The mission of the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) is to ensure that drugs marketed in the U.S. are safe and effective. The New Drug Application (NDA) process enables sponsors to formally propose that the FDA approve a new drug for sale and marketing in the U.S. The NDA aims to generate high-quality, robust clinical evidence to permit the FDA reviewer to assess product safety and efficacy.

This article provides an overview of the approval process to help guide you through common challenges and best practices for getting your clinical trials approved by the FDA.  

 

FDA Drug Approval Process 

The FDA approval process includes an analysis of the target condition and available treatments, assessing benefits and risks from clinical data, and strategies for managing risks. Depending on specific criteria, e.g., a new drug with a significant therapeutic benefit over existing therapies, approval may be expedited via the FDA Accelerated Approval route. The FDA has designations to encourage the development of certain drugs, including fast track, breakthrough therapies, and priority review.  

 

Pre-clinical Development 

Pharmaceutical and Biotech sponsor’s discovery and screening phase.  

 

Step 1. Animal tested  

During the pre-clinical stage, the sponsor develops a new compound to seek FDA approval. The sponsor tests the new compound on animals for toxicity, gathering basic safety and efficacy data from tests on multiple species.   

 

Step 2. IND Application  

The sponsor must submit an Investigational New Drug (IND) application to the FDA based on initial testing results, including the drug’s composition and manufacturing, and develop a plan for testing the drug on humans. Three IND types include an Investigator IND submitted by a physician who initiates and conducts an investigation, Emergency Use IND during emergencies, and Treatment IND for experimental drugs showing promise in clinical testing for serious conditions while the final clinical work is conducted. INDs are categorized as commercial or research (non-commercial). 

The FDA reviews the IND application to ensure that the proposed clinical trials do not subject human trial participants to an unreasonable risk of harm and verifies that the sponsor has adequate informed consent and participant protection in place.  

 

Clinical Trials 

The new drug goes through the sponsors’ Phase I, II, and III clinical trials. Each phase can take two years; however, the duration depends on several factors, such as patient recruitment and the rarity of the disease being treated. The FDA also supports decentralized clinical trials, which can be leveraged for drug safety monitoring to improve clinical trial participation. 

 

Step 3. Phase I: Safety 

Phase I trials, which typically have 20 to 80 healthy volunteers participating, are the first time the new drug is given to humans. Phase I trials emphasize safety, determine the best dose, and provide preliminary safety data. This phase aims to determine the drug’s most frequent side effects and how it is metabolized and excreted. Aware that a key FDA priority is to protect the rights, safety, and welfare of clinical trial participants, sponsors ensure that the design, conduct, analysis, and reporting of clinical trials comply with federal law and good clinical practice (GCP) guidelines. Further, sponsors work towards clinical trials that generate high-quality, robust clinical evidence to assess product safety and efficacy. To facilitate the drug development process, a shared objective of the FDA and sponsors is clear and effective communication, which goes both ways – a win-win.

Effective and timely communication between sponsors and the FDA throughout the FDA approval process improves understanding of mutual goals. As the approval process typically takes more than a year, the FDA acknowledges that new data will become available during this time, while changes may occur in clinical practice and regulatory requirements. Sponsors are encouraged to monitor any advances or changes and proactively inquire if or how they impact their drug development programs. To foster effective communication, sponsors should be mindful of different business cultures, communication styles, preferences, and documentation needs and adapt accordingly, as there is no single best communication method.  

 

Step 4. Phase II: Safety & Efficacy 

Phase II trials emphasize efficacy and typically have participants in the hundreds. The goal is for sponsors to collect preliminary data on whether the drug is efficacious and to obtain more safety data for a larger group of participants. In addition to clinical data collected and analyzed to demonstrate the safety and efficacy of the drug, patient experience data (PED) may be collected as part of clinical trials. Aside from their experiences, PED captures patients’ perspectives, needs, and priorities related (but not limited) to their symptoms and natural history of their condition, the impact on quality of life, and their preferences for outcomes and treatments.

The 21st Century Cures Act, which came into effect in 2016, requires transparency and accountability in the use of PEDs in drug and biological marketing applications. The FDA has policy targets to extend PED use. However, a recent study indicates that the industry faces challenges regarding pathways for submission and transparency in the use of PED in regulatory decision-making9. In response, the study authors recommend using existing meeting pathways to facilitate discussion about the development and use of PEDs. Additionally, they suggest that the industry drives best practices and standards by working with the FDA and other thought leaders to help integrate patient voices in drug development and FDA regulatory decision-making. 

 

Step 5. Phase III  

Phase III trials continue gathering more safety and effectiveness data and typically have thousands of participants. Additionally, these trials study different populations, different dosages, and the new drug in combination with other medications. In the case of accelerated approvals, the FDA may approve drugs before a Phase III clinical trial is conducted.

A recent webinar initiated by the FDA highlights common mistakes in integrated safety analyses in drug marketing applications. One of the common mistakes is not seeking FDA input early enough, with the recommendation of leveraging the FDA’s Type C meeting specifically on integrated safety planning.

Interested in learning more about the design of clinical trials? Here, you can find a detailed description of the purpose, process, and key characteristics of each phase of clinical research.

