Stent Gent

01/28/2011 08:54 AM |

As the saying goes, the plural of “anecdote” isn’t “data” -- that is unless the anecdote supports your theory.  Here’s a personal anecdote -- a story of how the system works.

Being adopted, I have no family history, so when I suffered through some late night chest pains I figured I’d better act on the warning signals. I called my GP and got a same-day consultation, resulting in a next-day referral to a cardiologist and a stress test.  Diagnosis – arterial blockage and an immediate referral to NYU Medical Center for an angiogram. 48 hours later I had two stents and was home – writing this report.

My situation is not unique but, being in the business of healthcare policy, some of the things that happened to me are indicative of some broader themes.

1. Facts vs. Fear

After being admitted into the cardiac unit, getting my wrist ID and giving some blood, my first visit was with a nurse practitioner who began her explanation of stents as follows, “You might have read some newspaper articles about how stents are over-used and dangerous.  That’s crap.  They save lives, they’re safe and it’s a lot more pleasant than open-heart surgery.”

This before she asked me what I did for a living.

2. The Evils of Pharmaceuticals

After the obligatory (and important!) lecture about the need to eat more healthfully and exercise more regularly, one of the resident’s said to me, “And we’re big believers in pharmaceutical intervention – don’t believe everything you read in the newspaper.” 

This before he asked me what I did for a living.

3. Problems with the FDA

When I told the interventional cardiologist that I was a former FDA associate commissioner and was at the agency when the first drug eluting stent was approved, his comment was, “That’s something you should be proud of.”

That, despite all the middle-of-the-night poking and prodding (and my roommate’s bed-rattling basso profundo snoring) made my visit a more meaningful and memorable experience.

4. The Cost of Innovation

As I walked in my own front door a mere 26 hours after surgery, full of piss and vinegar and ready for action, I remembered my father.  His first heart attack (at an age only slightly older than mine today) landed him in the hospital where his sternum was split open and a bypass performed. A dangerous operation followed by a lengthy hospital stay and a prolonged, home-bound period of recovery. That was then. The best there was at the time.  Top-notch 20^th century surgical technique and pharmaceutical therapy.  It was very expensive and left him with a scar the size and shape of a Sonoran Gopher Snake.

Over 20 years later, all I have to remember my surgery by is a small catheter incision and a handful of booklets on heart-healthy nutrition.

Which I plan to read and act on.

Tennis anyone?

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Friday reading

01/28/2011 01:35 AM |

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The phony connection between thimerosal and autism

01/28/2011 01:23 AM |

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Breast Implant Cancer Panic: Wakefieldism Rises Again

01/27/2011 04:05 PM |

Here is what the FDA concluded about a possible association between breast implants and a rare form of non-Hodgkins lymphoma called anaplastic large cell lymphoma (ALCL). Read more here.
 

It is not possible to confirm with statistical certainty that breast implants cause ALCL. At this time, data appear to indicate that the incidence of ALCL is very low, even in breast implant patients. Currently it is not possible to identify a type of implant (silicone versus saline) or a reason for implant (reconstruction versus aesthetic augmentation) associated with a smaller or greater risk.

The FDA also noted 3 in 100 million women per year in the United States are diagnosed with ALCL in the breast.  As in 0.000003% of women. 
 

There were 60 reported cases of ALCL in women with breast implants worldwide from 1997-2010.   The average time women between getting implants and a ALCL diagnosis was 8 years.   
 

Should women with implants be concerned?  The FDA suggests follow up for any persistent swelling or fluid build up.  And    cautions that over-reaction could lead to even worse problems for women:
 

“..if we biopsy every abnor­mality – such as a minor thick­ening or fluid accu­mu­lation adjacent to a breast implant – we’ll hike up the costs and, more impor­tantly, the com­pli­ca­tions asso­ciated: With every needle stick there’s a risk of infection, addi­tional scar for­mation and more. On the other hand, you wouldn’t want to overlook a treatable, early-stage lym­phoma. Women need to know of the risks of implants, which can only be deter­mined if doctors thor­oughly inves­tigate these sorts of complications.”
 

