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

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?"

Here is an edited version of the answer I provided.

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. And concerns kept multiplying, while confidence dwindled in the company's ability to fix the problems.

Recognize that "the buck stops here." Typically, Congress and the media are fascinated by what the CEO knew and when he knew it. But it is quite beside the point. The CEO is responsible and will be held accountable for the actions and failures of all the company's employees and contractors.

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 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 products 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 few take them seriously enough to practice and update them. I doubt many companies have plans that prepare them to deal with simultaneous 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 reviews that 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 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.

Please help me get this message into the hands of CEO's. The company and job you save may be your own.

Steven

Some related columns:

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

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 »

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 »

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 »

Clinical Trials: Gold Standard In Need of Improvement

There is an emerging crisis in the development of drugs, biologics and complex new medical devices. Clinical trials take too long, cost too much and often produce imperfect knowledge. Many promising medical products are not developed because of the difficulty and expense of proving safety and efficacy—a loss that is costly to society.

FDA Matters believes that the key lies in developing new approaches to generating rigorous data and analysis. Ultimately, this will require the re-invention of the clinical trial.

Clinical trials produce the knowledge that makes FDA approvals possible. Without them, we would all become test subjects in a dangerous game of medical trial and error. FDA (and patients) want a reasonable level of certainty about safety, efficacy and risk-benefit before medical products are marketed. Except in extraordinary cases, FDA should never be put into a position to accept less.

The clinical trial is, and must remain, the gold standard. To understand why, it is useful to look at another type of medical knowledge that is increasingly in vogue: analysis of real-world data. The Medicare Claims database would be an example. Another would be patient data compiled by large health plans. Analysis of real-world data sets is becoming a cornerstone of reimbursement policy and plays a significant role in comparative effectiveness determinations.

The supposed advantage is the ability to look at hundreds of thousands of patients and discern patterns that might not be seen in clinical trials. However, the association of data points tells us nothing about causality. It only signals where additional analysis is needed. Real-world datasets also lack rigor:

Real-world data sets → post-hoc analysis using uncontrolled variables + inconsistent definitions + incomplete data collection + questionable data accuracy

By comparison, clinical trials produce a wealth of reliable knowledge (albeit far from infallible). This can be expressed as:

Clinical trial data sets → prospectively-defined analysis using controlled variables + randomization of patients + double-blind protocol + placebo controlled + pre-defined standard for data collection and data integrity

"Prospectively planned" means a drug or device sponsor must declare in advance the precise findings that will determine whether the treatment caused a beneficial outcome. Sponsors are limited in their ability to go back afterward to "data dredge" for positive correlations that might be spurious. To some extent, all analysis of real-world data sets is data dredging.

"Controlled variables" means that the outcomes of patients in the clinical trial can be compared with some degree of reliability. In real-world data sets, you can never be sure.

"Randomization" and "double blind" work together to assure there is no bias in patient selection (e.g. putting healthier patients in one arm of the trial) and that neither patients nor medical staff knows who is getting the study drug.

"Placebo controlled" allows a reliable determination of the impact of treatment. Since some patients will improve regardless of whether they are getting treatment or placebo, treatment effectiveness is the differential between those who improve in one study arm over the ones who improve in the other.

"Pre-defined protocols for data collection and data integrity" assures that definitions stay constant and results from different trial sites and different investigators can be combined. In real-world data sets, no one has yet figured out why medicine is practiced differently in Boston compared to Hartford.

Taken together, these features of the clinical trial serve to produce reliable data that support a conclusion (or not) that the treatment caused the benefit. The challenge is to improve upon this gold standard while maintaining confidence in the results.

Future columns will explore how this might be done. Meantime, readers are encouraged to post their thoughts or send me their ideas.

Steven

Here are two earlier columns that partially address this topic:

Long-term Challenges Need Short-term Attention

December 13th, 2009

We are less than 7 months into the new Commissioner's tenure. Three or four years from now, she will be judged by whether she moved the agency forward in these areas. I think she has gotten off to a very good start, but there is immense amount of work still required. 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. Read the rest of this entry »

It’s 12 Years of Data Exclusivity

For an updated analysis, go to the May 2, 2010 column: Data Exclusivity and Bio-Similars: Both More and Less Than It Seems.Read the rest of this entry »

On several occasions, FDA Matters has asked Congressional staffers: how many of the Senators and Representatives understand that the follow-on biologics debate is about the amount of data exclusivity, not market exclusivity? In reply, I always get a smile that confirms my suspicion.

