Biosimilar

Approval processes

United States

In the United States, the Food and Drug Administration (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway. Additional Congressional hearings have been held. On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. Since 2004 the FDA has held a series of public meetings on biosimilars.

The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the Biologics Price Competition and Innovation Act of 2009.

The FDA has previously approved biologic products using comparability, for example, Omnitrope in May 2006, but this like Enoxaparin was also to a reference product, Genotropin, originally approved as a biologic under the FD&C Act.

In March 2015, Zarxio obtained the first biosimilar approval from the FDA. 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. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And 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 review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

In March 2020, most protein products that were approved as drug products (including every insulin currently on the market ) are scheduled to open up to biosimilar and interchangeable competition in the United States. However, "chemically synthesized polypeptides" are excluded from this transition, which means that a product that falls within this category won't be able to come to market as a biosimilar or interchangeable product, but will have to come to the market under a different pathway.

Background

Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches.

Recombinant therapeutic proteins are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.

After the expiry of the patent of approved recombinant drugs (e.g., insulin, human growth hormone, interferons, erythropoietin, monoclonal antibodies and more) any other biotech company can develop and market these biologics (thus called biosimilars).

The typical reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process (ranging from a change in the supplier of cell culture media to new purification methods or new manufacturing sites) was substantiated with appropriate data and was approved by the EMA.

The current concept of development of biosimilar monoclonal antibodies follows the principle that an extensive state of the art physicochemical, analytical and functional comparison of the molecules is complemented by comparative non-clinical and clinical data that establish equivalent efficacy and safety in a clinical "model" indication that is most sensitive to detect any minor differences (if these exist) between the biosimilar and its reference monoclonal antibody also at the clinical level.

The EMA has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same.

Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose. However, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status.

Generally, once a drug is released in the market by the FDA, it has to be re-evaluated for its safety and efficacy once every six months for the first and second years. Afterward, re-evaluations are conducted yearly, and the result of the assessment should be reported to authorities such as FDA. Biosimilars are required to undergo pharmacovigilance (PVG) regulations as its reference product. Thus biosimilars approved by the EMA are required to submit a risk management plan (RMP) along with the marketing application and have to provide regular safety update reports after the product is in the market. The RMP includes the safety profile of the drug and proposes the prospective pharmacovigilance studies.

Several PK studies, such as studies conducted by Committee for Medicinal Products for Human Use (CHMP), have been conducted under various ranges of conditions; Antibodies from an originator's product versus antibodies from a biosimilar; combination therapy and monotherapy; various diseases, etc. on the purpose to verify comparability in pharmacokinetics of the biosimilar with the reference medicinal product in a sufficiently sensitive and homogeneous population.

Nomenclature

In the European Union, no unique identifier of a biosimilar medicine product is required, as the same rules are followed as for all biologics.

The US decided on a different approach, requiring the assignment of a four-letter suffix to the nonproprietary name of the original product to distinguish between innovator drugs and their biosimilars. Japan has similar requirements. The suffix approach has been criticized on the grounds of compromising the INN system and delaying the marketing of biosimilars. Australia decided not to use a 4-letter suffix.

A version of the four-letter suffix has been proposed to the WHO as the biological qualifier (BQ). It is not part of the international nonproprietary name (INN), but is proposed to be managed under the same registry. The report 1 of the May 2017 WHO Expert Consultation on Improving Access to and Use of Similar Biotherapeutic Products, published in October 2017, revealed on page 4, that following the outcome arising from the meeting: "No consensus was reached on whether WHO should continue with the BQ... WHO will not be proceeding with this at present."

Bioparallel

Different from biosimilars, many new antibodies are being developed with the goal to be structurally different (to not violate patents) but functionally very similar to their reference drugs. Similarly, in advanced therapy medicinal products, such as Chimeric Antigen Receptor T-cell (CAR-T) therapy, the exchange of one component by a similar component (e.g. one promoter by another to drive CAR expression), generates structurally different, but functionally similar copies of drugs. There is no established term for such biologics, but the terms "bioparallels" or "me-too biologics" (in reference to me-too drugs) have been proposed. Within the current frameworks of the US and EU approval processes, these drugs require evaluation as new biological entities. Bioparallels compete with their reference medicines on price but have the advantage of being able to enter the market earlier.

