#95001: Expanding the Options: The Drug-Approval Process in the United States

Drug sponsors produce and test drugs for CDER to review. The sponsor must first submit a drug's proposed labeling and evidence demonstrating the product's safety and efficacy for a specific disease or condition. A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the new drug application (NDA) [6]. The drug can be approved if the review team determines the drug's benefits outweigh its known risks and that the drug can be manufactured in a way that ensures a quality product [7].

After CDER grants approval for a new drug to be marketed in the United States, the Center conducts post-marketing surveillance. It is not possible to predict all adverse effects of a drug based on clinical trials of limited duration using a limited population during drug development, so the FDA maintains a system of post-marketing surveillance and risk assessment programs to identify and monitor adverse events that did not appear during the drug-approval process.

Before President Roosevelt signed the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938 into law, manufacturers did not have to show that a drug was safe before it could be marketed. There were no scientific requirements for testing or approval nor were there any data submission requirements for companies marketing drugs. The FD&C Act of 1938 established the "safety" standards still in use today and subjected new drugs to premarket safety evaluation for the first time with two key changes:

Although the law did not specify the kinds of tests that were required for approval, the new authority allowed drug officials to formally block the marketing of a new drug or delay it by requiring additional data. Similarly, applications could be refused if test results did not show that the drug was safe or if the labeling was false or misleading for the proposed indication. The Act also gave regulators limited powers of negotiation over scientific study and approval requirements with the pharmaceutical industry and the medical profession [8].

No drug is absolutely safe, as all drugs have side effects. Therefore, safety is evaluated along with the benefits of the drug and how they appear to outweigh the known risks. Although there is no strict definition of how to evaluate a drug's risk versus benefit, the FDA requires an integrated summary of safety as well as updates of safety information within the Code of Federal Regulations (21CFR 314.50) [9].

The applicant must submit an integrated summary of all available information about the safety of the drug product, including pertinent animal data, demonstrated or potential adverse effects of the drug, clinically significant drug-drug interactions, and other safety considerations, such as data from epidemiologic studies of related drugs. The safety data must be presented by gender, age, and racial subgroups. When appropriate, safety data from other subgroups of the population of patients treated also must be presented, such as for patients with renal failure or patients with different levels of severity of the disease. A description of any statistical analyses performed in evaluating safety data should also be included [9].

The applicant must, under section 505(i) of the FD&C Act, periodically update its pending NDA with new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling and, if applicable, any medication guide. These "safety update reports" must include the same kinds of information (from clinical studies, animal studies, and other sources) and must be submitted in the same format as the integrated summary. In addition, the reports must include the case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event (unless this requirement is waived) [9].

The effectiveness requirement for drug approval was added to the FD&C Act in 1962 (as part of what is known as the Kefauver-Harris Amendments) following the worldwide thalidomide drug disaster of 1961. The 1962 Act made at least three significant changes [35]:

These new amendments explicitly stated that the FDA would rely on scientific testing and that new drug approvals would be based not only upon proof of safety but also on "substantial evidence" of a drug's efficacy (i.e., the impact of a drug in a clinical trial setting). Substantial evidence was defined in section 505(d) of the Act as [10]:

Since 1962, the FDA has overseen substantial refinements to the broad legal requirement that post-1962 new drugs be approved on the basis of "adequate and well-controlled" studies [11]. With regard to quantity, it has been the FDA's position that Congress generally intended to require at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness. The FDA's position is based on the language in the statute and the legislative history of the 1962 amendments. Section 505(d) of the Act uses the plural form in defining "substantial evidence" as "adequate and well-controlled investigations, including clinical investigation." Section 505(b) of the Act, which lists the contents of an NDA, also uses the plural "investigations." Language in a Senate report suggested that the phrase "adequate and well-controlled investigations" was designed not only to describe the quality of the required data but also the "quantum" of required evidence [12]. The three main goals of "adequate and well-controlled investigations" are to ensure:

Nevertheless, the FDA has been flexible within the limits imposed by the congressional scheme, broadly interpreting the statutory requirements to the extent possible when the data on a particular drug were convincing. In other cases, the FDA has relied on only a single adequate and well-controlled efficacy study to support approval—generally only in cases in which a single multicenter study of excellent design provided highly reliable and statistically strong evidence of an important clinical benefit (e.g., an effect on survival) and a confirmatory study would have been difficult to conduct on ethical grounds [10].

