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FDA’s Indifferent Attitude Towards the First Amendment

Monday, April 1st, 2013

The FDA doesn’t care about the First Amendment rights of the companies it regulates. It cares even less about the “free speech” rights of those companies’ sales and marketing representatives.

And why should the agency care? One of FDA’s primary missions is to protect the public health and safety of the American people from illegal, adulterated and misbranded products. Doing so involves restraining food, drug, device and cosmetics companies from committing fraudulent and deceptive acts that are not protected by companies’ commercial free speech rights.  

Nonetheless, FDA Matters envisions opportunities for FDA and industry to broaden permissible product communications. The key is understanding history, not constitutional law.


I recently participated in a forum at American University Washington College of Law on “Evolving First Amendment Protection of Commercial Speech” and offered up my mantra that constitutional analysis is largely irrelevant from FDA’s perspective. I said “largely” because FDA is still part of the federal government and can’t act arbitrarily. On the other hand, the agency mostly operates within the zone in which government is given the most leeway: where public health and safety is at stake and the threat is from commercial (as opposed to individual) speech.

History, not constitutional law, provides the best explanation. The sale of bad food and drugs—often accompanied by slick, deceptive pitches—goes back millennia and was even addressed as a problem in most ancient legal codes.

FDA’s own birth comes from a time when state regulation and inspection of food and drugs was minimal, inconsistent and often corrupt. It is hard for any of us to imagine what an unregulated market in food and drugs is like.  Yet, it is not so long ago.

The 1938 Amendments to the Food, Drug and Cosmetics Act gained popular support in part because of a traveling exhibit that portrayed the death and disability that resulted from patent medicines, counterfeit products, false medical and scientific claims, and adulterated and misbranded products. Lax to non-existent cosmetics standards were particularly singled out for their role in causing burns and blindness, as well as some deaths.

It is nice to imagine that this world is behind us, just an interesting piece of history. But it isn’t.

No industry regulated by FDA is immune from shoddy products, false claims, unscrupulous behavior and greed-induced threats to public health and safety.  I am sure that none of my readers count themselves among these “bad guys,” but they exist in the U.S., as well as globally.

Further, even the great and innovative companies—household names that we view with great trust—have often proven to be quite fallible. A certain amount of informal off-label promotion of drugs and devices is rightfully ignored–when good studies have been published, when the off-label indication is very close to an approved use, when assertions are made with great care about the extent of proven scientific knowledge.

In contrast, most of the off-label promotions that have resulted in billion dollar settlements with big-name drug companies have not been based on such close questions. Nor have they been the result of an individual salesperson crossing the line in some excess of enthusiasm.

Rather, the off-label promotions have been the product of marketing departments and sales managers who encouraged, empowered, or authorized the off-label promotion. There never seems to be a good answer as to who was supervising marketing and sales, which is why so many drug companies are now operating under government-negotiated corporate integrity agreements.

From FDA’s perspective, there are legitimate, well-documented reasons to scrutinize all companies: none are immune from the impulse to over-hype products to expand markets and sales beyond what FDA has approved. This is not a matter of FDA being over-fussy. It is the inevitable conclusion from about 4000 years of human commerce in food and drugs.

In the face of this, the First Amendment really has very little place. Commercial free speech does not extend to misleading statements, blatant fraud, or deception. FDA sees too much of this to ignore. 

FDA Matters believes the agency still has an obligation—but not a constitutional one–to clarify its standards, provide published guidance, and demonstrate acceptance that the Internet has fundamentally changed the nature of product promotion. The lack of FDA guidance on social media (first raised at an agency hearing 15 years ago) is particularly outrageous and the agency’s tendency to create de facto policy with enforcement letters is an abdication of responsibility.

The drug and device industry can also improve the situation. They need to stop looking at the current controversies in product promotion as noble causes involving sacred constitutional rights. If these industries have a claim to better treatment and clearer policies, it needs to be grounded in the contributions they make to improve public health and evidence of serious efforts to rid their companies of unscrupulous promotional practices.


I have written previously on some of the issues in drug and device promotion, as well as about opportunities for FDA and industry to reach accommodation:


Off-Label Promotion: Best Resolved by Congress, Not Courts     December 2012

On December 3, a federal appeals court ruled against one of the FDA’s untouchable restrictions on industry—thou shalt not promote the off-label use of pharmaceutical products. An industry that is little interested in constitutional law suddenly finds itself talking about the First Amendment. At stake: permitting off-label promotion undercuts the incentive for companies to thoroughly investigate the safety and efficacy of a drug for a second or third use.


Off-Label Uses Need to Become On-Label Indications  December 19, 2009

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.


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


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. 

