Medical Device Daily Washington Editor
FDA's release of a white paper last year to address the state of regulatory science at the agency was unveiled with some fanfare (Medical Device Daily, Oct. 7, 2010), but the arrival of the final document received no such pomp and circumstance yesterday. The reason for that might be that much of the content of the proposal has been covered, at least for the Center for Devices and Radiological Health, by recent published guidances.
In an Aug. 17 statement, FDA describes the plan as a “sweeping modernization of the science used in developing and evaluating“ the various products the agency oversees. FDA commissioner Margaret Hamburg, MD, said in the statement, “as new discoveries yield increasingly complex products, this strategic plan ensures that our experts are equipped to make science-based decisions resulting in sound regulatory policy,“ and that the plan “positions us to foster innovation through better science without compromising our high safety standard.“
Among the agency's ambitions is the development of a virtual physiological patient, complete with radiological imaging data in an effort to develop models of patient reaction to medical devices. FDA states that this will result in a library of validated models that will be accessible to researchers. However, similar efforts are underway by other entities as well.
The portion of the report dealing with “innovative emerging technologies“ includes the remark that FDA wants to find ways to “initiate first-in-human studies earlier in device development,“ although industry may view such a statement with a jaundiced eye, given the perception that the agency is growing increasingly leery of implantable medical devices. The document also mentions the agency's interest in “reaching out to manufacturers in areas of high public health need,“ as indicated by the device innovation initiative reported earlier this year (MDD, Feb. 9, 2011).
The “innovative emerging technologies“ portion of the document includes a section on nanotechnology, which also is the subject of a guidance the agency published earlier this year (MDD, June 15, 2011).
Those who think FDA's information technology infrastructure is lacking may be encouraged by a section stating that the agency will develop “a secure IT network environment . . . for scientific computing,“ an effort that will also “improve access to high-speed networking“ to allow the agency to process large data sets more quickly. Much of the recent emphasis on FDA's part where IT is concerned has to do with the variability and volume of adverse event reporting, but the report makes a much more prominent case for the agency's comparative effectiveness initiative, the Partnership in Applied Comparative Effectiveness Science (PACES), which FDA unveiled in 2008 along with the Agency for Healthcare Research and Quality. One of the larger tasks associated with this program, which will incorporate findings from clinical trials to establish comparative effectiveness, will be to convert legacy data into a format that can be processed electronically.
Under the third branch of the initiative, titled “Support New Approaches to Improve Product Manufacturing and Quality,“ the agency proposes to do some work that relates to pharmaceuticals. In this section, FDA states it will “investigate the effects of continuous manufacturing“ – in contrast to batch manufacturing – on product quality. This may be more of an issue for pharmaceuticals than for the hardware that goes into most devices, however, and indeed, this page makes a reference to the quality-by-design (QBD) program that has been underway at FDA's Center for Drug Evaluation and Research for at least half a decade.
On the other hand, the continuous process monitoring that is encoded in the QBD approach does offer makers of diagnostics some opportunities. The guidance notes that magnetic resonance technologies, along with mass spectrometry and Raman spectrometry hardware, are all elements that can be used to keep pharma manufacturing in spec under conditions of continuous processing.
The plan also mentions that FDA will evaluate the applicability “of various analytical technologies“ to determine bio-similarity, and will work on the math pertaining to assays and tests needed to ensure “consistent reproducible results,“ which again is given in the context of QBD.
In a statement e-mailed to Medical Device Daily, Janet Trunzo, executive VP for technology and regulatory affairs at the Advanced Medical Technology Association (AdvaMed; Washington), said the association is “reviewing the details of FDA's strategic plan for regulatory science.“ Trunzo also says that among the objectives spelled out in the document, AdvaMed is “interested in the agency's proposals that relate to FDA's stated mission of advancing regulatory science to speed innovation, improve regulatory decision-making, and get safe and effective products to people in need.“
Guidance on 522 post-market surveillance also out
Among the slew of recent FDA guidances for med-tech and diagnostics is one that updates the agency's use of section 522 orders, which was the subject of a 2006 guidance as well. There are a number of material differences between the two guidances, one of which is the absence of any mention of “least burdensome“ from the later edition. The omission of the language regarding least burdensome came up in a hearing of the Senate Health, Education Labor and Pensions Committee (Medical Device Daily, July 29, 2011), during which Sen. Richard Burr (R-North Carolina) alleged that FDA had issued an internal policy document in 2009 stipulating that the language be omitted from documents, purportedly in pursuit of consistency.
One of the differences between the two guidances is that FDA states in the later version that any 522 study ordered by the agency that qualifies as an “applicable device clinical trial . . . must comply with registration and results requirements“ as dictated by the statute. That, in turn, is dependent on a difference in the requirements for a 522 study, which the 2006 guidance suggested could be fulfilled with activities more in line with surveillance and registries. The new guidance states, however, that among the elements to be incorporated into a 522 study are study hypotheses, statistically justified sample size calculations, and primary and secondary endpoints. Later in the document, information about the range of potential 522 studies is offered, including retrospective cohort studies and active surveillance, the latter of which is described as including “ongoing, active systematic collection, analysis and interpretation of data.“
In contrast, the 2006 version of this guidance allows a sponsor to make use of registries, drawing data from sources such as Medicare records. The words “registry“ and “registries“ do not appear in the later document, however.
Among the provisions of the newer guidance that does not appear in the 2006 guidance is a set of criteria for pediatric devices. The 2011 guidance states that the regulation allows FDA to require 522 studies for devices that are not indicated for pediatric patients, but which may be “expected to have significant off-label use in pediatric populations.“ This, the guidance states, would necessarily qualify as an “applicable device clinical trial,“ and hence would be reportable as such.
The newer guidance also says that the language of the Food and Drug Administration Amendments Act of 2007 allows the agency to require a post-market surveillance study to run for as long as 36 months, although FDA indicates it will reserve the right to mandate a longer study period should the agency deem this necessary to “assess the impact of the device on growth and development.“
The portion of the new guidance dealing with the justification for issuing a 522 order says that FDA can issue such an order to clarify any “suspected problems reported in adverse events reports or in the published literature.“ The previous guidance mentions published literature as one of the sources that could trigger a 522 order, but the newer guidance spells this out in less ambiguous language. Another portion of the 2011 version says that among the elements FDA could review as justification for ordering a 522 study is any “theoretical scientific/medical concern from review of pre-market submissions.“