Types of Applications to register and market a new Drug and Biologic in U.S

The United States Food and Drug Administration (FDA) plays a crucial role in regulating the approval and marketing of drugs, biologics, and a wide range of other products, including food, pharmaceuticals, medical devices, and cosmetics. Companies and researchers seeking to introduce new products to the U.S. market must navigate specific application processes based on the nature of their products. Understanding the different types of FDA applications is essential to ensure compliance with regulatory requirements and streamline the approval process. This article outlines the major types of applications required to register and market drugs and biologics in the U.S.

The FDA’s regulatory framework, which includes laws, regulations, guidelines, and policies, ensures that these products meet strict safety, effectiveness, and quality standards. By balancing innovation with public safety, the FDA provides clear guidelines to manufacturers while ensuring that the products available to consumers are safe, effective, and accurately labeled. This framework governs the development, testing, manufacturing, and marketing of drugs and biologics, playing a vital role in safeguarding public health.

The applications can be classified into two different types.

Types of Applications to Register a Drug/Biologic:

The registration of drugs or biologics involves the following applications:

Types of Applications to Market a Drug/Biologic:

The marketing and commercialization of a drug/biologic involve the following applications:

Let us deep dive into each of the applications to understand and learn more comprehensively on definition, importance, types, and requirements.

Drug Master File (DMF): Definition, Importance, Legal Basis, and Types

A Drug Master File (DMF) is a confidential, comprehensive document to be submitted to the U.S. Food and Drug Administration (FDA) containing detailed information about the facilities, manufacturing, processing, packaging, and storing of a drug product or its components. The DMF serves as a reference for the regulatory review process and allows manufacturers to protect proprietary information while providing authorities with necessary details to ensure product safety, quality, and compliance.

Importance of a Drug Master File

The DMF is vital to the pharmaceutical industry for several reasons:

1. Protection of Confidential Information: The DMF enables manufacturers to protect their proprietary information related to manufacturing processes, raw materials, and formulation details. By submitting a DMF, companies can allow regulatory authorities to access critical data without revealing sensitive trade secrets to competitors or the public.
2. Regulatory Compliance: The DMF helps manufacturers comply with regulatory requirements for the approval and marketing of drug products. Regulatory bodies, such as the FDA, will use the DMF to assess the safety and quality of a drug, ensuring that it meets required standards before being marketed.
3. Facilitating Drug Approval: A DMF can simplify the drug approval process, particularly when used in conjunction with New Drug Applications (NDA), Abbreviated New Drug Applications (ANDA), or Biologics License Applications (BLA). By providing comprehensive information about manufacturing and raw materials, it allows for faster and more efficient regulatory reviews.
4. Ensuring Drug Safety and Quality: Through the information provided in the DMF, regulators can assess the consistency and integrity of the manufacturing process, ensuring that drugs are produced under controlled conditions and are safe for public use.

Legal Basis for Drug Master Files

The legal basis for the DMF varies depending on the regulatory region.

• In the United States, the concept of the DMF is governed by the FDA under Title 21 of the Code of Federal Regulations (CFR), Part 314. Specifically, 21 CFR 314.420 outlines the requirements for submitting and maintaining a DMF, which is often used in conjunction with applications like NDAs, BLAs, and ANDAs. The DMF provides a means for manufacturers to submit confidential manufacturing data to the FDA without disclosing proprietary information in the application itself.

Types of Drug Master Files

There are several types of DMFs, each tailored to different aspects of drug development and manufacturing:

1. Type I: Pharmaceutical Ingredients (Manufacturing and Packaging Sites): This type provides detailed information on the manufacturing, processing, and packaging of the drug substance, including facilities, equipment, and methods used.
2. Type II: Drug Substance (Active Pharmaceutical Ingredient): This is the most common type and contains information on the drug’s active pharmaceutical ingredient (API), including its chemistry, manufacturing processes, specifications, and stability data. It may also include details about the source of raw materials, controls, and testing procedures.
3. Type III: Packaging Materials: This type includes information on packaging components, such as containers, closures, and labeling materials used to package the drug product. It ensures that the packaging complies with safety and quality standards and does not interact negatively with the drug.
4. Type IV: Excipients: Excipients are inactive substances used in the formulation of drugs. Type IV DMFs provide detailed information on the excipients, their sources, manufacturing processes, and testing to ensure they meet regulatory standards.
5. Type V: Combination Products: These files contain information on products that combine drugs, devices, or biologics. Type V DMFs cover the development and manufacturing processes for such combination products to ensure that all components work together safely and effectively.