And the risk of dying?  Early diagnosis and treatment for all forms ALCL is essentially a cure.  And relative to the risks of dying from heart disease and diabetes the risks seem fairly insignificant. 
 

But if you read most of the media outlets and websites in the last couple of days you would have thought that implants were “linked” conclusively to an increased risk of cancer for every woman who has them:
 

Breast implants could put women at increased risk of rare cancer

Chicago Sun-Times - Monifa Thomas -

FDA looks for cancer link to breast implant patients

Boston Globe - Deborah Kotz -

Breast Implants May Be Linked to Rare Cancer

Wall Street Journal - Jennifer Corbett Dooren, Alicia Mundy -

Breast Implants Linked to ALCL, a Form of Blood Cancer, According to FDA

ABC News - Lara Salahi 

Breast Implant Link to Cancer Probed by US FDA After 34 Cases Reported

Bloomberg - Catherine Larkin

AP’s Matt Perrone did a great job reporting the real risk-benefit bottom line but the Huffington Post managed to turn his account inside out with this headline:
 

Breast Implants Cancer Link Found, Says FDA

MATTHEW PERRONE

Blogs were not much better for the most part:
 

Well: Breast Implants Linked to Rare Cancer

New York Times (blog) - Toby Bilanow 

Breast implants may cause rare cancer

CNN (blog)
 

WebMD FDA announced that there is a link between breast implants and a very rare form of blood cancer. Read more here 

Actually WebMD the FDA used the term “a possible association”
 

The rare exceptions:

FDA Reports on Association of Breast Implants and a Rare Form of Lymphoma

By Elaine Schattner, M.D., on January 27th, 2011

Read more here
 

and

About that Breast Implant/Cancer Risk … - Health Blog - WSJ

5 hours ago by Katherine Hobson
 

Even assuming 60 cases among 5 million women, that's about one case per 83333 women. http://blogs.wsj.com/health/
 

(Actually it is 60 cases among 5 million over 10 years but we should get the point)

Last week the media was congratulating itself for reporting that Andrew Wakefield was a fraud after giving him an evidence free pass for over a decade.  But as Gary Schweitzer warned:
 

“Unfortunately, journalism played a key role in promoting Wakefield's claims. The "Respectful Insolence" blog referred to one journalist as CBS' resident anti-vaccine propagandist. Around the world there were many other examples of journalists' unquestioning acceptance of the vaccine scares.
 

The BMJ reminds us that "the damage to public health continues, fuelled by unbalanced media reporting and an ineffective response from government, researchers, journals, and the medical profession."

 

Read more here

Didn’t take long for mainstream outlets to go back to their unhealthy habits…

 

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Franken Sense

01/27/2011 11:41 AM |

The Senator from SNL, Al Franken, has introduced legislation that would allow the federal government to negotiate lower drug prices for Medicare beneficiaries.

In other words, legislation that would abolish the Non-Interference Clause.

Franken says that his Prescription Drug and Health Improvement Act would cut prescription drug costs for seniors in Minnesota and across the country.

“When I travel around Minnesota, I always hear from seniors that they’re still paying far too much for prescription drugs,” Franken said.

That’s Franken nonsense.

Some things to consider:

"It is not obvious that allowing the government to negotiate with pharmaceutical companies will lead to lower prices than those achieved by private drug plans. Private plans like Kaiser or United are able to negotiate deep discounts with pharmaceutical companies precisely because of the plans' ability to say no – the ability to include some drugs and to exclude others, allowing the market to judge the resulting formulary. On the other hand, when the government negotiates, its hands are tied because there are few drugs it can exclude without facing political backlash from doctors and the Medicare population, a very influential group of voters. Neither economic theory nor historical experience suggests government price negotiation will achieve lower drug prices. Congressional Democrats need to be careful in making the logical leap from market share to bargaining power. Empowering the government to negotiate with pharmaceutical companies is not necessarily equivalent to achieving lower drug prices. In fact, neither economic theory nor historical experience suggests that will be the outcome. Members should think carefully before jumping on the bandwagon – this promise may bring just the opposite of what was ordered."