Off-Label Promotion: Best Resolved by Congress, Not Courts

Wednesday, December 12th, 2012


On December 3, a federal appeals court ruled against one of the FDA’s untouchable restrictions on industry—thou shalt not promote the off-label use of pharmaceutical products. An industry that is little interested in constitutional law suddenly finds itself talking about the First Amendment and whether, and on what grounds, the case will be appealed. 


Meantime, the court’s decision left FDA Matters torn between cheering and booing. Patients are poorly served if their doctor is prescribing drugs without being able to tap into all sources of relevant knowledge. However, permitting off-label promotion undercuts the incentive for companies to thoroughly investigate the safety and efficacy of a drug for a second or third use.


Benefits and abuses of off-label use. Off-label use is a medical necessity–an acknowledgement that the current inventory of approved drug indications is woefully inadequate to deal with the breadth, complexity and individual idiosyncrasies of human disease. All patients—but particularly those with rare diseases—would suffer grievously if physicians did not have flexibility with regard to the off-label use of pharmaceutical products.


Some off-label uses are supported by extensive published scientific studies, but no corporate entity or individual has the financial incentive to underwrite the FDA approval process. Many other off-label uses are in the evidence-thin realm of “we tried it for lack of alternatives and the patient seemed to be better.” The benefits of specific off-label uses are evaluated by published collections of expert opinions (known as compendia). The practice of prescribing off-label is monitored and approved (inconsistently) by payers.


If doctors can legally prescribe a particular drug for a specific use (albeit off-label), then companies ought to be able to provide “truthful and not misleading” information that they possess. Arguably, they can do so now (via reprints of scientific articles), but only in response to a physician’s request. This is a very limited means of disseminating information.*


The Struggle to Incentivize Approval of Second and Third Uses of Approved Drugs.  As I have written previously, it is in the public interest for off-label uses to become on-label indications. The agency is remarkably positive about deferring to the professional judgment of physicians, but would like to see every off-label use get the scrutiny necessary to assure it is safe and effective.

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 receive 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 gain 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.

Unrestricted promotion of off-label use would definitely undercut FDA. In such an environment, I believe that many companies will “game” the system by finding a comparatively easier first use for approval, then let sales for other uses build off-label. Nor do I think companies are universally concerned about “litigation commenced under states’ product liability laws for ineffective products and the resulting reputational harm from such lawsuits.”**


Congress, Not the Courts, Should Set the Ground Rules. By their nature, courts pick winners in these situations; they don’t create rules that maximize two competing public goods. I have been taught (and believe) that litigation is almost always the worst and most inefficient way to solve a problem. I consider this an example.


To achieve appropriate policy, Congressional action is needed.***  For many reasons, this may never happen. However, it is the only way to reconcile the competing and valid positions held by industry and FDA. I encourage Congress to try to bring peace to this area of contention.



*   Even without permissive policies, company sales and marketing practices are a source of constant problems, as discussed in Off-Label Promotion and Whistleblowing.


**  For those seeking a more legal and enforcement-oriented perspective on the court’s decision, including a number of critical nuances not covered here, I recommend  the FDA Law blog’s current analysis. The paragraph and the quote are based on that article’s description of why some commentators argue that off-label promotion is not a threat to FDA’s drug approval process.


***  A thorough and forthright FDA administrative proceeding (followed by guidelines or regulations) could also clear the air. This is unlikely because the agency generally lacks objectivity on a topic it feels so strongly about, plus the agency tends to respond to court directives, not act to break judicial deadlocks.  On a similarly thorny issue, the agency’s failure, after more than 15 years, to articulate sound policy (or any policy) on social media is indicative of why I don’t think the agency can resolve the “off-label promotion” issue by itself.

Adulterated Foods/Counterfeit Drugs: Punishment Should Fit the Crime

Thursday, November 29th, 2012

We should all be grateful for the considerable protection we receive from FDA against unsafe food, drugs, devices and other products. This is FDA Matters’ belated but heartfelt Thanksgiving message. Thank you, FDA.

What FDA cannot do alone—and for which we as a society need to step in—is to change the laissez-faire attitude, laws and enforcement affecting intentional contamination and counterfeiting of FDA-regulated products. When Americans die from intentionally tainted milk, counterfeit products or negligently compounded drugs, we need to recognize this as murder. Let’s step treating it as if it were white-collar crime.

Penalties for adulteration of food and brewed products date back as far as the Code of Hammurabi, nearly 4,000 years ago. While unintentional contamination is always a source of potential, even fatal, problems, this is distinct from the widespread and long history of intentional and fraudulent sales of foods as healthful and pure. While not as prominently featured, there is a parallel history of unsafe drugs, devices, cosmetics and other products–now regulated by the FDA and which form a fundamental part of the agency’s history and ongoing mission.  

