Different Types of Applications to Register a Drug/Biologic in USFDA

The registration of drug/biologic involves the following applications:

  • DMF – Drug Master File
  • IND – Investigational New Drug Application

DMF:

A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.

Important facts regarding DMFs

  • It is submitted to FDA to provide confidential information
  • Its submission is not required by law or regulations
  • It is neither approved nor disapproved
  • It is filed with FDA to support NDA, IND, ANDA another DMF or amendments and supplements to any of these
  • 21 CFR (Code of Federal Regulations) 314. 420
  • It is not required when applicant references its own information

Types of DMF’s

Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (No longer accepted by FDA)

Type II: Drug Substance, Drug Substance Intermediate, and material used in their Preparation, or Drug Product

Type III: Packaging Material

Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation

Type V: FDA Accepted Reference Information (FDA discourages its use)

IND:

It is an application, which is filed with FDA to get approval for legally testing an experimental drug on human subjects in the USA.

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 human and if the compound exhibits pharmacological activity that justifies commercial development.

There are two IND categories:

  • Commercial
  • Research (non-commercial)

There are three IND types:

  • 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.

  • Emergency Use IND allows the FDA to authorize use of an experimental drug in an emergency that does not allow time for submission of an IND in accordance with 21 CFR, Sec. 312.23 or Sec. 312.34.  It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
  • 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

 

 

 

Different types of applications to market a drug/biologic:

  1. NDA – New Drug Application
  2. BLA – Biological Licensing Application
  3. ANDA – Abbreviated New Drug Application

Legal Basis of Submission:

The legal basis for the submission of applications has laid down in the Federal FD & C act 21 CFR and PHSA relating to products for human use.

TypeExplanationLegal Basis
FullFull Dossier [NDA]505 (b)(1) 505 (b)(2)
GenericAbridged applications505 (j)
Bio-similarBiologic product351 (a) 351 (k)

New Drug Application (NDA

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.

Chemical Classification Codes for NDA:

NumberMeaning
1New molecular entity (NME)
2New ester, new salt, or other non-covalent derivative
3New formulation
4New combination
5New manufacturer
6New indication
7Drug already marketed, but without an approved NDA
8OTC (over-the-counter) switch

505 (b) (2) Application:

 505 (b)(2) application is a type of NDA for which one or more investigations relied on by applicant for approval were not conducted by/for applicant and for which applicant has not obtained a right of reference.

 Kind of application to be submitted  

  • New chemical entity (NCE)/New molecular entity (NME)
  • Changes to previously approved drugs

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:

New Drug Application (NDA)505 (b)(2) Application
All investigations relied on by applicant for approval were conducted by/for applicant and for which applicant has right of referenceOne or more investigation relied on by applicant for approval were not conducted by/for applicant and for which applicant has not obtained a right of reference
Generally, filed for newly invented pharmaceuticals.Generally, filed for new dosage form, new route of administration, new indication etc for all already approved pharmaceutical.

Biologic License Application (BLA)

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.

Review Classification Codes for NDA/BLA:

LetterMeaningNotesTime for Review
PPriority review drugTo represent an advance over available therapy6 months
SStandard review drugTo have therapeutic qualities similar to those of an already marketed drug1 year
OOrphan drugA product that treats a rare disease affecting fewer than 200,000 Americans10 months

ANDA:

It is an application filed with FDA, for a U.S. generic drug approval for an existing licensed medication or approved drug.

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.

HATCH-WAXMAN ACT:

Drug Price Competition and Patent Term Restoration Act, 1984

It 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.

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.

Important Definitions

Active Ingredient 

An active ingredient is any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.

New Molecular Entity (NME) 

A New Molecular Entity is an active ingredient that has never before marketed in the United States in any form.

Biological Product

Biological products include a wide range of products such as vaccines, blood and blood components, allergenic, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins.

Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources — human, animal, or microorganism — and may be produced by biotechnology methods and other cutting-edge technologies.

In general, the term “drugs” includes therapeutic biological products.

Generic Drug

A generic drug is the same as a brand name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use. Before approving a generic drug product, FDA requires many rigorous tests and procedures to assure that the generic drug can be substituted for the brand name drug. The FDA bases evaluations of substitutability, or “therapeutic equivalence,” of generic drugs on scientific evaluations. By law, a generic drug product must contain the identical amounts of the same active ingredient(s) as the brand name product. Drug products evaluated as “therapeutically equivalent” can expected to have equal effect and no difference when substituted for the brand name product.

 

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