The U.S. Pharmacopeia (USP) is an independent, non-governmental, not-for-profit organization that sets quality, purity and strength standards for medicines, food ingredients and other products sold in the United States. The FDA works closely with USP to enforce USP’s standards, which are often called monographs. These monographs, which manufacturers are legally required to follow when applicable, can be vital for many of our small molecule drug products. However, for biological products, adhering to a monograph may actually hinder progress and does not offer additional quality assurances.
Steven Kozlowski, M.D., who is the director of the Office of Biotechnology Products in CDER’s Office of Pharmaceutical Quality, explains the issue.
To what extent are biological products currently subject to USP monograph standards?
The concept of mandatory product-specific monographs for biological products is recent. In 1997, the FDA Modernization Act (FDAMA) harmonized the requirements for small molecule drugs and biologics, with some exceptions. This meant that if a biological product had a monograph, all manufacturers of the product would be required to adhere to it. Before FDAMA, compliance with any existing monograph for a biological product was optional.
What this means in practical terms is that if a company making a biological product went to the USP and submitted a monograph for the product, and if that monograph went through the vetting process and was accepted, then all other manufacturers of that product would be required to follow the monograph.
Do any biological products currently have a monograph?
To date, very few biological products currently have monographs. The vast majority of the most highly used biological products, including Humira, Remicade, Rituxan, Enbrel, Avastin, Gardasil, Prevnar, Herceptin, and Neulasta, do not currently have monographs.
It is also possible that a maker of an older product could ask USP to write a monograph for its product, and if it were approved, it could impact both existing and future products on the market.
Why is it not a good idea for biological products to have to adhere to a monograph?
A biological product is so inherently complex and variable that the established structure of the USP monograph standards process does not serve it well, and in fact, can impede technological progress or innovation.
The issue in part has to do with “sameness.” Small molecule drugs and their generic counterparts, which are typically chemically synthesized, must show that their active ingredient is the “same,” no matter who manufactures them. FDA supports these drugs being subject to monograph standards because their structures are well characterized and can be replicated. In contrast, most biological products are highly complex proteins or other by-products of living cells. They have a large number of attributes that are evaluated using analytical and other technologies that develop and advance rapidly. Tests and assays sufficient to characterize biological products often are themselves complex, manufacturing-process-specific, and/or patented.
The standard for biosimilars cannot be “sameness” due to the inherently variable nature of these biological products. Instead, the abbreviated approval pathway that was established for these products by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created a standard that includes “highly similar.” And while there is generally one way to show sameness, the approach to demonstrating highly similar may vary from product to product, and still meet all safety and efficacy criteria.
If one company establishes criteria for a biological product in a particular way that meets agency standards for safety and efficacy and a monograph was established for it, another company trying to develop a biosimilar for it may meet the agency’s rigorous standards for being highly similar, but not be able to meet the monograph criteria. This would block the biosimilar’s approval. In addition, companies may influence the development of a monograph by incorporating patented characteristics of their product that are not relevant to safety, purity or potency, further impacting competition. These would be unnecessary barriers to innovation and progress.
The BPCI Act was designed to ensure a clear pathway for approval of biosimilars and interchangeable products and is intended to balance innovation with consumer interests. Monographs for biological products do not align with these goals and may serve to burden competition for biological product development.
Are biological products without a USP monograph more likely to have quality problems or be unsafe?
No. Before FDA approves a biological product and allows it to be marketed, the agency reviews data regarding the product and its manufacturing processes and facilities in order to ensure that the manufacturer can consistently produce a safe and effective product.
Does USP have access to the same information that the agency has in order to establish monograph standards?
Generally, USP does not have access to the same breadth and depth of information about a biological product that the agency has as part of its review of investigational and marketing applications and postmarketing surveillance. To make fully informed determinations for approval, the FDA receives detailed, proprietary information about a product, including toxicology data, clinical data, safety data and other data that the company is not required to send to USP. This information allows FDA to ensure that individual biological products, which may vary by manufacturer, are each safe and effective, instead of just complying with certain pre-specified standards.
How does tying a biological product to a monograph stifle innovation or impede progress?
Consider a company that conceives of a novel or more efficient manufacturing process for a biological product that will make these drugs more accessible. The new process may trigger some variability in the product. If there is a monograph for that particular biological product in place that does not accommodate this change in manufacturing, the new product could not be approved. When it comes to transformational manufacturing for these products that could lead to better access, the rigidity of the monograph model may hamper progress. In contrast, the agency’s standards provide more flexibility to take into account product characteristics, without sacrificing safety or efficacy.
Does the FDA want to do away with USP monograph standards?
No. The FDA supports monograph standards for small molecule drugs, which are more easily standardized and do not impede innovation. Standards are a valuable tool. We also support optional standards for biological products that align with our flexible approach to account for the complexity of biological products. Any mandatory USP standards, however, would impede innovative technologies, as well as place unnecessary burdens on industry and on FDA reviewers.