Stanford Business School's Alain Enthoven and Kyna Fong

"Both the non-partisan Congressional Budget Office and Medicare actuaries have said they doubt the government could negotiate lower costs than the private sector. The theory behind Part D is that market forces and competition among drug plans, overseen by government, can achieve better results than a government-run program. The multitude of plans allows seniors to pick one that best meets their needs. Government price negotiation could leave people without drugs that manufacturers decide aren't sufficiently profitable under the plan. Medicare recipients account for half of all drug prescriptions. With that kind of clout, government might try to dictate prices, not just negotiate them. This could leave people without drugs that manufacturers decide aren't sufficiently profitable under the plan. The VA plan illustrates the point. It offers 1,300 drugs, compared with 4,300 available under Part D, prompting more than one-third of retired veterans to enroll in Medicare drug plans."

"Our View On Medicare Part D: Put Brakes On Drug Plan 'Fix,'" USA Today, 11/13/06

The bottom line here is that Part D is a tremendous success – due in no small part to the Non-Interference Clause.  Consider:

* The projected cost for Medicare Part D is $117 billion lower over the next decade than experts estimated just last summer. This means that over the 10-year period from 2008 to 2017, the estimated $915 billion cost of Part D fell to $798 billion.

Why?  Marketplace competition.

* And, according to a study published in the Annals of Internal Medicine, the Medicare drug benefit led to a 17 percent decrease in out-of-pocket expenses, or $9 a month, for seniors who enrolled in the new Medicare Part D benefit in 2006, the first full year prescription coverage became available in the federal health insurance program for the elderly and disabled.

* And the savings amounted to an extra 14 days of medicine for those who signed up, or a 19 percent increase in prescription usage.

Can Part D be made even better? Absolutely. But this is good news worth sharing -- and not because it helps any particular partisan political agenda but because it means that more Americans -- tens of millions of more Americans -- are getting access to the medicines (largely chronic medicines) that will help them live healthier lives. And this, in no small measure, significantly reduces more drastic medical interventions -- which in turn reduces our overall national health care spending.

We shouldn’t interfere with success.

By revoking the Non-Interference clause, Uncle Sam will be able to "negotiate" prices for Part D drugs.  That's kind of like negotiating with your hands tied behind your back and a gun pointed at your head.  There's also the potential for Uncle to dictate that Part D prices be tied to prices in other countries -- a kind of Medicare reference price.

“Direct negotiations” means price controls.  And price controls = choice controls.

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The Ryan health care message

01/26/2011 06:33 PM |

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Product over Process

01/25/2011 11:07 AM |

 “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:

The National Institutes of Health recently announced that it would be engaging in a billion-dollar effort to encourage the development of new pharmaceutical therapies. The New York Times headline for this story sounded innocuous: “Federal Research Center Will Help Develop Medicines.” But not everyone is so sanguine about this effort. Fox News, for example, re-ran the Times story under the header: “Obama Creating Billion Dollar Gov’t-Run Drug 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.

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Here Comes the Sun (Sentinel)

01/25/2011 08:13 AM |

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.

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Who Lost Innovation?

01/24/2011 04:02 PM |

Is America's innovation engine running out of steam?  And if so, can the government refuel the system by rearranging NIH money or spending more on R and D?

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. 


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The Post-Modern Prometheus

01/24/2011 07:22 AM |

“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.

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Bob Speaks!

01/20/2011 09:03 AM |

Have a look at Bob Goldberg musing on the issue of tabloid medicine.

Just click here .. and enjoy.
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EU Guinea Pigs

01/19/2011 01:13 PM |

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:

About 510(k) Recommendations

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Iron Mike on Social Media and the FDA

01/19/2011 10:41 AM |

"Everybody has a plan," mused Mike Tyson, "until they get hit."