The confusion is not limited to the Hill. The New York Times referred to "market exclusivity" in its article on industry winners and losers on the day of the key House vote. A prominent industry trade publication—whose staff clearly knows better—referred to "bullet-proof market exclusivity" in a story the next day. The San Francisco Chronicle got it right—perhaps because of the concentration of bio-pharmaceutical companies in the Bay Area.

None of this would matter if data and marketing exclusivity were similar to each other…or even of roughly equal value. They are not. The future of bio-similar products cannot be understood without grasping the difference.

Intellectual property (IP) protection comes in several forms—the more types you have for the longest possible time, the less likely you will have competition.

The most familiar is patent protection. You own a product, formula or process for a number of years set by law and subject to various other considerations. For example, Hatch-Waxman provides for patent extensions to cover part of the time that pharmaceutical products are delayed in regulatory review.

On the other hand, patents can be challenged both as to their legitimacy and when they expire, thus negating or shortening the patent. At the end of the patent's life, the product, formula or process is (at least potentially) in the public domain, available for copying.

Another form of intellectual property protection is market exclusivity. For a period of time, a regulatory approval agency (FDA) will not accept another application for the same drug and indication. The best-known example is the seven years of market exclusivity granted to orphan drugs.

Market exclusivity runs independently from the patent. It can also protect the ability to market a product that is unpatentable or for which the patent has expired. With some exceptions, market exclusivity cannot be challenged in court….meaning that there are situations where it is better than a patent. Note that market exclusivity is primarily about regulatory forbearance, not ownership.

Data exclusivity under the new law is about ownership of the safety and efficacy data that supported the reference (originator) product when it received regulatory approval. Specifically, for a period of 12 years, FDA cannot approve a bio-similar product using the data (owned by a different company) that supported the original approval.

Data exclusivity does not prevent a second company from generating their own data. Nor does it prevent FDA from deciding that a 200 person trial is sufficient when the original approval was based on 2000 patients. Further, the science of characterizing biological substances is likely to advance rapidly over the next few years, providing the potential for additional ways for a bio-similar product to satisfy FDA requirements.

Data exclusivity is valuable. The investment community's enthusiasm for the 12 years of protection is appropriate. However, patents and market exclusivity are extremely powerful barriers to competition….and data exclusivity is not.

In a future column, I will further explore the implications of these distinctions…particularly, my view that the new law will lead to significant growth in the biopharmaceutical marketplace for both innovator and bio-similar products.

If you are not a subscriber and don't want to miss that column and future analysis of FDA and bio-pharmaceutical issues, I recommend going to www.fdamatters.com to register for free updates.

Steven

Two earlier columns on this topic:

Follow-on Biologics: 1-2-3-GO

March 21, 2010

The long fight is over for follow-on biologic (FOBs). The Senate-passed version of health reform will become law, even while the larger fight continues over the reconciliation package. Within 10 days, FDA will be busy implementing an approval pathway for FOBs.

The world of biopharmaceuticals will never be the same, but not in the ways that many players expect. Here is FDA Matters' guide to understanding the next phase. Read the rest of this entry »

The Follow-on Biologics Market
June 23, 2009

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. There has been a lot of fuzzy thinking about what type of companies will be players and how they will position themselves. Read the rest of this entry »

Follow-on Biologics: 1-2-3-GO

The long fight is over for follow-on biologic (FOBs). The Senate-passed version of health reform will become law, even while the larger fight continues over the reconciliation package. Within 10 days, FDA will be busy implementing an approval pathway for FOBs.

The world of biopharmaceuticals will never be the same, but not in the ways that many players expect. Here is FDA Matters' guide to understanding the next phase.

Laws set the rules, but what happens next is remarkably dynamic and unpredictable. I was one of the Senate negotiators on the Patent Term Restoration and Drug Price Competition Act (Hatch-Waxman) and the Orphan Drug Act (ODA). What we thought would happen…and what actually happened…were not the same. Not necessarily better or worse. Just different.

We thought Hatch-Waxman would create an orderly world of patent extensions and generic approvals. We could not imagine the scandal in the generic drug office a few years later and would have been astounded that companies might still be litigating ground rules 25 years later.

The ODA was a triumph of good intentions, but would not have worked without the subsequent amendment redefining orphan drugs as affecting fewer than 200,000 Americans each year. We were not thinking about cancer patients. Yet they have been among those who have benefitted most by the ODA.

What will happen to FOBs will be just as dynamic and unpredictable.

