NIH and Drug Development: Dr. Collins’ New Initiative

Dr. Francis Collins, director of the National Institutes of Health (NIH), wants to create a new National Center for Advancing Translational Sciences (NCATS) at NIH.  The new Center would combine $700 million in existing NIH projects with, perhaps, an additional $300 million from new monies or other NIH programs. NCATS is intended as NIH’s “response” to the biopharmaceutical industry’s failure to produce more new drugs.

FDA Matters doesn’t see the sense of creating a public sector drug development company. Nothing suggests that government has either the requisite knowledge or experience to succeed. Yet, several people I respect are supportive of Dr. Collins’s initiative.

Advocates and critics of NCATS may not be talking about the same thing. NIH describes a very circumscribed process in which NIH quickly passes early research over to industry. NIH will do compound screening, animal studies and sometimes proof of concept human clinical trials. Since NIH already does this without a lot of fanfare, why create a new center rather than just highlighting the work?  

The NIH FAQ also promises that NIH will limit itself to less developed clinical areas where there is not yet commercial interest by industry. The notion that NIH will restrict itself in this way rather than pursue best scientific opportunities…is worth at least a raised eyebrow of skepticism.

Industry is frustrated by the difficulties of developing new medications and is actively searching for ways to do better. Maybe they could use some more help from NIH. Unfortunately, HHS and NIH have taken a less cooperative approach, trying to sell NCATS as a response to industry failures in new drug development, as if they are certain of the cause and know that NIH can do better.

It would be better if government officials focused instead on expanding NIH’s existing role in developing medical knowledge beyond basic research. Congress has shown considerable interest in this over the last few years and, until now, there have been few questions about whether NIH is overstepping its bounds.

NIH implies that NCATS will be a productive goad to an unproductive pharmaceutical industry. Whether this is justified, it would help the discussion if NIH were to be more upfront about its limited expertise in developing products to meet FDA’s standards for approval.

Because of the difference in the two agency’s missions, FDA’s standards are much higher and less forgiving. This is appropriate: we want NIH to advance knowledge; we want FDA to make sure that biopharmaceuticals are safe and effective.

Dr. Collins’ initiative also seems hasty in its desire to re-organize upwards of a billion dollars in NIH’s programs by October 1, 2011. It is seductive to imagine that problems can be solved by redrawing boxes on an organizational chart. Sometimes this works, but more often you get the Department of Homeland Security, an organization that is far less than the sum of its parts.

For the moment, there appears little talk about the possible impact on the rest of NIH if NCATS is created. If $700 million worth of programs is transferred to NCATS and Dr. Collins says he will squeeze more money from other priorities, how can existing institutes and centers not suffer? It would be quite unfortunate if basic research were to be devalued by the rise of translational science.

NIH, as an institution, may not be better off with NCATS.  In any case, new drugs are not going to pour out of NIH, as some seem to believe. 

I’d like to see a lot more public discussion of these issues. Let’s take the time to be sure that the integrity and productivity of NIH are not at risk and that the American people will receive tangible benefits.

Steven

NIH’s FAQ and website on the proposed changes: http://feedback.nih.gov/index.php/faq-ncats/

The interview of Dr. Collins by Gardiner Harris of the NY Times:

http://www.nytimes.com/2011/01/23/health/policy/23drug.html?_r=3&pagewanted=all#

From Pharmaceutical Executive on-line:
NIH Director On the Consortium’s New Remit
As the National Institutes of Health hits the headlines over its remit to help develop new medicines, Director Francis Collins talks about the new initiatives he sees as critical for innovation, industry, and public health.

Will the New Congress Be Good for FDA-Regulated Industries?

THIS IS THE LAST OF MY 2010 COLUMNS ON FDA AND THE NEW INCOMING CONGRESS. LINKS ARE AT THE BOTTOM OF THIS PAGE.

FDA Matters is hearing that FDA-regulated industries will benefit from the 2010 election. It is assumed that a Republican-led House and more Republicans in the Senate will benefit drug, device and food companies. After all, aren't Republicans more business-friendly and more concerned about perceived regulatory excess?

