New Drug Application: Understanding the NDA Process

The US Food and Drug Administration (FDA) was formed on June 30, 1906 with the passage of the Pure Food and Drugs act, although its origins can be traced back to 1848 and the creation of the Agricultural Division in the US Patent and Trademark Office (USPTO).

The FDA was initially established to regulate food and drug safety and prevent the sale of adulterated or misbranded products. However, when the Federal Food, Drug, and Cosmetic Act was passed in 1938, it set up the modern framework for the regulation of drugs in the US, expanding the agency’s responsibilities.

Now the FDA had the authority to approve or reject new drug products based on their safety and efficacy and to establish requirements for pre-market review and approval of new drugs. This allowed the FDA to enforce standards for the manufacture and distribution of drugs.

The requirement for pre-market evidence of a drug’s safety marked the inception of the New Drug Application (NDA). The firsts applications were submitted in the early 1940s, including applications for drugs that treated bacterial infections, hormone therapies, and mental health conditions.

These early NDAs set the stage for drug development and the FDA’s review and approval process for new drugs. Over the years, the FDA has reviewed and approved thousands of NDAs for new drug products.

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What Is an NDA?

When a company wants to market a new drug in the US, it must submit a marketing application to the FDA for review and approval. There are multiple types of marketing applications, including:

An NDA is a submitted request for permission to market a new drug product, including new molecular entities (NMEs), small molecules, biologics, vaccines, new combinations, new indications, and more.

The NDA must be submitted in a standard format, which is organized using the common technical document (CDT) format, a technical standard for all agency submissions starting from the IND phase. This format provides a standardized way of organizing and submitting regulatory information, and it helps to ensure that the information is consistent and easily accessible.

It’s typical for sponsors to use the Electronic Common Technical Document (eCTD) format, as it is regarded as the fastest delivery method to move the NDA process along between the sponsor and FDA.

Over the years, the application process has evolved to include more stringent requirements and greater scrutiny of the data submitted by drug manufacturers due to advancements in scientific understanding of drugs and their effects as well as increased public attention to drug safety and efficacy.

What Information Does the Application Need to Include?

An NDA application needs to tell the comprehensive story of the drug and include data the FDA can use to determine whether or not the drug is safe for humans to use as intended. Sponsors must include a wide range of required information, including:

  • A cover letter that summarizes the NDA and provides an overview of the information contained in the submission.
  • Administrative information about the sponsor of the drug, including the company name, address, and contact information.
  • Preclinical study results and laboratory tests, including information about the drug’s safety and efficacy in animal models.
  • Clinical studies results, including information about the safety and efficacy of the drug in human subjects, study design, and patient population.
  • Statistical analysis results of the clinical trial data, including information about the statistical significance of the results.
  • Drug information, including the drug’s composition, manufacturing processes, and proposed labeling. This includes the target product profile, annotated package insert, or the final package insert.
  • Manufacturing information, including the facilities and processes used to manufacture the drug. This is used to evaluate the drug’s quality and ensure that it is being produced in accordance with good manufacturing practices.
  • Patent information, including the status of patents covering the new drug, the claims made in the patents, licensing agreements, and information on any related litigation. This helps the FDA assess the eligibility of the drug for approval and determine if there are any legal or patent-related issues that need to be addressed.
  • Institutional Review Board (IRB) compliance information, including information on clinical trial protocols, ethical approvals, patient safety, and monitoring procedures. This helps the FDA assess the safety and efficacy of the new drug, ensuring that clinical trials were conducted in a manner that protects patient safety and respects patient rights.
  • Directions for use, including details on the recommended dose, administration, storage, handling, and labeling of the new drug, which helps the FDA determine if the drug will be safe and effective for its intended use, and if the instructions are clear and easy to understand for healthcare providers and patients.
  • Regulatory correspondence between the drug manufacturer and the FDA, including requests for additional information or clarification.
  • References cited in the NDA, including articles, reports, and other information sources.

This information is used together to demonstrate that the product is safe for its intended use and target population, that its benefits outweigh the known risks, and that it can be manufactured in a way that ensures a high-quality product, and can be safely marketed to and used by patients and consumers.

Why Is It An Important Part of Drug Development?

NDAs are essential to drug development because they serve as the primary mechanism for the FDA to evaluate the safety and efficacy of new drugs, providing the federal agency with the information it needs to make an informed decision about whether a new drug should be approved for marketing and what conditions should be attached to its use.

By requiring rigorous preclinical and clinical testing and a comprehensive evaluation of the data, NDAs help to identify potential safety concerns and ensure that drugs are only approved for marketing if they are safe and effective. This can ultimately lead to better patient outcomes and advances in public health.