The market was not waiting for the law to pass. Even though a legislatively-created FOB approval process was uncertain, Pfizer, Merck, Novartis, Teva and other major biopharmaceutical companies had already made decisions to be involved. Billions have already been spent or committed by companies before they knew the final FOB ground rules in the US.

More knowledge about the discovery, creation and manufacturing of biologics will be good for innovators, as much as imitators. Some of those biologically-similar products will themselves be innovative. As a result, many will require full approvals rather than being able to take advantage of an abbreviated FOB pathway.

Innovators will benefit from progress on characterizing biologic molecules, new testing methodologies and manufacturing improvements. To take a single example, the FOB market will force new investments in understanding immunogenicity that will benefit the entire industry, as well as patients.

FDA will be remarkably conservative for at least the next 5 years. FDA is ready for FOBs. Passage of the law gives the agency an important new public health mission: assure the safety and efficacy of biological products that will provide better access and greater affordability for life-saving and life-enhancing therapies.

Enthusiasm aside, the FDA is likely to be conservative in its policies and actions. They have not forgotten the problems in managing generic drug applications after Hatch-Waxman. They are fully aware of potentially big consequences in very small differences in biological products. They have lived through contaminated heparin and Genzyme's manufacturing problems.

FDA will want new safety and efficacy data from all applicants, with an emphasis on immunogenicity testing. Knowledge in these matters will increase rapidly and FDA will loosen up over time. But not soon…and in measured steps.

Steven

Here is an earlier column on the likely dynamics of the FOB marketplace.

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. There has been a lot of fuzzy thinking about what type of companies will be players and how they will position themselves. Read the rest of this entry »

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

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 »

Transition at PhRMA

Former Representative Billy Tauzin tendered his resignation this week, ending a 5 ½ year tenure as President of the Pharmaceutical Research and Manufacturing Association (PhRMA). When his successor is chosen, it will tell us a lot about how the pharmaceutical industry sees itself….and what the big pharmaceutical companies think is their next major challenge. Here is FDA Matters' analysis.

Congressman Tauzin has won some major battles for the association's members. Depending on the news story, his departure is linked to criticisms of the industry's health reform deal with the White House or to Board unhappiness with his management style. His contract is up this year, so the timing may be nothing more than a mutual parting.

Tauzin was hired in 2005. Immediately before, the otherwise successful battle for the Medicare Part D benefit had revealed how far the industry's relationship with Congress had deteriorated. Industry was feeling very insecure about reimportation, follow-on biologics, counterfeiting, access to generic drugs, and drug price negotiations. Among other things, Tauzin built relationships with Democrats, balancing the industry's traditional political strength with Republicans.

In retrospect, it seems obvious that PhRMA's new President would be well-connected and well-respected on Capitol Hill. Yet, PhRMA had never before looked to Congress for a leader to run the association.

Going back more than 30 years, the Congressman's four predecessors at PhRMA were politically savvy and experienced—but not of, or close to, Congress. Each was also quite different from another.

The first one I remember was Joseph Stetler, president during the 1970's. At the time, the pharmaceutical industry's greatest challenge was from the medical professions. There were complaints about industry influence on medical education and clinical practice…and questions about whether medical journals should carry ads from pharmaceutical companies.

Among Stetler's qualifications: he had been general counsel to the American Medical Association for 12 years.

Lewis Engman followed Stetler in the late 1970's, as the industry became more concerned about attacks on its business practices, notably efforts to keep generic drugs off the market. He was President during the negotiations on the Hatch-Waxman legislation in 1983 and 1984, which fundamentally changed the industry's business model.

Among Engman's qualifications: he had been chairman of the Federal Trade Commission.

His successor was Gerald Mossinghoff, who guided the industry through implementation of Hatch-Waxman. As generics were becoming serious market players, he moved PhRMA toward a more far-reaching and comprehensive positioning on the protection of the industry's intellectual property.

Among Mossinghoff's qualifications: he had been head of the US Patent and Trademark Office.

His successor was Alan Holmer. The pharmaceutical industry of the mid-1990's was feeling the pressure of globalization. Worldwide markets had become increasingly important. Trade barriers had begun to threaten the industry, which still had a strong domestic focus.

Among Holmer's qualifications: former Deputy US Trade Representative and a Deputy Assistant Secretary for Import Administration in the Department of Commerce.

Holmer was as accomplished and renowned as an international trade lawyer as his predecessors had been in their areas of expertise. Tauzin followed, filling the industry's need to mend fences and improve relations with Congress.

