FDA Faces Critical Juncture with FY 2010 Appropriations

On Thursday afternoon, June 11, the House Appropriations Subcommittee on Agriculture will have a mark-up that includes FDA appropriations for FY 2010 (starts October 1, 2009). This mark-up, and the one that will follow in the Senate, will be critical events in the capabilities and effectiveness of FDA for the next 5 to 10 years.

After years of drought for FDA, Congress has invested substantial new monies in the agency in FY 08 and FY 09. There are a number of reasons: strong Congressional champions, widespread media coverage of FDA problems, and the education and lobbying efforts of the Alliance for a Stronger FDA.

President Obama has started the FY 10 cycle with a request for a $295M increase for FDA. Given the long, bipartisan history of miniscule presidential requests for FDA, this was an important break with the past. While supporting the President's request, the Alliance is advocating for about $100M more.

Thursday's mark-up is the first time we will see how Congress intends to respond to the President's request. In addition, the mark-up may provide insight into the appropriations committee's view of new legislation that may give FDA significant new responsibilities in 2009.

Tobacco legislation—likely to pass the Senate this week—will be funded by user fees. After that, Congress is likely to pass a major expansion of food safety inspection capacity. Commissioner Hamburg has already stated that the agency does not have the resources to implement the House bill unless it receives new monies. Reimportation of drugs and follow-on biologics are less likely to be adopted than food safety, but are genuine possibilities this year. Each will be expensive.

The risk is that the gains of the last two years and another $300M for FY 10 will wind up paying for new responsibilities, rather than strengthening the agency. Hopefully, Chair Rosa DeLauro (D-CT) will reference these additional needs in her opening remarks. Or there might be committee language acknowledging the need for additional funds if Congress passes new laws that give FDA more responsibility.

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For those not familiar with the Alliance for a Stronger FDA, its 180 members represent the full range of agency stakeholders. They are strong advocates for increased appropriations for FDA and united in the belief that "a stronger FDA benefits everyone."

In the interest of full disclosure, I was one of the founders of a predecessor organization and now serve as deputy executive director of the Alliance. FDA Matters is not affiliated in any way with the Alliance.

The more members the Alliance has, the stronger its voice on Capitol Hill and in the media. If you want more information about the Alliance, write me at: sgrossman@strengthenFDA.org.

Many Facets to the Transparency Task Force

FDA's disclosure policies are intended to be a balance between "public right to know" and "company right to protect intellectual property that supports innovations." As such, every FDA policy has a risk-benefit to society, which evolves over time. Seen in this light, the new FDA task force on agency transparency is a legitimate inquiry. It probably should be repeated every 3 to 5 years.

Compared to products, it is much trickier to figure out when policies need to be changed and based on what criteria. Yet, it is possible, even now, to predict the broad outline of the task force report, due in early December:

Low-hanging fruit: There are policies and procedures whose revision is obvious when subjected to examination. For example, more of the senior people at FDA should be required to keep a public log of meetings with external stakeholders. This is fair as long as it includes contact with any interest group, not just industry.

More substantive changes requiring more work of FDA, but public interest clearly weighs in favor of disclosure: FOIA immediately comes to mind. My experience is to get a call from FDA asking if I want the information —12 to 18 months after a FOIA request. I never have gotten anything in a timeframe where I could use it.

Large changes requiring new policies or major re-working of existing policies: These are likely to invoke heated exchange now, but a year hence, everyone will wonder what the fuss was about. An example from the past: the policy of FDA and company briefing books being posted online two-days prior to an advisory committee meeting.

Major changes requiring legislation: These are the ones widely predicted by media, much feared by industry and least likely to happen. One such
proposal, advocated in a NY Times editorial, would substantially increase the amount of company data made available to the public before and after approval of medical products. Some change in this area will happen, but not much. The legislative barriers are too high, the lack of consensus too great, and caution will prevail because no one can be certain where the proper balance lies.

Hanging over all of this is the need for the agency to communicate better. As Dr. Sharfstein observed, sometimes the agency has a good explanation, but it "doesn't break through because of FDA's reputation for being uncooperative."

