Health and consumer safety are always top priorities for every nation. In the field of healthcare, ensuring the quality and effectiveness of medications plays an incredibly important role. The U.S. Food and Drug Administration (FDA) takes the lead in fulfilling this mission through a rigorous and meticulous drug approval process. This article will delve into exploring the FDA’s drug approval process, including key steps and evaluation criteria to ensure that only safe and effective medications are allowed to circulate in the market. Let’s dive into it with GOL!

The definition of drugs according to the FDA

According to the Food and Drug Administration (FDA) of the United States, drugs are defined as:

• A substance acknowledged by an official pharmacopeia or formulary.
• A substance designed for application in diagnosing, curing, alleviating, treating, or preventing diseases.
• A substance, excluding food, intended to influence the structure or functions of the body.
• A substance intended for incorporation into medication, distinct from devices or their components, parts, or accessories.
• Biological products fall under this definition and are typically subject to the same laws and regulations. Nonetheless, disparities arise in their manufacturing procedures, distinguishing between chemical and biological processes.

The FDA’s Center for Drug Evaluation and Research (CDER) evaluates and approves new drugs before they are marketed in the United States. It is responsible for both prescription and over-the-counter (OTC) drugs.

Companies must submit a New Drug Application (NDA) to introduce a new drug product into the U.S. market. Each application is assigned a New Drug Application number by FDA staff. One drug may have multiple application numbers if it comes in different dosage forms or routes of administration.

New drugs, like other new products, are often protected by patents during development. Patents safeguard the sponsor’s investment in drug development by granting them exclusive rights to sell the drug for the duration of the paten.

Read more: FDA approved vs FDA cleared: The differences you need to know

8 Stages of Drug development and review

Preclinical Testing in Animals

Before submitting an Investigational New Drug Application (IND), pharmaceutical companies often consult the FDA for guidance. Sponsors, including companies, research institutions, and other entities, are accountable for drug development. They present the FDA with preclinical test findings from laboratory animals and their proposed plans for human trials. The FDA evaluates the safety of proceeding with human testing based on this information.

IND Application

Initiation of Clinical Trials—Human trials can commence only upon the review of an IND by the FDA and a local institutional review board (IRB). The IRB, composed of both scientific and non-scientific members in hospitals and research establishments, supervises clinical research activities.

IRBs evaluate and approve the protocols for clinical trials, outlining criteria for participant selection, scheduling of assessments, medication types and dosages under investigation, study duration, objectives, and other pertinent details. Ensuring the ethical acceptability of the study, informed consent from participants, awareness of associated risks, and adequate protection of participants from harm are among the IRB’s responsibilities.

Phase 1 testing

Phase 1 trials typically involve healthy volunteers. The primary aim is to identify the most common side effects of the drug and frequently, its metabolic and excretory pathways. Typically, these studies involve 20 to 80 subjects.

Phase 2 testing

Phase 2 testing commences if Phase 1 testing does not uncover unacceptable toxicity. While Phase 1 focuses on safety, Phase 2 concentrates on efficacy. The objective is to gather initial data on the drug’s effectiveness in individuals with a specific disease or condition. Controlled trials are conducted where patients receiving the drug are compared to those receiving either a placebo or a different drug. Safety assessments persist, with short-term side effects being examined. Typically, Phase 2 trials involve anywhere from a few dozen to about 300 subjects.

Phase 3 testing

Upon conclusion of Phase 2, the FDA and sponsors negotiate the parameters for conducting large-scale Phase 3 studies. The frequency of FDA meetings with sponsors varies, but this represents one of the two primary junctures for discussion prior to the submission of a new drug application. The other common meeting point occurs pre-New Drug Application (pre-NDA), just before the application is submitted.

Phase 3 trials commence if Phase 2 demonstrates evidence of effectiveness. These trials gather further data on safety and efficacy, examining diverse populations, varied dosages, and assessing the drug’s compatibility with other medications. Typically, Phase 3 trials involve several hundred to about 3,000 participants.

Review Meeting

Postmarket requirement and commitment studies are mandated by the FDA or agreed upon by a sponsor, and they occur after the FDA has granted approval for a product to be marketed. These studies serve as a means for the FDA to collect supplementary data regarding the safety, efficacy, or optimal utilization of a product.

NDA application

The New Drug Application (NDA) is the formal process through which a drug sponsor petitions the FDA to review and potentially approve a new drug for commercial distribution in the United States. An NDA comprises comprehensive data from both animal and human trials, along with analyses of these data. Additionally, it includes details regarding the drug’s pharmacokinetics, pharmacodynamics, and manufacturing processes.