In recent years, China has gained some notoriety for its particularly strong stance against individuals who intentionally and willfully violated its food and drug laws for their own personal profit. In 2009, 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. Two years before that, China executed Zheng Xiaoyu, the head of China’s FDA for accepting bribes to allow untested drugs to be approved for marketing.

Leaving aside that many capital crimes in China would not be so here, the offenses involved in the two Chinese examples would certainly appear to merit long jail sentences in the U.S. However, that just doesn’t seem to be the case in the United States—at least looking at the history of food and drug problems in the US over the last 10 years. The massive growth in counterfeit drugs and devices (by definition, intentional crimes of mislabeling and adulteration) only reconfirms the appearance that we are not acting strongly enough to punish people and companies who are intentionally putting Americans at risk.

Why the difference in attitudes? 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. What’s missing in the U.S. (or so it seems) is the understanding that killing people with intentionally tainted food and drugs IS killing them with the same malice as using a gun.

What is different (and of concern) 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 about the effectiveness of capital punishment, one hopes that those considering crimes involving fake foods and drugs will think twice (and twice again?) before proceeding in China.

We haven’t sent the same strong message to would-be malefactors in the U.S. and those exporting to the U.S.

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. And we should be rethinking whether our own standards are in dire need of upgrading. These are not situations in which probation and forgiveness are the right approaches.


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 be likely to die. Such events occur more often than any of us want to acknowledge.

Drug Product Pricing 101: A Fundamental Issue Revisited

Friday, September 7th, 2012


Eighteen months ago, FDA Matters wrote about the firestorm created by KV Pharmaceuticals’ decision to “charge $1500 per dose for Makena, a drug that reduces the risk of pre-term delivery in pregnant women. The same therapy has been compounded in pharmacies for years at a cost of $10 to $30 per dose.”


Three months ago, K-V Pharmaceuticals filed for bankruptcy protection. This week, a federal judge rejected the company’s last-ditch effort to save itself by ruling that FDA had discretion to permit continued compounding of the drug.  


No one knows the “right price” for this or any other drug, but there are ways to rationally evaluate and guide product pricing decisions. Apparently, not everyone in industry knows this.


Value/pricing analysis helps companies determine an appropriate and defensible price. Some large pharmaceutical and biotech companies have the in-house capacity. Generally, small and medium-sized companies will use external consultants or consulting firms to assure a professional, unbiased process. However, it seems clear that some companies don’t bother to undertake a sophisticated analysis prior to setting prices.


In recommending a particular price or a range of prices, the consultant or consulting firm will look at three or more approaches…and then work with the company to make judgments about “best fit” or achieving consensus among a range of possible prices. Here are three examples of the approaches a consulting firm might use:


·         “Value-added” pricing. This values the company’s product (and supports a price) based on replacement or enhancement of current treatments in the same clinical category. In the case of an asthma drug, a value-added pricing approach would look at “savings” achieved by the reduction in hospital days, emergency room visits, and disability. Other system savings might be considered, such as the benefit of added compliance, the reduction in concomitant drugs, fewer side effects, etc. Any system “costs” (e.g. loss of productivity, treatment of adverse events) are also included in the model.


·         “Cost plus” pricing. This values the company’s product based on the development costs and achieving a reasonable return on investment (ROI).  This may include real, imputed and opportunity costs. Thus, the “cost” component is likely to be greater than the company’s actual expenditures. Pricing in this approach is highly dependent on the ROI variable and the likely timeframe before newer products or generics cut deeply into sales.   


·         “Comparable value” pricing. This looks at the pricing of products that have comparable characteristics or benefits, but may be in different clinical categories than the company’s product. For example, a new recombinant vaccine might be compared to the pricing increment when another vaccine was “upgraded” to a recombinant version. In the case of a unique therapy or breakthrough (e.g. a new drug for Huntington’s disease), an analogy is drawn to the most relevant situations in other treatment areas.


The analytic models are adjusted for a host of variables, such as the size of the potential market, the degree and rate of market penetration, and the likely product lifecycle. As noted, there is usually a consensus-building process where the consultant works with the company to determine a price that factors in the results of the different analyses.


Each consulting firm has its own approach, a proprietary model to distinguish their services from competing firms. These models add value and reach far beyond the basics I have described above.


Now you have an idea of how it’s done….or should be done. This analytic process should reduce objections to the pricing of a product and also prepare a company to defend its pricing decision. Controversy cannot always be avoided, but shareholders, patients, and payers are always going to respond better to companies who have backed their pricing with sound reasoning.




Disclosure: I am not affiliated with any consulting firm that does pricing analysis, nor is this a service I provide. However, if you are interested in the names of a few firms that are in this business, please contact me by e-mail at sgrossman@fdamatters.com.

