Benefit, Risk and the Coming Age of REMS

FDA supposedly swings back and forth between emphasizing "expedited approvals of promising therapies" and "extended pre-approval examination of every safety issue." Current thinking is that FDA is now leaning more toward the safety end of this spectrum.

FDA Matters thinks a lot of this is perceptual. Approval decisions reflect FDA's honest and relatively clear judgment on medical need, quality of the clinical data, and the risks and benefits of a specific product. Mostly, I can understand FDA's decisions, even when I don't agree. Still, there is a lot of tension within FDA and with various stakeholders about approvals versus safety risk.

In 2007, Congress thought it was doing FDA a favor by providing new tools to speed approvals while better controlling safety risks. The agency is now required, prior to approval of each drug and biologic, to consider the possible value of a Risk Evaluation and Mitigation Strategy (REMS) plan.

REMS replaced a succession of more limited FDA programs designed to decrease the risk that medical products result in adverse outcomes. Risk reduction might involve more detailed patient materials to be dispensed with a prescription, mandated patient counseling, restricted distribution channels (e.g. only specialty pharmacies) and so on.

Congress also thought it was doing industry a favor. The expectation was that REMS plans would provide a way for FDA to approve more drugs when there were important patient benefits, but also significant safety risks. Control the risks….and the benefits of a medical product will more often outweigh those risks. At least at the beginning, REMS plans helped FDA approve some drugs that had languished at the agency.

As I recollect, industry was, at best, lukewarm toward REMS and found it hard to see what favor Congress was bestowing on them. They feared that approvals would come with REMS plans that were so onerous that patient access to new therapies would be threatened (along with the company's hoped-for market). Many patient organizations agreed that REMS might inappropriately restrict patient access.

In an ideal world, physicians would prescribe omnisciently, always giving patients the right drug at the right dose to maximize the treatment benefit with little risk of bad outcomes. In turn, patients would diligently absorb and follow all drug information and instructions they receive, thus benefiting from the therapy with a negligible risk. And patients would always know what side effect or symptom meant they should return to the doctor. They would also know how the instructions attached to one drug related to instructions on another drug.

Instead, our current system is far from ideal. REMS remains the immediate best hope of reducing adverse outcomes and therapeutic failures. FDA recognizes this and has devoted substantial effort to making REMS work. For example, FDA is testing whether REMS by drug class and indication (e.g. opioids for long-term pain) can maximize patient benefit, level the playing field for competing products, and reduce the agency's workload.

Even more importantly, the FDA recently held two days of hearings to receive feedback from patients, industry, physicians, pharmacists and health plans. All have a stake in REMS plans that are effective without being onerous or confusing.

Based on my experience, it will take five years of debate, reaction, and conflicting demands for FDA to work out some fundamental and predictable rules for REMS plans. Gauging by the calendar and substantive progress, FDA is about halfway there.

Everyone in the medical products industries needs to keep an eye on the evolution of REMS. Its long-term success is critical to FDA's careful weighing of "expedited approvals of promising therapies" and "extended pre-approval examination of every safety issue."

Steven

Some earlier related columns:

When Abbreviated May Not Mean Faster or Easier
July 25th, 2010

FDA is working on an approval pathway for bio-similars, re-examining the way medical devices are reviewed, trying to upgrade the quality and speed of generic drug reviews and will soon be evaluating its process for granting accelerated approvals to drugs.

These seemingly unconnected activities all have in common that they are supposed to be abbreviated processes to get new products to patients more quickly without risking safety or quality problems. FDA Matters thinks FDA should articulate its philosophy about how these short-cuts should work and what standards apply in all instances. Read the rest of this entry »

"Safe": Many Meanings Complicate FDA Policymaking
May 23rd, 2010

FDA Matters is in favor of safe foods and safe medical products. Who isn't? If you are a consumer, maybe that's all that matters.

However, being in favor of safe foods and safe medical products is not enough if you are FDA, the media, Congressional authorizers and appropriators, OMB, and industry. It sounds good, but what does it really mean? In the FDA context, "safe" means many things, some of which are barely related to each other.
Read the rest of this entry »

Has FDA Slipped Back into Anti-industry Mode?
January 13th, 2010

An industry CEO wrote me to observe: FDA is returning to the anti-industry paradigm of the past.  His concern is understandable. Yet, I respectfully disagreed with him. It is natural to fear change. It is easy to confuse activism with ideology.

FDA Matters believes there are two perspectives from which to judge the situation of FDA versus industry. Read the rest of this entry »

For Twenty-Five Million Zebras: New Hope for Therapies

Several generations of North American trained doctors were taught: if you hear hoofbeats, think horses not zebras. This graphic image reinforced an important aspect of medicine for young physicians seeing mostly severely ill patients in tertiary care hospitals: if an otherwise healthy patient is coughing, it is most likely a bad cold. It is almost certainly not pneumonic plague.

What Congress, FDA, and NIH have learned over the last 30 years is that there are many more medical zebras in the United States than anyone imagined. NIH has catalogued nearly 7,000 rare diseases. More are being discovered all the time. Altogether, it is estimated that 25 to 30 million Americans are affected by rare diseases.

When I first became involved in health policymaking in the mid-1970's, the "war on cancer" was in its first, high-growth phase and cardiovascular disease was rampant. An "orphan drug" was one that would help third world diseases. During that decade, there were less than a dozen therapies developed for diseases that were rare in the US and elsewhere in the world.

The realization that there could be political strength in unity among those with rare diseases led to the creation of the National Organization for Rare Disorders (NORD) and the passage of the Orphan Drug Act of 1983 (ODA). A rare disease was defined as one that affects fewer than 200,000 Americans. Many rare disease populations are above 100,000, but far more are under a few thousand.

As a result of the ODA, more than 350 orphan products have been approved. The growth of biotechnology and the growth of orphan drugs have been closely aligned. Likewise, knowledge gained through orphan drug development has returned benefits for patients with more prevalent diseases.

More aggressive efforts are being undertaken to stimulate the development of orphan products. Just this year, FDA has been involved in:

• Helping to develop and work with NIH's Therapeutics for Rare and Neglected Diseases program (TRND), which is intended to move promising orphan drugs forward in the drug development pipeline until they meet FDA requirements for an Investigational New Drug (IND) application.
  
• Creating a new position, Associate Director for Rare Diseases in the Center for Drug Evaluation and Research, who will assist stakeholders and developers of drug and biologic products in navigating the complex regulatory requirements for approval of therapies for rare diseases.
  
• Developing the Rare Disease Repurposing Database that identifies drugs that are deemed promising for rare diseases and are already approved by FDA for another disease.
  
• Stepping up its training of medical product reviewers to devote more time and focus to the construction and analysis of small clinical trials.
  

These efforts have been welcomed by the rare disease community as important steps. Deservedly so.

But will these actions prompt a change in thinking at FDA? FDA claims that orphan drugs are reviewed with the same standards for safety and effectiveness as other drugs. This has become a barrier rather than an advantage.

When reviewing medical product applications for rare diseases, FDA needs to apply a somewhat difference set of rules to account for the special challenges of developing treatments for very small patient populations. Simply put, you can't expect a 500-person safety database in a disease that only affects 500 people.

With more than 25 million "zebras" roaming the United States, such special considerations seem the least we can do. It is imperative that we advance the scientific and regulatory knowledge that provides these patients with hope and, ultimately, with therapies.

Steven

When Abbreviated May Not Mean Faster or Easier

FDA is working on an approval pathway for bio-similars, re-examining the way medical devices are reviewed, trying to upgrade the quality and speed of generic drug reviews and will soon be evaluating its process for granting accelerated approvals to drugs.

These seemingly unconnected activities all have in common that they are supposed to be abbreviated processes to get new products to patients more quickly without risking safety or quality problems. FDA Matters thinks FDA should articulate its philosophy about how these short-cuts should work and what standards apply in all instances.

There is a constant tension between going faster and going slower in making any approval decision. No matter what it does, the agency will be criticized by somebody who thinks they should have waited longer or acted more quickly. The four abbreviated processes seem to bring particular problems because they challenge regulators to balance safety vs. risk and faster vs. slower. In addition, they tend to heighten the distance between companies that are winners and losers.

There is constant tumult around generic drugs. Is proving bio-equivalence really enough to prove two drugs will work the same and thus speed market availability of the generic? Given the relative ease of a generic approval, why does the Office of Generic Drugs have a large and ever-growing backlog?

Likewise, there are always questions about the medical device review process. In particular, the 510(k) approval process is never without skeptics. Many would like all complex devices to meet standards similar to drug approvals. Others point to the quicker pace of innovation and the more incremental nature of new devices as reasons to reserve more elaborate reviews for the most complex and groundbreaking devices.