I don't know what the PhRMA board is thinking with regard to a new President to succeed Representative Tauzin. It may not be a former member of Congress, as many assume.

History tells us that the new PhRMA President will reflect the Board's view of the state of the industry and its most pressing needs.

I recommend a bowl of popcorn and a comfortable place on the couch as we watch the pharmaceutical industry decide who they are and what they want to be.

Steven

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 »

Messages to the FDA-Regulated: Seven Columns to Re-read for 2010

This past year has been a tumultuous one for FDA-regulated industries as they struggled to provide new and safer medical products and safer foods, while weathering much criticism.

FDA Matters has explored a number of industry issues in 2009. As they evolve in the new year, I will continue to provide readers with my analysis and commentary. Meantime, here are seven columns that provide insight about FDA-regulated companies. They provide useful background for 2010:

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. There has been a lot of fuzzy thinking about what type of companies will be players and how they will position themselves. 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 »

The Beatings Will Continue…

….until the biopharmaceutical and medical device industries clean up their act.

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 »

Patients Come First

It is a distracting time for the biopharmaceutical and medical device industries. All this frenzy makes it a good time to stop, draw a breath and remember why seriously-ill patients care about the success of biopharmaceutical and medical device companies. Read the rest of this entry »

Black, White, Shades of Gray

Civil and criminal investigations are becoming more prominent in the world of FDA-regulated industries. Being FDA-regulated means "always worrying that you will have to say you're sorry." But it matters whether you are apologizing to FDA or trying to apologize to investigators. Read the rest of this entry »

FDA: Invisible Arbiter of What Constitutes Disease

The nature of disease and constantly changing definitions are pertinent to FDA, which often makes decisions on behalf of society that reshape our understanding of disease. Read the rest of this entry »

Internet Communications: FDA Needs to Divide the Issues to Conquer the Problem

Creating an Internet communications policy for regulated medical product companies is so daunting that FDA has largely ignored the responsibility. FDA needs a different approach. This is not a matter of a large, complicated problem with many facets. Rather, it is a number of smaller problems that can be addressed separately. Read the rest of this entry »

Steven

Scientific Reductionism and the End of Medicine

"For the last 400 years, science has advanced by reductionism ... The idea is that you could understand the world, all of nature, by examining smaller and smaller pieces of it. When assembled, the small pieces would explain the whole." (John Holland).

Have you ever heard someone accused of "reductionist thinking?" You probably will in 2010 because scientific reductionism is a critical, but rarely articulated, foundation of personalized medicine.

Reductionism is an attempt or tendency to explain a complex set of facts, entities, phenomena or structures by another, simpler set of constituent parts. Historically, scientific reductionism has held that all biology can be explained in terms of chemical reactions. In turn, these chemical reactions can be explained at the atomic level by physics.

An example of scientific reductionism is the belief that a blueprint for understanding and curing all disease will result from mapping genomes (human, bacteria, etc.). In effect, the complexity of biology ultimately yields to a much simpler paradigm based on de-coding the meaning of each component in the human genome and then delivering medical therapy personalized to the individual's genetic make-up. To oversimplify a little, biology then becomes a predictable "machine," subject only to additional reductions that yield smaller pieces and even more insight.

In contrast, many scientists believe that the complexity found in biology is more than just the inability of scientists to simplify the tangle of life and disease. No matter how much we know about genomic causation and associations, we will never have a full picture of life nor unlock the secrets to all diseases. These scientists believe that life is more than the sum of its parts. To them, reductionism is not wrong; it just produces an incomplete vision of biology because it cannot account for systems effects. A new field, systems biology, is trying to develop ways to understand the complex, irreducible biological qualities of life.

FDA Matters views scientific reductionism as a source of actionable knowledge. But just as the book, "The End of History," was more provocative than predictive, there is no "end of medicine" where human biology is reduced to the point of near-total knowledge and flawless cures.

Thus, personalized medicine will not defeat biological complexity. Further, the reductive process will incorporate knowledge from the human genome, but then take us past it into even more difficult and unpredictable challenges to understanding biology and curing disease.

Meantime, public policy is being shaped by the belief that biology and medicine will eventually yield answers that are concrete and totally reliable. But even when personalized medicine provides better targeted therapies, there will still be phase II and phase III clinical trials that inexplicably fail to show patient benefit. After approval, even the most well-documented and logical therapies may prove harmful and require modification or recall. FDA will need to constantly manage the expectations of Congress, the media and the general public to be sure that they understand that no amount of knowledge or evidence renders a medical therapy certain or riskless.