The NDA process also requires ongoing monitoring of the drug’s safety and efficacy through periodic reports and updates, providing a mechanism for public health officials and healthcare providers to receive accurate information about the drug.

Which Roles are Involved in NDA Preparation & Submission?

Planning, preparing, and completing an NDA is a complex and multi-disciplinary effort that involves many different job roles, from nonclinical scientists to chemists to data management teams, physicians, pharmacologists, and more:

  • Nonclinical scientists: Nonclinical scientists conduct preclinical tests to see if a new drug is safe and effective before it’s tested on humans. They perform lab and animal studies to see what potential side effects the drug may have, if it’s toxic, and if it’s effective. The results of these tests help the FDA determine if the drug is okay to test on humans.
  • Bioanalytical scientists: Bioanalytical scientists design and perform tests to measure the drug and its byproducts in biological samples. This information helps support the drug’s safety and effectiveness and helps determine the correct dosage.
  • Chemists: Chemists are responsible for making the drug and ensuring its high quality and consistency. They also help analyze the drug to confirm that it meets the standards outlined in the NDA.
  • Clinical operations professionals: Clinical research operations professionals are in charge of planning, carrying out, and managing clinical trials. They pick the study sites, enroll patients, ensure the trials are done correctly, collecting and analyzing data from the trials. The data collected supports the drug’s safety and effectiveness and determines the proper dosage.
  • Data standards analysts and managers: Data standards professionals ensure that the data collected during the drug development process is high quality, consistent, and compliant with regulatory requirements. This includes defining and maintaining data standards for collecting, storing, and analyzing data from preclinical and clinical studies.
  • Data management professionals: Data management professionals collect, store, and organize the data generated during the drug development process. This includes ensuring the accuracy and completeness of the data and that it is properly stored and backed up. Data management also supports data analysis and the preparation of NDA submissions.
  • Physicians: Physicians play a critical role in the NDA process, conducting clinical trials and evaluating the safety and effectiveness of the drug in human subjects. They are responsible for enrolling patients, administering the drug, monitoring the trial, and collecting data on the safety and efficacy of the drug.
  • Pharmacovigilance professionals: Pharmacovigilance professionals are responsible for monitoring the drug’s safety once it is on the market. This includes collecting, analyzing, reporting adverse events, and conducting post-marketing surveillance to identify safety concerns. The information gathered by pharmacovigilance is used to update the product label and to inform regulatory agencies and healthcare professionals of any new safety information.
  • Pharmacologists: Pharmacologists are responsible for understanding how drugs interact with the human body and how they affect different physiological systems. They conduct preclinical studies to evaluate the safety and efficacy of the drug and provide information on its mechanism of action, pharmacokinetics, and pharmacodynamics. The information generated supports the drug’s safety and effectiveness and determines appropriate dosing.
  • Legal professionals: Legal teams are involved in the NDA process to ensure that the drug development process complies with applicable laws and regulations. This includes reviewing the NDA submission to ensure that it complies with legal and regulatory requirements and providing guidance on any potential legal issues.
  • Regulatory affairs scientists and specialists: Regulatory affairs professionals ensure that the drug development process complies with regulatory requirements. This includes preparing the NDA submission, communicating with regulatory agencies, and managing the regulatory review process. Regulatory affairs are also responsible for ensuring that the drug is approved for marketing in a timely manner and that it meets the regulatory requirements for commercialization.
  • Medical writers: Regulatory medical writers prepare the NDA submission, which includes summarizing the data generated from preclinical and clinical studies and presenting the data in a format that meets regulatory requirements. This includes writing the clinical overview, clinical pharmacology, and statistical analysis sections of the NDA.

Each of these positions often play a critical role in the NDA process, and their collective efforts are necessary to ensure that a new drug is safe and effective for human use. Submitting an NDA with all the necessary data and information requires a lot of collaboration between all the different individuals and departments to be successful. Assembling a team right away can help streamline the application process.

When Should You Start Planning Your Application?

Beginning the planning process for an NDA should start as early in the drug development process as possible to ensure a successful outcome. Start as soon as you understand the drug’s mechanism of action, safety profile, and efficacy data from preclinical studies.

Doing so can help you stay ahead of regulatory requirements, avoiding potential roadblocks. It also provides you more time to gather your data and perform any additional studies that may be required to support the NDA submission, minimizing delays and ensuring you have enough time to format your application correctly.

Understanding the mechanism of action will help you determine the best approach for testing the drug in clinical trials, while the safety profile and efficacy data from preclinical studies will provide important information about the drug’s potential benefits and risks.