After an NDA is filed, an FDA review team of medical doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts evaluates whether the sponsor's studies show that the drug is safe and effective for its proposed use. This often requires demonstration that the benefits of the drug outweigh its risks for the patient population for which the drug is indicated. If the FDA decides that the benefits of a drug outweigh the known risks, the review team will approve of the drug and it can be marketed in the United States. But if there are problems with an NDA or if more information is necessary to make that determination, the FDA may issue a complete response letter [14]. A "complete response" indicates that FDA has completed its review and has found issues that must be addressed before the drug can be approved. A company has the option to re-submit their application for approval after addressing the issues cited by the FDA.

New drugs shape the practice of medicine by offering patients novel therapies for a wide array of common and rare conditions. There are many avenues for discovering new drugs, but researchers typically begin this process through one of the following methods [15]:

Thousands of compounds may be potential candidates for medical product development[15]. After early testing, however, only a small number of them remain promising enough for further study (Figure 1). After researchers have identified a promising compound for development, they conduct a series of experiments to learn about:

FDA DRUG DEVELOPMENT FUNNEL

Figure 1

Source [42]

During a new drug's early development process, the sponsor's primary goal is to determine if the drug is reasonably safe for human use and if its course of action, or pharmacologic activity, justifies commercial development. Preclinical studies are typically not very large but must provide detailed information on dosing and toxicity levels of IND products. The sponsor has three options for fulfilling this requirement [16]:

As discussed, the NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new drug, often called a new molecular entity. Data gathered during animal studies and human clinical trials, along with descriptions of manufacturing procedures and additional drug information, are part of the NDA. Overall, the NDA aims to provide the FDA review team with ample information needed to answer the following questions:

The NDA explains to reviewers what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed, and packaged. Key NDA submission requirements:

After the drug developer has filed the NDA to the FDA for review, the CDER review team has 60 days to decide whether the application is complete. The FDA review team thoroughly examines all submitted data on the drug and makes a decision to accept the application for review. If the reviewers determine the application is complete, they have 6 to 10 months to evaluate whether to approve the drug.

Each member of the review team conducts a full review of his or her section of the application. For example, the medical officer and the statistician review clinical data, while a pharmacologist reviews the data from animal studies. There is also a supervisory review for each technical discipline within the team. CDER inspectors may travel to clinical study sites to conduct a routine inspection. The agency looks for evidence of fabrication, adulteration, manipulation, or withholding of data. Then, the project manager assembles all individual reviews and other documents, such as the inspection report, into an "action package." This document becomes the record for FDA review. The review team issues a recommendation, and a senior FDA official makes a decision.

In cases in which CDER determines that a drug has been shown to be safe and effective for its intended use, scientists proceed to work with the applicant to develop and refine prescribing information, also referred to as the labeling. Labeling accurately and objectively describes the basis for approval and how best to use the drug.

Remaining issues often need to be resolved before the drug can be approved for marketing. In some cases, CDER requires the drug developer to address questions based on existing data. In other cases, additional studies are required. At this point, the developer can decide whether or not to continue further development. If a developer disagrees with an FDA decision, there are mechanisms for formal appeal.

It can take years to learn whether a drug truly impacts how a patient survives, feels, or functions [24]. For patients whose illness is potentially terminal, the length of time it typically takes for approval can be problematic. Accelerated approval allows drugs for serious conditions that fill unmet medical needs to be expedited during the review process and approved based on a surrogate or intermediate clinical endpoint [27].

