported effectiveness on a more limited basis.