US Congress, through the Biologics Price Competition and Innovation Act (BPCI Act) of 2009, created an abbreviated licensure pathway for biological products that are demonstrated to be biosimilar to or interchangeable with an FDA-approved biological product. This pathway was established as a way to provide more treatment options, increase access to lifesaving medications, and potentially lower health care costs through competition.
Are they like generic drugs?
Are they like generic drugs?
Biosimilars and generic drugs are versions of brand name drugs and are each approved through different abbreviated pathways that avoid duplicating costly clinical trials. But biosimilars are not generics, and there are important differences between biosimilars and generic drugs.
Generic drugs have the same active ingredients as those of brand name drugs. In addition, the manufacturer of a generic drug must demonstrate that the generic is bioequivalent to the brand name drug.
By contrast, manufacturers developing a biosimilar must demonstrate that the drug is highly similar to the reference product, except for minor differences in clinically inactive components. They must also demonstrate that there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness.
So what is a biosimilar?
So what is a biosimilar?
A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.
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To know more about a biological product, click here. In general, biological products are a diverse category of 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.
The proposed biosimilar product is compared to and evaluated against a reference product, which is a biological product already approved by FDA, to ensure that the product is highly similar and has no clinically meaningful differences.
As mentioned above, when a biosimilar is compared to a reference product, the two standards for comparison with a reference product are:
1. Highly similar
2. No clinically meaningful differences
What does it mean to be “highly similar”?
A manufacturer developing a proposed biosimilar has to demonstrate that its product is highly similar to the reference product by extensively analyzing (i.e., characterizing) the structure and function of both the reference product and the proposed biosimilar. State-of-the-art technology is used to compare characteristics of the products, such as purity, chemical identity, and bioactivity. The manufacturer uses results from these comparative tests, along with other information, to demonstrate that the biosimilar is highly similar to the reference product.
Minor differences between the reference product and the proposed biosimilar product in clinically inactive components are acceptable. For example, these could include minor differences in the stabilizer or buffer compared to what is used in the reference product. Any differences between the proposed biosimilar product and the reference product are carefully evaluated by FDA to ensure the biosimilar meets FDA’s high approval standards.
What does it mean to have “no clinically meaningful differences”?
A manufacturer must also demonstrate that its proposed biosimilar product has no clinically meaningful differences from the reference product in terms of safety, purity, and potency (safety and effectiveness). This is generally demonstrated through human pharmacokinetic (exposure) and pharmacodynamic (response) studies, an assessment of clinical immunogenicity, and, if needed, additional clinical studies.
An interchangeable product is a biosimilar product that meets additional requirements outlined by the Biologics Price Competition and Innovation Act. As part of fulfilling these additional requirements, information is needed to show that an interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Also, for products administered to a patient more than once, the risk in terms of safety and reduced efficacy of switching back and forth between an interchangeable product and a reference product will have been evaluated. An interchangeable product may be substituted for the reference product without the involvement of the prescriber.
So what is an interchangeable product?
An interchangeable product is a biosimilar product that meets additional requirements outlined by the Biologics Price Competition and Innovation Act. As part of fulfilling these additional requirements, information is needed to show that an interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Also, for products administered to a patient more than once, the risk in terms of safety and reduced efficacy of switching back and forth between an interchangeable product and a reference product will have been evaluated. An interchangeable product may be substituted for the reference product without the involvement of the prescriber.
For more on interchangeability, click here to read more.
The goal is to demonstrate biosimilarity between the proposed biosimilar product and the reference product, not to independently establish the safety and effectiveness of the proposed product.
The manufacturer of a proposed biosimilar product generates an array of data comparing the proposed product to the FDA-approved reference product in order to demonstrate biosimilarity. The comparative data are generated and evaluated in a stepwise fashion that begins with a foundation of detailed analytical (structural and functional) characterization and comparison of the products, moving on to animal studies if necessary and then to comparative clinical studies.