FDA is currently deciding how to implement the newly created bio-similar pathway. Many (this author included) have suggested that many products for which this abbreviated process was designed will find it advantageous to use the traditional approval route. Surely, this is not why new approval paths are created.

Accelerated approval allows drugs for significant unmet medical needs, primarily life-threatening diseases, to gain market access while further clinical testing is underway. It is not often used (nor should it), but in special cases it allows patients and their physicians to make their own judgments about the risk of the drug relative to the potential benefit. This process is likely to be reviewed now that a drug with accelerated approval proved unsuccessful in further testing.

FDA should always be looking to create greater predictability in its actions. Abbreviated processes hold the potential to benefit patients, increase access, lower costs, and promote innovation. The actual mix of FDA actions more often obscures this, leaving abbreviated pathways to look like an industry battleground rather than a reasoned way to maximize public good.

I envision FDA guidelines on abbreviated pathways that will tell agency employees, patients and industry about appropriate expectations, conditions for use of pathways, levels of proof, and avenues for appeals or to provide greater clarification.

Without this larger FDA view, we will have more of the same: abbreviated approval processes that are often not faster or easier….nor in the public interst.

Steven

For those readers still thinking about this month's Avandia advisory committee, which featured a sharply divided FDA, this recent column may be useful:

Dissent and Efficiency: Difficult Trade-offs for FDA
May 9th, 2010

FDA has a reputation for being tough on dissent, whether it comes from employees or regulated companies. It is often alleged that FDA employees with contrary views are re-assigned, marginalized or ousted. Within the regulated industries, there is a widespread belief that arguing with FDA has adverse consequences for a company.

Whatever the truth has been in the past, FDA is trying to develop an institutional cultural that welcomes and accepts dissent from employees, industry and other stakeholders. It is difficult, even messy, to do this. Yet, FDA's reputation and authority rests on showing that it listened to all competing views–without unreasonably slowing the decisionmaking process. Read the rest of this entry »

Hot Town, Summer in the City—2010

For the news media, the only FDA story this coming week will be the two-day advisory committee meeting reviewing the diabetes drug, Avandia. Based on an earlier article (link below), FDA Matters will be looking at how Dr. Hamburg's FDA handles the discordant voices coming from within the agency.

Missing from public dialogue is the extraordinary (perhaps unprecedented) number of large, consequential projects that FDA will be working on this summer. Every part of FDA is involved in some initiative that could become a "game-changer" for the agency.

FDA shares at least two summer issues with Congress: comprehensive food safety reform and drug safety reorganization. Food safety legislation has passed the House. A different version is awaiting Senate floor action. Since final legislation is not guaranteed, FDA is working hard to develop an approach that is not dependent on statutory changes.

Although drug safety is not an active legislative item, several senior Members of Congress have been persistently calling for re-organization and other changes in how drug safety is evaluated and tracked. The Avandia advisory committee meeting has providing focus for these critics, but their positions do not depend on the outcome.

FDA's efforts to stay in control of drug safety are reflected in at least three initiatives that FDA is working on this summer: creating workable risk management plans (REMS) to accompany drug approvals; safety issues that are becoming part of the negotiations on renewal of drug user fees; and continuing efforts to update Sentinel and related tools for tracking adverse events and safety signals in large populations.

FDA continues its efforts to clarify its policies on safety and effectiveness of medical devices. Pre-approval issues include possible changes in the 510(k) pathway. Post-approval efforts include better device tracking.

Follow-on biologics (now re-named bio-similars) are also keeping FDA busy. This is the first new drug approval pathway in 25 years and FDA has already declared itself ready to accept product applications. At the same time, the agency has acknowledged that there are multiple policy issues to be resolved before agency guidance will be available. What FDA decides now (both on applications and policy) will reshape the world of bio-pharmaceuticals.

Some other top-level agency initiatives with potentially large consequences:

• FDA is grappling with its role in comparative effectiveness research.
  
• The FDA's Transparency Task Force has just reported its findings and recommendations.
  
• Upgrading inspections and enforcement are an immediate and ongoing priority for the agency.
  
• FDA is building a new relationship with NIH through a series of initiatives that will fail without serious attention.
  

Around the agency, here are a few more that could bring significant changes:

• FDA, NIH, patients and industry are trying to upgrade research on rare diseases and increase approvals of orphan drugs.
  
• FDA has promised guidance later this year on medical product communications on the Internet and in social media.
  
• FDA is wrestling with antibiotic use in food animals and kicking up some controversy.
  
• Implementation of the year-old tobacco legislation is ratcheting up after various provisions became effective in June.
  

Even upcoming product reviews may have interesting consequences. Over the next few months, FDA will be looking at three new drugs to treat obesity. This is a difficult product category with a history of safety problems. Yet, millions of Americans are likely to use these products if they are approved.

Despite the number of potential "game-changers" I have identified…no one knows better than Drs. Hamburg and Sharfstein how incomplete my list is. Fortunately, FDA has a great staff. I suspect most of them will be overloaded this summer.

Steven

FDA commissioners need to stay focused on their legacy, while dealing with the mountain of important issues discussed in today's column:

Not Too Soon to Consider the Hamburg Legacy
May 27th, 2010

May 18 marked one year since Dr. Margaret Hamburg was sworn in as Commissioner of the US Food and Drug Administration. The challenges are great, the torrent of issues is never-ending and most days you can smile but you can't win. It may seem premature to be discussing "the Hamburg legacy." But you know that she is thinking about it (all commissioners do), so why can't FDA Matters talk about it? Read the rest of this entry »

My earlier column that relates to the Avandia advisory committee meeting:

Dissent and Efficiency: Difficult Trade-offs for FDA
May 9th, 2010

FDA has a reputation for being tough on dissent, whether it comes from employees or regulated companies. Whatever the truth has been in the past, FDA is trying to develop an institutional cultural that welcomes and accepts dissent from employees, industry and other stakeholders. It is difficult, even messy, to do this. Yet, FDA's reputation and authority rests on showing that it listened to all competing views–without unreasonably slowing the decisionmaking process. Read the rest of this entry »

FDA to Industry: Contractors R U

It seems a rather uncontroversial proposition: FDA-regulated companies are responsible for their vendors, including every contracted piece of work that is done on the company's behalf. If problems develop, it makes no difference whether a company did it…or a contractor did it for them. Two seemingly unrelated items this week suggest that FDA is becoming concerned about whether FDA-regulated companies are overseeing their vendors.

This is not just about contract manufacturing. FDA's concerns extend to company/contractor relationships in marketing, distribution, communications, clinical trials, pre-clinical development, etc. FDA Matters expects food and device companies to be under similar pressure to improve their oversight of vendors, since the concerns about contractor reliability should be similar.

Beyond the well-publicized quality control problems at some major companies, FDA may foresee industry-vendor relationships as a more general concern. Perhaps FDA sees controls on the burgeoning responsibilities of contractors (out-sourcing) as a natural extension of the agency's regulatory responsibilities. FDA may also be signaling to industry that it will do them no good to whine: our contractors let us down and, therefore, the company shouldn't be held accountable.

New rules for outsourcing drug manufacturing. The Wall Street Journal reported on a conference in Ohio at which FDA officials said they will propose strict regulations for companies that outsource drug manufacturing. The goal is to hold sponsor companies more accountable for their vendors, whether in the US or abroad. In the past three years, violations of good manufacturing practices (GMPs) have increased threefold for contractors, while remaining stable for sponsors.

Despite what some might consider an unwelcome extension of regulatory controls, the items discussed by FDA are fairly benign. It even seems a little odd that FDA does not already require them. Specifically, the FDA will propose rules that include:

• FDA warnings about manufacturing violations will go to both the contractor and the sponsor, not just the contractor,
  
• sponsors will be required to conduct on-site audits at contract manufacturing facilities to ensure the quality of production and the safety and purity of ingredients, rather than allowing sponsors to rely on off-site review of records and reports compiled by the contractor.
  

New standards for evaluating clinical trial protocols. Dickinson's FDA Webview covered an FDA presentation at the Drug Information Association meetings in DC about changes in the agency's oversight of clinical trial design and implementation. Company protocols will need to be accompanied by information about how the study incorporates "quality by design" (i.e. companies must plan quality into the project rather than assume it happens as a byproduct of earnest effort).

Henceforth, the agency will consider the "operational merit" of a proposed protocol in additional to the traditional review of "scientific merit." On a practical level, this means that FDA will want to know why the study will have 60 sites instead of 30, why sites were chosen, how investigators were selected, who's monitoring sites and how investigators will be trained.

FDA presented this in the context of clinical trial results that can be relied upon…..but it relates directly to an activity primarily done by company contractors, whether a contract research organization (CRO) or academic researchers.

However much the latter example (clinical trials) appears to differ from the former example (drug manufacturing), the principles are essentially the same. FDA is telling companies: you are responsible for your vendors and we want evidence that you are watching them much more closely than you have in the past.