One prominent futurist has said: if we can just live long enough, progress in medicine will allow us to live forever. I say: not so.

The nature of medicine will be quite different 20 years from now, but unpredictability will still be common. As we develop vast amounts of new biological and medical information, old uncertainties about diseases and drug development will be resolved. New uncertainties will emerge.

Steven

Off-Label Uses Need to Become On-Label Indications

A friend asked: what advice would you give a pharmaceutical company in the late stages of developing a new product that will be widely used off-label? The company's concern was that FDA might hold the first use to a very high, perhaps unrealistic standard to protect patients that might receive the drug off-label after approval.

In thinking about how FDA views this type of situation, I realized there were two very concrete things the company could do. Here is the FDA Matters analysis:

FDA controls the availability of prescription medicines and devices in the US. It does not control the practice of medicine. Once a drug/device is approved for marketing, any doctor can prescribe it for an indication that is not on the label of the drug or device. For example, narcolepsy drugs are often prescribed to enhance concentration and wakefulness in individuals without the disease.

The agency is remarkably positive about deferring to the professional judgment of physicians. Even still, FDA's mission is to protect the public health. It would like to see every off-label indication get the scrutiny necessary to assure it is safe and efficacious.

One of FDA's great fears is that off-label prescribing will become dominant in clinical medicine (as I am told it has in certain areas of oncology). FDA is concerned that companies will get approval for a first use, then (directly or subtly) encourage doctors to prescribe off-label. If this strategy is profitable, FDA worries that fewer and fewer companies will commit the time and money to get approval for additional indications. If a company can't promote off-label, then it is more likely to invest in clinical trials to gain approval of the additional indications.

There are two components to FDA's concerns.

First, does the company intend to do the studies to support additional indications for their product? FDA has been promised much by companies and often receives very little back.

Companies can address this FDA concern by having a clinical trial plan in place for any additional indication(s). Where FDA will permit subsequent trials to be initiated prior to first approval, doing so will further strengthen the company's case. A clear commitment to seek FDA approval for additional indications will reassure the agency that the first indication should be judged on its own merits; not elevated to a higher level by the agency's angst about subsequent off-label use.

Second, will the company try to build the market by promoting the off-label uses? By all appearances, companies often decide that off-label use will be so profitable and supplemental indications so expensive that it does not "pay" to do clinical trials for additional indications. And since companies have paid billions of dollars in fines over the last few years for off-label promotion, FDA assumes that such marketing will occur.

The path is open for a company to announce that they will be implementing the strictest possible controls on marketing and sales practices to prevent promotion of off-label uses of their product(s). In the case of a first approval of a product with multiple uses, such an announcement could assuage FDA's fears that the first use is the only indication that the company will seek.

There is a larger issue here, apart from the strategic and psychological aspects of getting a first approval for a specific product.

Getting more indications on-label should be a public health priority. FDA and industry need to discuss how to accomplish this.

Steven

Two prior columns touched on off-label use and off-label promotion:

Internet Communications: FDA Needs to Divide the Issues to Conquer the Problem
December 2nd, 2009

Creating an Internet communications policy for regulated medical product companies is so daunting that FDA has largely ignored the responsibility. November's FDA hearing on social media was an important step, but offered no sign that new policy will be announced anytime soon.

FDA needs a different approach. This is not a matter of a large, complicated problem with many facets. Rather, it is a number of smaller problems that can be addressed separately. Read the rest of this entry »

Off-Label Promotion and Whistleblowing
September 9th, 2009

Whistleblowing and off-label promotion of drugs and devices have become hot topics because of the September 2 Pfizer settlement with the federal government. While none of my views are specific to Pfizer, the company's settlement provides an opportunity to comment on off-label promotion….and to encourage bio-pharma and medical device companies to engage in deeper soul-searching. Read the rest of this entry »

Senate Debate on Drug Re-importation

FDA Matters was ahead of our time, publishing our thoughts on drug re-importation about ten weeks ago. Now the issue is being debated on the Senate floor.

At stake is whether Americans can have access to drugs being sold in overseas markets at heavily discounted prices.

Advocates point to the unfairness of Americans paying more for the same drugs, which are often manufactured in the same overseas plants and use the same suppliers as pharmaceuticals being shipped into the US. If re-importation is permitted, they envision large savings for government programs, health plans and individual patients. They also believe that safety can be assured by limiting re-importation to countries with US-level regulatory and safety controls, such as Canada.

