Dr. Hamburg Meet Dr. Collins

FDA and NIH are natural allies, with closely-related purposes as public health agencies. They share a similar worldview that "medical and scientific knowledge derived from random clinical trials" is superior to all other sources. I explored this in an earlier column at: http://www.fdamatters.com/?p=299.

Last week's announcement of Dr. Francis Collins to be NIH director provides a unique opportunity for FDA. Dr. Hamburg needs to meet Dr. Collins….and create a shared vision.

Government agencies are no different than corporate divisions: they crave positive attention, fight to accumulate bigger budgets and more personnel, and resist any attempts to lessen their autonomy. Tribal rules apply. Outsiders---no matter how well-meaning—cannot be assumed to have your organization's best interests at heart.

One could ask: why should FDA and NIH be different than this grim picture of organizational behavior? The answer is: they aren't. Except in rare cases, having a noble organizational purpose does not suspend the accumulative and suspicious culture that is inherent in any group.

There are countless joint initiatives and working groups that link FDA and NIH. Common purposes and a similar world view often push them together…but I am told that many of these meetings are productive only in a very narrow sense. Although the work gets done, the spirit of common purpose is often weak. Enthusiasm for power-sharing is low. Extending projects to related areas is sometimes never discussed. But opportunity is everywhere.

FDA and CMS relate in a different way. As described in my earlier article, the agencies do not have common purpose and do not have a shared view of what knowledge is important. Because of these fundamental differences, opportunities for shared initiative are limited and relations will always be strained. For FDA and CMS, good will and occasional joint successes can never overcome the distance between them.

Not so FDA and NIH. The two agencies working together are powerfully synergistic….and boundless in the benefits it could bring to Americans. The interest of NIH Institute and FDA Center directors is essential to building a better, more productive relationship. But it will never happen if it rests on their ability to overcome the cultural and tribal impediments.

Only Dr. Hamburg and Dr. Collins can set the proper tone, provide guidance and break down the barriers. Dr. Hamburg, meet Dr. Collins. Please.

Steven

Follow-on Biologics and the Dance of Legislation

Political scientists love to watch the dance of legislation. FDA watchers are eager to see how thorny agency issues will be decided by Congress. Both will be fascinated by the latest moves and turns in Congressional consideration of legislation on follow-on biologics (FOB).

I can't recollect an instance in which a House chairman faced such massive bipartisan opposition. But never count House Energy and Commerce (E&C) Committee Chairman Henry Waxman out. He has made a career of not having enough votes… and winning, anyway.

Mr. Waxman is proposing generics-friendly legislation (HR 1427). As the committee chair, he is well-positioned. Plus, he has 12 co-sponsors, including the chairman (Pallone) and ranking minority member (Deal) of the health subcommittee. Usually, this is enough to win outright or with only modest compromises.

But Waxman is in a stand-off with committee member and fellow Democrat, Representative Anna Eshoo. Her bill (HR 1548) is considered friendly to the biotechnology industry. She is joined by the ranking minority member of the full committee (Barton). Together they have amassed an extraordinary 108 bi-partisan cosponsors. This is one-fourth of the House's total membership!

Representative Eshoo has the momentum, having added 50 co-sponsors since April 15, compared to 2 for Representative Waxman. Further, Waxman is under pressure to include follow-on biologics in the health reform bill mark-up, duplicating the legislative situation in the Senate.

Chairman Waxman is reportedly resisting any effort to move legislation on follow-on biologics. He lacks the votes to prevail and must stall for enough time and leverage to work his political magic.

On the Senate side, Chairman Kennedy is sticking with a two-year old bipartisan compromise, which is much closer to the Eshoo position than to Waxman. He has put the FOB bill into the health reform legislation being considered by the Senate HELP Committee this month.

Enter the generic drug industry, Senator Schumer, and the AARP...and the Senate plot thickens.

The generic drug industry chose not to make a deal in 2008—in the reasonable belief they would do better with a Democratic Congress and President. They are hoping to retrieve the situation with Senator Schumer, who has introduced the Waxman bill in the Senate (S 726). His bill (and seven bi-partisan co-sponsors) assures that the Kennedy bill will not move forward without visible dissent. Meantime, the AARP reportedly told Senator Kennedy's staff that they will not support the HELP committee's health reform bill unless the FOB portion is modified to be more like the Waxman-Schumer bill.