No company can be stronger than its weakest vendors. FDA-regulated companies should start now to evaluate their contractors, then extend and strengthen their everyday oversight.

Steven

Wall Street Journal article: "FDA to Propose Tougher Rules for Outsourcing Drug Manufacturing," appeared on June 15, 2010. http://online.wsj.com/article/SB10001424052748704324304575307421660792654.html#articleTabs%3Darticle

Dickinson's FDA Webview, www.fdaweb.com, "Clinical Studies Will Need More Design Details: FDA," June 14, 2010 (by subscription or individual articles may be purchased) http://www.fdaweb.com/login.php?sa=v&aid=D5115187&cate=&stid=%241%24Wl1.n52.%24zGTEH.bvqbwrCcWcM%2FA3k .

Quality Control Woes: What's a CEO to Do?

June 2nd, 2010

Medical products companies are struggling to assure FDA and the American people that their products are "safe as manufactured and distributed." We don't know whether quality control has become lax, FDA is discovering more problems or industry has just had a run of bad luck. We do know that quality control relies on a lot of people maintaining tough standards…and that manufacturing is rarely a priority of a drug and device company CEO. Earlier this year, in the wake of Toyota's problems, FDA Matters asked: "what's a CEO to do?" Read the rest of this entry »

Is the New FDA Different than the Old FDA?

Two weeks ago, FDA Matters explored Dr. Hamburg's legacy, focusing on advocacy for resources, prioritizing regulatory science and upgrading enforcement. These will be accomplished before she leaves office. But is she making similar progress in creating "a new FDA?"

Judging by her first year's effort, FDA is becoming "new" in some important ways. Still, there are signs of retrograde attitudes and some ways in which FDA just doesn't seem capable of changing.

Although FDA has long called itself a "public health agency," it has been run by individuals who came from academic health centers. Dr. Hamburg and Dr. Sharfstein ran big city health departments. The agency's decisionmaking standard has become "what's best for the public health." I think this is becoming a core part of "a new FDA."

Dr. Hamburg has had new funds to work with, through both appropriations and user fees. Along with normal turnover, this means a substantial part of the agency workforce ten years from now will have been hired and trained during Dr. Hamburg's tenure. All by itself, this contributes to "a new FDA" that will reflect her stamp.

Dr. Hamburg is trying to create "a new FDA culture," a difficult task in any governmental agency. Thus far, it is defined by an intensity of activity and a broad range of initiatives. I see a new spirit within the agency: issues can be addressed if there is a public health impact, regardless of whether they would have been acted upon in the past.

The idea of "a new FDA" may be making less progress elsewhere at the agency. Traditionally, tougher enforcement has been cyclical. It will not become a constant force unless Dr. Hamburg chooses wisely for the new head of Office of Regulatory Affairs. The character of this person--FDA knowledge, superior leadership skills, new ideas about effectiveness and fairness, commitment to standards—will determine whether enforcement becomes a central part of "a new FDA."

And then there are parts of FDA that still look a lot like "the old FDA." Issue and activity silos are still the norm rather than the exception. Dr. Hamburg is setting a good example with her efforts to strengthen science agency-wide. But FDA cannot be considered "new" without substantial progress in making FDA and the American public the first loyalty of employees. It cannot be their branch, division or Center.

Despite sincere efforts by Drs. Hamburg and Sharfstein to clarify and expand upon agency positions and actions, public communications are still "old FDA." The agency is struggling with so-called new media (Twitter, Facebook, blogs, etc), while attacking industry for recognizing and acting upon this new form of communications. FDA cannot be "new" (or even current) until it provides insight, guidance and "leadership by example" in this area. Efforts at improving transparency at FDA need to acknowledge that a broader range of senior leadership needs to be available to the press on a regular basis.

A "new FDA" cannot be achieved without the strongest possible commitment to innovation--in actions and not just words. Critical Path and advocacy for regulatory science don't go far enough. Efforts to develop bio-markers and new statistical methodologies are worthwhile, but have the feel of "one-offs" instead of concerted efforts to systemically modernize the clinical trials system and the standards for FDA approvals.

Like her legacy, Dr. Hamburg's effectiveness in creating "a new FDA" is still unwritten. It is too soon to know if she will succeed. She gets an A for having chosen far-reaching, worthy legacy items. The effort to create "a new FDA" must be considered a B- so far, showing good aptitude but still in need of better application and follow-through.

Steven

Not Too Soon to Consider the Hamburg Legacy
May 27th, 2010

It may seem premature to be discussing "the Hamburg legacy." But you know that she is thinking about it (all commissioners do), so why can't FDA Matters talk about it? Read the rest of this entry »

Fortuitous Timing and Public Health Leadership at FDA
March 14th, 2010

Commissioner Hamburg and Principal Deputy Commissioner Sharfstein are very good leaders who have also benefitted from their prior public health experiences and the timing of their appointments. Here is FDA Matters' analysis: Read the rest of this entry »

Commissioner Hamburg's Most Important Personnel Decision
February 21st, 2010

With due respect to the many fine individuals that Commissioner Hamburg has recruited, FDA Matters thinks the most important appointment needs to be made soon: choosing the right person to be Associate Commissioner for Regulatory Affairs. Read the rest of this entry »

Not Too Soon to Consider the Hamburg Legacy

May 18 marked one year since Dr. Margaret Hamburg was sworn in as Commissioner of the US Food and Drug Administration. The challenges are great, the torrent of issues is never-ending and most days you can smile but you can't win. Nonetheless, I think it has been a very good first year for her and for Principal Deputy Commissioner, Dr. Joshua Sharfstein.

It may seem premature to be discussing "the Hamburg legacy." But you know that she is thinking about it (all commissioners do), so why can't FDA Matters talk about it?

Top-line: the agency has a renewed energy and sense of purpose, which I attribute to her leadership. She has been aided by something none of her recent predecessors have had: the flow of new monies. This has allowed her to make choices about priorities and invest time and manpower into them.

Dr. Hamburg's most important legacy will be whether she can sustain this momentum. FDA is still severely under-resourced. The FDA commissioner who can reverse this trend for more than a few years will always be remembered for that.

Improving regulatory sciences is apparently quite high on Dr. Hamburg's list and I have written favorably about it a number of times. I also know that a lot of FDA-watchers are puzzled by it. Here is FDA Matter's explanation:

"Regulatory sciences" 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" is most often thought of in relation to medical product approvals and food safety, but actually extends to every aspect of the FDA's responsibilities, including manufacturing, product tracking, laboratory procedures, post-market standards, sentinel monitoring, etc.

Accomplishing this—even getting it firmly launched—is a legacy item. We will all benefit if she succeeds…and we will certainly remember her for it.

A third area emerging as a legacy item is a new FDA toughness on enforcement. At one point, I had thought that this was a threshold item: Congress wouldn't let Dr. Hamburg address her other priorities unless she proved that she could assure the safety of medical products and food. That may even be how she thought of it a year ago.

This mission turned out to be more than just eliminating some marginal players and confirming that the mainstream regulated industries were playing by the rules. The past year, we have seen a number of established, name-brand companies held accountable for lapses that should not—by their own admission—have occurred.

One important consequence of inspections and enforcement is to keep everyone on their toes. Maybe CEO's of FDA-regulated companies are not asking tough enough questions or don't appreciate how much the company can be hurt by people many levels below them. If the behavior of mainstream industry is markedly improved and the agency is clearer and more predictable in its standards and enforcement actions, then this would be a powerful legacy for Commissioner Hamburg.

With a year in office, it's not too soon to discuss Dr. Hamburg's potential legacy. What do you think of my list? What would you add? Please post your comments or send them to me at sgrossman@fdamatters.com

Steven

Some previous columns that touch on each of these legacy items:

FDA: A Bargain at Two Cents Per Day Per American

March 28th, 2010

FDA touches every American many times each day. Today's investment (2 cents per day per American) is a pittance compared to the benefit of a strong FDA and the risk of an underfunded FDA. There cannot be many agencies in the US government that have such a vast scope of responsibilities and so few dollars to get the job done.

This is the powerful message that the Alliance for a Stronger FDA has been delivering to Capitol Hill. Even still, it will be a difficult year for any federal agency whose mission and responsibilities are growing. Read the rest of this entry »

CARS: The Vehicle for FDA's Future

October 25th, 2009

Since Labor Day, Commissioner Hamburg has spoken a number of times about the importance of regulatory science. She is right. FDA must have the scientific tools and methodologies to be a 21st century regulatory agency. FDA needs to define regulatory science, develop programs to support it, and package them in a way that will quickly bring recognition and funding. Read the rest of this entry »

Shaken to the Core: What FDA and FDA-Regulated Companies Can Learn from Toyota

February 25th, 2010

I do not believe that Toyota became a global success by cutting corners and ignoring safety concerns. Nonetheless, the company may not survive the investigations, the lawsuits, the civil and criminal fines, the securities litigation, the recalls (8.5 million cars so far), the loss of consumer confidence and the possible criminal indictments.

