Biosimilars Lecture

General Requirements 351(k) Application

- A 351(k) application must include information demonstrating that the biological product: - Is biosimilar to a reference product - Utilizes the same mechanism(s) of action for the proposed condition(s) of use -- but only to the extent the mechanism(s) are known for the reference product - Condition(s) of use proposed in labeling have been previously approved for the reference product - Has the same route of administration, dosage form, and strength as the reference product - Is manufactured, processes, packed, or held in a facility that meets standards designed to assure that the biological product continues to be safe, pure, and potent. - The PHS Act requires that a 351(k) application include, among other things, information demonstrating biosimilarity based upon data derived from: - Analytical studies demonstrating that the biological product is "highly similar" to the reference product notwithstanding minor differences in clinically inactive components. - Animal studies (including the assessment of toxicity) - A clinical study or studies (including the assessment of immunogenicity and PK or PD) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product.

Biomimic

- A biopharmaceutical, claimed to have high similarity with a given reference product, that has not undergone full clinical development and has not achieved regulatory approval according to the regulatory pathway for biosimilars. - Alternative terms: bipcopies, intended copies, non regulated biologics.

Biosimilar Comparative Clinical Study

- A comparative clinical study should be designed to investigate whether there are clinically meaningful differences in safety and efficacy between the proposed product and the reference product; not establishing de novo safety and efficacy. - Population, endpoint, sample size and study duration should be adequately sensitive to detect differences between products, should they exist. - Population can be novel/unapproved but justifiable to use as a test assay because of sensitivity (e.g., neoadjuvant breast cancer for biosimilar to Herceptin); biosimilar does not subsequently receive approval for that novel population/indication. - Endpoint can be novel/unapproved if it reflects activity of the product (e.g., VEGF for biosimilar to Avastin, anti-VEGFMAb) - Sample size and duration generally similar or less than in the original clinical trials, no need to re-establish efficacy (e.g., mortality) or long term safety. - Typically, an equivalence design would be used, but other designs may be justified depending on product-specific and program-specific considerations.

Biosimilar Agent

- A monoclonal antibody or fusion protein that has undergone a complete development process based on comparability to preclinical and clinical data on the reference product, with sufficient bioequivalence to meet regulatory approval. - Alternative terms: similar biotherapeutic product (used by the WHO), subsequent entry biologic (used by Health Canada), follow-on biologic (used in USA), biocomparables (used in Mexico). - A biosimilar is a biological product that is highly similar and has no clinically meaningful differences from an existing FDA-approved reference product

Adalimumab

- A randomized, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate PK equivalence of ABP 501 and adalimumab. - Adalimumab is a fully human monoclonal antibody that targets tumor necrosis factor alpha. - It is approved for the treatment of rheumatoid arthritis, psoriasis, ulcerative colitis, as well as active Ankylosing spondylitis. - Adalimumab is used to inhibit the progression of structural damage in rheumatoid arthritis, and severe plaque psoriatic arthritis. - Targeted biologics, including adalimumab, have demonstrated safety and efficacy in the treatment of autoimmune disorders, there wide-spread application may be limited due to their high costs. - ABP 501 is being developed as a biosimilar to adalimumab (Humira) - Adalimumab is a recombinant IgG1 monoclonal antibody (mAb). - ABP 501 is a fully human recombinant monoclonal antibody with the same amino acid sequence, pharmaceutical form and dosage strength as adalimumab (Humira). - It is not formulated with the same excipients as adalimumab and includes different buffer components and stabilizers. - ABP501 is being developed for the same indications, dosages, and route of administration as approved for Humira. - The drug product is supplied as a sterile, preservative-free solution for administration by subcutaneous (SC) injection.

Interchangeable Product

- An interchangeable product is a biosimilar product that meets additional requirements.

Generics Approvals by FDA

- Analytical studies are necessary - PK and bioequivalence studies are required.

Biologics Get a Special Exclusivity Period

- As part of the negotiations that set up the ACA law to allow biosimilars, biotech companies negotiated a 12-year exclusivity period after a biologic drug was approved before biosimilars could come onto the market. - That's longer than the five year average that small molecules get.

Biosimilar

- Biosimilar or Biosimilarity means: that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. - There are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

Types of Biological Products

- Blood derivatives - Whole blood - Blood components - Proteins - Human tissues - Vaccines (preventive and therapeutic) - Allergenic extracts - Cellular and gene therapies (DNA & RNA) - Xenotransplantation Products

FDA Stepwise Approach

- FDA has outline a stepwise approach tog enerate data in support of a demonstration of biosimilarity. - Evaluation of residual uncertainty at each step of data generation - Totality-of-the-evidence approach in evaluating biosimilarity - no "one-size fits all" assessment - There is no one "pivotal" study that demonstrates biosimilarity. - Biosimilars application must include biosimilarity data derived from: analytical studies (structural and functional analyses), animal studies (toxicity, PD, PK), clinical studies (human pharmacology, immunogenicity, and clinical comparison data)

Current Biosimilars Approved by FDA

- Filgrastim (Neupogen by Amgen - Zarixio by Sandoz) - Infiximab (Remicade Janssen - Inflectra by Pfizer: Hosprira) - Etanercept (Enbrel by Amgen - Erelzi by Sandoz) - Adalimumab (Humira by AbbVie - Amjevita by Amgen) - Infliximab (Remicade Jannsen - Renflexis by Merck)

Naming and Traceability for Biosimilars

- For marketing a biosimilar, should have its own brand name (trade name) in addition to the drug name as for all new medicinal products (sometimes not necessary)

Approval of Biosimilar Product

- Goal: to establish biosimilarity between proposed product and reference product, not to re-establish safety and effectiveness. - Approval of a biosimilar product is based on the integration of various information and the totality of the evidence submitted by the applicant to provide an overall assessment that the proposed product is biosimilar to the reference product.