Those saying and thinking these things may be in for a rude awakening. Even worse, they may find themselves nostalgic for the "good old days" (whenever those were). Everybody—FDA, industry, patients and consumers—is going to have a rough time over the next two years. Industry will be heard more often, but not always have the winning position.

To start with, the Republican House of Representatives is going to be asking lots of questions about policies and programming initiated by the Executive Branch during the last two years, including FDA.  Because of their backgrounds as heads of big-city public health department, Commissioner Hamburg and Principal Deputy Sharfstein are more prepared then most political appointees.

However, they have never experienced the volume or magnitude of these inquiries. Neither FDA nor any stakeholder benefits if FDA is busy answering Congressional letters or preparing for oversight hearings on the Hill…..instead of reviewing products, setting standards and conducting inspections.

Even in the Senate, oversight and investigations are going to make a big comeback. This is a byproduct of budget politics: if there is no money to spend and big divisions over authorizing legislation, then Members turn to investigations to fill the time and command national attention.

Beyond FDA, regulated industries are going to come under increased scrutiny. The incoming chairman of the House Oversight and Government Reform has already announced plans to investigate the over-use of expensive medical devices and probe the way food recalls are handled. Imported food, drugs and raw ingredients from China may be given oversight scrutiny. Current investigations are going to continue on quality manufacturing in drugs, biotech products and OTC drugs.

Senator Grassley, as Ranking Minority on the Senate Finance Committee, has held investigations of tax-exempt hospitals, non-profit advocacy groups, FDA and FDA-regulated industries. Senator Hatch, who will be Grassley's successor in the post, has already indicated his intention to continue many of Grassley's issues and to have a tough investigations staff.

The Alliance for a Stronger FDA has already established that consumer and patient groups, health professional societies, associations and industries have a common interest in a strong FDA through increased appropriations. In the face of the current budget-cutting fervor, it remains to be seen whether industry will be able to convince legislators that FDA needs more resources from general revenue.

Separate, but related: a year from now, the drug, biotech and medical device industries will be trying to limit the amount of new user fees they will be required to pay when user fees legislation is re-authorized in 2012. It is hard to see how business' complaining about excessive fees will prevail against Congress' need to increase FDA funding from sources other than general revenue.

From these examples, it is possible to see a larger theme. Republicans generally believe that industry, without too much government intervention, should be relied upon for job creation in the US. Most of the party rhetoric is focused on achieving these through reducing the federal budget, trimming federal regulations and regulatory agencies, and making sure that "the people" who voted for them in the last election feel they are being heard.

The FDA context is different. Most FDA-regulated companies want simplification of the regulatory requirements and more certainty in their implementation, but are not interested in eliminating FDA's regulatory structure or limiting its ability to assure public health and safety. Thus, industry would not benefit from efforts to starve, roll-back, harass or marginalize the agency. The worst-case for the next two years is that Congress might try all four and not listen to industry concerns about negative outcomes.

Steven

"Must-Pass Legislation" Key to FDA's Future
December 12th, 2010

FDA Matters believes that the 2010 election will profoundly affect the FDA's mission, priorities, funding, standards and work flow. Eighteen months from now, FDA's leadership team will probably be the same, but the agency won't be. At the moment, there is only one "must-pass" item on Congress' FDA agenda: the next round of user fee renewals that will come before Congress in the Spring of 2012. Read the rest of this entry

Two Strategies for FDA Legislation in 2011
December 5th, 2010

The current Congress has two primary FDA-related accomplishments: have been less visible: an abbreviated approval pathway for bio-similar drugs; and a food safety bill that may be enacted before Congress adjourns. FDA Matters believes that any FDA-related legislation will falter in 2011 if it does not follow the strategy behind one or the other of these efforts. Read the rest of this entry

