7.3: Processes for Drug Approval

IND Process for Biologics - 21 CFR 312

The FDA regulates clinical studies in the US, and unapproved drugs and biologics must be conducted under an Investigational New Drug Application (IND). The IND is continually updated with new protocols, study data, and annual reports. The IND for a biologic must contain administrative information, preclinical research results, any previous human experience with the drug, and the clinical protocol. It’s important to reiterate the IND is never approved; rather, it is pending, active, on hold, or partial hold. To learn more about IND in biologics, the OCTGT has a website called OCTGT Learn. On the site, there are many videos and activities to find out more about the approval process for Biologics, including this video on IND approvals.

Explore!

Approved Biologics are listed at the FDA website here: Approved Biologics. Look around the site – are there any classes of biologics that surprise you that the CBER regulates?

Click on “Biological Approvals by Year.” How many BLAs were approved in all of last year?

Find a BLA from this list that interests you. Summarize the product information and supporting documents.

Submitting a BLA

Biologic license applications (BLAs) are the formal submissions of data when companies are seeking approval to market a biologic in the United States. BLAs for biologics are submitted to CBER, and BLAs for well-characterized proteins are submitted to CDER. BLAs are like an NDA in that they must provide the efficacy and safety information required for approval for use in humans; administrative information, CMC information, preclinical and clinical studies, and labeling. There are two different types of BLAs: full, stand-alone BLAs (351(a)) filed for approval of an originator biological product, and abbreviated BLAs (351(k)) filed for approval of a biosimilar product. The BLAs are regulated under 21 CFR Parts 600-680. BLAs must contain administrative information, the CMC, preclinical studies, clinical data, and labeling

The Purple Book

“In 2014, the FDA released the Purple Book, a listing of all biological products. The Purple Book will serve as a helpful resource to assist the pharmaceutical industry in determining the earliest date at which a biosimilar or interchangeable product could be licensed. Because biosimilar and interchangeable biological products will be listed under the corresponding reference product, users can also easily see if there is a biosimilar product or interchangeable biological product licensed” (FDA.gov). Explore the purple book, here: www.fda.gov/drugs/therapeutic-biologics-applications-bla/purple-book-lists-licensedbiological-products-reference-product-exclusivity-and-biosimilarity-or

Biosimilars & BPCI Act

In 2010, President Obama signed into law the Affordable Care Act, which included the Biologics Price Competition and Innovation Act (BPCI Act) - an amendment of the PHS Act - to create an abbreviated licensure pathway for products that are demonstrated to be ‘biosimilar.' Biosimilars are biotherapeutic products that are interchangeable (similar regarding efficacy, safety, and quality) with the FDA-licensed product. They are not ‘generic’ in that they are not exact copies; the complexity of biologics precludes the ability for them to be identical.

The FDA has a Multi-Step Approach for Drug Approval for Biosimilars

1. Structural analysis
2. Functional assays (ex. Bioassays)
3. Animal data (ex. Toxicology)
4. Human Clinical Studies

Approval of a biosimilar application may not occur until 12 years after the date on which the reference product was first licensed. Patents of biological products are started to expire by 2012, and we quickly saw approvals for biosimilars. “On March 6, 2015, Zarxio obtained the first approval of the FDA. [9] Sandoz's Zarxio is biosimilar to Amgen's Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of the Affordable Healthcare Act. However, Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. Moreover, under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on a review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.” (Wikipedia, Biosimilar, 2017).

US Approved Biosimilars

https://en.Wikipedia.org/wiki/Biosimilar

Date of Biosimilar Approval	Biosimilar Product	Original Product
March 6, 2015 [20]	filgrastim-sndz/Zarxio	filgrastim/Neupogen
April 5, 2016 [21]	infliximab-dyyb/Inflectra	infliximab/Remicade
August 30, 2016 [22]	etanercept-szzs/Erelzi	etanercept/Enbrel
September 23, 2016 [23]	adalimumab-atto/Amjevita	adalimumab/Humira
April 21, 2017 [24]	infliximab-abda/Renflexis	infliximab/Remicade
August 25, 2017 [25]	adalimumab-adbm/Cyltezo	adalimumab/Humira
September 14, 2017 [26]	bevacizumab-awwb/Mvasi	bevacizumab/Avastin
December 1, 2017 [27]	trastuzumab-dkst/Ogivri	trastuzumab/Herceptin
December 13, 2017 [28]	infliximab-qbtx/Ixifi	infliximab/Remicade
May 15, 2018 [29]	epoetin alfa-epbx/Retacrit	epoetin alfa/Procrit
June 4, 2018 [30]	pegfilgrastim-jmdb/Fulphila	pegfilgrastim/Neulasta
November 28, 2018 [1]	rituximab-abbs/Truxima	rituximab/Rituxan

Biosimilar Products - Terminology

To understand biosimilar products and their regulation, it is necessary to be clear on the terms used to describe these types of products. The FDA recently released a consumer update web page on Biosimilars. The following are definitions and explanations from the FDAs training website on biosimilars.