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.
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The other repeal vote

01/19/2011 09:03 AM |

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.”

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Quote of the week

01/19/2011 01:27 AM |

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Those evil profit-driven insurance companies...

01/19/2011 01:21 AM |

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Obamacare and Mental Health Services

01/18/2011 11:19 PM |

http://spectator.org/archives/2011/01/18/obamacare-shreds-mental-health

The Right Prescription

Obamacare Shreds Mental Health Care

By Robert M. Goldberg on 1.18.11 @ 6:06AM

As the House of Representatives debates a bill to repeal Obamacare and start over, the Left will invoke the tragedy in Tucson as a reason to keep the law in place. Liberal bloggers and some patient groups are claiming that states are already cutting mental health budgets to balance budgets, Arizona among them. They will claim that overturning Obamacare, which offers mental health benefits through an expansion of Medicaid, would only deepen the danger. The New Republic's Jonathan Cohn provides the familiar liberal narrative: "We may never know whether a better mental health care system would have averted this massacre. But we can be sure that it would avert some future ones."

While we can't be sure a "better" mental healthcare system could stop an obsessed schizophrenic from committing violence, we can be sure that Obamacare will shred mental health treatment in America.

Cohn notes that we don't warehouse the mentally ill in asylums anymore. Instead, we warehouse them in jails. That's accurate enough to be misleading. Budgets for mental health everywhere soared and state mental hospital spending fell when Medicaid, in 1970, said it would pay for mental health care but not institutionalized treatment for people between the ages of 21 and 65. State psychiatric hospitals that provided long-term care closed and were replaced by psychiatric units of general hospitals with fewer beds. Or by prisons.

The emphasis on community-based or residential care has been well-intentioned and in the vast majority of cases has been fairly effective thanks to the introduction of medications that permit individuals to live free of psychotic episodes. In this respect, the pharmacological revolution made it possible for states to use Medicaid to rapidly expand treatment to millions of Americans. At the same time, because Medicaid was and is such an important source of money for states, it continues to skew mental health investment away from what's best for patients.

For example, while delivering care to people at home or at residential centers costs a fraction of doing so in a psychiatric hospital or prison, Medicaid won't pay to move people from hospitals to outpatient care and in some cases will only pay a smaller share of the less institutionalized setting. The savings can't be counted. Further, if states can generate more Medicaid dollars elsewhere -- and reduce mental health spending in the process -- they will. Federal Medicaid dollars cover about 40 percent of mental health programs and still have all the strings attached. So states that can get the federal government to cover a bigger share of other programs' costs -- nursing homes, for instance, or dialysis -- it will increase spending there.

Finally, as Harvard economist Richard Frankobserved, states have shifted much of their mental health funding into Medicaid, leaving funding for other programs bare. So now when states are faced with budget shortfalls it is mental health that is receiving the brunt of the cuts.

Obamacare will speed the hollowing out of mental health coverage thanks to its increased dependence on shoving most Americans into Medicaid. Obamacare proponents claimed they were protecting the mentally ill -- most of whom they would cram into Medicaid -- by barring states from limiting eligibility from what they now have.

Once again, mental health services are likely to be chopped. If states "save" money, the law requires it give a chunk of it to the federal government. Moreover, states can't raise money by imposing or raising copays on Medicaid beneficiaries.

That means two things. First, services will be cut indirectly by cutting what doctors are paid. Fewer doctors means the state will pay for less care.

Second, under Obamacare the cheapest drugs for Medicaid will get the most business. That means doctors have to start with the cheapest medication, not the medication that is right for a patient. Several studies conducted over the last decade by Stephen Soumerai show that such restrictions actually make mental illness worse and expose patients to dangerous side effects. As a result, less than half of all people in mental health programs under Medicaid stick to their treatment plan. And since medications are the key to better outcomes, the rationing undermines care across the board.

As Cohn observed, it is these people who "could benefit from therapy, drugs, and community supports -- frequently living totally normal, productive lives -- instead end up without treatment and sometimes without homes. Inevitably some of these people end up committing crimes, overloading a criminal justice system ill-equipped to handle them."