Biobetter

The term biobetter refers to a biological drug that is an improved version of an existing biological drug. Unlike biosimilars, the term biobetter is used informally without any official and universally accepted definition. While biosimilars try to copy an existing biological drug (the "reference medicine") as closely as possible, biobetters try to improve on it. Since the term biobetter is informal, there is no rule which regulatory pathway they need to go through to be approved. When the improvement to the original drug is merely in the formulation (thus, e.g., adding additional modes of administration), the drug might be regulated as a biosimilar. However, if the active pharmaceutical ingredient (API) has been modified, the drug needs to be evaluated as a new biological entity. Even without changes to the API, the biobetter needs to be evaluated as a new biological entity (requiring a biologics license application), if it shows better clinical outcomes compared to the reference medicine. The latter happened e.g. to Zymfentra, an antibody biosimilar that can be given subcutaneously, whereas its reference medicine infliximab was only approved for intravenous administration.

Australia

Biosimilars available in Australia include adalimumab, bevacizumab, enoxaparin, epoetin lambda, etanercept, filgrastim, follitropin alfa, infliximab, insulin aspart, insulin glargine, pegfilgrastim, rituximab, teriparatide, and trastuzumab.

Egypt

A research article about "Maximizing the benefits of using biosimilars in Egypt" proposed a regulatory framework for biosimilars in Egypt. The article summarized the recommendations of a number of stakeholders.

;Key Findings and Recommendations of the article

1. Pricing: The experts suggested a mandatory discount of 30–40% on the price of the first biosimilar compared to its originator, with subsequent biosimilars receiving additional discounts. It was also recommended that biosimilar prices be revised periodically, either annually or biennially.
2. Reimbursement: A significant emphasis was placed on using Health Technology Assessment (HTA), specifically cost-effectiveness analysis (CEA) and budget impact analysis (BIA), when manufacturers seek to extend reimbursement indications beyond those of the originator. Additionally, experts proposed that the first biosimilar, offering a minimum 50% discount compared to the originator, be granted immunity from removal from the formulary for a specified period.
3. Uptake: The study highlighted the need for policies that enhance both prescriber and patient acceptance of biosimilars. Strategies include disseminating educational materials, implementing financial incentives for prescribing biosimilars as first-line therapy, and using co-payments to encourage the choice of less expensive biosimilars over more costly biologics.
4. Post-Marketing and Pharmacovigilance: The importance of establishing registries and conducting real-world evidence studies to monitor biosimilar efficacy and safety was also emphasized. A pharmacovigilance framework specific to biosimilars and biologics was suggested to be more effective than the existing general framework.

European Union

Biosimilar medicines approved in the European Union (EU) are interchangeable with their reference medicine or with an equivalent biosimilar.

United States

As of October 2024, the US FDA has approved 60 biosimilars.

BPCI Act

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) is an amendment to the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to a Food and Drug Administration (FDA) approved biological product. The BPCI Act is similar, conceptually, to the Drug Price Competition and Patent Term Restoration Act of 1984 (also referred to as the "Hatch-Waxman Act") which created biological drug approval through the Federal Food, Drug, and Cosmetic Act (FFD&C Act). The BPCI Act aligns with the FDA's longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. The FDA has released a total of four draft guidelines related to biosimilar or follow-on biologics development. Upon the release of the first three guidance documents the FDA held a public hearing on May 11, 2012.

In 2018, the FDA released a biosimilars action plan to implement regulations from the BPCI Act, including limiting the abuse of the risk evaluation and mitigation strategy (REMS) system for evergreening and transitioning insulin and human growth hormone to regulation as biologics rather than drugs.

US approved biosimilars

References

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