Biosimilars Update: Keys for the Next Year and Beyond

Friday, June 22nd, 2012


The biosimilars market in the U.S. will not grow large overnight. However, over the next 4 to 10 years, a lot of companies are going to become players. During this same period, health plans, pharmacy benefit managers, Medicare, and Medicaid are going to start reaping savings by buying less expensive biosimilars. By a decade from now, sales of biosimilars will be creating new winners and losers in the overall biopharmaceutical marketplace.

In light of this, I was recently asked: what should a developer or investor be looking to achieve over the next year in the area of biosimilars? What should they be looking to achieve in the years after that?

Over the next year: Assuming the U.S. biosimilar law survives the upcoming Supreme Court decision (concerning the constitutionality of the President Obama’s health reform program), then the last roadblock to creating a biosimilar marketplace in the U.S. will have been eliminated.

The key, then, becomes: how quickly can FDA complete the multiple steps  necessary to establishing a viable system for evaluating and approving biosimilars. Here are some key indicators to watch in judging the agency’s progress:

  • the number of investigational new drug applications (IND's) being issued for biosimilars, which would be a “leading indicator” of slowdown or snags in FDA’s initial intake process;
  • publication of draft policy guidances dealing with critical details such as nomenclature, label warnings, unique names, etc. (until these issues are settled, FDA will be reluctant to approve anything);
  • revised estimates of how many fees the FDA expects to collect each year under the new biosimilars user fee program (a rough gauge of FDA’s view of its timeframe for approvals).

For those looking to be active in the biosimilars market, the next year provides an opportunity to build and strengthen relationships with payers (especially purchasing groups). Payers are going to be focused on the strength of clinical, animal and laboratory data comparing the biosimilar to the original biologic product. There will be a need for biosimilars to be offered at a discount to the cost of the original, but high-quality biosimilars with a 15%-20% discount will dominate the market over biosimilars of questionable quality with 30% to 40% discounts.

Similarly, it is not too soon for companies developing biosimilars to start working with practicing physicians—to calm their fears that they will be forced to use inferior biosimilar products that will result in treatment failures. While payers, not physicians, will drive this market—payers will avoid products likely to generate criticisms and resistance from physicians.  

Finally, for those interested in the biosimilars market–stay cool over the next year. Biosimilars are a sure bet for the long-term. However, it will (quite legitimately) take FDA some time to create the new complex approval pathway that is required.

Looking beyond one year. Stay cool is still good advice. Some companies are going to slip behind or drop their investments because of corporate pressures for short-term return on investment (ROI). The biosimilars market is a battle for the long-haul and will belong to those who are prepared to stay the course through the several years it will take for FDA to develop policies and implement them consistently.

Another potential restraint on developers’ and investors’ commitments over the next several years is the persistent allegation that the U.S. biosimilars market will be limited unless FDA makes a determination that a biosimilar is interchangeable with the original product. However, FDA has placed a low priority on establishing a pathway for determining that an approved biosimilar is also interchangeable with the original biologic product.   

This “controversy” is a throwback to the implementation of Hatch-Waxman in the 1980’s. At that time, substituting copies for originals was a new concept, quality was low, purchasing was decentralized, and doctors had no incentive to prescribe generics.  Allowing forced substitution of FDA-approved generic drugs because they were “interchangeable” was an important dynamic in the growth of the generic drug industry.

However, none of these same underlying conditions are present at the beginning of the U.S. biosimilars market—substitution is widely accepted, quality biosimilars will be available, purchasing is far more centralized, and physicians will have incentives to prescribe biosimilars. FDA designation of "interchangeability," key to generic drugs, is almost irrelevant to biosimilars.

As a final thought: the rise of generic drugs made it necessary for innovators to work harder to develop new, patent-protected products that were better than drugs available generically. The same dynamic is going to play out over the next 10 years for biologic products. The biosimilars pathway adds further urgency for innovator companies to be refilling their pipelines with products that are better than ones currently available.  

Spinal Cord Injury—Innovation Measured in Decades, Not Headlines

Monday, June 18th, 2012


We are undergoing a supposed “national crisis” in medical innovation.  Congress, FDA, NIH, and industry are involved in multiple initiatives to “cure” this problem. This is particularly visible now because the user fee reauthorization process is underway, but the state of medical innovation is always relevant because of our headline-driven, crisis-oriented culture. 

To FDA Matters, this approach profoundly distorts medical accomplishment. You can’t use “where are we today” to judge the success or failure of a medical research process that is inherently broad, iterative, uneven, filled with false starts and driven by cumulative success more often than miraculous breakthroughs. As a case in point, I offer efforts to achieve spinal cord regeneration.  

