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Public Workshop on the Scientific Considerations Related to Developing Follow-On Protein Products
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Sara Radcliffe
Managing Director, Scientific and Regulatory Affairs
Testifying on behalf of the Biotechnology Industry Organization
Before the Food and Drug Administration, HHS
September 14, 2004
The Biotechnology Industry Organization (BIO) appreciates the opportunity the Food and Drug Administration (FDA) has made available to stakeholders to discuss scientific and technical issues surrounding whether and how so-called "follow-on" protein products may be approved using an abbreviated approval pathway. BIO requested open and meaningful debate on these issues in its Citizen Petition submitted to the agency last year, because of our concerns that significant risks to patients will arise if biological products are approved based on less than the full complement of data necessary to show safety and effectiveness. BIO is also concerned that any safety problems that develop as a result of such approvals could undermine the confidence of physicians and patients in all biological products.
We welcome this meeting, and we also look forward to the scientific workshop FDA is planning for January 2005. We believe, however, as we stated in our Citizen Petition and in subsequent submissions to FDA dockets on this topic, that the questions about how FDA deals with follow-on protein products go beyond the scientific and technical considerations which are the focus of this workshop and include legal and policy issues. We look forward to FDA initiating a similar process to discuss the significant legal and policy issues presented by "follow-on" protein products.
BIO represents more than 1,000 biotechnology companies, academic institutions, state biotechnology centers, and related organizations in all 50 U.S. states and 33 other nations. BIO members are involved in the research and development of healthcare, agricultural, industrial, and environmental biotechnology products. Representatives from a number of BIO member companies engaged in the research and development of novel biotechnology-derived protein products are also speaking at today's workshop. BIO will present three general scientific and technical concepts that are grounded by the specific hands-on experience of BIO member companies; experience that is crucial to understanding biological products. In addition, BIO will submit written testimony containing more detailed responses to the 13 specific questions posed by the agency in its Federal Register notice for this meeting, and BIO will be an active contributor to the January 2005 workshop. Many of the points that we will present today have also been made in our Citizen Petition and docket submissions, which are available on our website at www.bio.org.
First, protein products are more complicated and more fragile than most traditional "small-molecule" drugs. Compared with the small molecules that constitute the active ingredients of chemically synthesized drugs, proteins almost always have a much higher molecular weight and greater structural complexity. Proteins may be modified by the addition of carbohydrates (i.e., "glycosylated") and by other post-translational modifications. Also, protein products can be mixtures of many molecular species, and can have unique impurity profiles, which are invariably dependent on manufacturing process.
Second, the nature of a protein product is closely dependent on the starting materials and processes used to make that product. Protein products are typically made in living systems, which have inherent variability. Minor changes made by a manufacturer to starting materials or to manufacturing processes can lead to changes in the product that may not be detectable by current technologies. These include changed impurity profiles and varying carbohydrate composition and glycan structure, which may alter the pharmacokinetic and pharmacodynamic properties of the protein product, and, ultimately, have effects on the product's safety and effectiveness when administered to patients. To ensure consistency in the characteristics of the final product, and to ensure consistent safety and effectiveness, the source material, manufacturing process, formulation, and storage conditions must be carefully kept within specifications and control limits that have been empirically determined by the manufacturer and presented for regulatory approval. Importantly, we mean specifications and control limits that have been functionally validated as applicable to a unique manufacturing process.
There are many steps involved in producing and purifying an active biological ingredient from starting materials, and these steps must remain consistent from batch to batch to ensure the quality of the final product. The types of cells used and any modification of those cells are crucial to the characteristics of the final product. The master cell bank is a unique entity, comprised of living cells; the cell lines and cell banks that would be used to make "follow-on" products would never be the same as those used by the innovator. The large-scale cell culture required to manufacture the necessary amounts of the desired protein is highly dependent on the vessels used, the components of the solution (including nutrients, growth factors, and sera), the type of fermentation process, and other conditions such as temperature, shear forces, phase, and enzymatic activity. Various and often sophisticated techniques are used for the isolation and purification of active moieties from cell culture, and the sequence and method of operation of these techniques are crucial to the final outcome. Purification steps necessary to remove undesired proteins and other impurities may result in altered forms of the desired protein, and this must be detected and prevented. On-going testing is essential during and after purification to rule out contamination and to confirm parameters such as amino acid sequence, glycosylation pattern, molecular heterogeneity and isoform profile, and potency - all of which may have an impact on a product's toxicology, pharmacokinetic and pharmacodynamic profiles, immunogenicity, and ultimately clinical safety and effectiveness. Changes to a protein product can not only render the product ineffective, but may also elicit an immune reaction which causes the body to attack endogenous proteins; the potential for eliciting such immune reactions is extremely difficult to predict using analytical testing or animal models.
