Postmarketing Safety: US FDA ‘Best Practices’ Include Weekly Adverse Event Screening For New Drugs
Executive Summary
Agency’s approach to risk-based postmarketing safety surveillance explained in new draft document issued under the 21st Century Cures Act; product characteristics and intended use guide the frequency and extent of adverse event report screening, with newer drugs undergoing weekly reviews for three years after approval.
The US Food and Drug Administration’s risk-based approach to postmarketing drug safety monitoring entails weekly screening of individual adverse event reports for three years after approval of certain drugs and biologics, the agency explains in a new draft document.
Products receiving weekly screening during their first three years on the market include: new molecular entities, novel biologics, biosimilars, and non-NMEs with new dosage forms or complex manufacturing processes.
In addition, individual case safety reports are screened weekly for homeopathic and compounded products.
Products receiving weekly adverse event report screening during their first three years on the market include: new molecular entities, novel biologics, biosimilars, and non-NMEs with new dosage forms or complex manufacturing processes.
The frequency and extent of screening of adverse event databases and medical literature is described in “Best Practices in Drug and Biological Product Postmarket Safety Surveillance for FDA Staff,” a draft document explaining the risk-based principles by which the FDA conducts ongoing postmarketing safety monitoring.
The draft was prepared by the Office of Surveillance and Epidemiology in collaboration with other offices in the Center for Drug Evaluation and Research, and with the Center for Biologics Evaluation and Research.
The document also discusses: special considerations for safety monitoring specific to certain product categories and target populations; the data sources used for postmarketing surveillance; and potential regulatory actions resulting from such monitoring.
21st Century Cures Act Requirement
The agency said the drug safety surveillance principles and best practices detailed in the draft document build upon lessons learned in preparing and publicly posting the summary analyses of adverse drug reaction reports previously required under the FDA Amendments Act of 2007.
FDAAA required the agency to prepare a summary analysis of adverse event reports received for drugs 18 months after approval or after use by 10,000 individuals, whichever was later. The summary analysis was to include identification of any new risks not previously identified, potential new risks, or known risks reported in unusual number. (Also see "New Drugs Get "Luck Of The Draw" In FDA's First Round Of 18-Month Reviews" - Pink Sheet, 15 Jun, 2010.)
The agency also was required to conduct regular, bi-weekly screening of the Adverse Event Reporting System database and post a quarterly report of any new safety information or potential signal of a serious risk identified by AERS.
In a 2016 study, the FDA concluded the statutorily-required summary analyses were largely redundant to surveillance practices in place at the time FDAAA took effect and were not an efficient use of resources. The summary analyses did not provide sufficient flexibility to take a risk-based approach based on various factors, including a drug’s characteristics and its projected use, the agency said. In addition, many drugs and biologics for rare diseases never met the 10,000-person threshold.
The 21st Century Cures Act of 2016 replaced the 18-month/10,000-patient analysis requirement with a directive that the agency post on its website best practices for drug safety surveillance activities for drugs and biologics. The Cures law also replaced the term “bi-weekly screening” with “screenings” and required the agency to develop and post best practices for drug safety surveillance using AERS.
AER Screening Frequency
While the frequency and extent of systematic postmarketing safety monitoring is guided by a product’s characteristics and its projected use, the draft document shows that the agency conducts weekly screening of individual case safety reports (ICSRs) for many types of products for three years following approval. (See chart)
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Product Type |
Frequency Of AER Database Screening |
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CATEGORY A |
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New molecular entities Originator biological products Biosimilars Non-NMEs that have: newly approved dosage forms or indications; extensions into new patient populations; complex pharmacokinetic or pharmacodynamic characteristics; complex compositions or manufacturing processes |
Weekly for newly received ICSRs At intervals coinciding with receipt of manufacturers’ periodic safety reports for all ICSRs since approval, including data mining |
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CATEGORY B |
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Homeopathic products Compounded products |
Weekly for newly received ICSRs |
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CATEGORY C |
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Any product in category A that is beyond 3 years postapproval Over-the-counter products Any product not in categories A or B |
Weekly for newly received ICSRs reporting AEs of interest Yearly (at minimum) data mining of all ICSRs since approval |
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Note: This table describes CDER’s grouping of products into categories. CBER follows similar principles but does not group products into categories. |
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The best practices draft document also outlines they primary types of safety information of interest to reviewers. These include:
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Important potential risks of the product recognized at the time of or after approval;
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Apparent increase in the severity or frequency of reporting of a labeled AE;
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Deaths, particularly in populations or in patients using the product for indications for which there would not be the expectation of death;
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AEs for which causal attribution to the product is biologically plausible;
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Reports of unlabeled, serious AEs;
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Serious AEs thought to be rare in the general population and associated with a high product-attributable risk;
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Interactions among different products;
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Reports of reduced effectiveness or efficacy;
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Medication errors resulting from confusion about a product's name, labeling, packaging or use;
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Off-label use, misuse, abuse and other intentional uses in a manner that is inconsistent with labeling;
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AEs reported or observed in a specific patient population; and
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AEs for which a Risk Evaluation and Mitigation Strategy is intended to mitigate the risk.
Special Considerations For Biologics And Biosimilars …
The document discusses unique considerations for certain categories of products, including biologics, biosimilars and generics.
Issues specific to biologics that must be addressed in postmarketing surveillance include immunogenicity, product manufacturing variability and risk of product contamination with infectious agents.
When it comes to biosimilars, the agency applies the same surveillance principles as NMEs and novel biologics approved under standalone biologics license applications.