In the mid-to-late 1970’s, I worked for an advocacy group that, among other things, represented the interests of medical research institutions. There was one Congressman on the right committee who was friendly to our cause and with whom we should have had a great relationship.

However, he had two key positions with which we could not agree. He was, simultaneously, the leading Congressional advocate for animal rights and perhaps the only Congressional advocate for spinal cord regeneration. We opposed his position on animal rights because we thought it would hinder medical research.

Surprisingly, we were also against his legislation that would stimulate medical research on spinal cord regeneration. We supported groups promoting the fight against cancer or cardiovascular disease because their proposals allowed NIH significant discretion to determine priorities. In contrast, we were against legislation that would require research on narrow and specific topics, such as spinal cord regeneration.

But our objection (and the vehemence of our objection) went well beyond that. The promise of biomedical research was so great, it was wrong to waste research monies on areas that held no promise.

After all, we thought, spinal cord regeneration was the stuff of science fiction. Despite the death and disability from spinal cord injury—an area of genuine unmet need—there was nothing that could be done. People could dream of a future world where medical science could achieve such miracles, but for the foreseeable future it was wasted money and unfairly gave hope to patients to suggest that spinal cord regeneration was possible.

Flash forward 30 plus years and the Congressman looks like a visionary….and the organization I worked for looks like unwitting advocates for the status quo. A rich base of scientific discoveries has improved supportive care, provided mechanisms for limiting the damage from spinal cord injuries and given reasonable hope that spinal cord regeneration is a possibility for humans in the next 10 to 15 years, maybe sooner. 

To gain perspective on this, along with a sense of NIH’s current commitment to this area of research, go to http://www.ninds.nih.gov/disorders/sci/detail_sci.htm and also follow some of the links from that site.

I don’t think we were fools in 1998 because we couldn’t see spinal cord regeneration as a promising research area. Despite the organization’s considerable expertise, we underestimated how far medical research could take us—given enough time, interest, commitment and funding. Also, in retrospect, it is remarkable how willing researchers are to contribute to a process of innovation and discovery for which someone else might eventually gain most of the credit.

Forgive me if I don’t see the crisis of “medical innovation” about which it is so fashionable to complain.

As a result of the user fee reauthorization legislation and other FDA and NIH initiatives, I foresee a more conducive regulatory environment for development and approval of medically-innovative products, particularly orphan drugs. The goal is to allow more flexibility, while maintaining rigor. However, these process enhancements are only valuable if there is a wealth of medical innovation, not a dearth of it.

There is more innovative medical research being done today than at any time in history. But the truly great achievements are usually built on many people’s work undertaken over many decades—and until near the end, they hardly ever rate a headline unless someone is intentionally hyping them. Look beneath the surface and you will find that medical innovation is alive and well and just needs our continued encouragement—via regulatory and funding support.  


FDA, Me and Maybe the Mafia—A True Story

Monday, May 14th, 2012


In honor of FDA Matters’ third anniversary, I am sharing a personal story. It reflects FDA’s history as a struggle of competing interests—where sometimes reasonable people disagree, often vehemently, while at other times it is obvious that indifference or greed are the driving forces.

Both are a fact of everyday life at FDA and in the FDA-regulated world. Here is my own little story and I still can’t say for sure whether it involved reasonable people or dark forces.

My first recollection of the artificial sweetener, saccharin (distributed under the brand name “Sweet‘N Low”) was a 1977 visit to the House health subcommittee’s staff office. It was overflowing with boxes that contained letters begging Congress to prevent FDA from removing saccharine from the marketplace.

Later that year, Congress passed the Saccharin Study and Labeling Act. This prevented FDA from acting for 2 years and required a warning label on the packaging that said “This product contains saccharin, which has been determined to cause cancer in laboratory animals.”  The law was extended seven times until the issue disappeared in the 1990’s. The labeling requirement was repealed in 2000.*

After I became a Senate staffer in 1979, I was responsible for shepherding through the 1981 and 1983 extension and probably the 1985 extension, which occurred just before I left the Hill.

These were simple bills—short, totally clear in their meaning, and noncontroversial. The only issue (and not a very large one) was that one committee member refused to consent to its unanimous adoption—which slowed the bill at committee and when it got to the Senate floor. I can’t remember any Senator expressing actual concerns about these bills. 

Sometime around 1983, I started receiving regular visits and calls from Joseph Asaro, Vice President of Governmental Affairs for Cumberland Packing, makers of Sweet ‘N Low and a business located near the Brooklyn docks. I remember him as pleasant, but terribly anxious that nothing stand in the way of extending the moratorium every two years.