FDA Matters hopes that the CEO's of FDA-regulated companies are paying attention. They need to understand that their company can be "shaken to the core," as Toyota has. Read the rest of this entry »

“Safe”: Many Meanings Complicate FDA Policymaking

FDA Matters is in favor of safe foods and safe medical products. Who isn't? If you are a consumer, maybe that's all that matters.

However, being in favor of safe foods and safe medical products is not enough if you are FDA, the media, Congressional authorizers and appropriators, OMB, and industry. It sounds good, but what does it really mean? In the FDA context, "safe" means many things, some of which are barely related to each other.

What are FDA's safety goals and their means to achieve them? What programs should they strengthen? What people should they hire? Each of these questions has different answers depending on what kind of "safe" is being considered.

In the food area I can think of at least three non-redundant contexts in which the meaning of "safe" is different.

First, we want our foods to be "inherently safe," a product that is formulated properly and with no negative impact on our health. We do not want to be offered "tomato and arsenic soup." For this FDA needs food scientists and regulators to determine ingredients that are "generally recognized as safe" and to assure that products conform to standards of identify for specific types of foods.

We also want foods to be "safe from intentional and negligent contamination." We do not want melamine in milk nor heedless disregard of procedures to prevent botulism, pesticide residues, etc. FDA requires well-trained inspectors, backed by laboratories to perform chemical and biological analysis of otherwise safe foods. Criminal investigators and prosecutors are also part of assuring foods are safe from intentional and negligent contamination.

We also want foods to be "safe from unintentional contamination" by bacteria, insects, fungi, and naturally-occurring toxins. To provide this protection, FDA needs epidemiologists, biologists and health professionals with public health training, along with laboratories that can do sophisticated analysis of pathogens.

Likewise, in the medical products area I can think of at least three non-redundant contexts in which the meaning of "safe" is different.

First, we want medical products (drugs, biologics and devices) to be "safe for use" before they can be marketed. The FDA's team is composed of scientists and statisticians who can: analyze the chemical and biological foundations of a product; dissect the degree of safety demonstrated in animal and human trials; and work with fellow regulators to determine the balance of risk and benefit.

We also want medical products to be "safe as used" once they are in the marketplace. For this, FDA increasingly needs public health, data and medical analysts who can: evaluate individual case reports and derive usable knowledge from population-based data, such as FDA's new Sentinel System. I think that post-market safety is often considered a mere extension of pre-approval safety. This won't be true in five years.

We also want medical products to be "safe as manufactured and distributed." This requires well-trained inspectors, backed by engineers and manufacturing and supply chain experts. Data systems are needed here, too, to track facilities, shipments, processors, importers, etc. Criminal investigators and prosecutors are also part of assuring safe manufacturing and distribution of medical products.

As can be seen, Commissioner Hamburg's challenge is much more complex than "hiring more safety people" or "investing more of the agency's budget on safety programs." As she defends her priorities, her position would be stronger if it rested on a comprehensive analysis of how the agency is working on all the different meanings of "safe."

Steven

PS: This is a conceptual analysis with strong real-world consequences. There are many situations where the lines I've drawn are not as clear as I've suggested. Also, I do not want to diminish the abilities of many FDA staff who routinely contribute to more than one type of "safety."

Improving safety and improving information technology go together. Two earlier columns reflect on this:

The Science Board's IT Report: Too Technical to Read, Too Important to Ignore October 18th, 2009

Some of FDA's most difficult tasks are: defining the agency's role in nanotechnology, creating a pathway for follow-on biologics, implementing a risk-based food safety system, and establishing the right policy for "new media" communications. All rolled together, they are not as complicated or important as transforming information technology (IT) at FDA. Read the rest of this entry »

Turning Data into Knowledge    June 2nd, 2009

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." Read the rest of this entry »

Dissent and Efficiency: Difficult Trade-offs for FDA

FDA has a reputation for being tough on dissent, whether it comes from employees or regulated companies. It is often alleged that FDA employees with contrary views are re-assigned, marginalized or ousted. Within the regulated industries, there is a widespread belief that arguing with FDA has adverse consequences for a company.

Whatever the truth has been in the past, FDA is trying to develop an institutional cultural that welcomes and accepts dissent from employees, industry and other stakeholders. It is difficult, even messy, to do this. Yet, FDA's reputation and authority rests on showing that it listened to all competing views--without unreasonably slowing the decisionmaking process.

Forming a consensus and "speaking with one voice" are logical and sensible for FDA, but not an accurate reflection of what happens when well-trained, analytically-oriented people gather to make a decision. FDA can acknowledge this….or feed the perception that senior managers impose their biases on subordinates. I believe this is the exception and not the rule, but there is no denying the perception.

FDA Matters sees three needed changes at FDA:

• Incorporate dissent into the decisionmaking process,
  
• Resist the urge to ignore, punish or marginalize dissent, and
  
• Tolerate the ambiguity of decisions made in the face of dissent.
  

Incorporate dissent. FDA makes decisions in an increasingly complex scientific environment in which there are bound to be disagreements. For example, reviewers focused on the risk-benefit of a medical product are often at odds with reviewers whose focus is safety.

Near the end of April, the Center for Devices and Radiological Health (CDRH) announced that FDA presentations at CDRH advisory committee meetings will reflect the diversity of views from the review group, rather than a unified, consensus analysis. In time, I predict this approach will be expanded to other advisory committees and a broad array of FDA activities. Dissenting views from other stakeholders, including industry, will also be increasingly visible as part of new processes.

Resist the urge to ignore, punish or marginalize dissent. This is incredibly hard to do and probably requires the most cultural change. We are programmed to exclude people who persistently disagree and who can't imagine themselves as being wrong. But sometimes they are right…and sometimes their concerns lead to better conclusions or better reasoning to support a decision. And the agency can hardly claim they have incorporated dissent if a consequence is exclusion or punishment.

Tolerate the ambiguity of decisions made in the face of dissent. One fear of empowering dissent is that every decision will look suspect, regardless of what decision was made. Visible dissent also invites Congress, media, advocacy groups and industry to second-guess the agency. At the moment, Congress seems particularly inclined to question the agency's decisions.

How does FDA adjust to the challenge of showing it listens to dissenting views, knowing it is inviting those disputes to be re-argued in multiple forums? One answer is that the agency must continue to work hard on increasing trust in the agency's decisionmaking. This is already a priority for Commissioner Hamburg.

It is inevitable that FDA will need to become more open to dissent. Thoughtful structures need to be put in place to channel it and not suppress it. The risk is that the agency will become less efficient as it spends more time on debating decisions….and less on making and implementing them. For those patients and companies looking for progress against disease, this is of the greatest concern. The supposed trade-off of dissent and efficiency needs to be confronted and thoughtfully resolved by FDA leadership.

Steven

This column has focused more on internal dissent within FDA, but industry also feels pressure not to question FDA. I often hear companies say they pushed hard on an issue and found the agency more open and willing to listen than they expected. On the other hand, two products were approved this year only after the companies persisted in the face of negative FDA decisions.

The announcement of new procedures at CDRH, including the change from unified, consensus presentations, is at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm209791.htm.

Center-Envy: Are Foods Doing Better than Drugs?

Several times this year, I have been told: FDA's food activities have been getting most of the new monies at the expense of human drugs (CDER) and biologics (CBER). But is it true that food activities (mostly CFSAN, the Center for Food Science and Applied Nutrition) are receiving preferred treatment?

FDA Matters ran the numbers to see. We conclude that center-envy is bad in its own right, but even worse when it is based on misinformation and misperceptions.

Here is a chart providing relevant comparisons over nine fiscal years, including the current one.

Center	FY 2002	FY 2007	FY 2010
FOOD--Total	$393 million	$457 million	$784 million
Center	-------$143 million	-------$159 million	-------$237 million
Field activities	-------$250 million	-------$298 million	-------$547 million
User fees	-------none	-------none	-------none
HUMAN DRUGS & BIOLOGICS--Total	$542 million	$746 million	$1.185 billion
Centers	-------$289 million	-------$349 million	-------$503 million
Field activities	-------$104 million	-------$113 million	-------$168 million
User fees	-------$149 million	-------$284 million	-------$514 million

Center, field activities and user fees combined. These are the number across the two rows marked "total." In FY 2002, the FDA's food budget was 72% of the amount allocated to human drugs/biologics received.

In FY 2007, it had declined to 61% and rebounded slightly to 66% in FY 10. Thus, over this 9 year period (8 appropriations cycles), funding for food activities has actually declined slightly compared to CDER/CBER.