For example, when acquired immunodeficiency syndrome (AIDS) became a leading cause of death among men 25 to 44 years of age in 1992, patients desperately needed access to therapies. Instead of evaluating whether an antiviral drug prolonged patient survival, the FDA reduced clinical trial time by using CD4 cell counts and measures of viral load as indicators for predicting increases in survival rates [25,26]. The FDA approved zidovudine based on these early indicators, known as surrogate or intermediate clinical biomarkers, and required the sponsor to confirm the predicted clinical benefits after approval. This process became known as accelerated approval [9].

A surrogate endpoint used for accelerated approval is a marker (e.g., a laboratory measurement, radiographic image, physical sign) that is thought to predict clinical benefit; however, it is not itself a measure of clinical benefit [9]. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality [9]. The FDA bases its decision whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint. Studies demonstrating a drug's effect on a surrogate or intermediate clinical endpoint must be "adequate and well controlled," as required by the FD&C Act [28,29].

Using surrogate or intermediate clinical endpoints can save valuable time in the drug-approval process. Of course, the drug company will need to conduct studies to confirm this surrogate endpoint predicts patients will achieve the predicted clinical endpoint, such as increased survival time, through Phase 4 confirmatory trials.

When confirmatory trials verify clinical benefit, the FDA will generally terminate the requirement. Approval of a drug may be withdrawn or the labeled indication of the drug changed if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the drug's associated risks. This could occur if a drug shows a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate.

FDA's fast track process facilitates the development and expedites review of such drugs that treat serious conditions and fill an unmet medical need. This authority was first created in a 1997 statute.

Determining whether a condition is "serious" is a judgment call. Generally, this decision is based on the drug's ability to impact survival, day-to-day functioning, and/or the likelihood that the condition, if left untreated, will progress from a less severe condition to a more serious one [29]. AIDS, Alzheimer disease, heart failure, and cancer are clear examples of serious conditions.

Drugs are directed at an unmet need if they are being developed to treat or prevent a condition with no current therapy. If there are available therapies, a fast-track drug must demonstrate some advantage, such as:

A drug that receives fast-track designation is eligible for some or all of the following:

Fast-track designation may be requested by the pharmaceutical company at any time during the drug-development process. The FDA will review the request and make a decision within 60 days based on whether the drug fulfills an unmet medical need for a serious condition.

After a drug receives fast-track designation, early and frequent communication between the FDA and the pharmaceutical company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

The authority to designate a breakthrough product was created in a 2009 statute. A "breakthrough" therapy may sound like a ground-breaking medical discovery or advancement, but only preliminary clinical evidence is necessary to show that a breakthrough drug may substantially improve existing therapies on at least one endpoint. The breakthrough therapy designation aims to speed the development and review of drugs intended to treat a serious or life-threatening disease alone or with other drugs.

It can be difficult to judge whether a drug's improvement over available therapy is substantial. This determination depends on the magnitude of the effect of treatment, such as treatment duration and the observed clinical outcomes. The preliminary clinical evidence should show a clear advantage over available therapy.

Substantial improvement on one or more clinically significant endpoints generally refers to an endpoint measuring an effect on irreversible morbidity and mortality or symptoms from the disease's serious consequences. A clinically significant endpoint can also refer to findings that suggest an effect on irreversible morbidity and mortality or serious symptoms, including:

A drug that receives breakthrough therapy designation is eligible for the following [36]:

If the drug sponsor requests breakthrough-therapy designation, the FDA can grant the designation after reviewing the submitted data if the agency believes the drug development program may meet the criteria for the designation. The remaining drug-development program can benefit from the designation [15].

Because the breakthrough-therapy designation intends to develop evidence supporting drug approval as efficiently as possible, the FDA does not anticipate that designation requests will be made after submission of the original biologic license application, NDA, or supplement. Designation requests should be received by the FDA before the end of phase of Phase 2 meetings. FDA will respond to these requests within 60 days [15].

Every drug marketed in the United States goes through the FDA's detailed review process. In 1992, however, FDA created a new two-tiered system aimed to improve drug review times: standard review (10 months) and priority review (6 months). A drug can earn priority review designation if it treats a serious or life-threatening condition and would significantly improve the safety or effectiveness of the treatment, diagnosis, or prevention of that condition if approved. Significant improvement may be demonstrated by [30]:

Although the FDA determines the review designation of every application, an applicant may expressly request priority review [15]. A drug's designation does not affect the length of the clinical trial period nor does it alter the scientific or medical standard for approval or the quality of evidence necessary.