Conclusion ABP 501

- In this phase 1 study, after a single 40mg SC injection, PK of ABP 501 was similar to that of adalimumab (USA) and adalimumab (EU). - The safety and tolerability of ABP 510 and adalimumab (US) and adalimumab (EU) were similar, as were the rates of developing antibodies ADAbs.

Challenges in Implementing Biosimilar Guidelines

- Is the efficacy of the biosimilar the same? - Is the potential toxicity or safety of the product similar to that of the RBP (reference biological product)? - Is the immunogenicity of the two products the same? The RBP and the biosimilar will often differ? - Does switching from the RBP to a biosimilar elicit an immune response or phenomena that is not foreseen? - Safety-related matters may also have unexpected consequences, clinically.

Purple Book

- Lists all approved biologics approved under 351(a) of the PHS Act as well as their approval dates and patent expirations. - Lists the dates that biosimilars of the reference products were approved - Also lists products approved as biosimilars and interchangeability status.

Study Design ABP 501

- Randomized, single-blind, single-dose, three-arm, parallel-group study. - Health subjects were randomized to receive ABP 501 (n=67), adalimumab, humira USA (n=69), or adalimumab EU (n=67) 40mg subcutaneously. - Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC). - AUC from 0 to last time point, and the maximum observed concentration (Cmax). - Safety and immunogenicity were monitored

Biological Products

- Regulated by the Food and Drug Administration (FDA) and are used to diagnose, prevent, treat, and cure diseases and medical conditions. - Biological products are a diverse category of products and are generally large, complex molecules. - These products may be produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell, and are often more difficult to characterize than small molecule drugs. - There are many types of biological products approved for use in the United States, including therapeutic proteins (such as filgrastim), monoclonal antibodies (such as adalimumab), and vaccines (such as those for influenza and tetanus).

Slow Reaction

- The EU has been approving biosimilars for years. - The FDA has been slow to approve biosimilars -- it took 5 years from when Obamacare was signed into law until the first biosimilar was approved in 2015. - European regulators have been approving them for years. - Zarxio, for instance, was approved in Europe in 2009 under the brand name Zarzio.

Intercahngeability

- The biological product is biosimilar to the reference product, it can be expected to produce the same clinical result as the reference product in any given patient, and 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 alteration or switch. - An interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

Reference Product

- The initial biopharmaceutical that has been approved by regulatory agencies for specific indications - Preclinical and clinical data regarding the reference product provide the basis for comparison of a biosimilar agent in the approval process. - Alternative terms: originator, innovator - A reference is the single biological product, already approved by FDA, against which a proposed biosimilar product is compared

Nature of Biological Products

- The nature of biological products, including the inherent variations that can result from the manufacturing process, can present challenges in characterizing and manufacturing these products that often do not exist in the development of small molecule drugs. - Slight differences between manufactured lots of the same biological product (i.e., acceptable within-product variations) are normal and expected within the manufacturing process. - As part of its review, FDA assesses the manufacturing process and the manufacturer's strategy to control within-product variations. - These control strategies are put in place to help ensure that manufacturers produce biological products with consistent clinical performance.

Extrapolation

- The potential exists for a biosimilar product to be approved for one or more conditions of use for which the reference product is licensed based on extrapolation. - Sufficient scientific justification for extrapolation is necessary. - Differences between conditions of use (e.g., indications) do not necessarily preclude extrapolation. - FDA guidance outlines factors to consider, including: MoA for each condition of use, PJK and biodistribution in different patient populations, immunogenicity in different patient populations, differences in expected toxicities in each condition of use and patient population.

Discounts Might not be that great for Biosimilars as with Generics

- The spending for larger clinical trials and marketing, combined with higher manufacturing costs, means that biosimilars are not sold for cheap prices that small-molecule generics can be sold for, which often go for 10% or less of the branded-drug proce. - Biosimilars will likely be priced closer to the price of the brand-name drug, depending on the amount of competition. - Novartis' Zarxio, for instance, launched at only a 15% discount to Amgen's Neuprogen.

Generics vs. Biosimilars

- They are NOT generics. - Small molecule drugs are what you typically think of as generic drugs - Because they are made through chemical synthesis or extracted from natural sources, the active ingredient is essentially identical. - Biologics are made in living cells. - It is nearly impossible to make an exact replica of a biologic unless a company follows the exact same manufacturing procedure as the company that makes the brand-name drug. - Since that's proprietary information, the manufacturers trying to duplicate the original drug do not have that the same cell line thus the biological products will not be entirely identical. - "Biosimilar" because changes in cell lines, growing conditions, expression times, purification process, and other variables can have minor changes to the drug. Biosimilars are similar - but may not be identical - to the brand-name drug.

Aim of the Study ABP 501

- To demonstrate PK similarity of biosimilar candidate ABP 501 relative to Humira reference product from the USA and European Union (EU) and evaluate safety, tolerability, and immunogenicity of ABP 501. - Biologic products (proteins and their formulations) may have different bioavailability. - The totality of evidence available to date suggests that ABP 501 is similar to Humira. - Results from analytical studies that evaluated identity, general properties, primary and higher-order structure, carbohydrate structure, isoelectric profile, purity and impurities, and thermal-forced degradation profiles have confirmed ABP 501 to be structurally similar to Humira.

Approval Requirements May Differ from Biosimilar to Biosimilar

- While approval requirements are generally the same for small-molecule generics -- typically they just have to show they're bioequivalent to the brand name drug in a small clinical trial -- that is not the case for biosimilars.