Opponents focus on the strict controls placed on drugs being manufactured for the American market and imported by US-regulated drug companies and wholesalers. While the world is awash in billions of dollars of counterfeit drugs, comparatively little enters the US under the current system. If counterfeits become more common, there is likely to be a significant increase in costly, sometimes deadly, therapeutic failures. This would jeopardize public health and wipe out much of the predicted savings.

Ideological positions have hardened on drug re-importation. There is far more shouting, far fewer efforts to reason and educate. How do we, as patients and consumers in a complex society, decide on the best path for Americans?

Years ago, a drug trade association ran a campaign with the seemingly-paradoxical theme: the only pill we don't test is the one you take yourself. The goal, as I recollect, was better public understanding of how testing and quality controls permeate every stage of drug development and manufacturing.

Because the actual pill can't be tested, the campaign made me realize that there is a critical leap of faith that the drug product you take is identical to the one that was originally shown to be safe and effective. This is not just a matter of chemical sameness, but also dissolution rates, absorption rates, purity, side effect profile, consistent safety and effectiveness across populations, etc.

I have the highest degree of confidence that a branded product is the same as the one that was originally tested and approved. I have nearly the same confidence in generics and regularly use them, although I have had at least one bad experience.

Beyond that, I become very concerned about drugs re-imported from overseas. Among the potential problems: ingredient substitution, inconsistent manufacturing, lack of quality controls, inadequate inspections, lack of corporate accountability, and the absence of a strict chain of custody that prevents counterfeits.

This risk is compounded because consumers, pharmacists and doctors might never know whether a therapeutic failure was a result of an individual's biology or because of an inferior copy or counterfeiting. At least with brand and generic drugs, the pharmacy puts the drug's name and manufacturer on the label of the bottle and we can reasonably assume the accuracy of the information.

I have no faith that re-imported drugs will, on a consistent basis, be identical to the original products in quality, safety and efficacy.

The promised price discounts from re-imported drugs don't justify the risk to my health from a therapeutic failure.

Steven

Internet Communications: FDA Needs to Divide the Issues to Conquer the Problem

Creating an Internet communications policy for regulated medical product companies is so daunting that FDA has largely ignored the responsibility. November's FDA hearing on social media was an important step, but offered no sign that new policy will be announced anytime soon.

FDA needs a different approach. This is not a matter of a large, complicated problem with many facets. Rather, it is a number of smaller problems that can be addressed separately.

Throughout this decade, FDA has clung to the view that the same rules apply to all media: print, broadcast and web communications. The mantra, "regardless of medium," has given them a moderately safe harbor in the midst of a storm of difficult issues.

There are a number of serious problems with imposing existing FDA regulatory policies onto web-based communications between companies and patients, physicians, and consumers. Above all else, it doesn't serve the interests of patients.

Most Americans want easy access to accurate, understandable health information that will answer their questions. FTC, FDA, patients and consumers all want the same thing: information that is "truthful and not misleading." It shouldn't matter if a drug or device company is the source of the information, as long as this is disclosed. Particularly troubling is that medical products company cannot go onto the web to post comments that counter or correct misinformation.

FDA has legitimate concerns about companies' public communications about their products via advertising, marketing, news releases, unsolicited reprints, websites, etc. For example, the agency wants all such external communications to contain a fair balance of benefit/risk information and reflect the approved label indications and its supporting science. FDA also wants to prevent companies from discussing off-label uses of medical products, even in accurate and neutral terms.

The agency has already made adjustments in its policies on presenting a fair balance of benefits and risks. Print ads can have the detailed information on another page; broadcast ads can refer to a magazine ad that contains product information. Given past compromises, FDA should be able to propose a solution for fair balance in web communications without waiting for comprehensive policies.

FDA already pre-reviews many ads to ensure claims about products are accurate, consistent with product labeling and supported by scientific and medical data. This could expand to include web copy of various sorts. Comprehensive policy is not required to get started on a limited, trial basis.

The web increases access to off-label product information by allowing greater access to news, medical journals and patient sites. This is on FDA's mind when thinking about developing Internet guidelines. The agency fears that widespread availability of off-label information will lessen a company's incentives to file for FDA approval for additional indications. Getting more indications on-label is a serious and important public policy issue that FDA and industry should be discussing. It is only incidentally about web communications.

A broad dissection of the virtues and limitations of the web might lead to comprehensive FDA guidelines on product communications on the Internet. But this may be years in the making and obsolete when issued.