Third, protein products are difficult to characterize. Even a relatively small and simple protein product is difficult to characterize, and the molecular structure of many proteins cannot be characterized fully with current technology. Thus, significant changes to the product that may occur through even a modest alteration in manufacturing process might be difficult or impossible to detect through end-product testing. Furthermore, improvements in our ability to characterize proteins through analytical testing may simply reveal more heterogeneity and complexity in approved protein products, rather than less.
While analytical and other non-clinical tests are becoming increasingly powerful and sophisticated, such tests remain limited in their ability to detect differences in manufacturing processes and changes in the final protein product that may affect clinical safety and effectiveness. For small-molecule drug products a straightforward dissolution assay or a bioequivalence study involving a small number of patients may be sufficient to demonstrate "sameness," but far more is required for a protein product. Demonstrating that known and unknown changes are unlikely to have impacted on the safety or effectiveness of a protein product requires substantial effort on the part of an original manufacturer that is intentionally making a minor change to its own manufacturing process. When innovator companies make changes in their own manufacturing processes, unanticipated changes in the product can and have occurred, and this is why FDA itself has regulated manufacturing changes for biologics so assiduously. Yet regardless of scrupulous oversight, the complex nature of biological manufacturing methods means that the manufacturing process used by a follow-on manufacturer will be different from the manufacturing process of the innovator. To establish with reasonable certainty that process differences and changes have not affected a protein product's safety or effectiveness, both innovator and follow-on manufacturers must rely not only on testing and characterization of the final product, but also on extensive development experience with the product, in-process testing, toxicology studies, in vivo pharmacokinetic and pharmacodynamic studies, and reagents and reference standards that are not typically available to another manufacturer.
While science is able to tell us much about some therapeutic proteins, this knowledge is inherently rooted in what is known about specific protein products. What is understood about a specific protein product's safety and effectiveness relates closely to a particular manufacturing process, and derives from the data obtained by the original manufacturer of the product. This manufacturer isolated and purified the active protein from selected cells; developed and refined a manufacturing process that provided for consistency in structure, purity, and potency; and tested the product's safety and effectiveness with substantial clinical trials. In cases where there is more than one approved product whose active component is a given therapeutic protein, each of the manufacturers separately conducted these activities and provided FDA with extensive data from clinical studies demonstrating their particular product's safety and effectiveness.
Because a follow-on manufacturer can never exactly duplicate the innovator's process, and because differences in process may result in differences in the protein product and its clinical effects, FDA must continue to apply consistent regulatory standards for all manufacturers, and FDA must insist on receiving the full complement of data necessary to demonstrate safety and effectiveness. A full complement of data is the set of data contained in the complete regulatory filing submitted by a manufacturer to the FDA (or other appropriate regulatory authority) sufficient to show safety and effectiveness. It includes all of the preclinical and clinical data needed to support the label being claimed. BIO does not support any regulatory framework that incorporates requirements for unnecessary preclinical or clinical testing. BIO believes, however, that it is only through a thorough assessment of safety and effectiveness, including clinical testing meeting all ethical standards, that patients can be assured that initiating treatment with or switching to a newly available product will provide them with the anticipated benefits and safety of the treatment.
Conclusion
FDA regulatory policies for "follow-on" protein products must differ substantially from the policies applicable to small-molecule generic drugs. This is true because of the inherent complexity of protein products; the dependence of the final protein product's characteristics and activity on its starting materials and on the processes by which it is produced, purified, formulated, and stored; and the difficulty of characterizing products with great molecular complexity and heterogeneity. We reiterate our hope that this meeting, and the conference to be cosponsored by FDA and the Drug Information Association that will take place early next year, will constitute the beginning of a truly deliberative public dialogue on follow-on protein products. The questions about future policy surely include scientific, technical, and medical considerations that will affect the outcome for patients, as well as legal questions impacting on the biotechnology industry's ability to sustain the innovation for which it is known. As BIO has requested on multiple occasions, we again ask that FDA expand its interactions with stakeholders to deal with non-scientific issues, especially the important legal questions regarding the agency's authority to consider for approval abbreviated applications for so-called "follow-on" protein products based on the data generated by pioneer companies, and used without their consent.
We believe the principles governing the debate about follow-on protein products are simple and clear: that regulatory requirements must be based in sound science; that patients deserve access to appropriately tested and competitively-priced therapies; that industry's ability to make innovative medical products available through research and development should be promoted; and, most importantly, that the health and safety of the patients served by both FDA and the biotechnology industry are preserved.
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