And in its infinite wisdom the Left seeks, through Obamacare, to force states to stick to failed strategies and refuses to give them the flexibility to do better by its citizens. Instead, it insists upon expanding a system that debases and imprisons, a system that is a shameful symbol of liberal intentions.

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The New BRAT Pack

01/18/2011 08:25 AM |

As negotiations for PDUFA V get serious, there seems to be a widening gap between what FDA wants (more resources) and what industry wants (more predictability). 

 

After all, as President Obama wrote today in the Wall Street Journal, “Sometimes, those rules have gotten out of balance, placing unreasonable burdens on business—burdens that have stifled innovation and have had a chilling effect on growth and jobs.”

 

And nowhere is this more in evidence than in the desire for a more formalized way to determine (and, indeed, predict) the benefit/risk equation.

 

The FDA is designing a five-item grid as a management tool to explain its risk-benefit decisions in a more concise format. The model that it has created as a working template confirms a truism about its drug approval tendencies that industry has suspected for years: the baseline for FDA approval is a high rating of the severity of the disease being treated and the medical need for the product.

The agency is developing a grid of the five basic factors that need to be addressed in any decision on the commercial availability of a drug. The top two are the seriousness of the condition addressed and the need for a new treatment of the condition. Then comes the traditional heart of the NDA package: analyses of clinical data on the benefits of the drug and the risks associated with its use.

The fifth fundamental factor is explicitly the level of risk management associated with the product. FDA is going to take it into consideration in every decision; sponsors who ignore or underplay the identification of who should use the product and who might use it will have a gap in their filings.

The grid proposal does not call for a fixed mathematical formula behind each approval. The agency has not tried to reduce the judgments in an approval decision to a rigid calculation.

Judgment?  You mean FDA decisions aren’t black and white? 

In the words of John Jenkins, disagreement "happens a lot in the decisions that we have to make. Very few of the decisions that we make on drugs are easy. Very few of the drugs we see have a dramatic overwhelming benefit with relatively no risk. We see that most drugs have marginal to moderate benefits on a population basis and they have general safety but they have the risks of serious toxicities at some low levels." In other words, every decision is "very complex."

That’s a good start, but there’s a better way forward.

 

A new paper in Clinical Pharmacology & Therapeutics, “Development of a Framework for Enhancing the Transparency, Reproducibility and Communication of the Benefit-Risk Balance of Medicines," calls for the creation of Benefit Risk Action Team (BRAT) framework, a set of processes and tools for selecting, organizing, summarizing, and interpreting data that is relevant to decisions based on benefit–risk assessments.

 

The authors argue (and quite persuasively) that BRAT provides a standardized yet flexible platform for incorporating study outcomes and preference weights as well as for communicating the rationales for decisions.

 

Some selected segments:

 

Assessing the benefit–risk balance of medicines is a prominent challenge facing all sectors of health care, from pharmaceutical manufacturers and regulators to prescribers to patients seeking to make more informed treatment decisions.

 

However, although benefit–risk assessments are at the center of decision-making, the current process relies primarily on expert judgment. Indeed, the Institute of Medicine (IOM) recently noted that “in both the pre-approval and the post-marketing setting, the risk–benefit analysis that currently goes into FDA decisions appears to be ad hoc, informal, and qualitative.Despite calls for a more consistent and robust process, a suitable framework for benefit–risk assessment of medicines has yet to emerge.

 

The advantages of developing and adopting such a framework are well recognized. By specifying the essential attributes that both regulators and companies should consider across the life cycle of a drug, the entire process of drug development, review, and approval would be strengthened. In the development and approval stages, the existence of a risk–benefit assessment sponsors and regulators and, as a consequence, between providers and patients, particularly with respect to medicines for which the benefit–risk balance is not straightforward (e.g., because of large and complex efficacy and safety data sets or because of inherent uncertainty regarding the available data).

