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The development of therapeutic antibodies, as well as therapeutics of other composition, is a time- and resource-intensive business. The process is highly regulated and the regulations change on a periodic basis. In the US, the Food and Drug Administration’s (FDA) procedures have been undergoing change every five years since 1992, when the Prescription Drug User Fee Act (PDUFA) was signed into law. This act must be reauthorized on a five-year basis and so PDUFA was followed by the FDA Modernization Act of 1997 and in 2002, reauthorization provisions were included in the Public Health Security and Bioterrorism Preparedness and Response Act. On September 27, 2007, the latest iteration, the FDA Amendments Act (FDAAA), was signed into law.
A distinguishing feature of FDAAA is its focus on management of drug risk. The act provided FDA with new responsibility and authority to manage the entire life-cycle of therapeutic products, including the authority to require risk evaluation and mitigation strategies (REMS) to manage risks and assure safe use of products, and labeling changes for serious safety issues that arise post-approval. An example of FDA’s use of their authority to require labeling changes is the recent requirement for updates to the prescribing information for infliximab, etanercept, adalimumab, certolizumab pegol and golimumab. Based on their review of safety data, FDA informed manufacturers that boxed warnings on labels must include information on an increased risk of lymphoma and other malignancies in children and adolescents treated with these products, the warnings section must describe reported cases of leukemia in adults, adolescents and children, and the adverse events section must include information on reported cases of new-onset psoriasis.1
The majority of mAbs are developed for serious or life-threatening diseases; treatments for these types of diseases commonly require management of risk in order to provide benefits to patients. While companies must follow directives for changes to approved product labels, FDA’s REMS requirements should be anticipated well in advance, potentially even at the time an investigational new drug application is filed. In particular, all significant safety signals apparent in the preclinical and clinical studies of candidate products (and related therapeutics) should be carefully evaluated and explored. FDA will provide input on REMS proposals, and early discussions with the agency may facilitate submission of the REMS with a marketing application. If identified late in the review process, the finding that a REMS is needed could trigger a second review cycle.
REMS may include medication guides, patient package inserts, communication plans for health care providers, and a timetable for REMS submission; however, additional elements to ensure safe use, such as patient registries and specific training or certification for those who prescribe, dispense or use the drug, may also be required.2 The FDA’s list of products with REMS approved after enactment of FDAAA (earliest REMS approval date is March 15, 2008; list updated as of October 30, 2009) includes a total of 89 products.3 Of these, the majority (66/89; 74%) have REMS that include a medication guide only. Four mAbs (certolizumab pegol, golimumab, ustekinumab and omalizumab) and one Fc-fusion protein (etanercept) are included on the list; two have medication guide only REMS (etanercept, omalizumab) and three have REMS composed of a medication guide and communication plan (certolizumab pegol, golimumab, ustekinumab). Sixteen additional products, including two mAbs (eculizumab, natalizumab), approved prior to the effective date of FDAAA that were deemed to have in effect an approved REMS are not included in the list of 89 products with approved REMS.4 FDA will require a REMS for denosumab prior to approval; the candidate is currently undergoing review by FDA for its potential as a prophylactic and treatment of post-menopausal osteoporosis and bone loss caused by hormone treatment of breast and cancer patients. The REMS will include a medication guide, communication plan and timetable for submission of assessments of the plan.
Of the 89 approved REMS, only six include elements to assure safe use and an implementation system. Five of these are REMS for small molecule products (alvimopan, ambrisentan, bosentan, eltrombopag, vigabatrin) and one is a REMS for a ‘peptibody’ (romiplostim) comprising two identical 269 amino acid single-chain subunits, each consisting of a human IgG1 Fc domain covalently linked at the C-terminus to a peptide containing two 14-amino acid thrombopoetin receptor binding domains. Romiplostim was approved by FDA for an orphan indication (treatment of thrombocytopenia in adults with chronic immune thrombocytopenic purpura). Elements to assure safe use included in the REMS are: (1) the product will only be prescribed by healthcare providers who are specially certified; (2) the product will only be dispensed by practitioners (physicians’ offices) and healthcare settings that are specially certified; (3) each patient treated with romiplostim must be enrolled in the Network of Experts Understanding and Supporting Nplate™ and patients (NEXUS) program for documentation of safe use conditions; and (4) each patient treated with romiplostim is subject to certain monitoring.5
Considering the current focus of FDA on safety and the potential complexity of the programs, companies should pro-actively prepare for potential REMS requirements. As the FDA and the healthcare industry gain experience with REMS, the question of how to determine the effectiveness of these programs in reducing or mitigating risk can be addressed.
Previously published online: www.landesbioscience.com/journals/mabs/article/10628