As a footnote: the task force exercise itself is going to prove instructive, if only because old habits die hard. A tip of the hat to fellow blogger Mark Senak for pointing out that the transparency task force blog: neither identifies who will be writing and posting blogs nor who will be responsible for accepting and rejecting public comments intended for the blog site. No doubt this will be remedied quickly, but the point is still significant: transparency and accountability are not part of FDA's DNA. New habits will take time, energy and experience to develop.

The June 3 Federal Register notice for the June 24^th public hearing of the Transparency Task Force:

http://edocket.access.gpo.gov/2009/pdf/E9-12902.pdf

The original NY Times article by Gardiner Harris on June 2:

http://www.nytimes.com/2009/06/02/health/policy/02fda.html?_r=1&scp=1&sq=gardiner%20and%20heartburn&st=cse

NY Times editorial on transparency and FDA on June 3:

http://www.nytimes.com/2009/06/03/opinion/03weds2.html?tntemail1=y&emc=tnt&pagewanted=print

Mark Senak's comments: http://www.eyeonfda.com/eye_on_fda

Reported in the June 4, Drug Daily Bulletin (free): enewsletters@fdanews.com

Turning Data into Knowledge

Through statute and directive, FDA has been asked to collect, analyze, interpret and utilize massive amounts of data. This includes biological, clinical, adverse event, production and distribution data, medical and food product tracking, and the Sentinel system for early discovery of potential drug safety problems. The systems are not in place to do any of this, at least not at the required level of sophistication. Even if they were, sifting valuable information from background noise is extraordinarily hard. As a result, FDA needs to manage Congressional and public expectations as to "what is possible and when."

Above and beyond its day-to-day information technology needs, FDA will require substantial monies to develop these new databases. Further, the agency lacks the data-mining experts needed to make sense of the data that is received. Such individuals are few and in high demand. Even were the agency given the funds to hire 100 of them this year, it would probably not come close to reaching this goal. Even when the required expertise is on-board, it is a difficult, iterative process to turn data into usable knowledge.

FDA must take account of the littered field of others' past failures and limited successes. Even programs that work well may have limited applicability to FDA's daunting task. The VA system operates with electronic medical records, a finite number of known participants and a partially closed system of care. The Drug Abuse Warning Network (DAWN) tracks only drug-related hospital emergency department visits and drug-related deaths reported by coroners and medical examiners. Each has key characteristics that are not present in tracking food and product use--and consequences--in a real world setting.

FDA has been told that the Medicare claims data set (provided by CMS) gives them a fast start along this difficult path. Perhaps not. I often use the following equation to explain:

Real world data sets = uncontrolled variables + inconsistent data collection + questionable data accuracy.

FDA is used to the type of knowledge derived from controlled clinical trials. In contrast, claims data is notoriously unreliable with few tools to identify and correct for systemic bias.

With very limited staff, FDA has done yeoman work on the initial phases of developing its Sentinel initiative. The goal is a nation-wide electronic safety monitoring system for post-market surveillance. It will use existing data from health systems, hospitals and insurers. An operational system will be a challenge. Creating one that minimizes false positives is more than just a challenge.

There are also some larger issues that will need to be addressed. Even with new hires throughout the agency, medical knowledge and food surveillance needs are growing faster than FDA expertise. Not every "cluster" leads to a medically or scientifically valuable insight. The consequences of premature responses and over-reactions are substantial and often severe. Nonetheless, the tendency in our society, even sometimes at FDA, is to forget that the association of data points often tells us nothing about causality. Finally, it is hard to know the implications of studies that show that more information often does not produce better decisions. This runs counter to FDA culture and is counter-intuitive to the way most of us think.

In sum, FDA has a large job in the area of information technology, data collection and data interpretation. In addition to the need for monies and expertise, there are inherent, as well as institutional barriers to success. Managing expectations will be a test for the new FDA leadership and the senior staff.

Welcome to FDA, Dr. Hamburg

Dr. Hamburg, you have advantages that previous Commissioners did not enjoy. For the first time in decades, there will be extra money to spend, granted by a Congress that will continue to invest in FDA if they see a pay-off. You will be working in the first two years of an administration, when bold plans have the best chance of being realized. You are working for a president interested in public health, a rare event in the last 70 years.