Excluding field activities from funding available for Center activities. "Field activities" is FDA-speak for investigations and enforcement. The funds supporting field activities are in each Center's budget, but are transferred to the Office of Regulatory Affairs (ORA). These funds do not support core Center activities.

If field activities in ORA are excluded over the nine year period, CFSAN grew by 60%. CDER and CBER (including user fees) grew by more than 150%. Thus, it is possible to conclude that the core functions of CDER and CBER have done far better than the core functions of CFSAN.

The pace has changed over the last 3 years. During this period, CFSAN grew by 67% compared to CDER and CBER's growth (including user fees) of 62%. Funding for drugs and biologics, which grew enormously through the mid-2000's, is now growing at a rate comparable to foods. However, for foods this means an increase of $78 million, while CDER/CBER grew by $384 million over the three years.

Excluding User Fees, as well as field activities. Core appropriated funding for the centers grew at about the same rate over both the longer and shorter period. For the nine years (eight appropriations cycles), CFSAN grew by 60%, CDER/CBER by 57%. For the last three years, CFSAN has grown by 67% compared to 69% for human drugs and biologics. In effect, the food and drugs centers have been treated almost identically, with user fees tilting the comparison dramatically in favor of CDER and CBER.

Bottom-line: Increases in CFSAN have gotten a lot of attention, but CDER and CBER budgets have grown by far more over the last nine years if user fees are included. If user fees are excluded, then CFSAN and CDER/CBER have grown at comparable rates over the nine year period and also over the last three years.

PS: In the President's FY 11 request, the proposed appropriations increase for CFSAN is larger than for CDER and CBER combined. However, all of the differential is in 87 people and $40 million that is being proposed for new food inspectors. If ORA is excluded, as well as user fees, the food increase and the drug/biologics increases are about equal on a percentage basis.

Steven

Two past columns have discussed the Office of Regulatory Affairs and a recent column urged less reliance on user fees to fund CDER.

The Uncrowned Prince of FDA
September 15th, 2009

Which FDA line manager has the most appropriated resources to work with in FY 09? Is it Janet Woodcock, head of the drug center or Stephen Sundlof, head of the food center? The correct answer: neither. Read the rest of this entry »

Commissioner Hamburg's Most Important Personnel Decision
February 21st, 2010

With due respect to the many fine individuals that Commissioner Hamburg has recruited, FDA Matters thinks the most important appointment so far has been Michael Taylor to be Deputy Commissioner for Foods. An even more important decision needs to be made soon: choosing the right person to be Associate Commissioner for Regulatory Affairs. Read the rest of this entry »

Wrestling for the Soul of FDA
March 17th, 2010

User fees are a bad way to fund FDA, a public health regulatory agency that oversees nearly a quarter of all consumer spending. It's not that user fees are corrupting. FDA is capable of making good and bad decisions without regard to where the money comes from. But user fees have the potential to erode public confidence in the agency. Read the rest of this entry »

Animal Welfare and FDA

A coalition of animal rights organizations has filed a lawsuit to force FDA to address issues about animal testing that were raised in its 2007 citizen petition (FDA Law Blog, www.fdalawblog.net). The animal rights organizations want FDA to mandate that companies consider non-animal tests before using animals. This is apparently the standard in the EU.

It would be nice if FDA answered their citizen petition. A "no" with explanation is all that is required. And FDA Matters believes that "no" is the right answer.

FDA now encourages the use of alternative, non-animal tests for pre-clinical safety, but most drug and biologic applications rely heavily on animal data. But what's the big deal? Is "mandating consideration of alternative tests by sponsors" really much different from "encouraging sponsors to use non-animal alternatives?"

According to the animal rights organizations, the new language would reduce or eliminate "ineffective and costly animal testing methods that fail to identify the dangerous and lethal effects of drugs and devices on humans, and yet needlessly inflict pain and suffering on millions of animals each year."  And therein, their real agenda is revealed. They want to discredit animal research in order to force use of alternative tests. You can hear them shouting: get rid of animal testing, even if it means an increased risk to humans.

Thankfully, FDA doesn't see it that way. Along with other government agencies and industry, it is working on the development, validations, and utilization of alternatives to animal testing. But this is hard work and progress does not appear to be rapid. Meantime, unlike the activists, FDA believes that animal testing provides critical information that could not be gotten any other way.

In an earlier column, I wrote that animal research and testing is one of FDA's (unacknowledged) core values. Using animals to gain insight is a vital first step in the development of new medical products. Before any safety or efficacy testing is permitted in humans, FDA must be satisfied with animal testing data submitted by the product sponsor. Pick any medical breakthrough and you will find animals were tested prior to humans.

Everybody should be for protecting the welfare of animals. Any means to lessen our dependence on research animals should be welcome. Animals should always be treated ethically and pain reduced or eliminated. The fewest number of animals should be used to reach a conclusion that can be relied upon.

There are elaborate arguments about whether animals should have rights or just have their welfare protected. For me, the choice is easy. I want a product or procedure tested in animals before it is given to me or my loved ones. I believe in protecting animals, but human rights come first.

In the face of animal rights activism, FDA seems willing to stand its ground. The FDA stakeholder community needs to "seize the day" and make clear where its stands. Those who benefit from animal research and testing (including consumers and patients) need to provide the manpower and financial resources to counter the animal rights movement in America and its threat to medical progress for humans.

The value of animal research in the life sciences is usually considered an NIH issue. FDA Matters believes that the FDA and its stakeholders need to be equally concerned.

Steven

The link to the FDA Law Blog article on the lawsuit is: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2010/04/fda-sued-by-animal-rights-advocates-and-ear-holistic-candle-advocates.html

My earlier column that relates to this topic:

Animal Research: One of FDA's Core Values

November 5th, 2009

Earlier this year, ABC's Nightline did a story about alleged abuses at the nation's largest primate research center. Fueled by this, the Great Ape Protection Act (HR 1326) now has 95 co-sponsors, compared to 29 sponsors on a similar bill in the last Congress.

The bill would virtually eliminate research using chimpanzees, even where there is no other animal model that could serve to predict safety in humans. This is a threat to animal research and, ultimately, to ourselves. The loss of chimpanzees would be a serious blow to research and would encourage animal rights activists to push for even more restrictions. Read the rest of this entry »

About FDA Matters

FDA Matters has grown steadily since I started it less than a year ago. My inaugural column was about the goals of the blog, but I have not written on the topic since or about my background and viewpoint.

I started the blog because of my frustration about how FDA was being described and analyzed during the period from Election Day to Dr. Hamburg's confirmation. In particular, I spent a month telling colleagues: it is not true that there is going to be a power-sharing arrangement where Dr. Hamburg will concentrate on foods, while Dr. Sharfstein will concentrate on drugs and devices.

Even though I had no inside information, it was so clear to me…and yet many people thought otherwise and were impossible to persuade. I wished I had a platform to speak out, so I created one and launched it about 6 weeks later!

My goal is to write a blog that provides fresh insights and new perspectives for the broader community of people "involved in FDA matters and for whom FDA matters." Hopefully, it is achieving that purpose by focusing on what the agency is thinking and how its actions are shaped by Congress, the media, stakeholders and external events. FDA Matters aspires to be a source of understanding about FDA, both directly and by stimulating dialogue.

Since FDA Matters began, one continuing theme has been the need to plan for FDA's future. Another has been how the public health backgrounds of FDA's leadership team make their thought process and actions quite different from any of their predecessors. Some themes I want to explore this year: re-inventing the clinical trial, the roll-out of the new regulatory pathway for follow-on biologics and improving regulatory science.

FDA Matters is not a voice for any interest group. The blog reflects my own analysis and commentary based on 35 years working in DC on health policy and legislative and regulatory issues. Earlier in my career, I was Health Staff Director and Counsel to the Senate Committee on Labor and Human Resources (now the HELP Committee). I had the great fortune to be one of the negotiators on the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) and on the Orphan Drug Act.

Subsequently, I was a Deputy Assistant Secretary for Health at HHS, responsible for policy development, planning and evaluation for the Public Health Service agencies. Since then, I have been a public affairs and regulatory consultant for a big firm, then started HPS Group, LLC in 2001 (www.hpsgroup.com).

One of my more recent accomplishments was helping to found the Alliance for a Stronger FDA (www.strengthenFDA.org). I serve (part-time) as the Deputy Executive Director of the organization. I believe strongly that FDA is dramatically underfunded and I write about this a lot. However, anything I write in FDA Matters is my own view and not that of the Alliance.

Over the years, my clients have included patient groups, health professions societies, research advocacy groups and individual companies. Many clients use me for legislative and regulatory analysis and to facilitate the development of policy and regulatory positions. Other clients use me for strategic regulatory counsel to help with development of medical products that are in phase II or phase III.

I welcome reader's comments, either posted on the blog or by e-mail. I would be pleased if readers helped me initiate two features of the blog: point/counterpoint exchanges and "Ask Steven About FDA."

