This article is a sequence of United States: Drug Approval Regulatory Process Part-I which describes the Investigational New Drug (IND) approval process, New Drug Approval (NDA), and Generic drug approval process. In this article, we will discuss the marketing approval process of Biologics, Biosimilars, Orphan drugs, and various approval pathways.

Which is the regulatory authority for biologics approval?

A biologic is regulated by The Center for Biologics Evaluation and Research (CBER)

CBER regulates if it is Cellular products, including products composed of human, bacterial or animal cells (such as pancreatic islet cells for transplantation), or from physical parts of those cells (such as whole cells, cell fragments, or other components intended for use as preventative or therapeutic vaccines).

  • Gene therapy products
  • Vaccines
  • Allergenic extracts
  • Antitoxins, antivenins, and venoms
  • Blood, blood components, plasma-derived products

In the United States, biological products are subject to a different premarket pathway, a biological product must be licensed pursuant to a Biologics License Application (BLA) showing it is safe, pure, and potent

Requirements for submission

Both paper and electronic submissions are acceptable.

The IND must contain
  • Information from preclinical studies
  • The product’s pharmacologic effects and mechanism of action and information on its ADME.
  • Chemistry, Manufacturing, and Control (CMC) information.
The NDA must contain
  • Applicants must submit a Form FDA 356h to the document control center at the Center for Biologics Evaluation and Research (CBER), a division of the FDA that specifically handles biologics.
  • A statement that the study was conducted in compliance with the requirements, or, 
  • If the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance
  • A full description of manufacturing methods; stability data of the product through the dating period
  • Summaries of results of tests performed on the lot/s represented by the submitted sample/s
  • Specimens of the labels, enclosures, and containers, and if applicable, any Medication Guide

Biologics approval process

IND process
  • Vaccines and biologics follow the same general pathway as for drugs.
  • Sponsor shall submit all the non-clinical data in case of IND to FDA, FDA inaction in 30 days triggers the study under the IND to proceed
  • The sponsor can initiate the clinical trials and process and review remains the same as of small molecules
  • For every phase of a clinical trial, the sponsor has to review and continue to the next phase of the trial
  • Once all the clinical trial data has been generated, the sponsor has to perform pre-approval meeting
NDA process
  • After a sponsor submits a BLA, the FDA assembles a review team and then evaluates, within the first 60 days after submission, whether it can file the application or refuse
  • For NDA the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research (CBER) of FDA on forms prescribed for such purposes, and shall submit data derived from nonclinical laboratory and clinical studies to prove safety, purity, and potency
  • Examination of biologics license application by USFDA: 
    • Examination
    • Availability of product 
    • Manufacturing process

The new biological products receive 12 years of data protection

Process flow

Regulatory for biosimilars

Biosimilars are a type of biological product that is licensed by the FDA because they are highly similar to an already FDA-approved biological product and have been shown to have no clinically meaningful differences from the reference product.

All FDA-approved drugs, including biologics and their respective biosimilars, undergo a rigorous evaluation. Biosimilars and their biologic reference products each go through the specific regulatory approval process but there are differences.

Requirements for biosimilars

  • Analytical studies
    • Comprehensive structural and functional characterization of the proposed product and the reference product using state-of-the-art technology
  • Animal studies
    • Animal studies may be performed, which could include animal toxicity studies, pharmacokinetic and pharmacodynamic studies, and immunogenicity assessments
  • A clinical study or studies are sufficient to demonstrate safety, purity, and potency of the proposed biosimilar product in one or more of the indications for which the reference product is licensed.
    • Clinical studies might consist of comparative human pharmacokinetic and pharmacodynamic studies, a clinical immunogenicity assessment, and head-to-head clinical studies

Along with the above data, interchangeable products shall include

  • The proposed interchangeable product is expected to produce the same clinical result as the reference product in any given patient;
  • For a product administered more than once to an individual, switching between the proposed interchangeable product and the reference product does not increase safety risks or decrease effectiveness compared to using the reference product without such switching between products.

The labeling of a biosimilar product may differ from the reference product in many aspects, such as having fewer indications, differences in administration, preparation, storage, or safety information

Process for biosimilar approval

  • A company interested in marketing a biosimilar product in the United States must first submit an application to FDA

Orphan drug regulatory

Designated orphan drugs and medical devices will be subject to a fast track drug development program, priority review, and accelerated approval.

The Center for Drug Evaluation and Research (CDER) reviews most orphan drug applications, and the Office of Orphan Products Development (OOPD) promotes orphan drug development and provides grants for the same. It is advised to contact these organizations regularly (Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development; West).

Orphan Drug Designation

The Orphan Drug Act (ODA) grants special status to a drug or a biologic product that is intended to treat a rare condition or disease, upon the request of the sponsor. The status is referred to as Orphan designation or Orphan status

FDA provides several regulatory and financial incentives for developing the orphan drug in rare diseases

Before the sponsor can apply for drug approval under the Orphan Drug Act and before the sponsors are eligible for incentives like the Orphan Products Grant, they must apply and receive the orphan designation from the FDA (Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development)

It is recommended that the application shall be done before the IND studies as it helps to design the trials when the requirements regarding clinical endpoints are known beforehand. 