Since a newly identified, serious AE may be specific to the particular biosimilar or associated with the class of biologics, reviewers include a review of data on the reference product as part of their evaluation to help determine whether the AE is associated with the specific biosimilar, as opposed to the product class.
“A high index of suspicion is maintained for clinical events reported for the biosimilar product that are not consistent with the safety profile of the reference product.” – FDA
“Report-level analysis is carried out to identify unusual or unique clinical presentations of labeled AEs. A high index of suspicion is maintained for clinical events reported for the biosimilar product that are not consistent with the safety profile of the reference product,” the draft document states. “Data mining of FAERS reports for the biosimilar product and the reference product is another approach to identify potential signals and AEs reported disproportionately for the biosimilar product.”
AEs for biosimilars may be reported by proprietary name or nonproprietary name, and reporters may inadvertently use the reference product’s proprietary or nonproprietary name to identify the biosimilar. “Reviewers keep these potential reporting limitations in mind to avoid misattributing the reported AE(s). Reviewers are encouraged to review the narrative report, as it may contain more information about the identity of the reported product.”
The agency has said pharmacovigilance and product identification concerns justify its requirement that biosimilars and newly approved biologics include a four-letter suffix in their nonproprietary names. However, the suffix policy remains a contentious issue for some biosimilar product sponsors and stakeholders. (Also see "Woodcock: Concerns About US FDA's Biosimilars Suffix Policy Detached From Reality" - Pink Sheet, 20 Mar, 2019.)
… Generic Drugs …
The potential for incorrect product attribution also is an issue in safety monitoring of small molecule generics. “Based on the reported information, reviewers may have great difficulty determining whether the drug used was the innovator drug or a generic,” the draft document states.
Safety surveillance for generics includes processes for detecting AEs possibly related to excipients and other product quality differences compared to innovator drugs, “as well as other unexpected or rare events that become apparent with increasing exposure to an active ingredient (of innovator and generic products) in a larger and potentially more diverse patient population.”
Reviewers also are on alert for reports of therapeutic failure or therapeutic inequivalence to the reference product.
“Reviewers screen for persistent or increasing reports that suggest that a single generic product may not be therapeutically equivalent to its reference listed drug, excessive numbers of reports in proportion to the distribution of a particular generic, or evidence that a generic does not have a significant clinical impact, including medication use errors,” the FDA said.
A generic drug’s complexity, as well as differences in the user interface compared with the reference product, also are areas of concern for postmarketing safety surveillance.
“Reviewers may focus their surveillance of generic products on solid oral products with modified-release mechanisms, drug-device combination products …, products with a narrow therapeutic index, and products with active ingredients that have highly correlated PK-PD relationships,” the document states. “Signals that are suggestive of a potential quality issue with a generic product are evaluated in a collaborative process with other FDA offices and in the context of other available data streams including, but not limited to, product distribution data and Field Alert Reports.”
… And Pregnant Women
The draft document includes considerations for specific patient populations, such as discussing the utility and imitations of exposure registries, observational studies, and electronic claims and health record databases in monitoring postmarketing safety in pregnant women.
ICSRs also provide another source of information to evaluate drug safety concerns in pregnancy. A series of similar reports of a distinct abnormality or a group of similar abnormalities can establish a strong causal association or signal the need for follow-up evaluations to assess potential risk, the agency said.
However, there are several factors to consider when evaluating ICSRs reporting potential congenital anomalies. These include:
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Physical and chemical nature of the product;
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Dose, duration, frequency and route of administration;
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Gestational timing;
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Concurrent products and comorbidities;
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Background prevalence of adverse pregnancy outcomes;
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Combined versus individual rates of birth defects; and
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Major versus minor birth defects.
“It is well known that data collected retrospectively may be subject to bias,” the draft states. “When analyzing data on adverse outcomes following in utero exposure, it is important that reviewers evaluate prospective reports, those in which information on the patient was collected after exposure but prior to knowledge of the pregnancy outcome, separately from retrospective reports, those in which the pregnancy outcome was known at the time of reporting.”
Prioritizing Potential Signals
ICSRs in the drug and vaccine AERS databases, as well as medical literature and other information sources (including manufacturers’ periodic safety reports and REMS assessments), are used to identify potential safety signals, which then are prioritized for more extensive evaluation.
“Identified signals are prioritized both within and across products,” the document states. “Prioritization is made based upon the nature of the AE, the seriousness of the outcome, the impact on the individual, and the impact on public health. When new information becomes available that may change the benefit-risk profile of a product, the signals are re-evaluated and reprioritized.”
“If insufficient evidence exists to support a causal association between the drug and AE, the AE can be considered an AE of interest for continued close monitoring.” – FDA
A multidisciplinary team conducts an integrated, comprehensive evaluation of the prioritized signal to determine whether and what regulatory action is indicated. “The team integrates the cumulative data gathered from all available sources, which includes ICSRs submitted to FAERS and VAERS, medical literature case reports, product utilization data, reporting ratios and epidemiologic assessments.”
The determination of whether a causal association exists between a product and an AE is based on the strength of evidence from the totality of data for the product, the agency said.
The multidisciplinary team may determine that regulatory actions are necessary. These could include: labeling changes; issuance of a drug safety communication; gathering additional data through a postmarketing study or trial; and requiring a new REMS or modifying an existing risk mitigation program.
“If insufficient evidence exists to support a causal association between the drug and AE, the AE can be considered an AE of interest for continued close monitoring,” the document states. “Regardless of regulatory action taken, FDA continues to monitor for new safety information that may change the determination.”
The agency is developing internal, supporting technical documents to guide implementation of the principles articulated in the draft document, which is open for public comment until 6 January.