It is not hard to predict that emergencies and crises will take up a lot of your time. So will the care and feeding of the Secretary, OMB, the President and Congress. FDA staff also needs attention, which you and Dr. Sharfstein have appropriately emphasized. There is likely to be tobacco legislation to implement and maybe a new food safety law.

In Long-term Challenges for New FDA Leadership, http://www.fdamatters.com/?p=171, I discussed some issues that may take years to complete, but should be started this year. I hope you will get to them.

Before you can do much long-term planning, you will have to deal with a backlog of policy issues and enforcement actions. This is to be expected when you are preceded by the end of an administration and by "acting" agency heads. Certain decisions just cannot be made until "permanent" leadership is in place.

More than any other activities, you will be judged in the short-term by how you handle the policy and enforcement backlog. These are the decisions that are most likely to animate external stakeholders. As a result, you may have to deal with misperceptions about your approach and your intentions.

Dealing with the back-log—perhaps as many as two or three major policy and enforcement decisions every week for several months—will strike many as hyperactive. They will extrapolate these actions into believing that you intend to govern that way. Eventually the pace will lessen into (merely) frenetic, but not before hard feelings may have set in.

You should communicate that you are dealing with a backlog, rather than planning to make so many major decisions on a regular basis. Emphasize, too, that most of the backlog was generated before you arrived, by FDA staffers operating under statutory or other imperatives. You agree with what staff proposed, but did not initiate it.

During Dr. Sharfstein's first two weeks, he signed the Internet advertising enforcement letters and committed to a review of class III medical devices. Neither was a new issue. The public-released packages reveal upwards of a year or more of FDA staff work behind each. Nonetheless, some saw this as evidence of Dr. Sharfstein's intent to be aggressive in confronting industry. A much better interpretation: these two issues waited for leadership that would be at FDA long enough to defend them.

Many of us hope that this is the start of a golden age at FDA. You are starting with a lot of good will and high expectations. To keep that momentum going, you and Dr. Sharfstein will need to act judiciously and communicate well as you work down the backlog.

Drs. Hamburg and Sharfstein: “The FDA as a Public Health Agency”

Wasting no time, Drs. Hamburg and Sharfstein have written an essay, entitled "The FDA as a Public Health Agency." (Available on-line at: http://content.nejm.org/cgi/content/full/NEJMp0903764). Noteworthy in the new essay is the "big tent" approach they plan to use. They repeatedly refer to consultation with regulated industries, consumers, patients, and the public. They describe specific areas for working more with CDC, NIH, CMS, and the Department of Agriculture.

Drs. Hamburg and Sharfstein touch upon a potpourri of agency issues:

• FDA should be judged by its success in assuring a safe and nutritious food supply and innovative, safe and effective medical products. This must go "beyond such intermediate measures as the number of facilities inspected or drugs approved."
  

• The potential good of a medical product or policy should be balanced against its potential harm. They add: "Some benefits are not worth the risk; some risks are worth taking."
  

• The focus of increased work with NIH should be on accelerating the development of cures. The focus of increased work with CMS should be the exploration of ways to shorten the time from approval to reimbursement.
  

• The focus of increased work with CDC should be on infectious-disease emergencies, outbreaks of foodborne illness, enhanced safety systems, and nutrition.
  

• A new approach to external affairs is foreshadowed by discussion of risk communication, more focus on the scientific basis of agency decisions, and greater transparency.
  

Both by words and tone, the overriding message of the Hamburg/Sharfstein article is that the FDA is a public health agency and will be run by the principles of public health as applied to the issues and opportunities facing the FDA. My May 15 commentary, "Public Health Leadership Comes to FDA," (http://www.fdamatters.com/?p=211) puts some additional texture on this:

It is a perfect time to put the agency in the hands of experienced public health leaders with real world experience. The answer to every question and pressing issue: we will explore what is right from a public health perspective, and then act accordingly. Public health does not require safety to be an absolute value that cannot be offset by other considerations. Innovation to restore health is just as much a public health value as safety.

Dr. Hamburg and Dr. Sharfstein have limited track records on FDA issues. This uncertainty breeds anxiety. Six months from now, everyone will see that the agency is being run by steady, pragmatic leaders. Indeed, it is quite difficult to run the public health department of a large city without these virtues.

