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Ensuring the Safety of FDA-Approved Generic Drugs

In 2021, FDA’s Office of Generic Drugs (OGD) created the Office of Safety and Clinical Evaluation (OSCE) to enhance OGD’s work in evaluating generic drug safety before approval and throughout the time it is available for sale in the United States. By realigning divisions focused on generic drug safety into one office, OGD created a single point of contact within FDA for generic drug safety and that enhances the efficiency of the review of the safety and effectiveness of generic drugs at the time of approval and beyond.

In this CDER Conversation, we sit down with William (Bill) Chong, M.D., director of OSCE, to learn more about the office’s work to review and coordinate information to ensure the safety of generic drugs on the U.S. market.

William Chong, M.D., director of the Office of Safety and Clinical Evaluation

Can you tell us about your office’s work and structure?

OSCE supports the timely assessment of generic drug applications, helps to ensure generic drugs and their brand-name counterparts have the same safety and efficacy profile, and monitors for potential issues after generic drug approval. 

OSCE has three divisions – the Division of Clinical Review (DCR), the Division of Pharmacology/Toxicology Review (DPTR), and the Division of Clinical Safety and Surveillance (DCSS). Broadly speaking, DCR and DPTR are involved in the scientific review associated with the generic drug approval process, and DCSS is more focused on the continued assurance of the safety and effectiveness of generics after approval, otherwise referred to as the postmarket phase.

How does OSCE evaluate and assess proposed generic drugs?

During the application review process, a generic drug applicant must show that its generic is the same as the brand-name drug it references, with few allowable differences. A proposed generic drug and its brand-name counterpart must have the same active ingredients, conditions of use, route of administration, dosage form, strength, and labeling (with certain limited exceptions). As part of the approval process, a generic drug applicant must show its generic will behave the same in the body as the brand-name, meaning it is bioequivalent. Generally, there can be differences such as in the inactive ingredients and packaging, and OSCE plays a role in assessing whether those differences could change the safety as part of ensuring that generic drugs have the same safety and effectiveness as the brand-name. Our role is to help ensure that the proposed generic can be substituted for the brand-name drug.

More specifically, OSCE evaluates the information submitted by generic drug applicants for any potential differences that may impact safe substitution of the generic for the brand-name drug among people who would use it. Another role we play in the assessment of generic drugs is in evaluating any differences that may exist in the user interface (the components that a patient interacts with to use the drug such as devices for dosing). Some drugs require that patients perform certain tasks to appropriately use the device, and OSCE works to make sure that allowable differences won’t impact the ability to correctly use the generic. For certain types of generic drugs, OSCE also assesses the information provided in support of establishing bioequivalence.

Generic drugs are held to the same standards of quality as those required for brand-name drugs. The office also evaluates whether differences in inactive ingredients or in the amounts of inactive ingredients used in a generic (as compared to its brand-name counterpart) might impact the safety profile. As part of this evaluation, we consider what is known about an inactive ingredient and whether the ingredient has been previously used in other approved drugs, which may include looking at CDER’s Inactive Ingredient Database.

The office participates in the assessment of impurities. With all drugs, there can be impurities (any component that is not a drug substance or inactive ingredient that can compromise the quality of a drug) either as a result of the manufacturing process or stemming from chemical breakdown over time. When our colleagues in CDER’s Office of Pharmaceutical Quality identify a question about an impurity in a generic drug, they consult with us to evaluate whether there may be safety concerns with either the impurity itself, or the amount of impurity in that drug.

How does OSCE ensure the safety of generic drugs?

While a big responsibility for OSCE is the surveillance of approved generic drugs, we also have a role to play even before the generic drug is approved. FDA’s regulations require the timely submission of serious adverse event reports (unexpected side effects) that occur during investigational generic drug bioequivalence studies. OSCE evaluates these safety submissions to assess whether there are any unexpected safety findings that could raise concerns about the proposed generic drug. In addition, we play a critical role in coordinating the establishment of risk evaluation and mitigation strategies (REMS) for generic drugs. REMS is a drug safety program that FDA can require for a certain medication with serious safety concerns to help ensure the benefits of the medication outweigh its risks. If a generic references a brand-name drug that requires a REMS, the generic drug is also subject to a REMS. This may require the generic drug to provide a Medication Guide which includes FDA-approved information about the drug or to comply with any elements to assure safe use.

For approved brand-name and generic drugs, FDA staff monitor and evaluate postmarketing reports to look for early signs of emerging quality issues. This can include postmarket surveillance (monitoring and investigating safety reports) and other pharmacovigilance activities (activities aimed at detecting and assessing possible safety signals) and OSCE is responsible for this work in generic drugs. We work with our pharmacovigilance colleagues in other CDER offices to obtain and coordinate information to ensure the safety of generic drugs for the American public and that they can be substituted for the brand-name. These pharmacovigilance activities allow us to identify if any unanticipated factors or variability arise that may impact the safety of the generic drug or how it is supposed to work and allow for a corrective action. 

Patients and health care professionals play a key role in these surveillance efforts. After a drug is on the market – whether brand-name or generic – patients and health care professionals can report adverse reactions or quality problems to FDA’s MedWatch program, which helps the agency track potential new safety or quality issues. OSCE conducts pharmacovigilance screening of generic drugs and analyzes the MedWatch reports that are submitted to detect any early signals of potential safety concerns. 

To supplement the MedWatch reports, we also evaluate potential safety concerns by using published scientific literature reviews, direct contact from patients or healthcare professionals to FDA, manufacturer reports, internal FDA databases, our past experiences with certain quality issues, reports from other regulatory agencies, data analytic tools and technologies, and market share data.

What happens when OSCE identifies a safety concern?

If OSCE identifies a concern before approval, we work with the applicant to gather additional information or to make changes to the generic so that we are confident it will have the same safety profile as the brand-name drug.

While all approved brand-name and generic drugs go through a rigorous review process, there are situations when we identify a possible drug safety concern after it has been approved. In these instances for generic drugs, our scientific experts review all the relevant data so that FDA can take appropriate action to safeguard public health. Our office investigations may lead to changes in how a generic drug is used or manufactured. For example, over the past decade, we have seen a few quality issues such as tablets breaking apart, patches not sticking, and tablets/capsules that may be too large for some patients to comfortably swallow. In these instances, we have recommended drug recalls or reformulations to address issues. We also work with our CDER colleagues to investigate and inform the public through Drug Safety Communications or other safety alerts and may request changes to the brand-name drug's label which would be carried over to the generic label as applicable. If there is a reason to believe that the generic is no longer substitutable for the brand-name drug, FDA may lower its therapeutic equivalence rating in the Orange Book such that it might not be able to be automatically substitutable at the pharmacy or propose to withdraw approval of the generic drug.

How does the office engage with stakeholders?

We regularly engage and collaborate with the generic drug industry, providers, pharmacy stakeholder groups, and other global regulators through participation in meetings, conferences, workshops and webinars. We also get feedback from patients and providers and educate the public through online postings, articles, webinars, and podcasts.
Additionally, patients and consumers can report concerns with their medicine through FDA’s MedWatch program

Patients expect and deserve safe, effective, high-quality medicines, and our goal is to ensure that approved generic drugs can be substituted for their brand-name counterpart with the expectation of the same clinical effect and safety profile when used in accordance with the labeling. OSCE works hard to make sure that this happens.

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