FDA and Election 2010: Oversight and Investigations
November 13th, 2010
 

President Obama's election and the distraction of health reform have distracted us from the disruption that divided government imposes on FDA. With the new Republican majority, the agency will find itself buffeted by political forces that are as concerned about "scoring points" as they are about improving government. FDA Matters thinks this will have a large impact on FDA, as well as the agency's stakeholders. Read the rest of this entry

FDA and Election 2010: Deficit Reduction and Appropriations
November 6th, 2010
 

So-called "wave elections"–where one party overwhelms the other–are particularly hard to judge. The ground rules are going to change dramatically– in ways that no one can fully anticipate. At first, each side refuses to compromise. Then, something happens that sets the pattern for whether people will work together and on what issues. This may take months to resolve or may occur before the new Congress arrives. As things change, FDA Matters thinks there are some key issues for FDA-watchers to monitor. Read the rest of this entry

FDA: A Hit and A Miss

FDA Matters has watched FDA handle the Avandia decision differently from any prior controversy. I like the new approach. In the same week, FDA provided a status report on its long-overdue social media and Internet communications policy. Because the agency's efforts have been glacial, the prospect of useful guidance is dim. I think this is a serious problem.

FDA's Handling of the Avandia Situation. A HIT

FDA Matters was heartened by the agency's deft handling of the Avandia situation. Previous columns have explored how hard it is to achieve cultural change at FDA and why it requires the Commissioner and the agency's senior leadership to be role models.

With the Avandia decision, the agency has demonstrated progress toward two related changes: improved transparency and allowing internal dissent to become part of the public dialog.

Transparency is not part of the FDA's DNA. Despite this, the agency has responded to the President's government-wide transparency initiative with a serious effort. In doing so, it has struggled--mostly against itself--in making its processes and decisions more readily available within and outside FDA.

The Avandia advisory committee meeting and the FDA website were remarkably transparent about the controversy and the details. To clarify the ultimate decision, Drs. Woodcock, Sharfstein and Hamburg authored a 1500-word explanation, which appeared in the New England Journal of Medicine.

Embracing dissent has always been hard for FDA. Its customary position of "speaking with one voice" is not an accurate reflection of what happens when well-trained, analytically-oriented people gather to make a decision. With Avandia, Commissioner Hamburg has conspicuously incorporated dissent into the process.

Cultural change at FDA is difficult and always takes time. The Avandia decision is a significant step forward, demonstrating that agency leadership is committed to changes and understands that it must serve as role models.

FDA's Handling of Policy Development for New Media: A MISS

As a rule, businesses do not like additional regulation. There are two exceptions: where it levels the playing field with competition and when it creates certainty on how companies should conduct their activities. These are the exact reasons why FDA-regulated medical products companies have repeatedly asked FDA to issue policy guidance on Internet activities.

As best I can tell, FDA's first hearing, "FDA and the Internet: Advertising and Promotion of Medical Products" occurred on October 16 and 17, 1996. http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm175775.htm. That's 14 years ago!

While FDA has studiously ignored the opportunity to provide policy guidance and regulation, the Internet has become a primary means of written and visual communication. Search engines control an ever expanding numbers of online interactions. Social media has flourished.

Apart from agency action against some companies for activities that many consider ethical and reasonable and a two-day hearing in November 2009…not much progress seems to have occurred toward providing more direction to industry. At a Food and Drug Law Institute meeting last week, the agency suggested a draft guidance--the first of many--may be issued later this year. Even assuming this occurs on schedule, it will take at least a year to finalize.

I suggested last year that FDA was mistaken to see Internet policy development as overwhelming. Rather, it is a number of smaller issues that can be addressed separately without a broad Internet policy. An additional advantage of this approach: it recognizes that any Internet policy guidance will be outdated before FDA can ever issue it.

After 14 years, this calls for the intervention of agency leadership, not continued delays.

Steven

Gardner Harris of the New York Times also observed the changes at FDA that have occurred as part of the Avandia decision. His column is at: http://www.nytimes.com/2010/09/25/health/policy/25avandia.html?_r=1&emc=eta1.

