Regulatory Issues: Biosimilars

List the 4 sections of the pyramid and state which sections will require more tests for a biosimilar product and why.

1. safety and immunogenicity 2. clinical pharmacology 3. nonclinical 4. analytical studies (req more tests, make biosimilars)

Define "biosame"

Follow-on biologic that are identical to the original - need no additional product development - use the same manufacturing lines as the original - launch immediately upon loss of exclusivity for the original biologic

Define "totality of evidence"

establish biosimilarity, not re-establish benefit

PHS Act

gave US Public Health Service responsibility for preventing the introduction, transmission and spread of communicable diseases from foreign countries into the US

which of the following would not be considered an agent for which a biosimilar could be developed? rituximab epoetin alfa insulin glargine methotrexate etanercent

methotrexate

What does extrapolation mean in terms of biosimilar approval?

regulatory guidelines permit extrapolation of clinical data from one indication to support biosimilar approval for use in an indication that was not directly compared to the licensed biologic in a clinical trial, but for which the reference product is approved - must be scientifically justified - based on "totality of evidence" from all stages of biosimilar development - reduced need for duplicative clinical studies

which of the following are biosimilars? - Semglee - Zarxio - Granix - Cyelto

semglee zarxio cyltezo

which of the following are biosimilars and interchangeable? - Semglee - Zarxio - Granix - Cyltezo

semglee and cyltezo

Of the 20+ products have been approved as biosimilars in the United States, are any considered interchangeable by the FDA? If so, which products are they, and are they currently marketed in the US?

yes semglee interchangeable with Lantus cyltezo interchangeable with Humira

PHS Act Biologics License Application (BLA)

Safety and efficacy must be demonstrated

Define "biobetter"

Drug in the same class, but not identical - target same epitope as reference product, but are altered, chemically or structurally - should achieve improved efficacy and/or safety over the reference product - biosimilars should perform as well as the original; biobetters should have advantages

PHS Act BCPI Act / 351(k)

Establishes an abbreviated pathway for FDA licensure of biologic products demonstrated to be biosimilar to or interchangeable with FDA-licensed reference product - Must demonstrate high similarity to reference - Interchangeable biosimilars require more data

FD&C Act Hatch-Waxman / 505(j) Abbreviated New Drug Application

- Allows drugs that are "identical or almost identical" to rely on previously submitted NDA info of the brand name drug as their reference material - does not require clinical studies or other proof of safety or efficacy - pathway used for approval of most generic chemical drugs - only grants 180 days of market exclusivity - pathway not applicable for biologics

What factors related to manufacturing and immunogenicity have limited the number of biosimilar products on the market to date? (4)

- Biologics have larger potential to cause immunogenic response --- Drug can become ineffective (neutralizing antibodies) --- Patient can have allergic reaction --- May require more safety testing, as processing changes could affect safety profile - Expensive - manufacturing process is highly specific for biologics (not easily reproduced) - develop product specific tests, assays, cell lines, propriety standards etc.

What is the definition of a biosimilar? How is it the same as an innovator product? How may it differ?

- a biological product that is highly similar to a reference biological product - no clinically meaningful difference between the biological product and the reference product (safety, purity, and potency of the product) - minor difference in inactive components *no 2 cell lines, developed independently, can be considered identical (small distinctions in cell line, manufacturing process, and surrounding environment)

What designation will a product need to receive in order to be substituted for an innovator product?

- they need to be deemed interchangeable - other products (that are biosimilar) can be dispensed only if the prescriber writes for that specific product - biosimilars cannot be treated simply as generic drugs

FD&C Act Generic Drug Amendment 505(b)(1) (3 bullets)

- traditional NDA route - contains full reports of investigation of safety and effectiveness - innovator drugs

What 5 stipulations does the BCPI Act have for determining if a follow-on product is biosimilar?

1. Analytical, animal, and clinical studies show that it is highly similar to the reference product (notwithstanding minor differences in clinically inactive components) 2. The two products have same MOA 3. The condition of use in the proposed product has been previously approved for the reference product 4. The route of administration, dosage form, and strength of the two products are the same 5. The manufacturing process provides for a safe product.