As extensive as CDER's premarket review process is, active post-marketing surveillance of adverse drug effects is also essential. Not all possible side effects of a drug can be anticipated. Clinical trials only involve several hundred to several thousand patients. So, the FDA maintains a system of post-marketing surveillance and risk assessment programs to identify adverse events (e.g., adverse reactions, poisonings) that did not appear during the drug approval process. The agency uses this information to update drug labeling and, on rare occasions, to re-evaluate the approval decision.

The FDAAA also gave the FDA new authorities and responsibilities to enhance drug safety. One of its provisions gave the FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from sponsors to ensure that the benefits of a drug or biologic product outweigh its risks. REMS are required risk management plans that use risk minimization strategies beyond the professional labeling to ensure that the benefits of certain prescription drugs outweigh their risks [33].

The FDA may require a REMS before or after approval if the FDA becomes aware of new safety information and determines REMS is necessary to ensure that the benefits of the drug outweigh the risks. The risk must be a serious risk that is documented in the drug's label. Essentially, a REMS is a safety strategy to manage a known or potential serious risk associated with a medication and to enable patients to have continued access to such medicines by managing their safe use.

Because medications vary widely, each REMS is also different. Elements to assure safe use are required medical interventions or other actions healthcare professionals must execute prior to prescribing or dispensing the drug to the patient. Some actions may also be required in order for the patient to continue on treatment.

The REMS@FDA website (https://www.fda.gov/rems) improves the organization of REMS information online and makes it easier for users to access comprehensive REMS information. Prescribers can search by the name of the REMS, an element of the REMS program, or by an active ingredient with a REMS. In each REMS, there is a section that explains what healthcare providers and pharmacists must know in order to prescribe and/or dispense a drug with a REMS. The site also features links to the prescribing information from the DailyMed site and to the Drugs@FDA information for a product.

The MedWatch program is for health professionals and the public to voluntarily report serious reactions and problems with medical products, such as drugs and medical devices. MedWatch also ensures that new safety information is rapidly communicated to the medical community to improve patient care. All data contained on the MedWatch form will be entered into the FDA Adverse Event Reporting System (FAERS) database. The MedWatch page includes sections on how to report an adverse event, safety information, and publications.

After a drug is approved and marketed, the FDA uses different mechanisms to assure that firms adhere to the terms and conditions of approval described in the application and that the drug is manufactured in a consistent and controlled manner. This is done by periodic, unannounced inspections of drug production and control facilities by the FDA's field investigators and analysts.

Manufacturers of prescription medical products are required by regulation to submit adverse event reports to the FDA. The MedWatch site provides information on mandatory reporting by manufacturers. In addition, drug manufacturers must submit either error and accident reports or drug-quality reports when deviations from current good manufacturing practice regulations occur.

The FDA receives medication error reports on marketed human drugs (including prescription, generic, and over-the-counter drugs) and non-vaccine biologic products and devices. The National Coordinating Council for Medication Error Reporting and Prevention defines a medication error as [37]:

CDER medication errors program staff reviews medication error reports sent to the Institute for Safe Medication Practices National Medication Errors Reporting Program and MedWatch, evaluates causality, and analyzes the data to provide feedback to others at the FDA.

Adverse events reported to the FDA's MedWatch program provide a vital source of information to the FDA. Today, resources are available to make reporting to MedWatch easier. Anyone can submit a report to MedWatch online at https://www.fda.gov/MedWatch. Reporting forms can be completed online or printed and completed by hand. In addition to reporting as a health professional, patients should be referred to the consumer form.

The FAERS is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The ultimate goal of FAERS is to improve the public health by providing the best available tools for storing and analyzing safety reports. The reports in FAERS are evaluated by a multidisciplinary staff of safety evaluators, epidemiologists, and other scientists in the CDER Office of Surveillance and Epidemiology to detect safety signals and to monitor drug safety. If a potential safety concern is identified in FAERS, further evaluation is performed, such as conducting studies using other large databases. Based on an evaluation of the potential safety concern, the FDA may take regulatory action to improve product safety and protect the public health, such as requiring changes to the drug's labeling. Drug safety labeling changes are published online.