For those interested in more coverage of FDA and social media, I recommend Mark Senak's Eye on FDA column at www.eyeoffda.com.

Is the New FDA Different than the Old FDA?

June 13th, 2010

Two weeks ago, FDA Matters explored Dr. Hamburg's legacy, focusing on advocacy for resources, prioritizing regulatory science and upgrading enforcement. These will be accomplished before she leaves office. But is she making similar progress in creating "a new FDA, including changes in agency culture?" Read the rest of this entry »

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

FDA has a reputation for being tough on dissent, whether it comes from employees or regulated companies. Whatever the truth has been in the past, FDA is trying to develop an institutional cultural that welcomes and accepts dissent from employees, industry and other stakeholders. It is difficult, even messy, to do this. Read the rest of this entry »

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. New policy will not 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 »

PhRMA’s Choice: A Man for All Reasons?

The Pharmaceutical Research and Manufacturers of America (PhRMA) has announced John Castellani as its new CEO and President. For the past 9 years, he has been the head of the Business Roundtable, a very successful association of corporate CEO's.

History tells us that the choice of a new PhRMA President will reflect the Board's view of the state of the industry and its most pressing needs. The new appointment continues that tradition.

At the outset, let me say that Mr. Castellani appears to be eminently qualified. He has roots in corporate America and has spent years steering a powerful association. He knows how to manage CEO's. Early news coverage has characterized him as a manager, straight-shooter and non-partisan (although he mostly contributes to Republican campaigns).

However, there is more to his appointment. In a column earlier this year (link below), FDA Matters examined the past five Presidents of PhRMA, going back to the 1970's. It is hard to imagine that the same association could be led by individuals with such different backgrounds. Yet, on examination, each appointment was appropriate for the industry's needs at the time they were appointed.

Whether the PhRMA search committees have acted intuitively or consciously, their choices have been spot-on to what the industry needed.

In the earlier column, I stated: When his [Tauzin's] 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. I think there are two such challenges faced by the bio-pharmaceutical industry:

• Strengthen solidarity with non-pharma industries, and
  
• Preserve its status as a major domestic industry, despite the growth and pull of globalization.
  

CEO's from other US industries are far more concerned about rising health care costs than the well-being of pharma companies. There have been moments when it seemed possible that broad industry groups might support positions affecting pharmaceutical companies that they would never support for their own companies.

For example, PhRMA would have great difficulty winning fights on re-importation and drug price negotiations if the rest of corporate America took the opposite position. To reduce or eliminate this possibility, who better to choose than the man who has represented the larger corporate community for the last 9 years?

With regard to the second challenge, PhRMA has successfully leveraged its status as a major domestic industry with a positive contribution to the American economy. This has helped soften the politically dangerous perception that American taxpayers, insurers and patients are cross-subsidizing the cost of medicines in other countries.

To sustain that leverage in the face of globalization, PhRMA needs to demonstrate that the US is still the home of the bio-pharmaceutical industry and that the growth of the industry is matched (or exceeded) by the economic benefit to the US. Who better to choose than a nationally-recognized advocate for policies to create domestic job growth and investment?

Some readers may say that these are not reasons enough to drive the choice of Castellani. Or they might argue that these are side-benefits rather than the primary point. I acknowledge that he is a "man for all reasons" and an obvious choice now that it has been announced.

I am intentionally looking at a larger perspective on the appointment, trying to see how it relates to the most important determinants of the long-term success or failure of PhRMA. My conclusion:

If John Castellani can maintain solidarity with corporate America, grow the perceived role of the pharmaceutical industry in the US economy, and manage the staff's communications and lobbying efforts….then everything should turn out fine for PhRMA.

Let me know what you think?

Steven

The press release announcing the appointment is at: http://www.phrma.org/news/news/john_j_castellani_lead_phrma_new_president_ceo.

An interesting profile: http://www.whorunsgov.com/Profiles/John_Castellani.

