Latest Drugwonks' Blog
“Skill without imagination is craftsmanship and gives us many useful objects such as wickerwork picnic baskets. Imagination without skill gives us modern art.”
-- Tom Stoppard
The savvy and prescient Tevi Troy (ex-HHS DepSec) writes about the NIH’s genetic desire to become a pharmaceutical company:
Even though people might differ on the interpretation, most everyone can agree on the underlying and problematic fact that the development of new pharmaceutical therapies has slowed in the United States. The Times story has two charts accompanying its article. One showed that research spending by the large pharmaceutical companies has declined in recent years. The second chart showed that the number of new pharmaceuticals approved by the FDA has been lower in recent years than it was throughout much of the 1990s. The government’s response to these troubling developments is to try to make the NIH into another drug developer, at a time when existing drug developers are having a difficult time getting their products to market.
The sad truth, however, is that this approach has not been successful in the past.
Tevi’s full article can be found here.
Florida Sun-Sentinel health columnist Nicole Brochu writes:
It has long surprised me, in an enviable kind of way, how the fight to beat breast cancer and bring awareness to this awful disease has mushroomed to the point where it essentially owns a color. Everywhere you go in October, the official Breast Cancer Awareness Month, people are wearing pink, from beefy pro football players to soccer moms and rock stars. So it did not come as a shock that when the FDA came out with a controversial decision revoking a drug used to treat advanced breast cancer, it lit the medical community afire with debate. There are some, like the FDA, who say Avastin's clinically proven benefits do not outweigh some serious side effects. In the piece below, Peter Pitts gives voice to the other side of the debate, and puts a face on the suffering some say would come if the government stands by its decision. Give it a read. If you are persuaded by his argument, there's an online petition to keep Avastin approved in breast cancer treatment.
My complete op-ed can be found here.
It is easy to feel or believe that innovation is flagging because by calling for a commitment to increase innovation it sounds like we are really doing something. That is, we identify a problem based on what we want to talk about rather than any real assessment of whether the problem is a cause of a great concern.
If we want to define innovation as discovery of new ideas or new concepts then it is absurd to say innovation is flagging. However if we define innovation as combining different technologies to produce new technologies that improve living standards (longer life, more wealth, better health, more convenience, etc) then the answer would be yes. America's approach to innovation is flagging. We are not producing new products using new techniques that democratize new goods and services as fast as we used to.
I won't go into all the factors of why that is so now. Rather, it is important to note that increasing government investment in innovation is not the answer. The idea that pumping more money into science -- even the effort to turn science into a concept -- will lead to new technologies and jobs in the future is wrong and flawed.
Top-down science has rarely played a role in innovation or technology advances. To the extent that it has or does is a result of improvements in technology that have reduced the uncertainty, time and cost associated with evaluating a scientific discovery's contribution.
Further, government entities are horrible at 'planning' innovation. Government can pay to have companies 'stumble upon new technologies' as Matt Ridley puts it. But it is no better at idenitifying, developing and democratizing them as large companies with bigger budgets and more scientists and more often it is worse. Government, like top heavy companies, inhibit risk taking and the rapid exchange of ideas and technologies that drives innovation. All valuable technologies are a combination of a host of other inventions and ideas. Economic growth and progress is a function of the velocity of such exchange. The notion that the in-house scientists at NIH -- while a great group -- can or is as inventive as tens of thousands of consumers, doctors, researchers around the world is laughable.
And yet everything about the new regulatory regime with its bias against allowing people to use new technologies or let industry talk to end users without getting government permission first will strangle innovation.
But don't expect the State of the Union to address that.
“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.
The final question from today's FDA press briefing on a 21st century pathway for medical devices was, "How will these changes help to reduce the medical technology gap between the US and the EU?"
CDRH Direcrtor Jeff Shuren's response was, "By increasing predictability and decreasing uncertainty."
That was before he said that EU regulators were using patients as "guinea pigs."
Hm.
Here's the FDA announcement:
FDA to improve most common review path for medical devices
Goals are to foster device innovation, protect patient safety
The U.S. Food and Drug Administration today unveiled a plan containing 25 actions it intends to implement during 2011 to improve the most common path to market for medical devices.
Key actions include:
- Streamlining the “de novo” review process for certain innovative, lower-risk medical devices,
- Clarifying when clinical data should be submitted in a premarket submission, guidance that will increase the efficiency and transparency of the review process,
- Establishing a new Center Science Council of senior FDA experts to assure timely and consistent science-based decision making.
These actions will result in “a smarter medical device program that supports innovation, keeps jobs here at home, and brings important, safe, and effective technologies to patients quickly,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health (CDRH).
Before marketing most lower-risk medical products such as certain catheters or diagnostic imaging devices, manufacturers must provide the FDA with a premarket notification submission.
These submissions are known as 510(k)s for the section of the Federal Food, Drug, and Cosmetic Act that describes this notification requirement. Generally, 510(k)s must demonstrate that a proposed product is substantially equivalent to another, legally marketed medical device that is also lower-risk.
In September 2009, CDRH set up two internal working groups to address concerns relating to the premarket notification process -- industry argued that the 510(k) process was unpredictable, inconsistent and opaque, while consumers and health care professionals argued that the review process wasn’t robust enough. At the same time, CDRH also asked the independent, nonprofit Institute of Medicine to study the program. That review is still underway.
In a transparent effort, CDRH sought public input during both the development and review of the two internal reports. The center held two public meetings in the Washington area and separate “town hall” meetings in Minneapolis, Boston and Los Angeles. The FDA also received 76 written comments to three public dockets from industry members, health care professional organizations, consumer groups, patient groups, third-party payers, venture capital groups, agency staff, trial lawyers, foreign regulatory bodies, law firms, individual members of the public, consulting firms and academic institutions.
The two working groups issued 55 recommendations in August 2010. After reviewing public comment, CDRH now intends to take 25 actions to improve the 510(k) program in 2011, including new guidance and enhanced staff training. CDRH also is giving the Institute of Medicine an opportunity to provide feedback on seven recommendations before making a final decision and is planning for a public meeting in April to seek additional feedback on two other recommendations.
Dr. Shuren announced the action plan today in an open letter to the public. “We look forward to implementing these changes in support of our overall mission: improving the health of the American public,” he said.
For more information:
For further musings on the FDA and social media, see this new article from the latest edition of the always excellent must-read Rx Compliance Report.
Genentech has formally asked the FDA to overturn last month’s decision revoking the approval of the drug Avastin as a treatment for breast cancer. In the request, Genentech argues that the agency erred in interpreting the data about the drug and toughened its standards for approval without informing the company.
“The company requests a hearing because it believes women with this incurable disease are entitled to Avastin as an FDA-approved choice and because FDA’s proposed withdrawal raises broader implications for the development of cancer treatments that should be discussed in a public forum,’’ the company says in its 98-page request.
Pending the outcome of any hearing, Avastin retains its approval for breast cancer.
As Andrew Pollack writes in the New York Times, “The F.D.A. has not decided whether to grant a hearing. It seems likely to do so, however, given how controversial this matter is, even attracting the attention of members of Congress.”
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
