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Even if some clinical testing is needed, generics makers argue that no one-size-fits-all testing approach is appropriate for the broad range of biopharmaceutical complexities.
After more than a year of discussion and delay, FDA now seems poised to develop formal guidance on how drug manufacturers should tackle the tricky task of developing and testing "comparable" or "equivalent" or "follow-on protein products." The last term reflects general agreement that FOPPs may be similar and comparable but not necessarily therapeutically equivalent to an innovator product and will require a different testing and approval process from that for conventional generic drugs.
At a hearing last June (2004) before the Senate Judiciary Committee on key issues related to follow-on biotherapies, then-chairman Orrin Hatch (R-Utah) said that legislation authorizing FDA to move forward with FOPPs was "inevitable." He urged biotech firms to stop stonewalling and engage in a constructive dialogue on legitimate scientific concerns, advice that appears to be generating grounds for consensus.
Because generic drugs offer a way to expand patient access to less costly medicines and to make the Medicare prescription drug benefit more affordable in coming decades, FDA officials are under pressure to articulate a clear pathway for manufacturers to test and assure the quality and equivalence of FOPPs. Biopharmaceuticals are proliferating and becoming more important for patient treatment, especially for serious and rare diseases, a trend likely to accelerate with the anticipated shift to more personalized medicines. Increased competition among biotech manufacturers not only promises to reduce product prices, but also to limit the risk of shortages; to encourage product refinement and improvement; and to limit human and animal testing.
Current FDA policies make it difficult and costly to develop generic versions of biopharmaceuticals. The laws that govern drugs and biologics differ in how they define product "sameness," a critical parameter for determining product equivalence and comparability. In light of current criticism of FDA for being too lax about drug safety, officials are leery of taking any action that might smack of lowering drug quality standards. Scientists and manufacturers acknowledge that biologics can produce immune system responses, opening the door to a debate over how much pre-clinical and clinical testing is needed to detect any problems with immunogenicity, toxicity, and carcinogenicity.
To ensure that all parties have ample opportunity to air their views on these controversial issues, FDA is proceeding at a very deliberate pace in developing new policies for marketing FOPPs. To this end, FDA co-sponsored a workshop with the Drug Information Association (DIA) in February to examine the scientific and technological issues related to FOPP development and marketing. This discussion followed up on an initial FDA open meeting on follow-on biologics held last September 2004.
FDA next will issue a background document recapitulating agency regulation of protein immunogenicity, characterization, impurities, pharmacology-toxicology studies, and clinical safety and efficacy. The plan is to lay out the scientific underpinnings for draft guidance on policy changes needed to approve FOPPs. Because the topic is complex, FDA may issue a set of "interlocking guidances" that address key scientific issues, explained Janet Woodcock, FDA acting deputy commissioner of operations. After issuing the draft guidance, the agency will hold another public forum to discuss the proposal before finalizing any regulatory approach.
A key rationale for establishing an abbreviated process for FOPP development and approval is that improved analytical technology makes it possible to produce and test the attributes of similar biopharmaceuticals made by different manufacturing processes, particularly less complex products such as insulin, human growth hormone, and erythropoietin. FDA has accepted reduced testing approaches in permitting biotech firms to make significant changes to manufacturing processes without conducting new clinical trials to prove that the changes do not alter product safety, efficacy, or quality.
Advances in mass spectrometry, circular dichroism, and near infra- red tools that have been refined for increased sensitivity can improve product characterization and more closely assess product similarities and differences. State-of-the-art characterization technology involves physiochemical, immunochemical, and in vitro biological studies, which may include protein sequencing, disulfide linkages, and three-dimensional structure. Scientists also are developing enzyme tests for predicting how an individual will interact with an experimental agent.
These advances may help innovator firms as well as follow-on manufacturers investigate more specifically the physiochemical and biochemical properties of proteins from the development stage through production. And expanded understanding of the role glycans play in shaping complex molecules also can help characterize proteins and identify product equivalence for multiple purposes.
Generics makers point to these technological advances as justification for reducing the scope of pre-clinical and clinical data needed to document that a similar follow-on product is equivalent to an innovator comparator product. Pharma companies counter that while pharmacokinetic (PK) testing may be sufficient to document bioequivalence and therapeutic equivalence for small molecules, more data from clinical trials is necessary to ensure the safety and efficacy of protein products. Innovators believe that full product characterization is critical for documenting sameness, but that clinical trials and documented compliance with good manufacturing practices (GMPs) also are required for a manufacturer to bring a follow-on biologic to market. At the February workshop, Amgen noted that it plans to conduct fairly large clinical trials for its products undergoing manufacturing process changes to ensure that a change in cell line does not produce adverse reactions or other safety problems.
The European Medicines Agency (EMEA) appears to agree with the innovator position. Even though some Eastern European generics firms have produced and marketed equivalent biotech therapies, EMEA asserted in a November 2004 policy statement that due to the complexity of biological products, "the generic approach is scientifically not appropriate."
Even if some clinical testing is needed, generics makers argue that no one-size-fits-all testing approach is appropriate for the broad range of biopharmaceutical complexities. Additional clinical studies should be required only when there still is uncertainty about product comparability following PK/PD studies and characterization, and some kind of abbreviated regulatory pathway should be possible even for more complex products.
At its public meeting last September, FDA officials expressed skepticism that a generics maker could fully address concerns about immunogenicity and potency without doing at least some clinical and preclinical testing. Agency experts acknowledged, though, that manufacturers should not have to repeat every innovator test to bring a follow-on protein to market and should be able to rely on added information that emerges with clinical experience in using a therapy.
Now experts appear to agree that a follow-on protein may not be identical to a comparator drug, but that it will be possible to document sufficient similarity to establish safety and efficacy. Keith Webber, acting director of the Office of Biotechnology Products in the Center for Drug Evaluation and Research (CDER) noted general support for establishing a hierarchy of testing and data requirements that relates to product complexity. He pointed to overall agreement that some biotech products are more complex than others due to intrinsic product features (size, shape); the possible presence of impurities and contaminants; the range of functional uses (as antagonist, agonist, enzymatic activity); and differences in patients health status and concomitant medication use.
The workshop provided FDA with academic support for establishing a framework for developing and marketing FOPPs. While there still is considerable uncertainty about the safety, efficacy, and manufacturing processes of any specific follow-on protein, Ajaz Hussain, deputy director of CDER's Office of Pharmaceutical Science, warned that overly risk-averse approaches that demand too much information or set standards too high could discourage innovation and block opportunities to improve patient care.
Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634, firstname.lastname@example.org.