It never seemed to sink in to him that passage of the extension was routine business of the most ordinary sort. The more I reassured him (so he wouldn’t call as often), the more solicitous he became. Then one afternoon, I received a call from my family—who lived on Long Island, maybe 20 miles from Cumberland Packing’s headquarters. That morning, a delivery truck had arrived with multiple cartons of Cumberland products, including several 1000-packet boxes of Sweet’N Low, and the message: let us know when you run out.**

Although it was probably meant as a generous gift (and didn’t violate any Senate rules), I was quite upset. I had mentioned to Mr. Asaro that I had grown up on Long Island, but never my family’s names or where they lived (and 30 years ago, pre-Internet, identifying people’s connections was a difficult task without such information.)

In my imagination (or maybe in actuality), I felt that I was being reminded that he knew where my family lived….and I needed to pay more attention to the legislation. Despite all efforts on my part to banish such thoughts, I admit I considered the possibility that Cumberland was involved in some way in organized crime and I had been threatened.

In 2006, an unauthorized history of Cumberland Packing was published and I found that my concern was well-founded, although perhaps not true. According to the book, a 1994 Washington Post article stated that Joseph Asaro had been “identified as an associate of the Bonanno crime family in a prosecution memo….” Subsequently, a New York Times article reported that federal prosecutors and Mr. Asaro’s attorneys denied there was any connection.***  

Threats, even implicit ones, are inherently scary—even if the goal was to make me do something that I was planning to do anyway and for which there was strong Congressional and public policy support. Even at the time, I didn’t really think my family was in “harm’s way.” Still, it made me anxious and self-conscious about what was otherwise a routine task.

Other than being an interesting tale, I hope it is a small reminder to every reader that there are employees of the FDA—sometimes inspectors, but more often in the Office of Criminal Investigations and their colleagues at the FBI and Customs—who do put themselves in “harm’s way” in order to protect us. These threats are invisible to most of us, but are no less real because we don’t see them.

We should salute and remember those who take these risks on our behalf, so that we can enjoy the benefits of a safe food and drug supply.


* Subsequent studies never strengthened the connection to cancer in humans. In 1985, FDA supported extension of the moratorium and in 1991 withdrew the proposal to ban saccharine from food. It was delisted as a possible carcinogen in 1997 and the warning label requirement was repealed in 2000. http://www.icarus-japan.com/pdf/Saccharin_English.pdf

** Thanks to my mother and sister for their memories of that day, still quite vivid nearly 30 years later.

*** Sweet and Low: A Family Story by Rich Cohen. Published by Farrar, Straus and Giroux, 2006. The material on the possible linkage with organized crime is a footnote on page 144.

Medical Innovation: The Dream of More Cures and More Industry Success

Monday, April 16th, 2012

Can we, as a society, stimulate medical innovation? If so, how? These are key questions facing Congress as it considers amendments to the FDA user fee reauthorization legislation. The answers are of central importance to FDA, patients and industry. So far, most of the “solutions” being considered by Congress (legislatively) and FDA (administratively) are worthwhile and likely to have a positive impact over time.

However, in FDA Matters’ view, the challenge of stimulating medical innovation mostly lies outside the policy sphere. Instead, achieving more cures and more industry success requires substantive and attitudinal changes inside the research and development process itself.

Simply put, most of what can be done externally to stimulate medical innovation is important, but marginal. The biggest changes must come from industry and academia.

  New biomedical knowledge   is being generated every day, some of it quite extraordinary. The challenge is aligning that knowledge into safe and effective medical products. That process requiring inspiration, ingenuity, luck, capital and incredible amounts of hard work. Unsurprisingly, success is hard to achieve.

Regulatory agencies, legislatures, patients, consumers and payers all have a role to play and can definitely influence the success of the research and development process and, thereby, stimulate medical innovation. However, all of those efforts come to naught unless there is:

  • an initial discovery or insight from researchers and inventors
  • followed by carefully planned development and clinical trials
  • concluding with proof that a medical product is safe and effective for its intended use.

 It is the researchers, development teams, product managers, and corporate executives, along with investors and shareholders, who hold the key to medical innovation.

Numerous CEO surveys say otherwise, with a plurality and sometimes a majority asserting that FDA is a major obstacle to their company’s success. However, these CEO’s are hardly objective judges of their own product pipeline. Very few ever acknowledge that regulatory concerns might be justified.  When faced with slow-moving projects, failed trials and agency rejections, the natural response of many is to blame FDA.  

Reality can be hard for CEO’s to accept. Medical innovation is a tough business, as witnessed by the startlingly large numbers of drugs (and to a lesser extent, complicated devices) that don’t survive late stage development. However, with a few exceptions, the inability to prove safety and/or efficacy–not FDA policy or reviewers– are the primary cause of product failures.