How Does the FDA Review Process Work?

The process includes several stages, beginning with an initial review and decision by the FDA to file the NDA or not, which must be made within 60 days of the application’s submission. If the team decides the application is complete, they have 6 to 10 months to decide whether to approve the drug for the market.

Then, the FDA’s Center for Drug Evaluation and Research (CDER) conducts a scientific review of the NDA, evaluating the data and information provided to assess the safety and efficacy of the drug.

The FDA’s Office of Regulatory Affairs will also conduct a regulatory review to ensure the NDA meets all of the FDA’s regulatory requirements. If deemed necessary, an Advisory Committee meeting may be held to provide independent expert opinions on the drug’s safety and efficacy.

Based on the scientific and regulatory reviews’ results, the FDA decides on the NDA and, if approved, issues a marketing approval. The NDA review process is critical to the FDA’s goal of ensuring that only safe and effective drugs are approved for use.

After all of the necessary steps and meetings have taken place, a final decision can be made based on the review of the NDA. If the drug is approved, the FDA sets conditions for its use, such as labeling requirements, post-marketing studies, and other commitments from the sponsor.

This evaluation process can sometimes take several years, but it is designed to ensure that new drugs are safe and effective for the intended population before making them available to the public.

What Is the Pre-NDA Phase?

The pre-NDA phase is a period of drug development that involves a combination of research and development, testing, and evaluation. It is critical to the success of the NDA process.

During the pre-NDA phase, drug makers conduct research to identify new drug candidates and evaluate their potential as treatments for various medical conditions, and it typically involves laboratory and animal testing.

Once the research has been completed, the drug maker moves on to pre-clinical testing, conducting more comprehensive safety and efficacy studies in animal models.

The primary goal here is to determine whether the drug can be safe and effective in humans and identify any potential toxicities or other issues that may arise during the clinical testing phase. The results of pre-clinical testing are then used to support the submission of an IND application.

What Is the Post-NDA Phase?

The post-NDA phase occurs after a new drug product has received FDA approval for marketing in the US and has been made available for prescription and use by patients.

It is an essential part of the drug development process, as it provides ongoing monitoring of the drug’s use and safety and can help identify any potential issues or concerns that arise. It can also include additional regulatory requirements.

Some key activities during the post-NDA phase include post-marketing surveillance, adverse event reporting, label updates, and risk management plans.

Post-marketing surveillance involves continuously monitoring the drug after it has been approved through post-marketing surveillance programs, such as spontaneous reporting systems and ongoing clinical trials. Adverse event reporting encourages healthcare providers and patients to report any adverse events associated with drug use to the FDA or the sponsor.

Label updates occur when new information about a drug’s safety or efficacy comes to light, and post-approval studies are sometimes conducted upon the FDA’s request to gather more information about the drug’s safety and effectiveness.

Risk management plans and strategies can be implemented to minimize the risk of harm to patients in the future.

By monitoring the drug’s performance and collecting additional data, the FDA and the sponsor can make informed decisions about its use and identify any necessary changes to its labeling or risk management strategies.

What Are Some Tips for Successful NDA Submission?

Here are several tips for successfully submitting an NDA:

  1. Start early: Plan the NDA submission process as early as possible. This will give you enough time to gather the necessary information, conduct clinical trials effectively and efficiently, and ensure that the NDA is complete and accurate.
  2. Thoroughly understand the FDA’s regulatory requirements: It will help to have a good understanding of the FDA’s regulatory requirements for NDAs, including the required format and content of the application. Most of this information can be found in the FDA’s guidance documents and regulations.
  3. Work with regulatory experts: Work with a team of regulatory affairs experts and legal counsel to ensure that the NDA is submitted correctly and meets all of the FDA’s requirements.
  4. Keep detailed records: Maintaining detailed and accurate records throughout the drug development process is essential for a successful new drug application. This includes records of all preclinical and clinical trials, as well as any interactions with regulatory agencies. Accurate record-keeping can help ensure that your application is complete and meets the regulatory requirements.
  5. Ensure that the data is complete and accurate: The NDA must contain all of the information necessary for the FDA to assess the safety and efficacy of the drug. Ensure that all of the data is complete and accurate and that it is presented clearly and concisely.
  6. Focus on quality: The FDA emphasizes quality, so it is crucial to ensure that the NDA is of high quality and meets the agency’s standards.
  7. Follow the correct format: Submit the NDA correctly, typically using the Electronic Common Technical Document (eCTD) format. This will help to ensure that the information is consistent and easily accessible.
  8. Address any questions or concerns: If the FDA has any questions or concerns about the NDA, be prepared to address them promptly and thoroughly.
  9. Work closely with the FDA: Engage with the FDA early in the development process and throughout the NDA submission process. The FDA may provide guidance on the types of data and information that will be required for the NDA and can help you understand the regulatory requirements.
  10. Be patient: The NDA review process can take several months or even years, so it is essential to stay patient with the FDA throughout the process.