 

In the post approval stage, the framework could ensure a more balanced assessment and communication of both benefits and risks, particularly as new safety issues emerge. Finally, the use of a framework would allow decision makers (DMs) to incorporate the views of other important stakeholders, such as patients and healthcare professionals. All of these improvements would result in decision-making processes that are more transparent, rational, and defensible. The Pharmaceutical Research and Manufacturers of America (PhRMA) have addressed the need for improved benefit–risk assessment by developing a structured, systematic, and transparent framework. The result of a 5-year effort by a team organized and facilitated by PhRMA, the Benefit Risk Action Team (BRAT) Framework is a progressive move toward benefit–risk assessment that seeks to incorporate all relevant aspects of benefit and risk. The focus is on both qualitative and quantitative analysis of benefit and risk outcomes. The current framework can incorporate weighting of outcomes but does not focus on calculation of overall benefit–risk scores. This paper reports on the design and rationale of the BRAT Framework.

 

The Brat Framework

 

Suitable for use by all stakeholders, the BRAT framework is a general platform for benefit–risk assessment. It facilitates the selection, organization, summarization, and interpretation of data and preferences relevant to the benefit–risk decision and also serves as a tool with which to broadly communicate the rationale for the decision.

 

Six steps represent the current process that structures and assists DMs, without constraining them. The actual decision is depicted outside the framework’s steps, to emphasize that, while the framework aids decision making, it does not replace clinical expertise and judgment.

 

1. Define the decision context. Define drug, dose, formulation, indication, patient population, comparator(s), and time horizon for outcomes, perspective of the decision makers (regulator, sponsor, patient, or physician).

 

2. Identify outcomes. Select all important outcomes and create the initial value tree. Define a preliminary set of outcome measures/end points for each. Document rationale for outcomes included/excluded.

 

3. Identify and extract source data.  Determine and document all data sources (e.g., clinical trials, observational studies) Extract all relevant data for the data source table, including detailed references and any annotations, to help the subsequent interpretations create summary measures.

 

4. Customize the framework. Modify the value tree on the basis of further review of the data and clinical expertise. Refine the outcome measures/end points. May include tuning of outcomes not considered relevant to a particular benefit–risk assessment or that vary in relevance by stakeholder group.

 

5. Assess outcome importance. Apply or assess any ranking or weighting of outcome importance to decision makers or other stakeholders.

 

6. Display and interpret key benefit–risk metrics. Summarize source data in tabular and graphical displays to aid review and interpretation, challenge summary metrics, review source data, and identify and fill any information gaps.Interpret summary information.

 

The paper concludes:

 

As discussed in the seminal 1998 report by the Council for International Organizations of Medical Sciences, benefit–risk assessment is the “heart” of determining the overall value of a medicine. But although a number of benefit-risk assessment approaches have been proposed, none has been widely adopted.

 

The lack of uptake may be attributable, in part, to the focus on developing quantitative tools before turning to the development of a fundamental, principled approach to benefit–risk decision making. The BRAT framework is designed as such a fundamental, principled approach. There is evident need for consensus on methods of conducting benefit–risk assessments, tools and processes to better design and evaluate drug development programs, methods to enhance regulatory discussions throughout a product’s life cycle, and tools to improve communication of benefit–risk assessments to clinicians and patients. The BRAT framework facilitates structured, systematic decision making via customizable tools and processes. The adoption and use of the framework will advance the rigor, transparency, and communication of the rationale behind benefit–risk decisions.

 

A companion paper, “Application of the BRAT Framework to Case Studies:  Observations and Insights,” discusses how, during 2008 and 2009, BRAT members collaborated with epidemiologists at RTI International in order to continue development of the framework and arrive at insights that would help enhance it. The framework was applied to three mock, or “constructed,” drugs in five patient populations. RTI and BRAT members organized feedback from selected regulatory and clinical stakeholders at three stages during the Framework applications. This article describes observations from these case studies and the insights gained by applying the Framework to them.