Most of all: I believe that a better FDA is worth the effort to stay involved. I hope you see it that way, too.

Steven

FDA: A Bargain at Two Cents Per Day Per American

FDA touches every American many times each day. Today's investment (2 cents per day per American) is a pittance compared to the benefit of a strong FDA and the risk of an underfunded FDA. There cannot be many agencies in the US government that have such a vast scope of responsibilities and so few dollars to get the job done.

This is the powerful message that the Alliance for a Stronger FDA has been delivering to Capitol Hill. Even still, it will be a difficult year for any federal agency whose mission and responsibilities are growing.

In recent testimony to the House and Senate Appropriations Committees, the Alliance focused on the large gap between FDA's responsibilities and resources. The Alliance also points to ways in which the agency's job becomes tougher each year—notably through increased scientific knowledge and rapid industry globalization.

In the style of David Letterman's Top Ten lists, the Alliance has its own list of 10 things they hope policymakers will know and remember about FDA:

• FDA is a comparatively small agency with a small appropriation: just $2.35B in 2010 to regulate products that represent a quarter of all consumer spending.
  
• Twenty-five years ago, FDA and CDC were the same size; today the CDC budget is nearly 2 1/2 times as large.
  
• A strong FDA is good for the US economy and for our balance of trade.
  
• FDA is an integral part of our response to public health emergencies, including defense against bioterrorism.
  
• FDA's appropriation is almost entirely staff costs, requiring nearly 6% increase each year to sustain program levels.
  
• After three years of good increases (thank you, Congress), FDA staffing levels from the 2010 appropriation have only just been restored to the previous high-level achieved in 1994.
  
• User fees serve valuable functions, but they are targeted and support only specific activities. They don't strengthen the FDA in carrying out its overall public health mission.
  
• All FDA stakeholders support a stronger FDA (consumers, patients, health professionals, and industry).
  
• FDA's responsibilities increase each year---through new mandates, globalization, and scientific complexity.
  

And the single most important reason (and the one raised at the beginning of this column):

• FDA touches every American many times each day. Today's investment (2 cents per day per American) is a pittance compared to the benefit of a strong FDA and the risk of an underfunded FDA.
  

To their credit, the Obama Administration has committed to cutting domestic spending by funding priority programs, rather than relying on across-the-board cuts. This is a challenge FDA can meet: showing that increased funding brings substantial benefits to the American people and is worthy of increases beyond what other agencies are getting.

Going from 2 cents to 3 cents per day doesn't seem like much, but it would add $1 billion to the FDA budget.

Steven

For purposes of disclosure, I am one of the founders of the Alliance for a Stronger FDA and serve as its deputy executive director. FDA Matters is not affiliated in any way with the Alliance.

For more information about the Alliance, send me a note at sgrossman@strengthenfda.org.

The Alliance for a Stronger FDA's House testimony is at:

http://fdaalliance.files.wordpress.com/2009/11/alliance-statement-house-appropriations-committee-fy-11.pdf

Wrestling for the Soul of FDA

User fees are acceptable if they pay for processing passports or extra services at national parks. I don't worry that the American public will lose confidence in the State Department or the National Park Service. This doesn't translate to every user fee and every government department.

User fees are a bad way to fund FDA, a public health regulatory agency that oversees nearly a quarter of all consumer spending. It's not that user fees are corrupting. FDA is capable of making good and bad decisions without regard to where the money comes from. But user fees have the potential to erode public confidence in the agency.

FDA Matters gets it. The agency needs more money to fulfill its mission and the Congress won't pay for all of the costs. In FY 10, nearly $700 million came from user fees charged to drug and device manufacturers and a few others. (This total and the remaining discussion omit tobacco user fees. No one thinks tobacco companies are getting favorable treatment for their monies!).

FDA received $2.345 billion from public funds in FY 10, more than three times the amount from user fees. It would take a long-time and a lot of user fees for the overall balance in the agency to be threatened.

The real story (and the worry for the future of the rest of the agency) is the Center for Drug Evaluation and Research (CDER). It receives about $750 million to run the drug approval process and other CDER activities (other than inspections and enforcement). Of that total, about $335 million comes from public funds (45%); $415 million from user fees (55%). How can it be good for industry to provide the predominant funding for CDER or any of the other FDA centers?

Nothing wrong is occurring. But the overreliance on user fees is confidence-eroding for Congress, media and the American public…and dispiriting for FDA staff.

Now is the time to raise and debate these issues.

• FDA has begun the public hearing process for the next drug user fee act (PDUFA V). Another round of user fee increases could push CDER into even greater dependence.
  
• The appropriations committees have started consideration of the agency's FY 11 appropriation. Under the President's request, existing user fees (excluding tobacco and proposed new fees) will grow about 15%, while public funds only 6%.
  
• Congress may pass new food safety legislation and the House version includes $220 million in new user fees to pay part of the costs of new responsibilities. This is about 20% of the food monies in the President's FY 11 budget request. This percentage could increase if Congress doesn't provide several times this amount from public funds to implement the law.
  

For fiscal and political reasons, user fees are here to stay and FDA will never be funded entirely from public monies. This should not blind us to the risk of FDA slipping into dependence on user fees. Nor should it blind us to how user fees are a drag on public confidence in FDA.

I believe that FDA, regulated industries, Members of Congress and other stakeholders agree with FDA Matters. Yet, you are unlikely to hear them say so. Each fears that FDA would shrink without user fees. Someone needs to go first and say: we will find public monies to keep FDA from becoming dependent on user fees.

The soul of the FDA may not be at stake. But we should not underestimate the damage to the agency from a public perception that user fees are darkening its soul.

Steven

At the March 10, 2010 House Appropriations Committee hearing, Commissioner Hamburg addressed the relationship between user fees and FDA decisionmaking:

…. [E]xamining the integrity of our decision making and ensuring that it is free from conflict of interest and other concerns is one of the most essential elements of FDA being able to do its work, being able to have the trust and confidence of policy makers and the public and certainly one of my highest priorities.  So we take it very seriously. We have established firewalls in terms of the use of user fees. We are committed to a science-driven decision making process, and it's a dynamic concern. We can't just sit back and say our systems are in place, move onto the next issue. It's something we have to continually be monitoring, continually responsive to concerns as they're raised and ensuring that we have the right checks and double checks.

My earlier blog column on this topic:

It's Time to Change CDER Funding

    September 17th, 2009

As most readers know, bio-pharma companies pay user fees, based on activities (such as submitting a New Drug Application) and on the number of their manufacturing facilities. The amounts are set by law. As part of the arrangement, FDA agrees to certain performance goals, which are also specified in law.

We often hear how dependent CDER is on user fees. The actual numbers are startling and deserve to be well-aired. Read the rest of this

Fortuitous Timing and Public Health Leadership at FDA

At the end of March, Commissioner Hamburg will have been at FDA for 10 months and Dr. Sharfstein for a year. They are very good leaders who have also benefitted from their prior experiences and the timing of their appointments. Here is FDA Matters' analysis:

Public Health vs. Academic Medicine. Since at least the mid-1970's, FDA commissioners have come from academic health centers or government. Not one had run a public health agency at the federal, state or local level. In contrast, Dr. Hamburg spent 6 years leading the New York City Health Department. Dr. Sharfstein was recruited from his job heading the Baltimore City Health Department.

The difference is largely unappreciated. Running an academic health center is inwardly focused, with the goal of making a highly-complex institution run well. The primary outputs are patient care, research, and teaching.

Power in an academic health center is widely shared and interaction based on collegial ties. External forces, particularly the government political process, are often intermittent and remote and crises rarely come from outside the organization. Accountability is a virtue, but often not a requirement. Diplomacy and people management are the primary skills.

In contrast, a city public health agency is externally focused, with the goal of improving the health of a population. The primary outputs are programs of intervention and education, along with regulations. The structure in a public health department is hierarchical at every level.

The commissioner is integral to the political process and must be responsive to the Mayor and the City Council. External forces drive much of the activity. Crises are so frequent as to become routine and accountability is a necessity. Diplomacy and people management are valuable skills, but the premium is on concrete actions occurring in real-time, even if someone's feelings are bruised.

FDA is very much like a big-city health department, only minimally like an academic health center. This gives an enormous advantage to Drs. Hamburg and Sharfstein.

FDA in 2010: A Chance to Grow Stronger. In a hostile and uninterested environment, the very best leadership can survive, but not prosper. The new FDA leadership team is fortunate to have the best situation in 30 years for improving FDA.

FDA's budget has grown over the last three fiscal years, providing the new Commissioner with resources to strengthen the agency and prioritize initiatives. Over much of the prior two decades, the agency received annual increases close to, or below, inflation. There is not much new you can do when you are struggling to fund pay raises and rent increases.

