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Biologics Approval Pathways in the USA:

Existing Regulatory framework for biologics approval in the US:

Two laws were enacted to regulate drugs in the USA: The Federal Food, Drug, and Cosmetic Act (21 USC § 301, FD&C), and the Public Health Services (PHS) Act (42 USC § 262; PHS).
FDA was empowered by the US government to enforce the Federal Food, Drug, and Cosmetic Act and other laws including a few section of the Public Health Service Act.

There are two divisions in the FDA: Center for Drug Evaluation and Research (CDER) and The Center for Drug Evaluation and Research (CBER).

CBER deals with biological products exclusively  and CDER mainly regulates Chemical drugs but in 2003 FDA has transferred few biological to CDER. Information about biological which was transferred to CDER is mentioned in the second section of this article.

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In 2010, the PHS Act was amended to create an abbreviated approval pathway for biosimilars, or biologics which can be considered “highly similar” or interchangeable with FDA authorized drug (reference drug).

This pathway is also known as the Biologics Price Competition and Innovation Act (BPCIA) of 2010 and it is quite similar in concept with the Hatch-Waxman Act of 1984 for generic drugs.

On June 30, 2003, FDA transferred some of the therapeutic biological products that used to be evaluated and regulated by CBER (Center for Biologics Evaluation and Research) to CDER  (Center for Drug Evaluation and Research).

CDER will take care of regulatory aspects including premarket review and persevering with oversight, over the transferred product. In regulating the products assigned to them, CBER and CDER will seek advice from each other often and on every occasion necessary.

Categories of Therapeutic Biological Products Transferred to CDER

  • Monoclonal antibody (invivo use only)
  • Therapeutic protein (obtained from  plants, animals, or microorganisms, and recombinant protein)
  • Immunomodulators (Except vaccine and allergenic product)
  • Growth factors, cytokines and monoclonal antibodies which are meant to modify the production of hematopoietic cells in in vivo.

    Drug approval Process by CDER

Categories of Therapeutic Biological Products Remaining in CBER

  • Cellular products: Human cells, bacterial or animal cells and components of these cells.
  • Gene therapy products.
  • Vaccines 
  • Allergenic extracts
  • Antitoxins, antivenins, and venoms
  • Blood and Blood components
  • Plasma and Plasma Derived products

For combination products, “Intended mode of action by which part” is checked. If a product is a combination of Drug A and Biological B but Mode of action is due to Biological B then as per the assigned category (see above categories), the application will be transferred to either CDER or CBER.

Present Regulatory Pathway for Biologics in US:
1. 351 (a)
2. 351 (k)
3. 505 b(2)

351(a) or Stand Alone Pathway or BLA (Biological License pathway):
It comes under PHC act and it is a traditional pathway used for approval of innovator biologics. Safety and Effectiveness data need to be submitted along with application. 

It is like New drug application (505 b(1)) pathway for drugs which are reviewed by CDER. Robust information about manufacturing facility is also required in BLA application.

351(k) Pathway: It also comes under PHC act. The application is submitted by the manufacturers in order to get a product reviewed as a biosimilar or interchangeable which is considered to be “highly similar” to an FDA licensed reference product.

Let’s know about FDA given definitions:

Biosimilar or Biosimilarity definition  :

“that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and 

there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.” As per FDA

Interchangeable or Interchangeability Definition: 

“the biological product is bio-similar to the reference product; 

it can be expected to produce the same clinical result . as the reference product in any given patient.

for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.” as per FDA

Please note that Interchangeable product may be substituted with Ref product without the consent of a Doctor.

Reference Product Definition:

“ the single biological product, licensed under section 351(a) of the PHS Act, against which a biological product is evaluated in an application submitted under section 351(k) of the PHS Act” As per FDA.

 FDA decides which of the following studies are necessary to be included in the application:  
Analytical Studies – Check of comparability between the biological and reference product. It is also done to know any minor difference in clinical inactive ingredients.

Animal Studies – It is done for evaluation of toxicity.

Clinical Studies – Assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD) to establish the safety of the product in the condition of use.

It is important to note that biological product may not be evaluated against more than one Reference product.

General Requirements of 351(k) pathway

  • Intended product Is biosimilar to a reference product;
  • Mechanism of action should be same as reference product
  • Intended Indication for approval should be same to that of Reference product
  • Same Route of administration
  • Same dosage form, strength as per the reference product
  • Detailed information about facility, where Intended product  is manufactured, processed, packed, or held to ensure its safety, purity and potency.
505(b)(2) Pathway:

Prior to the enforcement of  BPCIA to till today 505(b)(2) pathway could be used for certain biologicals. Similar to 351(k) pathway, this pathway allows the applicant to rely on the safety and effectiveness data of a previously-approved product.

The 505(b)(2) pathway is available for a relatively narrow category of biologics specifically, those that had been approved under an New drug application (NDA) before the BPCIA was signed into law in 2010. Examples can be found at below source.

Must Read: Big Change in FDA process for Biologics:



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