The United States Food and Drug Administration (FDA) serves as the principal regulatory authority overseeing the safety, efficacy, and labeling of diverse products, including pharmaceuticals, medical devices, and biopharmaceuticals. This whitepaper explores the multifaceted role of the FDA in safeguarding public health while fostering innovation within the pharmaceutical industry. Key focus areas include an overview of the FDA's regulatory functions, drug approval pathways, and considerations for successfully obtaining market authorization in the United States.
Through a comprehensive examination of regulatory strategies, preclinical research, clinical trials, New Drug Application (NDA) submission, and post-approval commitments, this whitepaper provides valuable insights into the complexities of navigating the FDA approval process. Additionally, it delves into the intricacies of FDA approval fees and the challenges encountered in submitting Investigational New Drug (IND) or New Drug Application (NDA) applications. By identifying regulatory compliance, data requirements, communication strategies, and resource allocation as key challenges, this whitepaper offers practical recommendations for overcoming obstacles and achieving successful market entry.
Ultimately, this whitepaper underscores the critical importance of strategic planning, adherence to regulatory guidelines, and collaborative engagement with regulatory authorities in facilitating the successful introduction of new drugs to the U.S. market. Through a concerted effort to address these considerations, pharmaceutical companies can enhance patient access to innovative therapies and contribute to improved public health outcomes.
The United States Food and Drug Administration (FDA) is a federal agency within the Department of Health and Human Services responsible for protecting and promoting public health. The FDA oversees the regulation of various products, including food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), veterinary products, and cosmetics.
The FDA's primary functions and responsibilities are as follows.
The FDA regulates products that account for about 20% of the U.S. consumer spending, ensuring that these products are safe, effective, and accurately labeled.
Before products like drugs, medical devices, and vaccines can be marketed in the U.S., they undergo rigorous testing to demonstrate their safety and efficacy. The FDA reviews data submitted by manufacturers to ensure these products meet the required standards.
The FDA conducts inspections of facilities involved in the manufacturing, processing, packing, or holding of FDA-regulated products to ensure regulatory compliance.
The FDA enforces regulations by taking actions against companies that violate them, including issuing warning letters, recalls, seizures, injunctions, and criminal prosecution when necessary to protect public health.
The FDA provides healthcare professionals, industry stakeholders, and the public with information on drug safety, nutrition, and emerging health threats.
The FDA supports its regulatory mission by conducting research and fostering innovation, offering guidance to developers of new medical products.
The FDA plays a critical role in responding to public health emergencies, such as foodborne illness outbreaks, natural disasters, and emerging infectious diseases. It closely collaborates with other federal agencies, state and local governments, and international partners to coordinate responses and mitigate health risks.
The FDA's primary goal is to protect and promote public health by ensuring the safety, efficacy, and quality of products within its regulatory purview impacting nearly every aspect of healthcare and consumer products in the United States.
Several pathways exist for the approval of new drugs or new indications for existing medications through the FDA. These pathways involve various processes for submitting drug product applications. Two common routes are the 505(b)(2) and the Abbreviated New Drug Application (ANDA). Additionally, FDA regulations in Title 21 CFR Parts 312 and 314 cover the Investigational New Drug Application (IND) and the Application for FDA Approval to Market a New Drug (NDA), respectively. These pathways play a crucial role in expediting drug development and regulatory approval, helping safe and effective drugs reach the market efficiently.
Drugs can follow multiple approval pathways through the FDA, typically beginning with an Investigational New Drug (IND) application based on pre-clinical data. There are three types of IND applications: Investigator IND, Emergency Use IND, and Treatment IND. All require information regarding animal pharmacology and toxicology, manufacturing information on composition and stability, and proposed clinical indications.
Once clinical trial data shows efficacy on standard endpoints in a disease state, the sponsor (individual, corporation, or manufacturer responsible for drug development) submits a New Drug Application (NDA). However, not all drugs that file for an IND progress to an NDA, as they must demonstrate clinical benefit to continue. There are three types of NDAs below.
505(b)(1):Traditional pathway
505(b)(2): Drugs with similar active ingredients to a previously approved drug
505(j): Abbreviated New Drug Application (ANDA): Bioequivalent drugs (generics)
Obtaining approval from the FDA for pharmaceuticals involves several steps, as illustrated below:
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Preclinical Research (for Pharmaceuticals):
Clinical Trials:
New Drug Application (NDA) or Biologics License Application (BLA):
FDA Review:
FDA Approval or Complete Response Letter (CRL):
Post-Approval Commitments and Requirements:
FDA Inspections:
Throughout this process, communication between the sponsor and the FDA is critical, with opportunities for dialogue during pre- submission meetings, application review, and post-approval discussions. Compliance with FDA regulations and guidelines is essential for successful approval and ongoing marketing of the product.
505(b)(1) Application
A 505(b)(1) is an NDA application that requires full reports of investigations of safety and effectiveness investigations conducted by or for the applicant, or for which the applicant has a right of reference. Known as “stand- alone” NDAs, are submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic (FD&C) Act .