This NEJM essay demonstrates that having "limited track records on FDA issues" has not stopped Drs. Hamburg and Sharfstein from having a good sense of the issues and well-developed ideas about how to improve FDA. Ultimately, we, as readers, learn from the essay that Drs. Hamburg and Sharfstein have the knowledge and commitment to address the challenges faced by FDA.

Orphan Drugs Return to Center Stage

Years of quiet success by the rare disease community have built to a moment where orphan drugs are once again at center stage. At the National Organization for Rare Disorders (NORD) policy summit last week, former FDA commissioner David Kessler led a blue-ribbon panel in front of an overflow crowd of more than 300. This past Wednesday, NIH launched a 5-year, $120 million program called Therapeutics for Rare and Neglected Diseases (TRND).

Four factors are driving this renaissance:

• Large unmet need. There are nearly 7000 rare diseases, but only about 200 have treatments. In the aggregate, between 25 and 30 million people in the US have a rare disease.
  
• Companies and Patients Have a Well-Defined Common Cause. In the area of rare diseases, patients cooperate, encourage and defend companies that develop and produce the medications they need. More patients may need high blood pressure medicines, but few of those patients care as dearly.
  
• Orphan drugs have been a central driver in the growth of biotechnology, a trend that may be accelerating. Orphan drugs come with incentives and can be profitable. New scientific knowledge in genomics and other cutting-edge technologies tend to favor well-characterized rare diseases.
  
• Challenges to orphan drug development, approval and marketing may be less than for drugs with more common indications. This increases the appeal of orphan drugs to large companies and may be a key to the survival for smaller companies.
  

While orphan drugs might seem favored, it is still a difficult path to an approved product. The purpose of the new NIH program is to get more promising orphan drug compounds through the expensive pre-clinical development process. Success rates during this phase are so low that it is often called "the valley of death" for start-up and small companies.

At the NORD summit, there was extended discussion of development, reimbursement and access issues. NIH's new program bears directly on drug development, while FDA enumerated a number of ways it assists companies and researchers. Some are mundane but necessary, such as more realistic requirements for the number of patients to be enrolled in trials. Other items represent serious re-thinking, such as a willingness to consider a disease's natural history as a control and openness to cross-over studies (i.e. each patient goes through drug and placebo stages and serves as their own control). A challenge given to NIH and FDA by the panel was to help characterize disease progression through research and patient registries.

Until recently, orphan drugs have tended to do better with payers than other expensive products because high costs are offset by low volumes. Nonetheless, no rare disease patient in the US can assume they will have access to the drugs they need. The British board overseeing UK coverage has demonstrated a willingness to deny access to care for cost reasons. Health care reform, follow-on biologics, comparative effectiveness and inequities between Medicare Part B and Part D are among the areas where rare disease patients and orphan drugs will have to find a path that works.

For readers interested in more information about orphan drugs, I recommend going to NORD's website, www.rarediseases.org, or the FDA website, www.fda.gov.

There is a free conference on June 4, hosted by the US Chamber of Commerce Foundation. Registration is required. http://ncf.uschamber.com/orphan_drugs/.

On July 15 and 16, there is a Rare Disease Leadership Summit in Arlington, Virginia. I will be presenting on "Personalized Medicine and the Future of Orphan Product Development." There is a fee for this one. More details are at: www.cbinet.com/raredisease.

Access to Experimental Drugs: Hard Cases Make Bad Law

I oppose open access to early-stage therapies. However, hard cases make bad law. This was amply demonstrated by the riveting front-page article in Sunday's New York Times, "Months to Live: Fighting for a Last Chance at Life." This is a must-read for anyone concerned about terminal illness or early access. Definitive rules are hard to develop, especially while heart-strings are pulled hard.

The reporter, Amy Harmon, follows the agony of a family whose son/husband/father has ALS (amyotrophic lateral sclerosis). There is a product previously on the market for a different use that allegedly provides relief from progression of the disease. Unfortunately, the firm that was developing it was restrained by a patent settlement. The company that won the patent dispute did not want to acquire responsibility for a population/use it had no intention of serving.

As is usually the case, FDA was torn between compassion today and assuring that clinical trials can still be undertaken in the future. The two companies and FDA also know how rare it is for internet-hyped medicine to prove useful.

To the reporter's credit, she doesn't blame either of the companies or FDA. The story is impactful and honest in chronicling the family's frustration--without choosing good guys and bad guys.