What 2 additional stipulations does the BCPI Act have for determining if a follow-on product is interchangeable?

1. It can be expected to produce the same clinical result as the reference product in any given patient 2. The risk, in terms of safety or diminished efficacy or switching between the products, is not greater than the use of the reference product without such alteration.

biosimilars are expected to cost ___ %less that the reference product

15-30%

State which pathway would be most appropriate for approval of: insulin, growth hormone, calcitonin, and/or complex proteins or antibodies (such as Factor VIII, filgrastim, or adalimumab).

Insulin: 505 (b)(2) Growth hormone: 505 (b)(2) Calcitonin 505 (b)(2) Complex proteins or antibodies (such as Factor VIII, filgrastim, or adalimumab): 351(k)

What is the current status of biosimilar naming, and what are the arguments for and against unique INNs?

Interchangeable biosimilars share the same individual nonproprietary name (INN) - unique INN could confuse patients and prescribers - maintaining INN reinforces comparability to brand drug - use of unique names could cause problems within pharmacy management and payor systems - unique INNs not necessary for accurate reporting of ADE (use NDC instead)

FD&C Act

Laws giving FDA authority to oversee safety of food, drugs, and cosmetics "drugs" generally approved via FD&C

Define "intended copy"

Noncomparable biotherapeutic products

In what reference will biologics be listed, including whether they are interchangeable?

Purple book

What would the Biosimilar Insulin Act of 2020 have allowed for in terms of product interchangeability had it passed (or if it passes in future)? Why is this currently being considered for insulin and not other biosimilars?

Would allow for biosimilar insulins to automatically be granted interchangeability designations If problems occur, and inadequate clinical response happens, patients could identify the failure within an hour and correct it

Is Zarxio™ marketed as a biosimilar in the US? Granix™? If not, how were they approved?

Zarxio: yes Garnix: no, they were approved under standard BLA pathway for a drug to be considered a biosimilar it has to be approved as under 351K BLA

What is the definition of a follow-on protein? Are they simple or complex proteins?

a biopharmaceutical approved or on track for approval by the FDA as a generic - generally restricted to simple proteins/peptides

FD&C Act Hatch-Waxman / 505(b)(2)

a drug that is significantly difference from innovator, but sufficiently similar to be approved - allows at least some of the safety and efficacy info required for approval to come from studies not conducted by or for the applicant - relatively fast-track approval, esp for those that represent a limited change from an existing or approved drug - including a limited range of biologics (less complex) - product could qualify for 3-7 years of market exclusivity - permits applicants to file an NDA that does not contain full reports of clinical studies providing safety and efficacy (paper NDA) - intended to motivate innovation without requiring duplication of previous studies - instead, references a previously approved innovator product - pathway is not applicable to biological products approved under the terms of section 351 of Public Health Service Act - Is applicable to some less complex proteins and peptides - mostly hormones and certain medical enzymes

what is the law that gives the FDA authority to approve biosimilars?

biologics price competition and innovation act of 2009

what systems allow for glycolsylation?

animal cells yeasts might NO ECOLI

Define orthogonality.

assays that use different chemical or physical mechanisms to measure the same attribute

Explain the difference between the various modes of drug approval discussed in class, understand that the PHS and FD&C Acts operate separately from one another, and select which would be the most likely way for a particular type of product to be submitted (note that not all options on this list are appropriate for proteins)

not a question. just read these will be questions on a different slide

Define critical quality attribute

the essential properties of the originator reference product that must be matched

Are proposed biosimilars compared to other biosimilars of the same originator product, or compared to the originator product alone?

the originator product alone

Why might a pharmaceutical company prefer to submit a drug through the BLA pathway instead of the biosimilar pathway (351(k))?

· Biosimilar pathways presents uncertainty in timing or cost · Company has the sales and marketing infrastructure to market a new molecule · Company wants a jump on biosimilar competitors · Company wants the opportunity to market the product as a differentiated approved molecule