Read more: A Guide to Drug Master Files

Application Reviewed

Upon receipt of an NDA, the FDA has a 60-day window to determine whether to accept it for filing and subsequent review. Incomplete applications may be refused if essential studies or data are absent. As per the Prescription Drug User Fee Act (PDUFA), the FDA’s Center for Drug Evaluation and Research (CDER) aims to review and make decisions on at least 90 percent of standard drug NDAs within 10 months of receipt. Priority drugs have a shorter review goal of six months. (Refer to “The Role of User Fees” for further details.)

“It’s the clinical trials that take so long—usually several years,” explains Sandra Kweder, M.D., deputy director of the Office of New Drugs in the CDER. “The emphasis on speed for FDA mostly relates to review time and timelines of being able to meet with sponsors during a drug’s development,” she clarifies.

The FDA’s drug approval and development process

The significance of FDA approval

FDA approval of a drug signifies that data regarding the drug’s effects have undergone review by CDER, and it has been determined that the drug offers benefits that outweigh its known and potential risks for the intended population. The drug approval process follows a structured framework, which includes:

• Analysis of the target condition and available treatments: FDA reviewers assess the condition or illness the drug is intended to treat and evaluate the current treatment landscape. This analysis provides the context for weighing the drug’s risks and benefits. For instance, a drug designed to treat patients with a life-threatening disease lacking other therapies may be deemed beneficial despite associated risks.
• Assessment of benefits and risks from clinical data: FDA reviewers evaluate clinical benefit and risk information provided by the drug manufacturer, considering any uncertainties resulting from imperfect or incomplete data. Typically, the agency expects two well-designed clinical trials to validate findings, ensuring they are not due to chance or bias. However, in certain cases, such as with rare diseases, convincing evidence from a single trial may suffice. The evidence of the drug’s benefit for the target population should outweigh any associated risks and uncertainties.
• Strategies for managing risks: All drugs carry risks. Risk management strategies include an FDA-approved drug label outlining the drug’s benefits, risks, and how to detect and manage risks. In some instances, additional measures, such as a Risk Management and Mitigation Strategy (REMS), may be necessary to address risks effectively.

While many FDA risk-benefit assessments and decisions are straightforward, some scenarios involve uncertain benefits and risks that may be challenging to interpret or predict. There could be differing conclusions between the FDA and the drug manufacturer, or among FDA review team members. As a science-driven organization, the FDA relies on the best available scientific and technological information to make decisions through a deliberative process.

Accelerated Approval

Accelerated Approval is a mechanism designed to expedite the approval of new drugs, particularly those addressing serious or life-threatening conditions and offering therapeutic benefits surpassing existing treatments. This pathway permits the approval of a drug based on its effect on a “surrogate endpoint” or an earlier occurring clinical endpoint that may not be as robust as the standard endpoint used for approval but is reasonably likely to predict clinical benefit. It is particularly beneficial for diseases with lengthy courses where measuring effects necessitates extended periods.

Upon entering the market, drug manufacturers must conduct post-marketing clinical trials to validate and elucidate the drug’s benefits. If subsequent trials fail to confirm the predicted clinical benefit, the FDA retains the authority to rescind approval.

Since its inception in 1992, the Accelerated Approval pathway has facilitated the introduction of numerous drugs targeting life-threatening diseases, significantly influencing disease management. Notable examples include many antiretroviral drugs for HIV/AIDS treatment, which reshaped treatment approaches, and several targeted cancer therapies that have emerged through this pathway.

Drug Development Designations

The FDA utilizes various approaches to incentivize the development of specific drugs, particularly those that may offer the first available treatment for an illness or exhibit significant benefits over existing therapies. These approaches, known as designations, are tailored to address distinct needs, and a new drug application may receive multiple designations if applicable. Each designation is aimed at ensuring timely availability of therapies for serious conditions, balancing benefits with risks.

• Fast Track: This process streamlines the development and accelerates the review of drugs targeting serious conditions with unmet medical needs, based on promising animal or human data. Fast Track expedites the delivery of important new drugs to patients. Drug companies must formally request participation in the Fast Track process to benefit from its advantages.
• Breakthrough Therapy Designation: This designation expedites the development and review of drugs intended for serious conditions, where preliminary clinical evidence suggests significant improvement over available therapies. Drugs with Breakthrough Therapy designation are also eligible for Fast Track status. Drug companies must request Breakthrough Therapy designation to avail of this designation’s benefits.
• Priority Review: Priority Review aims to expedite FDA action on an application within six months, compared to the standard 10-month review period. This designation directs FDA attention and resources toward evaluating drugs that could substantially enhance the treatment, diagnosis, or prevention of serious conditions.