I have had my own lessons in this. It was a crisp New England morning almost 20 years ago. I was helping a company prepare for a "shut the plant down" demonstration by AIDS activists determined to gain access to an experimental therapy. The drug had never been tested in humans. Nor, as I recollect, did it have significant animal testing to back it up.

Given these factors, it seemed like a particularly poor choice for early-access. Understandably, the activists saw this as a dire situation where taking on extraordinary risks was a choice they should be able to make for themselves. There are no good guys or bad guys in this type of situation.

The ALS situation is more nuanced than the one I faced 20 years ago. There appears to be safety data, but probably not at the dose levels that ALS patients would use. There is anecdotal support for the drug's use, although such reports are notoriously unreliable. The ALS case does not necessarily raise what I consider a fundamental issue: should totally untried drugs be available on open access.

Generations of law students have been taught: hard cases make bad law. This certainly applies here. And FDA can never win. One recommendation would be to upgrade the review function and include some outside ethicists and scientific advisors in the process. However, the publicity that would come from doing so might have the effect of doubling or tripling the number of requests, many totally baseless.

The NY Times logged 165 comments in less than 2 days. Clearly the story (and the underlying issues) touched people. What advice would you give FDA in handling demands for early access where there is some data, but not enough to be sure of anything?

The article and the comments posted to NYT website: http://www.nytimes.com/2009/05/17/health/policy/17untested.html
http://community.nytimes.com/article/comments/2009/05/17/health/policy/17untested.html?nl=health&emc=a7

Public Health Leadership Comes to FDA

The world will soon realize that the new FDA leadership--Dr. Hamburg and Dr. Sharfstein-- come from an entirely different mold than their predecessors. When Dr. Hamburg is sworn in, she will formally begin an era of public health leadership at the agency. FDA staff and agency stakeholders will eventually come to appreciate that this difference is good for FDA.

It is a perfect time to put the agency in the hands of experienced public health leaders with real world experience. The shift will be both interesting and salutary. Notably, there will be a consistent standard in decisionmaking. The answer to every question and pressing issue will be: we will explore what is right from a public health perspective, and then act accordingly.

FDA staff and agency stakeholders argue for their position by saying they are advancing the public health, while secretly believing that other factors will drive the final decision. It is disarming, then, for the Commissioner to actually treat "public health benefit" as the agency's North Star.  Of course there will be many disputes, but everyone will have to build their rationale on public health grounds, knowing that it is the real basis of decisionmaking.

Several misunderstandings drive concerns about public health leadership at FDA. Public health is about helping people and communities to get healthy and stay healthy. Prevention is preferred because it preserves health, while therapies "only" restore health. Preferring prevention is not the same as being against therapy. Public health is not anti-therapeutic nor could any FDA commissioner be anti-therapeutic.

Public health does not require safety to be an absolute value that cannot be offset by other considerations. Innovation to restore health is just as much a public health value as safety. Dr. Hamburg has affirmed this.

What it means to run a big city health department has also been misunderstood. The imperative to act is immediate and real, but you learn that "what appears to be real" has to be examined before any decisions are made. Nothing you're told can be relied upon until it had been rechecked and sometimes double and triple re-checked. An over-simple example: reports about unsanitary conditions in a restaurant might just be from the eatery across the street that has lost business.

Dr. Hamburg and Dr. Sharfstein have limited track records on FDA issues. This uncertainty breeds anxiety. Six months from now, everyone will see that the agency is being run by steady, pragmatic leaders. Indeed, it is quite difficult to run the public health department of a large city without these virtues.

Long-Term Challenges for New FDA Leadership

When Dr. Hamburg arrives, she will face a number of competing priorities, along with a large backlog of policy and enforcement decisions that have waited for permanent leadership. There is a risk that important long-term challenges will go unaddressed…merely because they are not part of an immediate crisis or subject to pressure by the Secretary, the President, or Congress. Two or three years from now, these are the items that everyone will look back upon and say: we should have gotten started sooner.

Here is my list of seven such challenges:

Integrating new science into traditional clinical trials. Constructing real-world clinical trials has never been more difficult. In many clinical areas, we are moving from targeting disease symptomology toward impacting fundamental biological processes. Preventive treatments raise different issues than curative treatments. Two or three generations of products (in trials now and over the next few years) are "at-risk" unless the Critical Path is accelerated and expanded and other "clinical trial improvement" initiatives are developed.

