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Understanding the Process for FDA Approval and Expedited Review

From the early phases of clinical development to New Drug Applications and beyond, all companies looking to bring new drug products to market must work closely with the U.S. Food and Drug Administration (FDA). Specifically, the FDA’s Center for Drug Evaluation and Research (CDER) is responsible for evaluating new drugs before they can be sold. Evaluations by CDER are meant to prevent medical fraud and provide both providers and patients the necessary information to inform proper use of medications. Once companies get the center’s stamp of approval for their new drug products, they pass perhaps the most anticipated and important milestone in the regulatory process, and can prepare for launching their products to consumers.

So, how does the FDA make its decisions concerning approvals? What can companies do to challenge FDA approval decisions? And what are the different avenues that companies can pursue to expedite the FDA approval process?

This article will detail the various potential regulatory approval pathways, including the steps to FDA approval and expedited review designations. Previous articles have covered U.S. regulatory pathways and data and market exclusivities for companies looking to bring new drugs to market.

FDA Approval

FDA approval, as defined by the agency itself, is when “data on the drug’s effects have been reviewed by CDER, and the drug is determined to provide benefits that outweigh its known and potential risks for the intended population.” When determining whether a drug will receive approval or not, the FDA utilizes a framework that considers:

Most drugs evaluated by the FDA will be given a standard review, meaning that the agency will take action on a company's drug application within 10 months of submission.

Analysis of Target Condition and Available Treatments

In order to establish context for considering a drug’s risks and benefits, the FDA analyzes the target condition that a drug is seeking approval for as well as the current treatment landscape. When completing this part of the review, the FDA will evaluate a drug seeking approval for a non-life-threatening condition with many existing treatments on the market differently than a drug seeking approval for a life-threatening condition that does not have any existing treatments. The review process for drugs seeking approval for life-threatening and rare conditions will be covered in greater detail below under the Expedited Review Designation section.

Assessment of Risks and Benefits from Clinical Data

To grant approval to a drug, the FDA must find evidence that the clinical benefits of a drug to its target population outweighs any of its risks. In coming to this determination, the FDA expects drugmakers to submit results from two well-designed clinical trials to eliminate any chance or bias from evaluating just one clinical trial. The agency will then review this data to assess benefits and risks while also looking for any uncertainties stemming from imperfect or incomplete data. For products seeking approval under the 505(b)(2) pathway, the FDA allows drugmakers to submit results from existing clinical trials or FDA findings of safety and efficacy for previously approved drugs.

As with analyzing the target condition and treatment landscape, the FDA considers context when making decisions around its assessment of risks and benefits from clinical data. For example, for drugs developed to treat rare diseases where conducting multiple trials is not feasible, the agency may make its evaluation from just one clinical trial if the data is convincing.

Strategies for Managing Risks

Managing risks for drugs typically entails including an FDA-approved label, which describes the drug’s risks and benefits as well as how to detect and manage the risks.

For drugs with serious risks, the FDA will add a Boxed Warning, also known as a “black box warning,” to the drug’s label. The criteria for a Boxed Warning may include the following:

  1. There is an adverse reaction so serious in proportion to the potential benefit of the drug that it is essential that it be considered in assessing the risks and benefits of using a drug

  2. There is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug

  3. The FDA approved the drug with restrictions to assure safe use because the FDA concluded that the drug can be safely used only if distribution or use is restricted

As mentioned in the criteria for Boxed Warnings, for drugs with serious safety concerns manufacturers may need to implement a Risk Management and Mitigation Strategy (REMS) to ensure the benefits of the treatment outweigh the risks. While all drugs have FDA labels, only a few treatments will require a REMS program.

The purpose of a REMS program is to manage a specific serious risk through informing, educating, and reinforcing medication use behaviors and actions that encourage safe use of the treatment. REMS can range from being less restrictive (e.g. providing a medication guide to patients) to more restrictive (e.g. administration limited to certain healthcare provider locations).

Janssen’s Spravato (esketamine) nasal spray is an example of a drug with a REMS program. Due to the risks of serious adverse outcomes resulting from sedation and dissociation caused by Spravato administration, and abuse and misuse of Spravato, the drug is only available through a restricted distribution program and is intended for use only in a certified healthcare setting. For Spravato administration, patients must be under direct observation of a healthcare provider and are required to be observed by a healthcare provider for at least 2 hours. Additionally, Spravato must never be dispensed directly to a patient for home use.

The FDA continues to monitor the safety of drugs in post-marketing surveillance and will issue Boxed Warnings or require updates to REMS programs in light of newly emerged safety concerns.

Expedited Review Designations

Beyond the regular FDA approval process, the agency provides expedited review designations for companies developing certain kinds of drugs. Examples of drugs that may qualify for an expedited review designation include drugs that may be the first treatment for a condition and drugs that have significant clinical benefit over existing treatments on the market. The purpose of these review designations is to ensure that treatments for serious conditions can be made available to patients as soon as the FDA deems that their benefits outweigh their risks.

Priority Review

When the FDA assigns a priority review designation, it means that the agency will be evaluating an application for a drug that, if approved, would have significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to a standard application. If a drug application receives priority review, the FDA will take action on the application in 6 months instead of the 10-month timeline for standard review applications.

According to the FDA, examples of significant improvements include:

● evidence of increased effectiveness in treatment, diagnosis, or prevention of the target condition

● elimination or reduction of drug reactions that limit treatment,

● enhanced patient compliance that is expected to lead to an improvement in

serious outcomes

● evidence of safety and effectiveness in a new subpopulation

The FDA decides on the review designation for every application, though a company can request that its application receive priority review. The FDA is expected to inform the applicant of a priority review designation within 60 days of receiving the original application.

Fast Track

Applications for drugs being developed to fill an unmet medical need by either treating a serious condition for which no other treatment exists or offering some substantial benefit over existing treatment may be considered for fast track approval. Fast track designation often leads to earlier drug approval through early and frequent communication with the FDA. The applicant must request Fast Track designation, and the FDA is expected to decide whether to grant the designation within 60 days of the request.

Breakthrough Therapy

NDAs/BLAs that present preliminary clinical evidence that a drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s) for a serious condition may qualify for breakthrough therapy designation. A breakthrough therapy designation applies to a combination of a drug (either alone or in combination with other drugs) and the specific use for which it is being studied. A separate breakthrough designation request must be submitted for each proposed development program. The applicant must request Breakthrough Therapy designation and the FDA is expected to decide whether to grant the designation within 60 days of the request.

Accelerated Approval

NDAs/BLAs being developed for long‐term endpoints, such as increased survival or decreased morbidity, that are difficult to measure efficiently in trials may qualify for accelerated approval based on surrogate endpoints. In clinical trials, a surrogate endpoint (or marker) is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship. The applicant is later required to confirm efficacy in post‐market clinical trials (Phase IV).

Notable drugs approved through the accelerated approval pathway include many retroviral treatments for HIV/AIDS as well as targeted oncology treatments.


In the high stakes environment of drug development and commercialization, understanding the FDA approval process and expedited review designations is essential to ensuring that new products receive the regulatory approval needed to enter the market.

T o learn more about how IPD Analytics helps companies navigate the U.S. regulatory landscape and beyond, take a look at our Life-Cycle Insights solution.


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