Submitting a successful NDA requires careful planning, a commitment to quality, and the help of regulatory affairs experts and legal counsel. These tips can help ensure that your NDA is complete, accurate, and meets all of the FDA’s requirements, increasing the chances of a successful outcome.

What Does the Drug Development Process Look Like Overall?

Developing a drug to submit for an NDA generally involves several steps, all of which need to happen in subsequent order. These steps include discovery and development, preclinical research, clinical research, FDA review, and FDA post-market safety monitoring.

Discovery and development involves identifying a potential target for a drug, finding and optimizing compounds that have potential activity against the target.

Preclinical testing involves conducting laboratory and animal testing to determine the safety and efficacy of the drug. If preclinical studies go well, the company can submit an IND application to the FDA, providing information about the drug’s composition, manufacturing processes, testing results, and the plans for clinical trials.

If the IND application is approved, the company can then conduct clinical trials to evaluate the drug’s safety and efficacy in humans. Trials are categorized into three phases, each involving an increasing number of patients.

If all three phases are completed, and the clinical trials are a success, the company can submit an NDA for approval, including detailed and updated information about the drug, its composition, the clinical trial results, and proposed labeling.

The FDA reviews the NDA and evaluates the data submitted by the drug maker, and conducts inspections of the facilities to ensure the product is being produced following good manufacturing practices.

After a thorough review, the FDA can approve or deny the drug for marketing in the US. The agency may determine that additional information is needed or request additional testing or data.

This is a high-level way to look at the steps to getting a drug approved for marketing in the US, which can take several years and require significant time and resources. The NDA submission and approval process alone is quite time-consuming, but it aims to ensure that new drugs that reach the market are both safe and effective and that the public can access accurate and reliable information about the medicines they take.

When Can a Drug Be Commercialized?

Commercialization can begin after FDA drug approval. Once the product has been approved to sell and market, the sponsor can start producing and selling the drug to healthcare providers and patients. This process involves a variety of manufacturing activities, including:

  • Launch planning: The sponsor develops a plan for launching the drug, including strategies for marketing, distribution, and pricing.
  • Manufacturing and distribution: The sponsor starts manufacturing and distributing the drug on a large scale to meet the demand of healthcare providers and patients.
  • Marketing and promotion: The sponsor starts promoting the drug to healthcare providers, patients, and payers through various channels, including direct-to-consumer advertising, detailing to healthcare providers, and outreach to specialty pharmacies and managed care organizations.
  • Sales and revenue: The sponsor begins generating revenue from the sale of the drug and continues to monitor its performance in the market.

This is a critical stage in the drug development process, as it represents the transition from an experimental product to a marketed product available to patients.

Successful commercialization depends on many factors, including the size of the target patient population, the drug’s pricing and reimbursement status, and the competition in the market.

The Vital Role of NDAs from Discover to Delivery

A New Drug Application (NDA) is a request submitted to the FDA seeking permission to bring a new drug product to market. This includes new molecular entities (NMEs), small molecules, biologics, vaccines, new combinations, new indications, and other similar products.

The submission process is organized using the common technical document (CTD) format, which is a standardized format used for all submissions to regulatory agencies, starting from the IND phase. The electronic CTD (eCTD) is considered the quickest and most efficient method for exchanging information between the submitting party and the FDA during the NDA process.

The accuracy and quality of your preclinical and clinical research, and your overall NDA submission, will play critical roles in receiving approval for a new drug product, and will depend on various factors, including the experience and expertise of the research team, the design and conduct of the preclinical and clinical trials, and the quality of the regulatory documentation.

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With the proper equipment, you can ensure that the data generated during preclinical testing is high quality and supports the overall objectives of the NDA. It’s worth noting, however, that simply having new equipment is not enough to guarantee a successful NDA.

Lab equipment must be used appropriately, and your research team must analyze and document the generated data properly. The equipment must also be used following good laboratory practices (GLP) to ensure the reliability and validity of the data generated.

New equipment alone won’t guarantee successful studies and an NDA submission, however, it can help you generate more accurate results, streamline workflows, increase throughput, and meet higher standards and regulations.

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