FAQ Regarding the Importation of Human Drugs

Which drug standards are assessed during the importation process?

Imported drugs are required to adhere to the FDA’s criteria for quality, safety, and effectiveness. The FDA ensures compliance with the following requirements, where applicable:

• Registration
• Listing
• Drug application
• Drug labeling
• Current Good Manufacturing Practices (cGMPs)

How does the FDA ensure compliance with drug requirements during importation?

FDA entry reviewers are equipped to confirm adherence to relevant product standards. They rely on information supplied to the FDA in the importer’s entry transmission, including:

• Declared Manufacturer
• Declared Importer/Consignee
• Product Description
• Affirmations of Compliance (A of C)
• Intended use code

These declarations are cross-referenced with data in FDA’s internal systems. If the information aligns, compliance is confirmed; discrepancies may prompt FDA to seek further information or detain the product. Additionally, FDA conducts field examinations and analyzes samples to ensure compliance with standards and labeling requirements.

Submitting accurate entry data and A of C codes expedites the review process, potentially allowing for electronic processing and avoiding manual review. FDA’s screening tool, PREDICT, verifies declared information against internal data systems.

Please note that: Inaccurate or incomplete information may delay entry review.

How to Register and List?

Foreign drug manufacturers, packagers, relabelers, or salvagers intending to import their products into the United States must register with the FDA beforehand and renew this registration annually. As part of this process, they are required to designate a U.S. Agent and disclose all known importers.

Additionally, these establishments must provide the FDA with a comprehensive list of each drug they manufacture for commercial distribution. This listing information needs to be updated semi-annually, in June and December, with any changes promptly communicated to the FDA.

How does the FDA verify registration and listing during importation?

The FDA confirms the registration of the declared manufacturer and the listing of the product by cross-referencing the information provided to the FDA with its own drug registration and listing databases. Additionally, the FDA ensures that the foreign manufacturer has identified the declared importer or consignee in their registration. In cases where discrepancies arise, the FDA may require further information or detain the product until the issue is resolved.

What are types of Drug Applications

Drug applications come in various forms, each serving a specific purpose in the regulatory approval process before a drug can be imported into the U.S. These include:

• New Drug Application (NDA)
• Abbreviated New Drug Application (ANDA)
• Investigational New Drug Application (IND)
• Biologic License Application (BLA)

How does the FDA verify drug application information at the time of importation?

To verify drug application information during importation, the FDA conducts a thorough assessment. When necessary, the FDA cross-references the declared New Drug Application (NDA), Abbreviated New Drug Application (ANDA), Biologic License Application (BLA), or Investigational New Drug Application (IND) with its own data systems. Failure to provide, or inaccuracies in, the NDA, ANDA, BLA, or IND details can potentially impede the entry review process. In such cases, the FDA may request additional information or detain the product until discrepancies are resolved.

Products requiring an NDA, ANDA, BLA, or IND that lack proper documentation are subject to refusal. It is crucial to ensure accurate and complete submission of application information to facilitate the importation process without delays.

FDA regulations on Drug Labeling 

Drug Labeling, as regulated by the FDA, encompasses specific requirements that apply to all drug products imported into the United States. The FDA conducts a review of drug labeling at the point of importation to ensure compliance with these regulations. The nature of labeling requirements varies depending on the type of drug product. For instance, over-the-counter drugs, prescription drugs, investigational drugs, and drugs imported for drug efficacy studies (DESI drugs) are subject to distinct labeling requirements in addition to general provisions governing drug labels.

GOL – A reputable FDA registration service provider

Compliance with FDA regulations is a mandatory requirement for businesses looking to export food, cosmetics, drugs, and medical devices to the U.S. market. However, this process involves complex procedures and consumes a considerable amount of time, posing challenges for many businesses.

Hiring an agency for support is an effective solution to address the FDA compliance puzzle. GOL takes pride in being a reputable provider of FDA consultancy and registration services for clients in the following fields:

• Food
• Cosmetics
• OTC Drugs
• Medical devices

With an experienced team of experts deeply knowledgeable about FDA regulations, GOL is committed to delivering the most professional and effective services, including:

FDA Consultancy:

• Clarifying FDA regulations inquiries
• Providing updates on laws and new regulations
• Guiding businesses in developing tailored FDA compliance strategies

FDA Registration service:

• Assisting businesses in preparing complete and accurate registration files
• Ensuring registration files meet all FDA requirements
• Representing businesses in submitting and monitoring the registration process
• U.S Representative Office to coordinate with the FDA

Contact GOL today for a free consultation and receive optimal solutions for FDA compliance!