Investigational New Drug (IND): Definition, Importance, Legal Basis, and Types

An Investigational New Drug (IND) is a designation given to a drug or biologic that has not yet been approved by regulatory authorities for public use but is undergoing clinical trials to evaluate its safety and efficacy. In the United States, the FDA requires an IND submission before clinical testing of a new drug can begin, whether the drug is being tested for a new indication, formulation, or in a new patient population. The IND allows researchers to initiate clinical trials while ensuring that the drug is tested in a controlled, ethical, and scientifically rigorous manner.

During a new drug’s early preclinical development, the sponsor’s primary goal is to determine if the product is reasonably safe for initial use in humans and if the compound exhibits pharmacological activity that justifies commercial development.

Importance of an Investigational New Drug

The IND is essential in the drug development process for several reasons:

1. Regulatory Oversight and Safety Monitoring: The primary importance of an IND is to ensure that the clinical testing of a new drug is conducted in a safe and ethical manner. The FDA reviews the IND to confirm that the proposed clinical trials are designed to minimize risks to participants and that the drug’s potential risks and benefits are adequately understood before human testing begins. The IND application includes safety data from preclinical studies, information about the proposed clinical trials, and details on the drug’s composition and manufacturing processes.
2. Facilitating Clinical Trials: The IND is a necessary step in obtaining approval to conduct clinical trials in humans. Without this approval, researchers are prohibited from testing a new drug in people. The IND ensures that the clinical trials will be well-designed to gather the necessary data on the drug’s safety and efficacy.
3. Data Submission for Future Marketing Approval: By submitting an IND, companies or research organizations begin the process of generating clinical data that will be used in future regulatory submissions, such as the New Drug Application (NDA) or Biologics License Application (BLA). This data is crucial in determining whether a drug will be approved for widespread use.
4. Transparency and Ethical Standards: The IND process includes ethical oversight, such as Institutional Review Board (IRB) approval for trial protocols. This ensures that participants are informed about the risks and benefits of the clinical trials, further promoting transparency and protecting patient rights.

Legal Basis for the IND

The legal foundation for the IND is primarily outlined in Title 21 of the Code of Federal Regulations (CFR), Part 312, which governs the submission and handling of INDs in the United States. Under these regulations, a sponsor must submit an IND to the FDA before initiating any clinical trials. The IND must include preclinical study data, a proposed plan for clinical testing, manufacturing details, and information about the drug’s pharmacology, toxicology, and potential adverse effects.

The Federal Food, Drug, and Cosmetic Act (FDCA), which grants the FDA authority to regulate drugs, further provides the legal framework for IND submissions, ensuring that all clinical trials involving new investigational drugs comply with the law.

Types of INDs

There are two categories of IND.

1. Commercial IND: This type is submitted by a pharmaceutical company or organization intending to develop the drug for commercial distribution. It involves the testing of a new drug or biologic product that may eventually be marketed once clinical trials are completed and the drug is proven safe and effective.
2. Research IND: A research IND is typically submitted by an investigator or research institution, often for exploratory studies or academic research. It is not necessarily aimed at commercial development but allows researchers to study the drug in clinical trials under FDA supervision.

