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10 BioPharm International eBook March 2020 www.biopharminternational.com ing "safe innovation" and offering developers "meaningful guidance" on complex clinical questions (3). It also established established draft guidance to help clarify what will be needed in order for a new therapy to be eligible for orphan drug designa- tion and its benefits, which include: • Tax credits for clinical testing • Exemption from some pre- scription drug user fees • The possibility of seven years of patent exclusivity. This designation is extremely important for gene therapies, because more than 70% of the current pipe- line targets rare diseases (i.e., dis- eases that affect fewer than 200,000 patients) (4). The agency has asked for comments on this draft guidance from industry and will be accepting them until April 29, 2020. This article offers brief summaries from new draft and finalized guid- ance documents and compiles initial commentary from legal and regula- tory experts on their significance. ORPHAN DRUGS According to FDA's draft guidance (5), orphan drug designation can only be granted if the developer can show that the new therapy is differ- ent from, and clinically better than, previously approved treatments (i.e., that it shows greater efficacy, improves patient safety, or signifi- cantly improves the level of overall patient care). E xtrapolating lang uage f rom traditional biopharmaceuticals to the gene therapy space and apply- ing the principles behind orphan drug regulations (21 Code of Federal Regulations 316.3(b)(14) (ii)), which focus on the "macromolecule," and principal molecular structure, FDA is focusing on the transgene (genetic mater ial that is being injected into the patient) and the vector (the carrier used to deliver the genetic material). When considering two gene thera- pies that have been designed to treat the same condition, FDA will cur- rently consider a new gene therapy different from an existing one if: • The two products express dif- ferent transgenes (encoding different enzymes) and have or use different vectors. • They have or use vectors from different viral classes (e.g., gammaretrovirus, as com- pared with adeno-associated virus), even if they express the same transgene. If two therapies express the same transgene with or without the same vector, FDA may still consider them different depending on final product features and how they contribute to the overall therapeutic effect, accord- ing to the draft guidance. CMC INFORMATION IN THE IND One of the most significant differ- ences between the draft CMC guid- ance of 2018 and the final guidance is increased understanding that CMC data and core quality by design information, such as critical qual- ity attributes (CQAs) and manufac- turing processes and controls, may not be available during the earliest stages of an IND. The guidance states that not all sections of the common technical document (CTD) need to be completed before the IND is sub- mitted and that sponsors can add material to their application as devel- opment progresses. "As your product progresses through development, the list of potential CQAs may be revised as your knowledge of the product increases," notes the guidance (6). The final guidance also spells out, explicitly, the need for quality con- trol testing and control functions and manufacturing departments to be separated, which, some experts have pointed out, may be for the benefit of academic laboratories that have never manufactured before and are only familiar with lab research practices (7). The guidance also pro- vides more detailed information on drug substance vs. drug product, a distinction that is much more obvi- ous in traditional biopharmaceuticals than in gene and cell therapies. For Module 2 of the IND, which focuses on quality information, the guidance explains CQAs and how to identify, measure, and test for them in gene therapy, for both drug sub- stance and drug product. It also sug- gests that they be established as early as possible and notes their impor- tance to analytical studies required to show product comparability (5). The guidance also emphasizes the importance of evaluating prod- uct characteristics during early clini- cal development to ensure ability to assess process controls, manufactur- ing consistency, and stability, noting the importance of having these sys- tems in place for expedited develop- ment programs. This portion of the guidance also explains how vectors should be defined, whether as drug product or drug substance, asking developers to select an option and explain their definition (8). MANUFACTURING AND CONTROL INFORMATION The final CMC guidance document goes into a lot of detail on how to present data in Module 3, which covers the manufacturing process and control information, and offers examples from current gene thera- pies, including viral-based, micro- bial-based and ex-vivo genetically modified types (8). It also includes a detailed section on cell banking sys- tems for starting materials and their importance. In this section of the IND, devel- opers will need to provide informa- tion on drug substance and product, facilities and equipment and infor- mation on adventitious agent safety. Hacker noted the following as key Regulatory Sourcebook Gene and Cell Therapies