The U.S. Food and Drug Administration (FDA) last week issued three draft guidance documents on biosimilar product development to assist industry in developing such products in the United States.
- Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
- Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
- Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
“When it comes to getting new biosimilar products on the market, FDA has taken an innovative approach to supporting their development at every step of the process,” said Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research (CDER). “These draft documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers.”
The Patient Protection and Affordable Care Act (PPACA), signed into law by President Obama on March 23, 2010, amended the Public Health Service Act to create an abbreviated approval pathway — under section 351(k) — for biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product.
Biological products are therapies used to treat diseases and health conditions. They include a wide variety of products including vaccines, blood and blood components, gene therapies, tissues, and proteins. Unlike most prescription drugs made through chemical processes, biological products generally are made from human and/or animal materials.
The FDA defines a biosimilar as “a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.”
Through this new approval pathway, biological products are approved based on demonstrating they are biosimilar to, or interchangeable with, a biological product that is already approved by the FDA, which is called a reference product.
The following three guidance documents provide the FDA’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to the agency. Among the key points in the new FDA guidance:
- Biosimilars will be reviewed as a package, with the FDA considering the totality of the evidence
- FDA is taking a stepwise approach
- Biosimilar does not mean identical
- Biosimilarity and interchangeability are sequential decisions. They can be done in the same 10-month approval period if that is requested initially. If interchangeability is requested later in the approval process, it extends the approval period.
- Interchangeability will require a switching study.
- The reference product has to be FDA approved; European approval is not sufficient.
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.
This is draft guidance is intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting or filing a 351(k) application to the FDA. It describes a risk-based “totality-of-the-evidence” approach that the FDA intends to use to evaluate the data and information submitted in support of a determination of biosimilarity of the proposed product to the reference product. The FDA recommends a stepwise approach in the development of biosimilar products.
Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product.
This guidance provides an overview of analytical factors the FDA will consider in assessing biosimilarity between a proposed therapeutic protein product and a reference product for the purpose of submitting a 351(k) application. The sponsor must with extensive analytical, physicochemical, and biological data show that its product is highly similar to the reference product notwithstanding minor differences in clinically inactive components.
Questions and Answers.
This is particularly aimed at questions about the early stages of the FDA review process. The question and answer format addresses questions that may arise in the early stages of product development, such as how to request meetings with the FDA, addressing differences in formulation from the reference product, how to request exclusivity, and other topics.
Discussion
In a teleconference with reporters, Rachel Sherman, MD, director of the FDA’s Office of Medical Policy in CDER said the Agency has been “in business” since March 2010. So far, there have been 35 pre-IND meeting requests and 21 pre-IND meetings, and 9 INDs have been submitted.
No applications have been submitted, and the application review is a 10-month clock. Thus, the earliest the first biosimilar could be approved in the U.S. is, realistically, 2013 or later, and later is more likely. Among the other points Dr. Sherman made were:
- A biologic product is usually made in a living system, but that does not have to be the case. Some biologics can be made synthetically.
- The FDA does not want unnecessary studies to be done, to subject patients to needless studies. This suggests that the FDA is trying to minimize but not eliminate the clinical trial burden on biosimilar developers, but clinical trials will be a must for any biosimilar that wants an interchangeable designation.
- The FDA plans a public meeting on these guidances “soon,” but she didn’t say when that would be.
Asked if most biosimilar drugs will need to be studied in clinical trials, Dr. Sherman said, “We are trying to send the signal that it is not onesize- fits-all. It is product-by-product…Think of two buckets: (1) de novo programs started now or recently and those more tailored to our specifications; and (2) products developed in Europe…that may or may not have clinical data, and the question will be what kind of bridge we can make with those to the U.S. market.
We do expect, because the products are so large and complex and typically can provoke an immune reaction – are highly immunogenic – that all will have immunogenicity studies. But the matter of human testing will depend on the product, what is known structurally about it, perhaps safety signals with the host [reference] product. The message we are trying to send is it is not one-size-fits-all.”
Which products will be considered interchangeable and in which circumstances? Dr. Sherman said, “Interchangeability is a separate standard under the law. First a product has to be deemed biosimilar…Once a product is deemed biosimilar, it is eligible for an interchangeability determination. That requires additional study, a clinical study, that switching back and forth doesn’t change the safety profile. Whether it is switched is typically by law something done at the state level.”
If a company applies for interchangeability with the original biosimilar submission, the whole process will be reviewed within 10 months. If the company applies later for interchangeability, it starts a new clock, which would add time to the approval, but not another 10 months. Dr. Sherman said, “If you are eligible for licensing as a biosimilar, you can request interchangeability. [Biosimilarity and interchangeability] are sequential.”
However, interchangeability will require a clinical trial, and some sponsors may opt not to seek interchangeability. Dr. Sherman said, “If you reach biosimilarity you might [go for interchangeability]. You are eligible. But you, as a manufacturer, might decide you are not interchangeable. You might decide to develop those data later on…It is up to the manufacturers to decide if they want to pursue interchangeability.”
Is interchangeability going to be difficult to achieve? Yes. Dr. Sherman said, “That is going to be a pretty high bar…We have to know absolutely for certain that going back and forth between products does not diminish efficacy or affect safety. It is a separate determination and sequential…It is not conceivable to me that we could make an interchangeability decision without clinical data…This would be a switching trial…back and forth more than once. If you were in this trial, you would get compound A, then compound B, then back to compound A, and you might switch again, depending on our level of concern based on the animal model or what we know about the product.”
Will there be future guidances on specific classes of drugs? No. Dr. Sherman said, “That has been the European approach. We are not sure. At the moment we are trying to get the most bang for the buck…That has not been the path we’ve thought would most efficiently expedite development of these products.”
The FDA’s authority to approve biosimilars came from the Patient Protection and Affordable Care Act (ACA) which went into effect in March 2010. That is a new abbreviated approval pathway, 351(k). What happens if the Supreme Court overturns ACA? Dr. Sherman said biosimilars could still be approved, “We have put forward a scientific roadmap on how to develop this type of product. This is not a new thought process for us. We have approved proteins that are not biologics, that are regulated as drugs under FDAAA, under 505(b)…such as generic enoxaparin [Sanofi’s Lovenox]…So from a scientific point of view, this guidance is going to be useful under any regulatory or legal paradigm.”
FDA will seek public comment on the guidance documents and instructions on how to submit comments will be announced in an upcoming Federal Register notice. In finalizing the guidance documents, the agency will consider the information received from the public.