There are several types of INDs, each designed for different clinical and regulatory scenarios:

1. An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.
2. Expanded Access IND (Compassionate Use): This type of IND is submitted when there is a need to provide investigational drugs to patients with serious or life-threatening conditions who have no other treatment options. It allows access to a drug outside of clinical trials, typically when the drug is still under investigation but may offer potential benefits for patients in desperate need.
3. Emergency Use IND: This is a special type of IND used in emergency situations, where patients are in immediate need of a drug that is not yet approved for use. The FDA may grant emergency use of an investigational drug to treat a patient if no other viable treatment options are available.
4. Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

New Drug Application (NDA): Definition, Importance, Legal Basis, Classification Codes, and Types

A New Drug Application (NDA) is a formal request submitted to the U.S. Food and Drug Administration (FDA) for the approval to market a new drug product in the United States. It includes comprehensive data on the drug’s safety, efficacy, and quality derived from clinical trials, laboratory studies, and manufacturing processes. The NDA is a critical step in the drug approval process, as it provides the FDA with all the necessary information to evaluate whether a new drug should be approved for public use.

To read and learn more about drug developement stages from discovery to regulatory approival, please go through the detailed and comprehensive article in our database.

Importance of an NDA

The NDA plays an essential role in the pharmaceutical industry and drug development process. Its importance lies in several key areas:

1. Ensuring Public Safety and Health: The primary purpose of the NDA is to ensure that new drugs are safe and effective for their intended use. Through the NDA, the FDA assesses whether the benefits of the drug outweigh the risks, based on data from preclinical and clinical trials. This helps protect public health by ensuring that only drugs meeting stringent safety and efficacy standards reach the market.
2. Regulatory Compliance: The NDA process ensures that pharmaceutical companies comply with federal regulations before they can market a drug. By submitting an NDA, companies must meet the FDA’s rigorous guidelines, ensuring the drug’s manufacturing process, labeling, and testing align with regulatory expectations.
3. Streamlining Drug Development: While the NDA process is lengthy, it provides a structured pathway for drug approval. Manufacturers are required to provide extensive data, but the NDA submission also allows them to demonstrate the science behind their product, which is critical for achieving regulatory approval.
4. Market Authorization: Once the NDA is approved, the drug can be marketed and sold in the United States. This marks the final step in the drug development process, allowing manufacturers to introduce their product to healthcare providers and consumers, potentially improving patient care and treatment options.

Legal Basis for the NDA

The legal foundation for the NDA is found in the Federal Food, Drug, and Cosmetic Act (FDCA), which grants the FDA authority to regulate drugs in the U.S. The FDA’s requirements for NDA submissions are outlined in Title 21 of the Code of Federal Regulations (CFR), Part 314 and Part 312. These regulations specify the documentation, data, and information needed for a drug to be approved for sale in the U.S.

The FDA reviews the NDA to ensure that the drug has undergone adequate clinical testing to establish its safety, efficacy, and quality. Additionally, the FDA evaluates the drug’s proposed labeling, which must include accurate information about the drug’s intended use, potential side effects, and proper usage instructions.

Types of NDAs

NDAs can vary depending on the nature of the drug and the specifics of its development. Key types of NDAs include:

1. New Molecular Entity (NME): An NME is a drug that contains an active ingredient never before approved for marketing in the U.S. NMEs are subject to the most thorough reviews due to the lack of existing data on the substance. When the sponsor of a new drug believes that enough evidence on the drug’s safety and effectiveness has been obtained to meet FDA’s requirements for marketing approval, the sponsor submits to FDA a new drug application (NDA). The application must contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. If the NDA is approved, the product may be marketed in the United States.  For internal tracking purposes, all NDA’s are assigned an NDA number.
2. 505(b)(2) NDA: This type of NDA allows a company to rely on existing data (such as published studies or data from another manufacturer) to support the approval of a new drug. It is typically used for drugs that are not entirely new but involve modifications, like new formulations, routes of administration, or indications.
3. Abbreviated NDA: This type of application is submitted for generic drugs. Generic manufacturers must demonstrate that their product is bioequivalent to the branded drug and can use the existing clinical data from the reference drug to support their application. An Abbreviated New Drug Application (ANDA) contains data that, when submitted to FDA’s Center for Drug Evaluation and Research, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product. Generic drug applications are called “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.  Instead, a generic applicant must scientifically demonstrate that its product is bioequivalent (i.e., performs in the same manner as the innovator drug). Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public.
4. Biologics License Application (BLA): Although not an NDA per se, the BLA is a similar process for biologic products, such as vaccines and gene therapies. It involves the same rigorous review and approval process but is distinct due to the biological nature of these products. Biological products are approved for marketing under the provisions of the Public Health Service (PHS) Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product. A biologics license application is a submission that contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology and the medical affects of the biologic product. If the information provided meets FDA requirements, the application will be approved and a license is issued allowing the firm to market the product.