Instead, discussion should focus on each of FDA's concerns, of which I have mentioned three. Most can be dealt with now. Some will turn out not to be Internet policy concerns at all. There is no reason to wait for some overarching Internet policy.

Steven

As additional background, here is FDA Matter's interpretation of the dynamic nature of web communications:

Web 1.0 (one-way dissemination of information) is a more flexible and customizable way of delivering the same messages as print and broadcast. We are several years into the next phase, Web 2.0 (interaction and dialogue). Just emerging is Web 3.0 (intelligent software gathers and interprets information and dialogue). Print and broadcast can only duplicate Web 2.0 and 3.0 functions by transferring their content onto the web, at which point they face the same lack of clarity from FDA.

Here is a related FDA Matters column:

Patients Come First
November 11th, 2009

It is a distracting time for the biopharmaceutical and medical device industries, with health reform, mega-mergers, and a constant stream of new investigations by US Attorneys and others. All this frenzy makes it a good time to stop, draw a breath and remember why seriously-ill patients care about the success of biopharmaceutical and medical device companies. 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. Those executed were the dairy farmer and milk salesman who were at the center of the scheme. The general manager of the dairy company, Sanlu Group, received a life sentence after pleading guilty.

A little over two years ago, China executed Zheng Xiaoyu, the head of China's FDA for accepting bribes to allow untested drugs to be approved for marketing. His deputy was given a death sentence that sources believed would be commuted to life imprisonment.

Should we be thankful that we live in a "civilized" society where executions are rare and limited to murders, rapists and child molesters? Even a sentence of "life imprisonment" is rarely meted out to non-violent criminals.

Or should we wonder why we aren't we more serious about intentional gross negligence that has the likely outcome that someone will die? I believe the Chinese would argue that the farmer and the salesman were as responsible as if they had held a gun to the head of six children and murdered them. In the US, the consequence of murdering children in this fashion would likely be execution or life imprisonment.

This suggests that we are not so far apart from the Chinese in our outrage at murder and toward murderers. This has been part of the rules of civilization for several millennia, but not respected in all countries of the world today. We should be thankful to live in a society that considers the most severe punishments as appropriate for murder.

What is different (and interesting) is the concept of a heinous crime. The worst possible interpretation is these were commercially-motivated executions, designed to show the world that the Chinese are tough and their products getting safer. Even still, six murders were involved in the milk tainting case and one purpose of punishment is deterrence. Whatever we may think, those considering crimes involving fake foods and drugs will think twice (and twice again?) before proceeding in China.

We haven't sent the same message to would-be malefactors in the US. Given this, we should be thankful to FDA for every day we don't encounter willfully adulterated foods and intentionally fake and dangerous drugs and devices.

Steven

PS: To anticipate and deflect some outraged feedback, this column is specifically about gross negligence where the person knew or should have known in advance that someone would die. Such events occur more often than any of us would acknowledge, although it is not an "every day" event in the United States.

November 24. 2009 news story on executions in the tainted milk scandals:

http://news.yahoo.com/s/ap/20091124/ap_on_bi_ge/as_china_tainted_milk/print

July 10, 2007 news story on the execution of the head of China's FDA:

http://www.nytimes.com/2007/07/11/business/worldbusiness/11execute.html

FDA: Invisible Arbiter of What Constitutes Disease

According to Wikipedia, "disease" refers to any condition that causes pain, dysfunction, distress and social problems. (http://en.wikipedia.org/wiki/Disease). What constitutes disease is more varied and changeable than this definition might suggest.

The nature of disease and its constant changes are pertinent to FDA, which often makes decisions on behalf of society that reshape our understanding of disease.

Some diseases are culturally-defined. Homosexuality has long been treated as a disease or medical disorder. Scientific knowledge and societal attitudes have shifted over the last 25 years. Homosexuality is increasingly viewed as a variation on human behavior, rather than a disease or condition. FDA would never consider an "anti-homosexuality pill."

In the opposite direction, obesity has long been a symbol of wealth and well-being. Today, it is being redefined as a disease, complete with claims that it is an epidemic. FDA decided obesity was a "disease" years ago and has considered a number of "anti-obesity pills."

Other diseases reflect new thinking about what constitutes illness. Examples would include post-traumatic stress disorder, attention-deficit hyperactivity disorder and restless leg syndrome. FDA has approved drugs that treat each of these.