The most contentious issue in both Houses is the length of time during which innovator companies can prevent a FOB from being approved based on the innovator's research. This so-called "data exclusivity" should not be confused with the far-more-desirable "market exclusivity," which is not part of any bill.

In round numbers, Waxman is proposing 5 years of data exclusivity, Eshoo 14 years and Kennedy 12 years. There is no objectively correct number—just differing beliefs in how much time is needed to make sure that the growth of an FOB market doesn't reduce incentives for innovation. An average of the three numbers suggests a compromise of about 10 years.

Enter the Federal Trade Commission and the White House…and the whole plot thickens further.

The FTC analysis—featured at a House hearing and widely covered in the media—contends that no data exclusivity is needed to preserve incentives for innovation. Now there are four numbers and the average is 7.5 years. Last week, the White House jumped in to officially advocate for 7 years.

The endgame on data exclusivity is becoming clear. It will be between those who will accept seven years and those who will insist on at least 10 years. Even knowing this, it is hard to tell whether and when the logjams will be broken in the House and Senate.

The unfolding politics of FOBs are going to make for a fun summer and may creep into football season! Someone is likely to score a touchdown (or learn to dance the tango)!

Steven

Save the Critical Path—Part 2

Transforming FDA into a first-class, 21st-century regulatory agency will not be easy. It requires planning, commitment and a broad vision. Science-based decisionmaking is a central part of the transformation, but it doesn't just happen by itself. Regulatory science needs to provide the tools, standards and knowledge for FDA to handle an ever-more complex world of science and commerce.

To meet this challenge and provide a broad vision, FDA Matters has proposed the creation of the Center for the Advancement of Regulatory Sciences (CARS). It puts FDA's science and FDA's future at the heart of the agency, where the commitment can be constant and everyone won't be running off to meet the next crisis.

"Save the Critical Path-Part 1" appeared ten days ago: http://www.fdamatters.com/?p=317. Here are some questions I have been asked since then.

What is regulatory science?

There is no standard definition for "regulatory science," although the term is widely used and generally understood. It means the tools, techniques and knowledge needed by food and medical product regulators to carry out their public responsibilities.

Fundamental to the concept is that consumers, patients and regulated industries benefit when regulators have sophisticated, state-of-the art capabilities and use them transparently, so that no stakeholder has to guess about the agency's approach. "Regulatory science" extends to every aspect of the FDA's responsibilities, including manufacturing, product tracking, laboratory procedures, post-market standards, sentinel monitoring, etc.

What are the key characteristics of CARS?

The purpose of CARS is to build the science-based decisionmaking capacity at FDA by creating and validating new scientific knowledge, tests and standards. It should produce greater consistency and predictability in the agency's regulatory activities.

CARS must be FDA-driven and funded with public monies. It must be an FDA initiative with stakeholder input, not an agency-stakeholder partnership. These characteristics are essential to obtaining and retaining Congressional support. There can be no ambiguity: this is FDA's initiative and the program's direction is coming from within FDA.

Consumers and industry benefit from an FDA that is more sophisticated in its approach, more capable in its actions, and more confident that its decisions are scientifically-derived.

Why can't Critical Path and the Reagan-Udall Foundation achieve CARS' purposes?

In Europe it has. The EU's Innovative Medicines Initiative (IMI) is multi-hundred million dollar program designed to address the main causes of delay in pharmaceutical R&D and encourage more rapid discovery and development of better medicines. In Europe, it is acceptable that this is done through a public-private partnership and it contributes to the strengthening of EMEA and national drug regulatory agencies.

If this approach were viable in the US, the Critical Path would be more deeply funded by Congress and the Reagan-Udall Foundation would be ready to accept private funding on a par with the IMI.

Neither has happened. Despite the good intentions of their advocates, there is little evidence it will. A public-private partnership of this type, heavily dependent on private support, will always make the activities and the results suspect in the US. Maybe it shouldn't be that way, but it is the reality we face as friends of the FDA.

CARS is an attempt to redefine these efforts and make them into wholly public activities that can draw broader acceptance and achieve quicker results. The goals of the Critical Path and the Reagan-Udall Foundation are a stronger, more future-oriented FDA based on improved regulatory science. If we can keep it public and FDA-centric, then this becomes possible again.

The Follow-on Biologics Market

Since the debate began several years ago, the policy and politics of follow-on biologics (FOB) have been driven by assumptions and projections of the anticipated market. In my opinion, there has been a lot of fuzzy thinking about what type of companies will be players and how they will position themselves. The Federal Trade Commission report, released last week, is just the latest illustration.