 

FDA’s New Drug Application (NDA) Review 

The FDA’s New Drug Application (NDA) review process is a crucial step in ensuring the safety and efficacy of new pharmaceutical products before they reach the market. This comprehensive evaluation involves rigorous scrutiny of clinical data, manufacturing processes, and labeling information to ensure that new drugs meet the stringent standards set by the FDA. By thoroughly reviewing each NDA, the FDA aims to protect public health while fostering innovation in the pharmaceutical industry.

Step 6: Review Meeting 

Before an NDA submission, the FDA has a review meeting with the sponsor. Sponsors must familiarize themselves with the FDA guidance for formal meetings, which covers the principles of good meeting management practices and standardized procedures for requesting, preparing, scheduling, conducting, and documenting formal meetings.  

 

Step 7: NDA Application 

In this step, the sponsor submits the NDA, which tells the drug’s whole story, to formally ask the FDA to approve the drug for marketing in the U.S. The documentation required in an NDA includes all animal and human data, analyses of the data, information on how the drug behaves in the body, as well as how it is manufactured, processed, and packaged. Along with clinical results, the NDA must include the proposed labeling, safety updates, drug abuse information, patent information, any data from studies that may have been conducted outside the U.S., institutional review board (IRB) compliance information, and directions for use. 

 

Step 8: Application reviewed 

Once received, the FDA has 60 days to decide whether to file for review. If the FDA chooses to file the NDA, the FDA Review team is assigned to begin evaluation of the sponsor’s research and findings on the drug’s safety and effectiveness. The team has six to ten months to examine all submitted data thoroughly to arrive at a decision. As part of the review process, the FDA’s safety surveillance begins early in the product’s life cycle. It includes considering appropriate measures to continue assessing safety if and when the drug gains FDA approval. FDA inspectors also travel to clinical study sites to conduct routine inspections. Once ready, the project manager assembles all individual reviews and documents into an “action package,” which becomes the record for FDA review. Based on the review team’s recommendation, a senior FDA official makes a decision.  

 

Step 9: Drug Labeling 

The FDA reviews the drug’s professional labeling to ensure appropriate information is communicated to healthcare professionals and consumers, including a summary of the essential scientific evidence needed for its safe and effective use. In postmarket monitoring, the FDA has recognized the need to add clinically meaningful data in prescribing information for already-approved drugs when appropriate. 

 

Step 10: Facility inspection 

The FDA inspects facilities where the FDA-regulated products will be manufactured. The inspection is a careful, critical, official onsite examination of the facility to verify that it complies with federal law. 

 

Step 11: Drug Approval 

FDA reviewers will approve the NDA or issue a response letter. If remaining issues need to be resolved before approval, e.g., addressing questions based on existing data or conducting additional studies, the sponsor can decide whether or not to pursue further development. If the sponsor disagrees with the FDA decision, they can formally appeal.  

 

Post-marketing 

Consistent with its mission to protect and advance health, the FDA monitors the safety of products over their life cycle and takes regulatory action when needed. As it is not possible to identify all risks or predict all drugs’ effects during clinical trials, post-marketing monitoring, where the sponsor must submit periodic safety updates, is critical. The FDA’s post-marketing safety system detects unexpected severe adverse events and takes definitive action, e.g., if new risks are discovered, they are added to the labeling.

To better understand the impact of the FDA’s historical issuance of post-marketing commitments/post-marketing requirements (PMCs/PMRs) as novel targeted cancer therapies entered the market, a recent study analyzed all FDA oncology approvals from 2010 to 2022. The researchers found that PMC/PMR issuance broadly increased over time and that most dose-related PMRs/PMCs were for new molecular entities (NMEs). Kinase inhibitors (KIs) and antibody/peptide drug conjugates (ADCs/PDCs) were highly represented, reflecting their novelty and safety profile uncertainty.

Novel oncologic therapies are changing the treatment landscape. The expectation from the FDA is that sponsors reassess the traditional approach to dose-finding studies, e.g., more comprehensive approaches through multiple cohorts or expansions, using simulations and models, and a deeper understanding of the patient’s pharmacokinetic/pharmacodynamic (PK/PD) to mitigate the risk of unnecessary toxic effects over multiple dosing cycles. In January 2023, the FDA released a draft dose optimization guidance emphasizing the need to collect appropriate dose–exposure-response data and other pertinent PK/PD information to comprehensively assess the benefits versus risks of new oncology drugs and biological products.  

 

TFS HealthScience: Your CRO Partner in Clinical Development 

TFS HealthScience (TFS) is a global, mid-size contract research organization (CRO) with over 800+ employees worldwide. TFS has extensive experience managing all aspects of regulatory affairs, supporting all phases through clinical development to market authorization and product maintenance. Our senior staff offers more than 30 years of successful submission experience, including medical writing services and interacting with regulatory agencies worldwide. 

TFS will be your trusted regulatory services CRO partner from discovery through development to market authorization and product maintenance. Contact a TFS team member today to learn more or request a proposal for our full-service CRO solutions across multiple therapeutic areas, as well as strategic resourcing solutions.