  • The request for designation must be submitted to the OOPD 
  • The applicant does not need to have animal toxicology data; only the results of efficacy studies conducted in an animal model for the human disease are needed (“Electronic Code of Federal Regulations”). 
  • The applicant may provide clinical data, animal studies, or in vitro data, but if sufficient information exists in published literature, that may suffice (Antos).

Required dossiers

  • A statement that the sponsor requests orphan-drug designation for a rare disease or condition, which shall be identified with specificity.
  • The name and address of the sponsor; the name of the sponsor’s primary contact person and/or resident agent including title, address, telephone number, and email address; the generic and trade name, if any, of the drug, or, if neither is available, the chemical name or a meaningful descriptive name of the drug; and the name and address of the source of the drug if it is not manufactured by the sponsor.
  • A description of the rare disease or condition for which the drug is being or will be investigated, the proposed use of the drug, and the reasons why such therapy is needed.
  • A description of the drug

The nutraceuticals approval process in the USA

A dietary supplement is a product that contains one or more of the following dietary ingredients

  • Vitamin 
  • Mineral 
  • Herb or other botanical
  • Amino acid
  • A dietary substance for use by humans to supplement the diet by increasing the total dietary intake of that ingredient; and 
  • A concentrate, metabolite, constituent, extract, or combination of any of the above. 

FDA regulates dietary supplements under a different set of regulations than those covering conventional foods and drug products.

  • The dietary ingredient is divided into two categories for the purpose of legal registration.
  • The product which is found in the market on or before 15, October 1994 is known as “Grandfathered” or “Old Dietary Ingredient” (ODI).
  • These products are allowed to continue their stay in the market by checking their safety signals. 
  • The products which are placed in the market after 15 October 1994 or the changes made to the ODI are considered as the New Dietary Ingredients (NDI)
  • The manufacturer needs to get the premarket clearance from the FDA for the said products to place it in the US market. Centre for Food 
  • Safety and Applied Nutrition (CFSAN) is the responsible body for such processes for the NDI.

Required documents

  • The name and full address of the applicant 
  • Name of the product,(includes any binomial name if it is a herb/botanical)
  • Description About the product which states: a) Level of NDI in Product b) Labelling statement/conditions for recommended use 
  • Safety Evidence (may include a history of use, in case of changed ODI; published articles for NDI) 
  • Concerned Authorities signature from the manufacturer or distributor of the Dietary Supplement.

Regulatory Process

  • FDA does not approve the dietary supplement as any other drug product; it is the responsibility of the manufacturer/Distributor to claim the safety of the product by submitting the relevant documents regarding the safety of the Dietary Supplement. 
  • The USFDA has released the GMP regulations for the Dietary supplements which are applied to all the foreign companies and domestic companies.
  • This GMP regulation specifies the requirements for Manufacture, Package, label, or hold of dietary supplements.
  • Dietary supplements do not need approval from the FDA before they are marketed. Except in the case of a new dietary ingredient, where pre-market review for safety data and other information is required by law

When shall the manufacturer notify?

  • The Dietary Supplement Health and Education Act (DSHEA) requires that a manufacturer or distributor notify FDA if it intends to market a dietary supplement in the U.S. that contains a “new dietary ingredient.” 
  • The manufacturer (and distributor) must demonstrate to FDA why the ingredient is reasonably expected to be safe for use in a dietary supplement unless it has been recognized as a food substance and is present in the food supply.

What are the various approval pathways?

Accelerated approval process

Accelerated drug approvals allow faster approval of drugs that treat serious diseases, the approval is faster because the effectiveness of drugs is based on the surrogate endpoints such as blood test, X-ray results rather than waiting for clinical trial results

Qualifying criteria

AND generally provides a meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on an intermediate clinical endpoint

When could you apply?

Discuss early on development point

Features of this approval process

Approval based on the effect on the surrogate endpoint or intermediate clinical endpoint

Fastrack approvals

Here sponsors can submit portions of the application as the information becomes available (called rolling information) instead of waiting for all the data to come. This is for drugs for unmet needs or life-threatening diseases

Qualifying criteria

Would treat a serious condition (variously defined) AND nonclinical or clinical data demonstrate the potential to address an unmet medical need

When could you apply?

With IND application or open IND

Features of this approval process

Development and review are expedited, including the use of the rolling review

Breakthrough Therapy designation 

Breakthrough Therapy designation expedites the development and review of drugs that are intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy. A drug with a Breakthrough Therapy designation is also eligible for the Fast Track process. The drug company must request a Breakthrough Therapy designation.

Qualifying criteria

AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies

When could you apply?

With IND application or open IND

Features of this approval process

  • All fast track features
  • Intensive guidance on efficient drug development during IND
  • Organizational commitment involving senior managers

Priority review 

Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease.

Qualifying criteria

AND if approved, would provide a significant improvement in safety or effectiveness

Features of this approval process

Shorter clock for review of marketing application (6 months compared to the 10- month standard review)

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