505(b)(2) Application
A 505(b)(2) application is an NDA that includes full reports on safety and effectiveness, where some information for approval comes from studies not conducted by or for the applicant, and for which the applicant has not obtained a right of reference . This may include, the FDA’s prior findings on a listed drug’s safety or effectiveness or published literature.
505(j)/Abbreviated New Drug Application (ANDA)
An ANDA, submitted and approved under section 505(j) of the FD&C Act, is used for a drug product that is a duplicate of a previously approved drug. It relies on the FDA’s finding that the reference listed drug (RLD) is safe and effective, and cannot be submitted if clinical investigations are required to establish safety and effectiveness. An ANDA must show that the proposed generic product is the same as the RLD in active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and is bioequivalent to the RLD.
Need for 505(b)(2) and 505(b)(j) pathways
The development of the 505(b)(2) and 505(b)(j) pathways was driven by challenges in the pharmaceutical industry, including patent expirations, cost and time concerns in traditional drug development, regulatory hurdles, and the need for innovation. The Drug Price Competition and Patent Term Restoration Act of 1984 (also known as the Hatch-Waxman Amendments) added sections 505(b)(2) and 505(j) to the Federal Food, Drug, and Cosmetic Act (FD&C Act), establishing abbreviated routes for NDAs and ANDAs approvals. The 505(b)(2) pathway provided a regulatory framework for approving modified or repurposed drugs, leveraging existing safety and efficacy data for the active ingredient. The 505(b)(j) pathway facilitated the approval of generic versions of drugs, addressing specific regulatory considerations. Overall, these pathways aimed to streamline drug development, encourage innovation, and improve access to medications.
General Content Comparison of Applications
| 505(b)(1) NDA | 505(b)(2) NDA | 505(j) |
|---|---|---|
| Preclinical | Preclinical | - |
| Clinical | Clinical | - |
| Chemistry, Manufacturing, Controls (CMC) | CMC | CMC |
| Pharmacokinetics (PK) & Bioavailability | PK, Bioavailability, Comparative Bioavailability | Bioequivalence |
| Labeling | Labeling | Labeling |
| Patent Information | Patent Information | - |
| Patent Certification (if applicable) | Patent Certification | |
| Exclusivity Request | Exclusivity Request | - |
| - | Exclusivity Statement | Exclusivity Statement |
(Source: Abbreviated Approval Pathways for Drug Product: 505(b)(2) or ANDA, 2019)
The FDA currently uses four “alternative” approval processes, each with unique eligibility criteria and specific benefits for sponsors. Except for the Breakthrough Therapy designation, these processes are applied at the New Drug Application (NDA) stage.
A priority review designation means FDA’s goal is to act on an application within 6 months.
These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
(Source: Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review, 2023)
There are multiple FDA approval processes for pharmacologic therapies and drugs for various conditions. Understanding these processes and their relationship to high drug costs, access to care and treatments, and the use of generics and bioequivalents is a high priority to modify treatments within the evolving therapeutic landscape. Unique situations such as the COVID-19 public health emergency, underscore the importance of patient safety and timely access to breakthrough treatments as science advances. Maintaining a credible drug development system, free from political interference, is crucial to providing safe and accessible drugs to patients.
FDA Advisory Board
The FDA Advisory Board is a group of independent physicians and other clinicians that meets to discuss New Drug Applications (NDAs with FDA reviewers and the product’s manufacturer. This advisory team includes physicians, pharmacists, chemists, pharmacologists, statisticians, and patient representatives. These meetings typically last one or two days.
Following the meeting, the Advisory Board makes a recommendation – usually through a vote - on whether to approve the new drug. While the FDA often follows the Board’s advice, it is not obligated to do so.
Cost to Bring a Drug to the Market
Developing a new drug and bringing it to market can cost billions of dollars. A study by the London School of Economics estimated that the median cost to be $985 million, while other studies have suggested costs up to $2.6 billion. Therapeutic class can also impact costs; for instance, drugs for cancer and immunomodulators have a median cost up to $2.7 billion.
Post-Drug Approval
After final approval, the drug becomes available for physicians to prescribe. However, market entry may be delayed due to patents disputes, manufacturing issues, or controlled substance designation from the DEA.
Drug pricing is typically disclosed post- approval. However, unlike in many other countries, the FDA does not consider drug pricing or economic factors as part of its approval process.
MedWatch Safety Program
Once on the market, the drug company continues to report adverse reactions and other clinical data to the FDA. Patients and healthcare providers can also report side effects or other concerns through the FDA’s MedWatch Program. If a new risk is identified, the FDA updates the product label to ensure public awareness.
Successfully bringing a drug to the U.S. market requires navigating regulatory requirements and achieving market authorization. Key considerations include:
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By addressing these factors and collaborating closely with regulatory authorities, pharmaceutical companies can enhance their chances of successfully placing a drug on the U.S. market, thereby, improving patient access to innovative therapies.