This does not absolve FDA, just places the focus on the companies, where it belongs. For its part, FDA knows it can do better and is committed to supporting medical innovation For example, the agency has already agreed (on its own initiative and through support of legislation) that:

  • Some medical products should be moved along faster in the process than they are now.
  • More early-stage meetings with companies would reduce late-stage problems.
  • Greater flexibility is needed with particularly promising compounds.
  • Areas of unmet medical needs and where trials are particularly challenging should be given more attention.  
  • Development of new methodologies, such as  adaptive trials and proper use of patient-reported outcomes, is a key component of advancing regulatory science.

FDA and Congress seem to be doing a good job of working on these issues. We will see the results in the user fee reauthorization process and other amendments, as well as new policies and pathways being developed at FDA. Hopefully, we will also see Congress support these activities through increased appropriated funding of FDA.

These external changes planned by Congress and FDA are valuable in their own right and will certainly result in some good approvals that might not otherwise have occurred.

However, stimulating a significant increase in approvals of medically-innovative products requires industry to: support more biomedical and bioengineering discoveries, carefully plan development, and achieve proof of safety and efficacy. This past week, the CEO of Eli Lilly, which faces patent expirations and generic competition, stated “I don’t think we can save [cost-cut] our way out of the enormous challenge we face. The best course is to maintain our focus on advancing our pipeline.” 

Exactly so. While FDA and Congress are doing their part, our focus shouldn’t wander too far from where it belongs. The key to medical innovation is better and smarter drug and device development. Nothing will help patients or companies if medical innovators don’t innovate.


The FDA Matters “Guide to the User Fee Reauthorization Process”

Monday, March 19th, 2012

The prescription drug (PDUFA) and medical device (MDUFA) user fee programs, which run for 5 years, must be renewed by September 30 of this year (last day of the current fiscal year).  House committee staff has just released a 205-page first draft of reauthorization legislation. The Senate has starting releasing drafts on specific issues and has a March 29 hearing scheduled.

Because the PDUFA and MDUFA provisions are pre-negotiated by FDA with industry and patient groups, they are likely to change little. Congress’ focus will be on the backlog of FDA-related legislative proposals that have accumulated while awaiting a “must pass” FDA legislative vehicle. This is FDA Matters’ guide to the process and likely amendments.

To understand the unfolding process for user fee reauthorization in 2012, it is useful to think in terms of four levels of legislative proposals that Congress will consider.

Level One: Renewal of Existing Legislation and Uncontroversial New User Fees. In addition to PDUFA and MDUFA, there are two other programs on the same 5-year reauthorization cycle. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) are certain to be reauthorized and may be made permanent.

In this same level are two proposed new user fee programs: the Generic Drug User Fee Act (GDUFA) and the Biosimilars User Fee Act (BSUFA).  These have gone through an abbreviated version of the PDUFA and MDUFA negotiation process, meaning that the FDA proposals reflect input from industry, patient groups and other stakeholders.

Level Two:  Areas of Strong Consensus to Act; Specific Provisions Not Yet Agreed Upon. Despite Congress’ deep partisan differences, there are several areas in which both political parties appear to be in general agreement about adding programs or strengthening authorities at FDA. 

In this level are proposals dealing with drug shortages, incentives for antibiotic drug development, import safety, a core set of medical device process reforms, and some adjustment in the FDA “accelerated approval” pathway for drug and biological products. There is also consensus for dealing with drug supply chain integrity (e.g. anti-counterfeiting), which may be advanced as a separate bill this spring or be folded into the reauthorization legislation.

For the most part, the consensus to act in these areas does not yet include specific legislative language that has bi-partisan support in both the House and Senate. So negotiations are certain, may even be testy at times…but final agreements are near-certain.

Level Three: Areas of Disagreement Where Compromises Are Possible. Ultimately, committee leadership will have to deal with FDA amendments where there are sharp disagreements or a lack of consensus that action is needed.

The two most prominent such issues are the extent of medical device reform and the amount of change needed or appropriate for the drug approval process. In both areas, there is a more limited, core set of proposals that are in level 2.

As with all such areas of disagreement, compromises may ultimately develop. Unlike the issues in level two, these proposals start with disagreements that may lead to negotiations, but with no assurance of inclusion in final legislation.

Beyond those mentioned, the list of issues and amendments that might be offered (and controversial) is limitless, but it is possible that we will see Congress again debating drug re-importation, re-opening the 2010 biosimilars legislation or even considering amendments to Hatch-Waxman. There may also be food safety amendments.

Level Four: Proposals to Dramatically Re-shape FDA and Likely to Be Rejected. A small number of Members of Congress think FDA’s role should be significantly smaller. They see radical surgery on the agency mission as the necessary response to the restraints they feel the agency imposes on industry and on patient access to new therapies.