Further, it matters when a Commissioner serves in the Presidential life cycle. As a rule, there is a lot of policymaking in the first few years of a Presidency and comparatively little in the later years. If policy improvements are to be made at FDA, 2010 is the time.

In addition, President Obama is alone among the post-war presidents in his interest in public health. Inadvertently, this was reinforced last year when he had to handle the peanut crisis himself because there were no confirmed appointees at DHHS. President Obama knows what FDA does and has a feeling for why it is important.

None of this is to take anything away from Drs. Hamburg and Sharfstein. They deserve credit for progress occurring at FDA. They are fortunate to have experience and timing that are likely to take them further than most of their predecessors.

Steven

Shaken to the Core: What FDA and FDA-Regulated Companies Can Learn from Toyota

I do not believe that Toyota became a global success by cutting corners and ignoring safety concerns. Nonetheless, the company may not survive the investigations, the lawsuits, the civil and criminal fines, the securities litigation, the recalls (8.5 million cars so far), the loss of consumer confidence and the possible criminal indictments.

FDA Matters hopes that the CEO's of FDA-regulated companies are paying attention. They need to understand that their company can be "shaken to the core," as Toyota has.

What's a CEO to do?

First and foremost, believe (really believe) that bad things can happen to you and your company. Being FDA-regulated means "always worrying that you will have to say you're sorry." Foods, drugs and devices are central to our everyday life. By their nature, problems are to be expected. Deadly consequences are never more than one mistake or misjudgment away.

Don't assume that you can limit the damage. Problems escalated quickly for Toyota, revealing flaws in the company's process and attitude, not just its products. Most of the product lines are involved. And concerns keep multiplying, while confidence dwindles in the company's ability to fix the problems.

Recognize that "the buck stops here." Congress and the media are fascinated by what Mr. Toyoda knew and when he knew it. But it is quite beside the point. His public humiliation and the likely ruin of the Toyota brand are going to occur regardless of his level of knowledge. The CEO is responsible and will be held accountable for the actions and failures of all the company's employees and vendors.

Trust, but verify. In a large, multi-national company, there are an endless number of decisions.

Hiring good people and delegating is "necessary but not sufficient." Even the best employees find it difficult to tell their boss about a serious issue that might require costly pre-emptive action. It's too easy for them to think: last year's worst fears never materialized, so maybe today's concerns won't turn out to be bad either.

Don't drink the Kool-Aid. Everyone wants to be part of the team--to believe in the product they are creating. It becomes hard to be objective about the good and bad points of what one's company and team are doing. The CEO needs to believe the worst is possible, ask the tough questions and be skeptical when everyone responds "we're okay."

Your crisis management plan is not enough. Crisis planning is a step-child of corporate communications. Not enough companies have such plans and even fewer take them seriously enough to practice and update them. I doubt many companies have well-honed plans that prepare them to deal with multi-system failure.

In a hurricane of adversity, it is unavoidable that companies will be "shaken to the core." As with real storms, the survivors will be those who built sounder structures, monitored performance closely, and put plans in place for the "once in a hundred years" event that devastates everything.

Such preparation does not happen naturally and cannot be delayed until the storm clouds appear.

However, CEO's can commit to running "shaken to the core" reviews—to anticipate and prevent problems, as well as prepare for dealing with the worst. FDA Matters sees at least three keys to success in this type of "360 degree" inquiry:

• no person, project, product, or process can be protected from review,
  
• employees need to know that they can speak up confidentially and without fear of reprisal, and
  
• outside experts are needed to perform reviews and audits, because no one can be sufficiently objective about their own work or team.
  

And yes, FDA Commissioner Hamburg is a CEO….. and this column applies to FDA as much as it does to any FDA-regulated company.

Steven

Some related columns:

Executions in China: A Thanksgiving Message

November 24th, 2009

Sometimes it takes other people to give us a perspective on our own values. Read the rest of this entry »

Black, White, Shades of Gray

November 13th, 2009

Civil and criminal investigations are becoming a more prominent feature in the world of FDA-regulated industries. People who never gave any thought to this….suddenly find themselves needing to understand how investigations work. Read the rest of this entry »

The Beatings Will Continue…
November 1st, 2009

It has been an expensive year for pharmaceutical companies. Billions of dollars have been paid to federal and state governments and whistleblowers in settlement of allegations and lawsuits. The complaints include off-label marketing and overcharging Medicaid, but there are many others. Read the rest of this entry »

Commissioner Hamburg’s Most Important Personnel Decision

With due respect to the many fine individuals that Commissioner Hamburg has recruited, FDA Matters thinks the most important appointment so far has been Michael Taylor to be Deputy Commissioner for Foods. An even more important decision needs to be made soon: choosing the right person to be Associate Commissioner for Regulatory Affairs.

Not so many years ago, the Associate Commissioner for Regulatory Affairs—who heads the Officer of Regulatory Affairs (ORA)—was the #2 or #3 person at FDA, depending on whether there was a principal deputy. If the commissioner was abroad or unavailable, the person with the regulatory affairs portfolio was next in line. This changed at some point, but I am not sure when or why.

The head of regulatory affairs oversees all of the inspection and enforcement activities of the agency. This is an extraordinarily powerful position, even though very few people know who heads ORA or much about it. FDA seems to consciously downplay the leadership, mission and importance of the office.

Yet, the Associate Commissioner for Regulatory Affairs controls more than one-third of the FDA's appropriated budget and oversees about 4,000 people spread across the US and the world. Last year, I proclaimed the head of regulatory affairs to be "the uncrowned prince of FDA."

On January 27, FDA posted a job notice seeking a new Associate Commissioner for Regulatory Affairs. Since the job has been vacant, the responsibilities have been carried out by an "acting" associate commissioner. Applications must be received by February 24.

The FDA needs a permanent head for the Office of Regulatory Affairs…and the sooner the better. Congressional and media attention have increasingly focused on FDA's capacity to perform effective inspections and rigorously enforce the law. The agency's good name and public credibility are tied to success in these areas. If the FDA's rigor as a regulator comes into questions, its ability to undertake initiatives elsewhere in the agency may ultimately flounder.

Since the Commissioner has so many roles, she needs someone to be the highly-visible, public face of tough FDA enforcement. Two decades ago, when I worked at HHS, the Inspector General was a former professor who had become the supervisor of the organized crime units in the FBI's Chicago Office. He was a good, smart man and a friend…but you knew immediately that you didn't want to be a target of one of his investigations. FDA needs someone like him.

I don't have any particular candidate in mind. Even if the "acting" associate commissioner were to be promoted, he would have more authority than at present.

Getting the right Associate Commissioner for Regulatory Affairs is Commissioner Hamburg's most important personnel decision. Once a decision is made, I hope she will see the value of creating a stronger profile for both the office and the office-holder.

Steven

The job posting is at:

https://jobs.smartbrief.com/action/listing?listingid=E5035373-B323-472F-8D7F-A765DE87A093&briefid=3e572e18-3fbc-11d5-ad13-000244141872&sid=9ae0455d-fd94-42bf-aca1-47b8d3adbfa7

Earlier columns relevant to this topic:

A New Food Agency Has Become Unnecessary (For Now)

January 15th, 2010

FDA Matters applauds the appointment of Mr. Michael Taylor to be the first Deputy Commissioner for Foods at FDA. With more authority, experience and stature than any previous food leader, he has the opportunity to shape and re-shape food regulation and the safety of the food supply. Because Mr. Taylor will be outstanding in this new post, the campaign for a separate food agency will go away, at least for a couple of years. Read the rest of this entry »

Executions in China: A Thanksgiving Message

November 24th, 2009

Sometimes it takes other people to give us a perspective on our own values. Read the rest of this entry »

The Uncrowned Prince of FDA

September 15th, 2009

Which FDA line manager has the most appropriated resources to work with in FY 09? Is it Janet Woodcock, head of the drug center or Stephen Sundlof, head of the food center? The correct answer: neither. Read the rest of this entry »

FDA’s Growing Presence Outside of the Washington Beltway

The federal government is closed for the fourth straight day. However, it would be more accurate to say: closed in the DC area. A significant part of FDA is open and has been all week....making this a good time for FDA Matters to acknowledge and explore the growth of FDA in places far from the Washington Beltway.

Overseas Offices. FDA's commitment to creating overseas offices has been widely praised and deservedly so. The ultimate goal is to have FDA employees and offices in every area of the world where there are significant amounts of commerce in FDA-regulated products or their constituent ingredients. If food and drug problems can be identified and fixed near the beginning of the supply chain, then America becomes less dependent on successful inspections of cargoes entering the US.

FDA has created permanent offices in China (Beijing, Shanghai, and Guangzhou) and India (New Delhi and Mumbai) over the last two years. It has also upgraded and formalized its presence in Latin America (Costa Rica, Chile, and Mexico City) and Europe (Brussels and London).