The Food Drug and Cosmetics Act provide the agency some leeway in how it looks at disease. The term "drug" means, among other things:

• "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and
  
• articles (other than food) intended to affect the structure or any function of the body of man or other animals." (FD&C Act, Section 201(g)(1)).
  

This dual definition has allowed the agency to finesse the issue of pregnancy. I assume that birth control and fertility drugs are viewed as affecting the structure or function of the body. The agency would not want to claim that pregnancy is a disease or that preventing (or causing) it constitutes disease treatment.

FDA seems to make these judgments without any fanfare. My own benchmark is the formalization of erectile dysfunction (ED) as a disease. I expected FDA to go through some extra, visible steps, to show that it had considered whether ED was a disease for which therapies were appropriate. I did not see this occur during the FDA review or at the time of approval.

The question "is this a disease" doesn't come up every day at the agency. When FDA does make judgments, it appears embedded in the work rather than a notable event.

One of the great future challenges will be for FDA to decide if "anti-aging" drugs are possible. The answer may be "yes," pointing to the function and structural changes that are clearly made by aging and the opportunity to stabilize and reverse them. This would allow anti-aging to be a drug's formal indication for prescribing and would be allowed as a label claim.

If "no," then sponsors of anti-aging drugs will need to show a direct link between their drug and an aging-related disease, such as diabetes or dementia. My understanding is that most anti-aging pipeline drugs are being developed on the assumption that FDA is not ready to decide and that "anit-aging" may never be an approved indication.

When the aging issue becomes timely, FDA will be there to decide. It will bring more experience to the process than most FDA watchers realize.

Steven

Black, White, Shades of Gray

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.

Being FDA-regulated means "always worrying that you will have to say you're sorry." But it matters whether you are apologizing to FDA or trying to apologize to investigators.

If you did something that the agency considers "wrong," then the best response is to admit it forthrightly and act quickly to undo your mistake. FDA program staff or inspection/enforcement staffs are more likely to work with you to resolve the situation if they feel you have been cooperative, honest and contrite.

While a good approach for most situations, it may not suffice if you are under investigation by FDA's Office of Criminal Investigations, the HHS Inspector General, the Department of Justice, US Attorneys, State Attorneys General or any of several committees of Congress.

Investigators have a different way of thinking, something I learned while a Senate staffer in the early 1980's.

In general, investigative staff saw the world in black and white. There were good guys and bad guys.

The investigators' objective was to expose wrong-doers and make sure they never had the opportunity to do wrong again. It rarely occurred to the investigators that intent, extraneous events or misunderstandings might provide reasons to temper their judgments. Dealing with such nuances was not part of their job nor did they try to understand the wrong-doer or why the problem occurred.

As a legislative staffer, my world was painted in shades of gray. No good guys, no bad guys….just other legislative staffers with whom I needed to work in order to achieve my chairman's legislative objectives. I could not have done my job if I held absolute views about people or policy. I was in the business of nuances.

I suspect that most individuals in FDA-regulated industries are like me. The constant search for bad guys is not part of their jobs or temperament. They have no special insight or experience in dealing with investigators who view the world in such sharp contrasts of good and bad.

It is never a positive experience to be sitting across the table from an investigator. All options are likely to be bad ones, including public humiliation, civil liability and criminal prosecution. Exoneration is a remote possibility, even if you fervently believe you have done nothing wrong.

An FDA-regulated company can limit their exposure to such situations. This requires systems that review and monitor company actions at a very granular level. It requires a level of transparency that makes most companies nervous. It requires prompt action to dismiss any employees who violate company rules and any supervisors who looked the other way. No exceptions can be made, even if it includes someone from the executive suites.

Companies that follow this path are less likely to become the target of an investigation. A company under investigation that can document strict programs--prospectively initiated and rigorously enforced—will usually do much better than one promising "never to do it again." A pre-existing company commitment to tough enforcement may be the only way to get an investigator to consider your alleged wrongdoing in shades of gray, rather than black and white.

Steven

My earlier columns related to this topic are:

The Beatings Will Continue… November 1st, 2009

….until the biopharmaceutical and medical device industries clean up their act.Read the rest of this entry »

Off-Label Promotion and Whistleblowing September 9th, 2009

Whistleblowing and off-label promotion of drugs and devices have become hot topics because of the September 2 Pfizer settlement with the federal government. While none of my views are specific to Pfizer, the company's settlement provides an opportunity to comment on off-label promotion….and to encourage bio-pharma and medical device companies to engage in deeper soul-searching. Read the rest of this entry »