The possibility exists for amendments that might substantially reduce the agency’s jurisdiction over medical devices or significantly roll back the 1962 Kefauver Amendments that require drugs to demonstrate efficacy (not just safety) before entering the market. There is no reason to think there is a majority in either the Senate or the House for such radical reform or substantial reduction in FDA’s mission. Nonetheless, such proposals may be offered.

Conclusion.  In enacting a timely reauthorization of the user fee programs, Congress will need to consider a range of legislative proposals. As these are offered and discussed, this FDA Matters analysis provides a guide to understanding Congressional activities.


This blog column is a much-shortened version of an article I wrote that appears in the March 2012 issue of Scrip Regulatory Affairs, entitled “Reauthorizing US FDA User Fees: A Slow-Moving Train Wreck?” Readers interested in a copy of the longer article should contact me at sgrossman@fdamatters.com.

Why is Drug Discovery So Hard (and Expensive)?

Monday, March 5th, 2012

Notwithstanding herbal medicines and the re-emergence of leeches as therapy, it is only in the last 70 years that physicians have had proven medical science to support “the healing arts.” Potions and procedures of dubious value have been replaced by powerful medicines that treat infections, heart disease, diabetes and mental illness.

While the benefits are clear, the difficulties and cost of creating new medicines are a source of widespread frustration to patients and industry alike. FDA Matters is impressed that current efforts to speed up drug discovery are gaining momentum.  At the same time, the nature of human biology dictates that the creation of new therapies will never be easy or inexpensive.

Recently, Matthew Herper of Forbes wrote about the “truly staggering cost of inventing new drugs”, a range he put at $4-11 billion per success! The point is that every success is bearing the cost of a staggeringly-large number of expensive failures.

The chart at the end of this column shows that about 10,000 compounds are screened to produce about 250 compounds that are promising enough for pre-clinical and early clinical testing. In turn, this produces five compounds in late stage clinical testing and only one approved drug. As a result, efforts to improve drug discovery have two goals:

  • early identification of compounds with the highest  probability of proving safe and effective, and
  • the ability to discern and discard promising-looking compound that are, nonetheless, likely to fail at later stages.

The growing consensus behind these goals has pushed collaboration and innovation much faster than would otherwise be expected. Identification and validation of biomarkers, pharmacogenomics, toxicology databases, and new compound screening methodologies are among the many approaches to enhance the discovery process.

NIH has committed to speeding early drug discovery through the just-launched National Center for Advancing Translational Sciences  (NCATS). I admit that I was skeptical when it was first proposed because it looked like NIH wanted to compete with industry. However, NCATS’ is appropriately focused on generating useful early-stage drug discovery tools, data and methodologies that will be made widely available and are complementary and supportive of industry efforts. (The advocacy group, Faster Cures, recently held an informative webinar with NCATS’ leaders. Here are links to the audio and accompanying slides.)

FDA has acknowledged the need to be more attuned to advancing medical innovation as an integral part of the agency’s role in promoting the public health.  This was reflected in FDA’s October, 2011 report, Driving Biomedical Innovation: Initiatives to Improve Products for Patients and by its willingness (during user fee negotiations and other venues) to commit to more early-stage meetings with companies. In addition, FDA has committed resources to creating and validating new tools and methodologies for drug discovery. Most important of all, FDA recognizes the need to act on the critical next stages after drug discovery by creating a more predictable regulatory pathway that minimizes the time that it takes safe and effective new medicines to gain approval.

All these activities taken together may produce dramatic improvements on the front end of drug discovery. This would provide the ability to focus on the “most promising, least likely to fail” compounds and reduce the number of expensive failures. In some cases, companies and regulators might know enough from the initial discovery screening to shorten or narrow pre-clinical and clinical testing.

The new focus and activity on drug discovery is reason to be hopeful….but these efforts will take time to bear fruit. The process of taking a compound “from bench to bedside” must still be measured in years.

Optimism should also be tempered by realizing that the human body is almost always more subtle than we can discern, even with the best predictive tools.  New uncertainties emerge, even as new biological information resolves old uncertainties about diseases and drug development.

No matter how much we know, there will always be clinical trials that fail, sometimes quite miserably, just when everyone is most sure that the solution is logical and success guaranteed. That’s why drug discovery will never be easy or inexpensive.


The last two links connect readers with earlier columns on biological complexity:  Is the Human Body Just An Exquisitely Intricate Machine? and Scientific Reductionism and the End of Medicine. For those interested, there is a third column on this topic: Personalized Medicine in Perspective.

Development of New Therapeutics is Slow, Expensive and Failure-Prone

http://www.fastercures.org/train/tools/documents/022712_NCATS.pdf  (slide 14) 


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