Reporting of adverse events and medication errors by healthcare professionals and consumers is voluntary in the United States. The FDA may receive these adverse event and medication error reports directly or from the manufacturer who made the drug or biologic product. If a manufacturer receives an adverse event report, they are, in most cases, required to send the report to FDA. The reports received directly from healthcare professionals/consumers and the reports received from manufacturers are both entered into FAERS [34].

Under specific circumstances, the FDA will award priority review vouchers to sponsors of rare pediatric disease product applications that meet certain criteria. In addition, a sponsor who receives an approval for a drug or biologic for a "rare pediatric disease" may qualify for a voucher that can be redeemed to receive a priority review of a subsequent marketing application for a different product.

In 2019, the FDA issued a draft guidance titled RarePediatric Disease Priority Review Vouchers: Guidance for Industry. This guidance explains how FDA plans to implement the section of the act that defines a rare pediatric disease. It also describes the process by which sponsors who are interested in receiving rare pediatric disease priority review vouchers may first request designation of their drug or biologic product ("drug") as a drug for a "rare pediatric disease." While such designation is not required to receive a voucher, requesting this in advance will expedite a sponsor's future request for a priority review voucher.

The Orphan Drug Act allows a drug or biologic product that treats a rare disease or condition to be granted special orphan designation or "orphan status" upon request of a sponsor. For a drug to qualify for orphan designation, both the drug and the disease or condition must meet certain criteria specified in the Orphan Drug Act and the FDA's implementing regulations. Orphan designation qualifies the sponsor of the drug for various development incentives of the Orphan Drug Act, including tax credits for qualified clinical testing. A marketing application for a prescription drug product that has received orphan designation is not subject to a prescription drug user fee unless the application includes an indication for other than the rare disease or condition for which the drug was designated.

A sponsor seeking orphan designation for a drug must submit a request for designation to Office of Orphan Products Development with the information required [39]. Each designation request must stand on its own merit. Sponsors requesting designation of the same drug for the same rare disease or condition as a previously designated product must submit their own data and information in support of their designation request. The granting of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval. Safety and effectiveness of a drug must be established through adequate and well-controlled studies.

The objective of the patient-focused drug development initiative is to gather patient perspectives on the disease severity and current therapeutic options available for certain disease areas. This information is a critical aspect of the FDA's decision making in the drug-review process because it establishes the context in which regulatory decisions are made. The FDA convened with patient stakeholders to host 24 meetings on specific disease areas between 2013 and 2017. Each meeting resulted in a Voice of the Patient Report summarizing the input provided by patients and patient representatives [40].

MedWatch alerts provide physicians and the public with timely new safety information about human medical products. These alerts can impact treatment and diagnostic choices made by healthcare professionals and their patients. Safety alerts may relate to human drugs, medical devices, vaccines and other biologic products, dietary supplements, and cosmetics.

Physicians can submit a MedWatch Online Voluntary Reporting Form to report problems (e.g., adverse events, medication error reports) related to an FDA-regulated drug. Healthcare professionals may also report these issues to product manufacturers. Manufacturers are required to send any adverse event report to the FDA, as specified by regulations. Reports the FDA receives directly or from manufacturers are entered into FAERS.

The Drug Safety Labeling Changes database informs the public of approved safety labeling changes. Among these labeling changes are updates to boxed warnings, contraindications, warnings, adverse reactions, or patient package insert/medication guide sections of the drug label. Changes to labeling data made before 2016 are available on the MedWatch website.

News about approved drugs and other medical products approved since 2014 are posted online on the press announcements webpage. Subscription to the CDER New email list will result in updates on drug topics, including new and generic drug approvals and drug shortages. Additionally, Drug Trials Snapshots provide clinicians and consumers with information about newly approved drugs and who participates in clinical trials for these drugs.