 

The author’s conclude:

 

The BRAT Framework appears to be of value in the different settings and case studies considered. As the Framework is further developed, we continue to seek feedback to facilitate improvement and adoption of its principles and processes by both companies and health authorities for regulatory review.

 

Because benefit–risk assessment for a drug is rarely straightforward, the Framework or similar tools for elucidating the relevant data can help facilitate discussions between sponsors and regulatory agencies, help communicate complex information to other stakeholders, enhance the transparency of assumptions and decisions, and provide support for difficult regulatory benefit–risk decisions.

 

The Framework processes and associated documentation of all decisions, rationale, and data could also provide an audit trail for past decisions and can inform the design of future clinical trials. Coupled or integrated with other tools, the Framework can …be an important factor in improving evidence-driven decisions on whether and under what circumstances therapeutic benefits outweigh associated risks.

 

Industry seeks clarity. They want bright lines. They want to know the rules. They want predictability. This may sound simple and fair, but inside the FDA it has proven to be a fractious bureaucratic kulturkampf.  “Change is not required,” as management guru W. Edwards Deming once said. “Survival is not mandatory.”  And that doesn’t mean change for show, for politics – it means thoughtful, timely, strategic change that enhances the public health.  And that kind of change requires not walking on egg shells – but breaking them. 

 

It’s time for the FDA to welcome the BRAT Pack to the drug regulatory process.

 

As the President writes, “Our economy is not a zero-sum game. Regulations do have costs; often, as a country, we have to make tough decisions about whether those costs are necessary. But what is clear is that we can strike the right balance. We can make our economy stronger and more competitive, while meeting our fundamental responsibilities to one another.”

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Wake(field) Island

01/14/2011 08:27 PM |

According to a new study from Columbia University (published in the American Journal of Public Health) health advocacy groups aren't disclosing their financial ties to industry.

 

The study compared Eli Lilly’s disclosures of $3.2 million in payments to 161 health advocacy groups in the first half of 2007 with the groups’ own disclosures.

 

Only one-quarter of the groups acknowledged Lilly’s support anywhere on their public Web sites, the study said. Only one in 10 disclosed Lilly as the sponsor of a specific grant, and none of them disclosed the exact amount.

 

Interesting – except that these Columbia Lions used two quarters of information from 2007 (the first year companies started disclosing and before patient groups got up to speed) and from just one company. Based on this shoddy data set the authors conclude that, in 2011, patient organizations aren’t disclosing their financial relationships with industry. Mention of these, er, design flaws in the mainstream media reporting on this study?  Zero.

 

And no explanation as to why the research team didn’t use more recent data from 2009 with multiple companies. 

 

Can you say “Wakefield?”

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Roxane, you don't have to put out the red light

01/14/2011 08:00 AM |

But make the label bright yellow.

Roxane Laboratories is reissuing its high-potency morphine with a redesigned label bearing bold colors, a boxed warning and other precautions following deaths and other serious adverse events due to misreading of the dosage - six months after the director of FDA's Division of Medication Error Prevention and Analysis said publicly that the company's standardized use of label colors was causing confusion.

The redesigned label uses color to make sure prescribers and patients understand the dosage for Roxane's 100 mg/5 mL morphine sulfate oral solution and can distinguish it at a glance from lower-strength Roxane morphine products.

Where the old label used brown lettering on a white background, the new one uses a bright yellow background on multiple sides of the product, so that it is distinct from other Roxane morphine products that still use a white background. Also, the new high-potency label gives the drug name, strength and concentration in white lettering on a red background.

The problem and the solution were both foreshadowed at a June 24 workshop FDA sponsored on medication errors At that meeting, Marissa Craddock, a regulatory affairs/labeling specialist for Roxane, said that the company uses brown on most of its drug labels, but distinguishes the highest strengths with red.

"A lot of the types of errors that we see, especially with the Roxane product line, are really attributed to that brown ... that's used across all the products," Carol Holquist director of FDA's Division of Medication Error Prevention and Analysis, said. "It's really great that you differentiate strength, but it's really hard to tell what product's in there."

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