FDA drug approval fees are significantly high compared to other regulatory fees in the United States:
For latest information on fees please refer to the link below -
Prescription Drug User Fee Amendments | FDA
The high FDA drug approval fees are reflecting the complexity and length of the drug evaluation process. The Prescription Drug User Fee Act (PDUFA) allows the FDA to collect fees from pharmaceutical companies to expedite drug approval. While these fees are substantial, they have contributed to faster approvals since the program’s inception in 1992. In 2007, the fees covered over 51% of the cost of reviewing and approving new drugs. However, some consumer groups have raised concerns about the potential conflict of interest when a significant portion of the FDA's funding comes from the industry it regulates.
Submitting Investigational New Drug (IND) or New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) can present numerous challenges due to the complex regulatory landscape and the stringent requirements. Here are some key challenges faced by sponsors during the process:
Navigating these challenges requires careful planning, attention to detail, and close collaboration between sponsors and the FDA to facilitate a successful submission and approval process for IND/NDA applications.
Prachi Bhatnagar is a medical writer (Regulatory Affairs) specializing in Pharmaceuticals Clinical Affairs and Medical Writing, with over three years of hands-on experience in the industry. She has successfully supported multiple drug submissions for U.S. FDA, showcasing her in-depth understanding of regulatory requirements and submission processes.
Prachi has also conducted thorough medical reviews on Veeva Promo-Mats, ensuring compliance with the ABPI and EFPIA Codes of Practice. She has authored a range of critical regulatory documents, including Clinical and Non- Clinical overviews.
She is skilled in developing and implementing comprehensive regulatory strategies by conducting feasibility analysis, defining regulatory requirements, and efficiently coordinating with cross-functional teams. Her dedication to regulatory excellence and global compliance has made her a key contributor towards successful market entry for various pharmaceutical products.
She has also been a key contributor towards placing personal grooming product which involved thorough knowledge of chemicals consumer goods regulations across globally which comprises of Europe, U.S., APAC region.
Upon receipt of a De Novo request, the FDA will conduct an acceptance review. The acceptance review is an administrative review to assess the completeness of the application and whether it meets the minimum threshold of acceptability. If any of the acceptance elements are not included, a justification has to be provided for the omission.
To aid in the acceptance review, it is recommended to submit an Acceptance Checklist as per the guidance document with the De Novo request that identifies the location of supporting information for each checklist element.
The De Novo request will not be accepted and will receive a Refuse to Accept (RTA) designation if one or more of the elements noted as RTA items in the Acceptance Checklist are not present and no explanation is provided for the omission(s). However, during the RTA review, the FDA staff has the discretion to determine whether the missing checklist elements are needed to ensure the De Novo request is administratively complete to allow the De Novo request to be accepted.
Within 15 calendar days of the Document Control Center receiving the De Novo request, the FDA will notify the requester electronically of the acceptance review result as one of the following:
Once the De Novo request is accepted for substantive review, the FDA conducts a classification review of legally marketed device types and analyzes whether an existing legally marketed device of the same type exists. This information is used to confirm that the device is eligible for De Novo classification.
During the substantive review of a De Novo request, the FDA may identify deficiencies that can be adequately addressed through interactive review and not require a formal request for additional information.
If the issues and deficiencies cannot be addressed through interactive review, an Additional Information letter will be sent to the requester. If an Additional Information letter is sent, then the De Novo request will be placed on hold. The requester has 180 calendar days from the date of the Additional Information letter to submit a complete response to each item in the Additional Information letter.
Note: The response must be sent to the DCC within 180 calendar days of the date of the Additional Information letter. No extensions beyond 180 days are granted. If the FDA does not receive a complete response to all deficiencies in the Additional Information letter within 180 days of the date of the letter, the request will be considered withdrawn and deleted from the FDA's review system. If the De Novo request is deleted, the De Novo requester will need to submit a new request to pursue the FDA's marketing authorization for that device.
The requester must submit their response to an Additional Information letter in electronic format (eCopy), to the DCC of the appropriate center. The response should—
The final step is the De Novo request decision. Under MDUFA IV, the FDA's goal is to decide about a De Novo request in 150 review days. Review days are calculated as the number of calendar days between the date the De Novo request was received by the FDA and the date of the FDA's decision, excluding the days a request was on hold for an Additional Information request.
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Abhishek Kumar is an SME in Medical Device Regulatory Affairs, Quality Assurance, and Clinical Affairs with over 13 years of experience. He has led the EU MDR-2017/745 sustenance program, identifying business opportunities for sales teams, and managed the engagement program for a US-based medical device company. He has supported the gap assessment, remediation, and submission of 45+ Technical Documentations as per EU MDR, and created 40+ CERs for Class I, II, and III medical devices according to MEDDEV 2.7.1 Rev-4. Additionally, Abhishek has developed proposals for global markets, including Europe, US, ASEAN, China, Taiwan, and Japan, and prepared and implemented regulatory plans for NPD in 90+ countries by analyzing feasibility, defining requirements, and coordinating cross-functional teams.