My own analysis suggests there will be multiple market entrants vying for market share and creating price competition. It will take some patience until we get there, but it will happen. In this environment, it will be important to stimulate investment in new, innovative biological products. Without reasonable time to recoup costs, new product development will slow.

I started to think about the nature of the FOB market last year when predictions about FOB's started to jar my sensibilities. The FTC's report is just a larger platform for advancing questionable analysis. There are two economic principles that are central to understanding the issues.

First concept: shadow pricing. The first generic drug is usually priced about 20% to 30% below the innovator product. The innovator doesn't compete on price because they know that the generic will be continuously re-priced to stay the same increment below the innovator's price. This is called "shadow pricing." As each new entrant joins this market, competition erodes this structure until prices fall significantly. FTC believes that there will only be one or two competitors in each segment and shadow pricing will limit price competition.

Second concept: barriers to entry. Generally speaking, the more it costs to be a part of a market, the fewer players will enter it. At this moment, generic drugs have a low barrier for entry. In contrast, the FTC believes that there will be significant barriers to entry in the generic biologics market. Only the largest biologic products will draw any competition. And only a handful of companies will develop FOB's because of the expense of putting together a safe and effective product, combined with the $250M to $1B estimate for a new facility to make these products.

There are two significant errors in the FTC analysis. First, FTC fails to recognize the generic drug market evolved into what it is today because of the way it was structured in 1984. The key Hatch-Waxman trade-off--additional patent protection for market access for generics—has worked extraordinarily well. If FTC had made the same comments in 1984, there would be neither an innovative pharmaceutical industry nor a booming generic drug industry today.

Second, FTC fails to account for the likely impact of innovation in the FOB marketplace. For example, more refined methodologies will evolve for characterizing biologics. Ways will be found to build facilities less expensively and to streamline production.

FTC states that lack of interchangeability and direct substitution will limit market penetration for FOB's. The problem with this viewpoint is that the market is already saying otherwise. Teva and Sandoz (Novartis' generic subsidiary) will be in the FOB market from the beginning. Merck, J&J, Pfizer, Amgen and others are positioning themselves to join within a few years. All are well-financed and have experience competing in crowded markets. Why would they commit billions to a market that can't be penetrated?

Over time, innovation will bring costs down. Competition will bring prices down. It seems unlikely that shadow pricing and high barriers to entry will characterize the FOB market in ten years.

My vision of a multi-player FOB market with price competition does not answer the question: how much intellectual property protection is needed for innovators? It does say the FTC is wrong to argue for none.

Steven

FTC's testimony to the House Energy and Commerce Committee is at:

http://energycommerce.house.gov/Press_111/20090611/testimony_harbour.pdf.

Seven Challenges for FDA--revisited

Most current readers of FDA Matters were not receiving these posts during the first week when we examined seven long-term challenges for FDA. Today's column updates this topic. It underscores the need to plan for FDA's future and not let the day-to-day demands consume all the available time.

Each of these challenges requires substantial effort. Two or three years from now, these are the items that everyone will say: "glad we started early."

Here is an updated version of the seven 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 a new paradigm of altering fundamental biological processes. These issues need a broader, more systemic examination, as well as more resources applied to Critical Path and other clinical trial improvement initiatives.

Balancing safety with patient risk and need. All FDA approvals represent a balance between risk and benefit. There is a lot of variability in what the agency views as acceptable risk for patients with life-threatening conditions. FDA often undervalues the needs of patients with disabling conditions that are not life-threatening. In most FDA activities, medical and scientific expertise and insight is the key to decisions. Creating better risk-benefit judgments is different: patients are the experts on what they feel and believe and on what risks they would accept for what benefit. Meaningful dialogue requires that patients lead this process, not be an afterthought.

Sifting valuable information from background noise. 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, and medical and food product tracking. FDA lacks the sophisticated systems it needs. Once these systems are developed, it is still a difficult, highly iterative process to distinguish meaningful patterns from background noise and to create actionable intelligence.

Managing globalization, rather than just responding to it. 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. Food and drug tracking, recall authorities and overseas offices are necessary, but they are not sufficient to meet this challenge.

Resisting the bias toward negative decisions. Uncertainty is inherent in all positive decisions. Taken to the extreme, excess caution could force the whole world of food and drugs to 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. Systematic review of all decisionmaking processes could be an important corrective.