Balancing safety with patient risk and need. Severely-ill patients deserve more balanced and more patient-centric policies with regard to dangerous treatments that have proven to provide great benefit to some patients (NB: "proven" does not mean phase 1 or early phase 2 trials). The Risk Evaluation and Mitigation Strategy (REMS) program helps, but these issues need a broader, more systemic examination.

Sifting valuable information from background noise. FDA is building a Sentinel system for early monitoring of problems, has access to the Medicare database and will be collecting incredibly large amounts of information about safety, food and drug imports, global product supply lines, clinical trials, patient registries, etc. It is a difficult, highly iterative process to distinguish meaningful patterns from background noise…in order to create actionable intelligence.

Managing globalization, rather than just responding to it. This is closely related, but distinct, from food import safety, heparin contamination and related crises. There needs to be a comprehensive, multi-year plan for managing globalization, including a budget for Congress to consider and fund. Tomorrow's problems need to be identified and addressed before they become even bigger issues. Offices in China and India are necessary, but by no means sufficient.

Resisting the bias toward negative decisions. Up to a point, caution is the appropriate response to uncertainty. Yet uncertainty is inherent in all positive decisions. Taken to the extreme, the whole world of food and drugs could slow down, and then stop. The correct balance is not achieved by a memo or a speech, but by day-to-day actions and enhanced communications. Systemic review of all decisionmaking processes is the ultimate corrective.

Staying focused on priorities. FDA's responsibilities greatly exceed its resources. Some mission creep is inevitable; some new responsibilities may be needed to benefit society and the public health. But sometimes FDA will need to say "no." Such moments are difficult. "No" will never be accepted by policymakers or the public unless FDA is clearer in defining, justifying and explaining its priorities. Again, this must be addressed comprehensively.

Keeping the Best and the Brightest. FDA cannot succeed without a high-quality and committed workforce. Public service is an important attraction of working at FDA. It cannot be allowed to go out of style. Increased appropriations provide the opportunity to rationalize workloads, reduce burn-out, and build morale.

Do you have items you would add to this list? If so, post comments with your suggestions.

Please focus on issues and projects that have long-term consequences and take time to develop…but for which there is no immediate crisis or pressure.

We will take the suggestions, compile a list and send it to Drs. Hamburg and Sharfstein.

Steven

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FDA Matters: A Prologue

FDA Matters will provide fresh insights and new perspectives for the community of people "involved in FDA matters and for whom FDA matters." Our goal is to create an information community around the mission and activities of the Food and Drug Administration.

It is fashionable to use blogs to advance strongly-held, singular viewpoints. FDA Matters will be different. It will focus on what the agency is thinking and how its actions are shaped by Congress, the media, stakeholders and external events. It will be a source of understanding about FDA, both directly and by stimulating dialogue.

One continuing theme will be the need to plan for FDA’s future. As long as FDA moves from crisis to crisis, it can never create the orderly systems that increase effectiveness and provide predictability of action.

FDA Matters is not a voice for any interest group. The blogs will reflect my views, formed from more than 30 years working on policy and politics in DC. Every reader is encouraged to share their views through posting comments and other features.

Between my blog and posted comments, FDA Matters is likely to air many criticisms of FDA. Whenever possible, I will offer constructive suggestions for improvement and kudos for jobs that are well done. The FDA employees I know have demonstrated intelligence, commitment and fairness. They deserve our support, even if we disagree about agency policies and actions. Readers are encouraged to post comments in the same spirit.

Are there problems at the agency? Are bad decisions being made alongside good ones? Of course, on both counts. As FDA Matters will amply demonstrate, people of good will can hold opposite views about FDA and its policies and actions.

FDA Matters will reach out through several short blog columns each week, point/counterpoint exchanges, and an “Ask Steven About FDA℠” feature. The very best opportunities to learn and share are to get involved yourself—by posting your comments and adding the benefit of your experience and insights.

Sign up, stick around for a few columns, and give FDA Matters a chance to gain momentum and grow. A better FDA is worth the effort to stay involved.

Steven

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