“Be steady to your purposes and firm as a rock. This ice is not made of such stuff as your hearts may be; it is mutable and cannot withstand you if you say that it shall not.”
Mary Shelly, Frankenstein or The Modern Prometheus
Our good friend Tim Franson, one of the Founding Fathers of PDUFA, opines on the future of the program he helped create.
Opinion
Clinical Pharmacology & Therapeutics (2011) 89 2, 169–171. doi:10.1038/clpt.2010.301
Has the FDA Amendments Act of 2007 Impaired Drug Development?
T. R. Franson
B&D Consulting, Washington, DC, USA
Abstract
Perched at the midpoint of ”v.4” of the Prescription Drug User Fee Act (PDUFA-4), better known as the US Food and Drug Administration Amendments Act (FDAAA), it seems presumptuous to draw critical conclusions based on an “interim analysis” of this work in progress. Because drug development is a complex process measured in decades, one must rely on “surrogate markers” to impute FDAAA outcomes. Even so, there are many indications that the FDAAA has doused the fires of innovation, in scope, spirit, and interim results.
Before dissecting the FDAAA’s status, one must first consider it in context retrospectively. The FDAAA is built on the accreted foundation of PDUFA-1 (1992), the PDUFA-2/FDA Modernization Act (1997), and PDUFA-3 (2002), but the FDAAA is notably different from its predecessors in focus and character.
PDUFA-1 was conceived because FDA appropriations were inadequate to support timely review of new drug/biologic applications (NDAs/BLAs), when even “breakthrough” candidates required 2–3 years for processing. Industry and the FDA agreed to commit new funding—as user fees—to performance improvements for these review processes. The “bargain” was that the FDA could channel PDUFA funds to hiring new reviewers and thus commit to more timely, predictable review of applications that were intended to expedite innovations and thus improve public health. No guarantee of favorable action was involved, although this is often misrepresented by critics.
It worked. Review backlogs were cleared via timely approval actions without any increase in drug safety issues. PDUFA-2 extended improvements to development milestones (for additional fees) pre-submission, and is regarded by most observers as successful in benefiting patients as well as in refining review processes. PDUFA-3 expanded review improvements and for the first time included funding beyond the preapproval process for basic early postapproval safety. All PDUFA agreements grew out of discussions between agency and industry representatives and were further refined by Congress. Shortfalls in appropriations over time served as a key factor in accepting user fees as a means to offset gaps in FDA funding to enable timely new cures for patients.
However, the FDAAA has dramatically deviated from its predecessors by shifting focus away from preapproval development improvements to place major emphasis on postapproval safety and enforcement concerns, to a magnitude unprecedented in scope and amount, as compared with prior PDUFAs. Despite a doubling in 5-year user fee funding from industry ($2.4 billion in 2007–2012, compared with $1.2 billion in the preceding 5 years of PDUFA-3), the focus of the FDAAA has clearly exhibited a tipping point for postapproval emphasis (the FDAAA had generally been viewed as a domain ideally supported via congressional appropriations instead of from industry, to avoid perceptions of the “fox guarding the henhouse”).
As evidence of this shift, of the approximately 90 line items listed on the FDA’s FDAAA implementation website (which covers drugs, devices, and other areas), a dozen are dedicated to postapproval safety (especially for risk evaluation mitigation strategies, or REMS) and numerous enforcement provisions, with a single item devoted to access to development compounds for patients with life-threatening diseases. No implementation items explicitly address innovation, development improvements, or benefit–risk refinements. Therefore, the prevailing perceptions of postmarketing safety issues reset the allocation of PDUFA funds from expediting new drug review processes (and thus patient access to new cures) to concentrated oversight and control for previously approved drugs and biologics. The issue is not whether postapproval risk management is an important discipline deserving more attention, because improvements in this area are vital to patient well-being. But the PDUFA was not conceived for that purpose. Advances in preapproval developments from prior PDUFAs are being diluted by activities that should be supported by appropriated funds (which have been maintained at starvation level since PDUFA-1 authorization), and PDUFA funds should not be fiscal band-aids for any appropriation shortfalls beyond timely review of NDAs.