Staying focused on priorities. FDA's responsibilities greatly exceed its resources. Some mission creep is inevitable and some new responsibilities may be needed to benefit society and the public health. But sometimes FDA needs 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. 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 or e-mail me at sgrossman@fdamatters.com.

Note: Each of these challenges will be explored individually in separate posts.

The first of these: "Turning Data into Knowledge" was posted on June 2 and can be found at: http://www.fdamatters.com/?p=275.

The second: "Save the Critical Path-Part 1" was posted on June 17 and can be found at: http://www.fdamatters.com/?p=317.

Steven

Save the Critical Path—Part 1

The American public and the global marketplace wish to have access to innovation—whether in medical products or foods. Simultaneously, there are strong countervailing concerns about product safety. Both occur within an environment in which FDA's knowledge and tools are inadequate and failing.

The Critical Path program and related initiatives in CFSAN and other centers are designed to meet this challenge. Unfortunately, there has never been a sustained agency-wide commitment to these efforts. Further, most of Congress has not embraced the Critical Path, either conceptually or with substantial funding.

Only a strong, well-resourced FDA will have the time and manpower to address the future and give sponsors and other stakeholders the guidance they need. This can only be accomplished with monies that are specifically set aside for advancing regulatory science. It must be a major function of FDA, organized and funded separately from the divisions with every-day product responsibilities. In short, FDA needs to have an organizational home to promote knowledge and create standards in the regulatory sciences.

FDA Matters proposes the creation of a new entity at FDA: the Center for the Advancement of Regulatory Sciences (CARS). It will work with all centers (food, vet med, biologics, devices, drugs) to meet their existing, ongoing and future needs for knowledge, tools and standards.

Functionally, CARS should operate with the center directors as the primary clients and with the goal of helping each Center achieve its mission. CARS must be FDA-driven with stakeholder input, not an agency-stakeholder partnership. This is essential to obtaining and retaining Congressional support

The new Center should be closely aligned (through grants, contracts and strategic partnerships) with knowledge and expertise in academic medicine and other government agencies. The benefit to FDA of creating such relationships was an important part of the FDA Science Board report (December 2007). The Science Board found that external collaborations were underdeveloped and were particularly crucial for FDA in dealing with emerging sciences and technologies.

An initial funding level of $200 million per year would emphasize the importance of advancing regulatory science. It is vitally important that these funds be appropriated; none of the funds should come from user fees. There should be no ambiguity: this is FDA's initiative and the program's direction is coming from within FDA. This amount is about 10% of FDA's current appropriated budget and far more than the current investment in Critical Path and related initiatives.

There are a number of barriers---not least the bias toward current results, rather than future development. Yet, there are good reasons why Congress, FDA and all FDA stakeholders should support advancement in the regulatory sciences. Food and medical academia should also be supportive: CARS makes them into an FDA partner and stakeholder.

CARS is about the future of FDA. Let's embrace that future and show why it is worth such a large investment.

Notes:

Part 2 will appear next week and provide additional supporting arguments for CARS.

If you have questions about CARS that you would like answered in next week's column, please send them to me or post them below as a comment.

Readers are encouraged to register on the site to receive regular updates. Registering also provides the opportunity to post comments.

Steven

sgrosssman@fdamatters.com

“The Principal Makes the School” and Other Thoughts for the New Tobacco Center

My experience has been that "the principal," not the teachers, is the key to having a great school. Outstanding principals attract the best teachers and get maximum performance from everyone. The point for Dr. Hamburg: picking the right director for the new tobacco center is your only mission-critical job. All the other details can be handled by your staff and the new center director.

Here are some of the keys to successfully implementing the new tobacco legislation:

Minimize transfers from other parts of FDA. This probably violates some important management principle about letting people bring their talents to the job that interests them most. Still, FDA's budget is growing quickly and its responsibilities even quicker. There are dangers to FDA's overall mission if existing teams are diluted by a large number of transfers to the new center.

Manage the new tobacco center as if it were a separate agency. There will be crises and hearings, complaints and campaigns aimed at the tobacco center. FDA needs to create a self-sufficient center that minimizes the distractions for the rest of FDA. There is one reality that cannot be avoided: the Commissioner has only 24 hours per day.