Consequently, rather than generating the same full profile of nonclinical and clinical data as the reference product, a manufacturer that shows its proposed biosimilar product is highly similar to and has no clinically meaningful differences from the FDA-approved reference product may rely in part on FDA’s previous determination of safety and effectiveness for the reference product for approval. This generally means that biosimilar manufacturers do not need to conduct as many expensive and lengthy clinical trials, potentially leading to faster access to these products, additional therapeutic options, and reduced costs for patients.
A biosimilar product application must include data demonstrating biosimilarity to the reference product. This usually includes data 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 an assessment of toxicity; and
- A clinical study or studies sufficient to demonstrate safety, purity, and potency of the proposed biosimilar product in one or more of the indications for which the reference product is licensed. This typically includes assessing immunogenicity, pharmacokinetics (PK), and, in some cases, pharmacodynamics (PD) and may also include a comparative clinical study.
- The proposed interchangeable product is expected to produce the same clinical result as the reference product in any given patient; and,
- For a product administered more than once to an individual, switching between the proposed interchangeable product and the reference product does not increase safety risks or decrease effectiveness compared to using the reference product without such switching between products.
Do all biosimilar applications have the same types of data?
When considering licensure of a biosimilar product, FDA reviews the totality of the data and information, including the foundation of detailed analytical (structural and functional) characterization, animal studies if necessary, then moving on to clinical pharmacology studies and, as needed, other comparative clinical studies.
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| (c) FDA |
Why do we need an abbreviated approval pathway for biological products?
The abbreviated licensure pathway does not mean that a lower approval standard is applied to biosimilar or interchangeable products. In fact, the data package required for approval of a biosimilar or interchangeable product is extensive. If a biosimilar manufacturer can demonstrate that its product is biosimilar to the reference product, then it is scientifically justified to rely on certain existing scientific knowledge about the safety and effectiveness of the reference product to support approval. This allows for a potentially shorter and less costly drug development program for a biosimilar.
Can a biosimilar be approved for an indication that is approved for the reference product even if the biosimilar is not directly studied in that indication?
A biosimilar product may be approved for an indication without direct studies of the biosimilar in that indication. If the total evidence in the biosimilar application supports a demonstration of biosimilarity for at least one of the reference product’s indications, then it is possible for the biosimilar manufacturer to use data and information to scientifically justify approval for other indications that were not directly studied by the biosimilar manufacturer. This concept is called “extrapolation” and is critical to the goals of an abbreviated pathway—improving access and options at a potentially lower cost.
To read more about approval for additional indications and extrapolation, click here.
Can biosimilars be substituted for reference products by pharmacists?
Substitution of a biosimilar for a reference product is a matter of state pharmacy law and is a decision that is generally outside of FDA’s regulatory role.
Once interchangeable biological products are available in the United States, some states may permit a pharmacist to substitute an interchangeable product for the reference product without consulting the prescriber—a practice commonly called pharmacy-level substitution.
Can a biosimilar or interchangeable product be used in patients who have previously been treated with the reference product?
Biosimilars and interchangeable products can be used in patients who have previously been treated with the reference product (treatment-experienced), as well as in patients who have not previously received the reference product (treatment-naïve). Before approval of the biosimilar product, FDA may request additional data that looks at safety information for treatment-experienced patients who undergo a single transition (single switch) from a reference product to a biosimilar product.
As part of the approval process for interchangeable products given more than once, manufacturers must show that patients can be switched back and forth between the reference product and the proposed interchangeable product without an increased risk in terms of safety or diminished efficacy.
To know more about a biological product and whether it is a reference product, a biosmilar, or an interchangeable product, click on the Purple Book, which is an online resource that lists licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations.
So, in short, as a healthcare provider, you will be hearing a lot about biosimilars in the coming years, both from the pharmaceutical industry, as well as in relation to patients using these drugs.
FDA’s Center for Drug Evaluation and Research (CDER) has approved seven biosimilars to date. To know more about the currently approved biosimilars, click here.
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