• "A generic drug is bioequivalent to a brand name drug in dosage form, safety, and strength, route of administration, quality, performance characteristics, and intended use. Generic drugs are chemically identical to the brand-name drug. As a result, different manufacturers can produce what are essentially exact copies of the brand name product" (fda.gov).
• "Biological products are medical products which are larger and more complex molecules than drugs, and therefore are harder to characterize. Many of these products are produced in a living system, such as a microorganism or plant or animal cell. The nature of biological products creates unique challenges that do not exist in small molecule drugs. There are many types of biological products."
• "A reference product is a biological product approved by the FDA under the Public Health Service Act based on a full complement of product-specific data, including nonclinical and clinical data. A biosimilar product is approved based on a showing that it is highly similar and has no clinically meaningful differences regarding safety, purity, and potency (safety and effectiveness) from the reference product" (fda.gov).
• "A biosimilar product is a biological product that is highly like the reference product with minor differences in clinically inactive components. It has no clinically meaningful differences in safety and effectiveness from the reference product. Biosimilar products will have some differences from the reference product because of the complexity and inherent variability of biological products. However, these differences must not result in clinically meaningful differences regarding safety, purity, and potency (safety and effectiveness) as compared to the reference product" (fda.gov).

Test Your Knowledge!

Review this FDA course on Biosimilars. You can click on the webinar link and also download the slides: https://www.accessdata.fda.gov/cder/bio/course/framework/index.html

1. In your own words, define a biosimilar and a reference product.
2. What is the difference between a generic drug and a biosimilar?
3. What year were biosimilars approved for marking in the US?
4. What is the BPCI Act, and why is it important for biosimilars?
5. True or False: To approve biosimilars, the FDA requires companies to independently establish safety and effectiveness for the biosimilar.
6. True/False: Slight differences between the biosimilar and reference products are okay and expected.

Complexity of Biosimilar Manufacturing

There is an inherent variability like biological products – and it is important to ensure lot-to-lot variation is minimal and has no effect on safety and efficacy. A small change in production may have a significant effect on the product. Therefore, it's important to understand this variability to maintain product quality, potency, safety, and efficacy. The degree of variability should be characterized and controlled within specifications to assure lot-to-lot consistency. This variability is limited by testing the in-process material and final product to ensure that the important quality attributes of the product are kept within an expected range. According to the FDA, Critical quality attributes are physical, chemical, biological, or microbiological properties or characteristics of a product that defines the product's function and may affect safety and efficacy.

Here are some relevant specification terms to familiarize yourself with:

1. Acceptable Variability: Some degree of variability is acceptable if the intended use is unaffected by this variability.
2. Variability Controls: Variability is tightly controlled by understanding, monitoring, and validating the manufacturing process and assessed by lot release specifications.
3. Specification Defined: A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described (fda.gov).
4. Specification Criteria: Specifications establish the set of criteria to which a drug substance, drug product, or materials at other stages of the biological product's manufacturer should conform to be considered acceptable for its intended use.
5. Lot Release Specification: Lot release specifications are quality standards that are proposed and justified by the manufacturer and approved by the FDA as conditions of approval to ensure the product is safe and effective over its shelf life.

Abbreviated Approval Pathway

A biosimilar product can be approved based on existing knowledge about reference products – including safety and effectiveness of the reference product. The goal of approval is to demonstrate it to be biosimilar to a reference product and allows products are manufactured faster and at a lower cost than other biologicals without having to repeat clinical studies in humans. The important aspect of the abbreviated approval pathway is a robust analytical characterization of the product, which must demonstrate through structural and functional testing the product to be biosimilar to the reference product. All the general requirements in place for a biological product apply to a biosimilar product including a comprehensive CMC in addition to following CGMP regulations. Although this abbreviated pathway offers a shorter timeline for approval of the biosimilar product, this product must still meet the same manufacturing standards as a biological product. The FDA has a rigorous and science-based approach for the development and approval of biosimilar products.

Characterization of a Biosimilar

1. Analytical Studies
2. Animal Studies
3. Clinical PK/PD studies
4. Clinical Immunogenicity assessment
5. Additional Clinical Studies

There is one important point to note about any differences that arise. Residual uncertainty about biosimilarity is a concept related to differences observed between the proposed biosimilar product and the reference product, and whether those differences could affect safety, purity, or potency (safety and effectiveness). When differences are identified, they must be evaluated to determine the potential impact. Any potential impact of the differences in safety, purity or potency (safety and effectiveness) should be addressed and supported by appropriate data and information. If there is any uncertainty of biosimilarity of the product to the reference standard after completing analytical, animal, and PK/PD studies and immunogenicity assessment, the manufacturer may have to perform additional clinical data to address this uncertainty. The FDA uses the data in its entirety on a risk-based assessment to approve the product.