Audit-proof the accounting for the tobacco user fees. It is 100% certain that there will be challenges as to whether the user fees are accurately paying for all the costs. FDA should bring in someone from outside (maybe from GAO or a big accounting firm) to create a cost accounting system that is parallel to, but separate from, the rest of FDA

Let's return briefly to the question of picking the best "principal" to head the new tobacco center. Ideally, the person would have broad governmental experience, close-up familiarity with FDA, a public health and regulatory perspective and the presence and stature not to dissolve during a critical press conference or a heated Congressional hearing.

The inclination may be to hire a public health leader who has led the fight against smoking. Unfortunately, most of these leaders lack experience as regulators.

Kate Rawson of the RPM Report floated a name in March that should be given serious consideration: Dr. Steven Galson, the acting surgeon general. She cites his experiences at CDC, EPA and as head of CDER at FDA.

I don't know whether he is interested and this is not an endorsement. Dr. Galson does have the ideal credentials I have suggested: broad government experience, close-up familiarity with FDA, public health and regulatory perspective and the gravitas and presence to handle the heat. He has the added advantage of not depriving FDA of existing leadership in order to staff the tobacco center. Another name being discussed: Mitchell Zeller, a former associate commissioner and director of the FDA's Office of Tobacco Programs. While not a physician, he also has many of the characteristics that Dr. Hamburg should be looking for.

Kate's RPM column can be found here:

http://therpmreport.com/Free/cdb495e7-06f4-4dbe-b265-41b0227d9381.aspx?u

FDA and NIH: Natural Allies

Tension between CMS and FDA is a fact of life at HHS. This is not surprising because they have fundamentally different missions and world views. An analysis of the FDA-CMS relationship leads to an interesting conclusion: FDA should be doing a lot more with NIH because they have complementary missions and similar world views. They are natural allies.

FDA's mission is the approval of safe and effective therapeutic agents. It believes that actionable knowledge comes from prospective, randomized, double-blind controlled clinical trials. Its view of individualized patient treatment: it should be based on the results of rigorous clinical trial information. Yet, they do not impose this on physicians, who may practice medicine as they see fit. FDA will consider information from observational trials, natural history controls and medical literature, but these generally supplement information derived from clinical trials.

In contrast, CMS' mission is to pay for the health care of individuals eligible for coverage through statute. They try to assure health care access that maximizes quality and minimizes public cost. To them, actionable knowledge is retrospectively derived: therapies approved by FDA and treatments reviewed favorably in compendia and having support in a broad cross-section of medical literature. Increasingly, CMS is interested in supplementing these sources with more retrospective data: population studies and analysis of claims data and electronic medical records. Ultimately, CMS' target population is beneficiaries, not patients. Knowledge about the needs of classes of beneficiaries is usually thought sufficient without reference to individualized needs.

While my FDA vs. CMS comparison involves some sweeping generalizations, it also explains a lot of behavior. For example, CMS kept offering its Medicare claims data to FDA and, for a long time, FDA wasn't interested. FDA has now accepted the Medicare data from CMS. However, the dialogue will always be limited by CMS' perception that they are giving FDA an extremely valuable tool and FDA's perception that it is potentially useful, but of limited value. As noted in an earlier post: FDA believes that retrospective "real world" data sets = uncontrolled variables + inconsistent data collection + questionable data accuracy. In short, nothing that FDA would base a safety or efficacy decision on…unless it had no choice.

If you look at what type of knowledge counts to FDA, its natural ally is NIH. They both believe in the virtue of prospective clinical trials as the basis of actionable knowledge. NIH generates more clinical trials—directly or through grants—then any other entity in the world.

FDA and the National Eye Institute provide a model of cooperation that should be fostered FDA-wide and NIH-wide.  NEI had started to work with endpoints based on medical imaging and biological evidence of disease progression. FDA's standard endpoint was still: how many lines on an eye chart had the patient improved or regressed. From working together, both NIH and FDA have advanced knowledge in the field and moved closer to standards appropriate for an increasingly sophisticated therapeutic area.

NIH-funded trials often have to be re-done because FDA won't accept the endpoints or some other aspect of the clinical trial design. In many of those instances, NIH should be running trials with different endpoints to advance clinical knowledge or validate those endpoints. Many times though, early coordination would reduce the chances that expensive trials will need to be repeated….and patients might get beneficial therapies quicker.  A high level of coordination should be possible because NIH and FDA share similar values about the importance of knowledge derived prospectively. There are differences between them, but they are ones of degree, not kind.

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.

-------------------------

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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