Chemical Classification Codes for NDA:

Changes to approved drug products for which 505(b) (2) application should be submitted:

1. Change in dosage form
2. Change in strength
3. Change in route of administration
4. Substitution of an active ingredient in a formulation product
5. Change in formulation
6. Change in dosing regimen
7. Change in active ingredient
8.  New combination Product
9. New indication
10. Change from prescription to OTC
11. Naturally derived or recombinant active ingredient
12. Bioequivalence

Differences between NDA and 505 (b)(2) Application:

NDA Classification Codes

The FDA uses specific classification codes to categorize NDA submissions based on the type of drug and its intended use. These codes help streamline the review process and provide clarity regarding the drug’s regulatory pathway. Some key classification codes include:

• P (Priority Review): Drugs that offer significant improvements in the treatment of serious diseases or conditions are eligible for priority review. This expedites the review process, allowing faster access to new therapies.
• S (Standard Review): Drugs that do not offer major advancements but meet the basic standards for safety and efficacy are reviewed under the standard procedure.
• O (Orphan Drug): Drugs developed for rare diseases, affecting fewer than 200,000 people in the U.S., may receive special considerations and benefits through the Orphan Drug Program.
• F (Fast Track): Drugs intended to treat serious conditions and fill an unmet medical need may qualify for Fast Track designation, allowing for more frequent interactions with the FDA and accelerated review.

HATCH-WAXMAN ACT:

Drug Price Competition and Patent Term Restoration Act, 1984

HWA established the modern system of generic drugs in USA. Hatch-Waxman amendment of the federal food, drug and cosmetics act established the process by which, would be marketers of generic drugs can file Abbreviated New Drug Application (ANDA) to seek FDA approval of generic drugs. 

Patent Certifications:

As per the Hatch and Waxman act, generic drug and 505 (b) (2) applicants should include certifications in their applications for each patent listed in the “Orange Book” for the innovator drug. This certification must state one of the following:

P1 – Patent information relating to such patent has not been filed;

P2 – Such patent has expired;

P3 – Patent will expire on a particular date; or

P4 – Patent is invalid or will not be infringed by the drug, for which approval is being sought.

A certification under paragraph I or II permits the ANDA to be approved immediately, if it is otherwise eligible. A certification under paragraph III indicates that the ANDA may be approved when the patent expires.

Paragraph IV of the act, allows 180 day exclusivity to companies that are the “first-to-file” an ANDA against holders of patents for branded counterparts.

To read and learn more about Hatch-Waxman Act, please go through the detailed and comprehensive article in our database.

180-day Exclusivity:

An incentive of 180 days of market exclusivity provided to the “first” generic applicant who challenges a listed patent by filing a paragraph IV certification and thereby runs the risk of having to defend a patent infringement suit.

To read and learn more about types of exclusivities, please go through the detailed and comprehensive article in our database.

Conclusion

The FDA’s regulatory pathways reflect its commitment to ensuring safe, effective, and high-quality medical products for the U.S. market. Each application type whether an NDA for innovative drugs, an ANDA for generics, or a BLA for biologics caters to the unique characteristics of the product and its intended use.

By navigating these pathways effectively, sponsors can bring life-saving therapies to market while maintaining the highest standards of public health. Understanding these application types is essential for pharmaceutical and biotech professionals seeking to succeed in the competitive and highly regulated U.S. healthcare market.

This comprehensive guide highlights the importance of aligning regulatory strategy with product development goals, paving the way for safe and timely market entry.