Is this a matter of “blame” or of unintended consequences? In all prior PDUFAs, Congress has approved the general construct of FDA–industry agreements, and although all parties might share ownership of that bureaucratic process, the issue now is that the FDAAA has resulted in the FDA and industry being diverted from new drug development and thus falling prey to the law of unintended consequences. With FDAAA implementation being redirected to postapproval matters, the promulgation of rules, regulations, guidances, and process steps for REMS and other new programs has consumed the attention and resources of the FDA. This assessment is evidenced by the 2008 announcement by the FDA’s Center for Drug Evaluation and Research (CDER) of a one-year moratorium on NDA performance goals due to the diversion of agency staff to implementing FDAAA provisions—in essence, a redistribution of effort from innovation to postapproval oversight. The CDER 2009 performance report is further testimony to that shift, with only 4 of 12 critical performance metrics achieving target results. The change is also illustrated by an increasing number of “complete-response” actions instead of final decisions for first-cycle NDAs.
These observations are intended not as a criticism of the FDA but as a persuasive indication of the unintended result of predominant FDAAA postapproval work that causes a deemphasis on innovation and development. The agency is doing exactly what was agreed with industry and authorized by Congress. Unfortunately, those actions do not advance the best interests of patients in terms of expediting the availability of innovations for unmet medical needs.
Aside from the immediate impact of FDAAA implementation, the domino effect from that process in both the FDA and industry is staggering. Since the inception of REMS, almost 150 such programs have been imposed, at considerable expense of time and effort by FDA staff and subsequently by staff at sponsor companies, all of whom must reallocate time and efforts from drug development to REMS development and implementation. There is no doubt that REMS and similar efforts are rational efforts to better address safety (or, ideally, “benefit–risk”) considerations, but it should not be occurring at the expense of FDA and industry efforts in innovation. The downward trend of first-cycle approvals and overall NDA/BLA throughput since the inception of the FDAAA can be viewed as an unfortunate consequence of postapproval focus and is entirely contrary to the intent with which the PDUFA was constituted.
Perhaps the predominance of FDAAA postapproval work would be less cause for concern were it not for multiple concurrent negative forces impacting innovation, including escalating patent expiries, a drought of NDAs, and threatened price controls. Moreover, a recent survey ranked the United States 40th out of 40 countries in rate of change in innovation capacity over the past decade. Superimposed on the “distraction coefficient” at the FDA due to FDAAA implementation burdens is the speculation by some that “Pharmageddon”—a global meltdown of pharma R&D capacity—is upon us. Although such a doomsday scenario may be overblown, current circumstances hardly give the United States bragging rights with respect to medical innovation.
Even more distressing is the trickle of new cures in a care environment where the need for new preventive and chronic therapies is ever more pressing. As one telling example, amid an epidemic of diabetes mellitus acknowledged by the World Health Organization and other authorities, new requirements for long-term cardiovascular studies for new type 2 diabetes medicines have recently led at least four companies to suspend major programs in that research domain. Perhaps some of the FDAAA trends—such as the low risk tolerance regarding primarily safety concerns in development programs, in contrast to more balanced benefit–risk assessments—are actually serving as disincentives to innovation.
As a final consideration of the delusory character of the FDAAA, prior PDUFA interactions were conducted in an environment of desired collaboration. One could argue that the “personality” of the FDAAA may have reflected the more adversarial nature of the political and professional settings within the United States; if this is true, it is not in the best interests of public health. The current acrimony evident in the interactions of industry vs. medical journals vs. regulators vs. practitioners is a disturbing milieu quite distinct from the spirit of less than a decade ago when provincial interests could be set aside (at least in some situations) to collectively focus on the “right things” for patients. Although I am not accusing any constituency, such as the FDA or industry, of being motivated primarily by self-interest, it is conversely reasonable to point out that when all parties are worried about shoring up their defensive positions in an adversarial setting, it detracts from collectively focusing on the original intention of bringing innovation to patients in an appropriate and timely manner.
To conclude, there are reasons to be hopeful that the current dismal trends in tone, focus, and productivity can be reversed by collective attention to restoring basic interests. A reemphasis on benefit–risk instead of safety in isolation, along with a commitment to collaboration—remembering that disease is the enemy, not each other (and that this foe is a huge but vulnerable adversary, with many chronic diseases being manageable or preventable with effective programmatic approaches)—should be cornerstones in refocusing on the throughput of new cures in the development process. Using the PDUFA-5 platform as an opportunity to resolidify the foundations of innovation in regulatory processes would be a rational first step in such a journey, which could be accompanied by adequate appropriations to support postapproval oversight, allowing the full complement of PDUFA funds to be devoted to preapproval enhancements. Without such redirection, we should be very concerned that our collective R&D enterprise will remain a house divided that cannot stand and will not serve patients optimally.