Other areas, such as the Middle-East and Asia/Africa, are still overseen from FDA headquarters, but with an increasing local FDA presence in those areas. Likewise, headquarters handles various treaty arrangements (e.g. with Canada and Mexico) and relationships with international organizations.

Growth in Field Staff. Since 2006, FDA employees assigned to "field activities" has grown from 3450 to 4200. These individuals work for the Office of Regulatory Affairs (ORA) and are involved in inspections and enforcement. ORA personnel represent about 45% of the total FDA staff paid out of the agency's appropriations (non-user fee) budget.

According to FDA's website, over 85 percent of ORA's staff works in 5 Regional Offices, 20 District Offices, 13 Laboratories, and more than 150 Resident Posts and Border Stations.  This means more than 3500 FDA staffers in ORA are conducting government business away from headquarters.

National Center for Toxicological Research. NCTR is less well-know, but an important part of FDA. Its 210 employees are located in Jefferson, Arkansas, far from snowy DC. Its webpage was updated yesterday, so we know they are at work.

NCTR defines itself as conducting "FDA mission-critical, peer-reviewed, critical path (translational) research targeted to develop a scientifically sound basis for regulatory decisions and reduce risks associated with FDA-regulated products."

In plainer language, they are the applied sciences part of FDA, focused on toxicology and toxic effects of food, drugs, packaging materials and so on. As Commissioner Hamburg's campaign to promote "regulatory science" gains momentum, NCTR will be a key part of the effort.

In total, nearly 4,000 FDA staffers work outside the DC metropolitan area. This is a good thing, since the nation's food and medical products don't stop because Washington, DC had back-to-back blizzards.

Steven

For more about FDA's overseas offices, go to: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm185769.htm

For more information about the Office of Regulatory Affairs, go to: http://www.fda.gov/AboutFDA/CentersOffices/ORA/default.htm

For more information about NCTR, go to: http://www.fda.gov/AboutFDA/CentersOffices/NCTR/WhatWeDo/default.htm

Has FDA Slipped Back into Anti-industry Mode?

An industry CEO wrote me to observe: FDA is returning to the anti-industry paradigm of the past.  His concern is understandable. Yet, I respectfully disagreed with him. It is natural to fear change. It is easy to confuse activism with ideology.

FDA Matters believes there are two perspectives from which to judge the situation of FDA versus industry.

The first perspective is relative. The nation elected a liberal Democratic president committed to change. He had the opportunity to appoint an ideological FDA commissioner…someone who would have seen FDA's mission as re-regulating the entire FDA world after 8 years of perceived neglect.  

Instead, the President appointed Dr. Margaret Hamburg, an experienced administrator whose strength is pragmatic approaches to public health problems. As I have written before, being a big city health commissioner predisposes and reinforces pragmatic rather than ideological thinking.

Compared to what might have been in a Democratic administration with Democratic congressional majorities…FDA and Dr. Hamburg are a lot more open to industry concerns than could be expected.

The second perspective is thematic.  Commissioner Hamburg has been explicit about embracing innovation and recognizing that a safety-only perspective is counter to the public health. New medical products are more than just hope; they relieve suffering, restore functioning, strengthen families and sometimes they provide cures. These are all public health values, too.

The ongoing revolution in biological sciences is very much on Dr. Hamburg's mind. The commissioner speaks often about how FDA needs to strengthen and expand regulatory science at FDA to develop the tools necessary to evaluate increasingly complex medical products.

This is definitely pro-industry. An FDA that is ill-equipped and uncertain is one that won't be able to evaluate new science or recognize subtleties. FDA's default response then becomes "no." Dr. Hamburg does not want this to happen any more than industry does.

Some of the alleged anti-industry initiatives need to be seen in context.

Almost all FDA-regulated companies intend to abide by the law. Yet, there are lots of missteps that go unrecognized and lots of evidence of people cutting corners or being outright frauds. In the face of this, FDA enforcement had become lax. For the most part, companies are being pushed into greater vigilance of their own actions…..where good and bad practices may mean life or death for some patients and consumers. While painful to some, I don't see this as anti-industry.

Context is also important in assessing whether the current review of the medical device approval process is anti-industry, which some believe. I see the review as long overdue, given the importance of medical devices and the arcane way in which they are approved. A comprehensive re-examination has not occurred in more than 15 years. In the end, I think FDA and the Institute of Medicine (IOM) are going to reach conclusions that are "uncomfortable but acceptable" to industry. The industry will be able to flourish once the controversy is behind them.

It hurts FDA, as well as industry, if there are fewer new drug and device approvals or if systems cannot be put in place to make our food safer. The success of FDA-regulated industries is important to FDA.

Dr. Hamburg understands this and is acting accordingly.

Steven

Some related columns from FDA Matters:

Public Health Leadership Comes to FDA. FDA leadership–Dr. Hamburg and Dr. Sharfstein– come from an entirely different mold than their predecessors. They have begun 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. Read the rest of this entry »

CARS: The Vehicle for FDA's Future. Commissioner Hamburg has spoken a number of times about the importance of regulatory science. She is right. FDA must have the scientific tools and methodologies to be a 21^st century regulatory agency. FDA needs to define regulatory science, develop programs to support it, and package them in a way that will quickly bring recognition and funding. Read the rest of this entry »

Executions in China: A Thanksgiving Message. Sometimes it takes other people to give us a perspective on our own values. Today, Associated Press reports that two men were executed in China for tainting milk powder with melamine, an industrial chemical. The adulterated milk killed at least six children and reportedly sickened more than 300,000. Read the rest of this entry »

"No Surprise" That Medical Devices Are Under Scrutiny. My column entitled, "Re-Evaluating the Medical Device Approval Process" was not widely-read. I assumed it was because everyone already knew that a review was underway at FDA, with more activity coming. Apparently, I was wrong. Read the rest of this entry »

Stigmatizing the Obese and Criminalizing Food

Well-meaning policymakers are constantly advocating for specific solutions to societal problems. They intend to create a better world and often they do.

In the process, their good purpose is sometimes hijacked by unintended consequences. FDA Matters believes this is the inevitable fate of policies that tell Americans what foods they are allowed to eat.

I applaud the enthusiasm of public health advocates for their anti-obesity initiatives and hope a large number of Americans will cut their food intake and make wise food choices. Unfortunately, unintended consequences are likely to neutralize these public health efforts, resulting in little or no net progress against obesity. It is a wasted opportunity.

Stigmatizing the obese. I suspect that most obese people (1/4 of the American population) already experience substantial negative feedback about their weight. It comes from family and friends, strangers in the mall, and the persistent cultural message that "thin is in." Obese people surely feel they are under assault from the world around them.

In the current environment, the self-worth of obese people is under attack by society…and ill-will toward the obese is increasingly acceptable. These are not effective ways to encourage behavioral changes.

Public health may not have caused the cultural shift toward stigmatizing obesity…but the public health community has a responsibility—by its utterances and its campaigns—not to make the situation worse.

These are foreseeable, albeit unintended, consequences of campaigns to reduce obesity. Public health should not be complicit. There is still time to send a more nuanced message that discourages ridicule of individuals who are obese and provides more encouragement and assistance to those who struggle to lose weight.

Criminalizing Food. Efforts to restrict access to foods that are sugary, fatty, salty, high-calorie, etc. are also doomed to failure. People want these foods. And by now Americans should understand that prohibition is not an effective public health strategy.

Where access to foods is restricted, black markets will form. A recent BBC news story describes an enterprising English lad who was caught selling "crisps" (British equivalent of our potato chips) at his school. He was suspended for violating the school's "healthy snacks policy." With true entrepreneurial spirit, he had also marked up the price.

Things are just starting to heat up on this side of the Atlantic. Last year, New York City decided to severely limit school bake sales and regulate what foods are allowed in school vending machines. Ironically, sports programs are likely to be the hardest hit by loss of income from these sources.

We are not to the point of criminalizing foods. But I worry that moralism about food is on the ascendancy. It is absurd to be worrying about "food pushers" lurking on the edge of the school grounds trying to corrupt our youth. It is sad to see time, energy and money diverted from what really counts: improving nutritional education and increasing support for obese people who want help losing weight.

Our relationship to food is both complex and highly emotional. By all means, let's spread the public health message that obesity has serious personal health consequences. But we need to do it in a way that helps people, not hurts them. To do this, we must be careful that the unintended consequences don't ruin the good that could be achieved.

Steven

The BBC story on the student suspended for selling unhealthy snacks on school grounds:

http://news.bbc.co.uk/2/hi/uk_news/england/merseyside/8412310.stm

A description of the situation in New York City:

http://www.nytimes.com/2009/10/03/nyregion/03bakesale.html?_r=2&scp=1&sq=bloomberg%20and%20bake%20sales&st=cse