An interesting analysis: http://www.muckety.com/John-J-Castellani/96246.muckety

My earlier column:

Transition at PhRMA
February 14th, 2010

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. Read the rest of this entry »

FDA, Female Sexual Desire and the Media

This week's hottest bio-pharmaceutical story was the June 18 FDA advisory committee's review of a drug to treat hypoactive sexual desire disorder (HSDD). The committee did not recommend approval of the drug, but encouraged the sponsoring company and others to continue working in this area.

What struck me most was the contrast between the seriousness of the advisory committee in deciding whether the treatment was safe and effective in treating a genuine medical disorder and the inability of the American media to report the story objectively or sympathetically.

The New York Times had at least four articles—two news stories and two commentaries. The coverage in three of them gives focus and space to whether HSDD is a disease, whether biopharma companies create diseases, and the legacy of Victorian beliefs about sex. These were not part of the advisory committee meeting or issues raised by FDA.

The New York Times gave credence to the views that HSDD is primarily caused by bad lovers and high expectations and that the primary remedies are talk therapy, ending relationships and lower expectations. In short, they featured "experts" dueling on tangential, almost ideological, issues reflecting their professional self-interests.

Other than speculation on the number of women affected, there was little space devoted to the unmet medical need. Of most concern, there was no apparent attempt to provide a patient's perspective or interview a patient. Yet, this would seem routine for a news story concerning drugs being reviewed by FDA---especially where the drug treats a condition for which there is no approved therapy.

To find source material on patient perspectives, NY Times writers needed to look no further than a thoughtful NY Times magazine article from November 2009. Need to talk to a patient? Call the article's author or one of the researchers he mentions.

Fortunately for patients, FDA had long-ago decided the answers to the questions that the media deemed to be hot topics. In May 2000, the Division of Reproductive/Urologic Drug Products (DRUP) issued a draft guidance for industry entitled, Female Sexual Dysfunction: Clinical Development of Drug Products for Treatment. The guidance deals with the difficulties of proving safety and efficacy. It raises no concerns about whether female sexual dysfunction exists nor does it question the value of products being developed to treat the condition.

There is a solid history of FDA playing a critical, but totally unheralded role, in shaping and reshaping our society's understanding of disease.

For example, homosexuality was long treated as a disease or mental disorder. For at least the last two decades, it would be unthinkable for FDA to consider an "anti-homosexuality pill." For hundreds of years, obesity has 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 treating each of these.

FDA seems to make these judgments without any fanfare. The question "is this a disease" doesn't come up every day at the agency. When FDA does make these judgments, it appears a routine part of the process and not a notable event.

Maybe in the future, the media will have a better grasp of why this is so and respect FDA authority and good judgment about such matters. Meantime, for the benefit of women with HSDD, FDA's role and earlier decisions are a very good thing.

Steven

Disclosure: Since I don't usually write about specific drugs, it may be useful to state that I am not working on HSDD for any of my clients nor am I doing any work for the company whose drug was reviewed.

The origins of my views are in a November 2009 column, entitled: "FDA: Invisible Arbiter of What Constitutes Disease," at http://www.fdamatters.com/?p=646. I have re-used some of the examples from that article, which was focused on whether FDA issues would ever approve an "anti-aging" drug.

Here are the four recent New York Times articles:

http://www.nytimes.com/2010/06/17/business/17sexpill.html

http://www.nytimes.com/2010/06/19/business/19sexpill.html

http://www.nytimes.com/2010/06/27/business/27stream.html?fta=y

http://www.nytimes.com/2010/06/27/opinion/27Paglia.html?th&emc=th

Here is the earlier New York Times Magazine article:

http://www.nytimes.com/2009/11/29/magazine/29sex-t.html

Prioritizing patient needs is not just a media issue. I have previously criticized industry for not acknowledging that "Patients Come First." http://www.fdamatters.com/?p=632

I have also questioned FDA when it went astray in "One Disease + Two Concerns = FDA's Need to Communicate Better and Modernize Standards." http://www.fdamatters.com/?p=430

FDA to Industry: Contractors R U

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

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

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

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

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

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

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

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

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

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

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

Steven

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

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

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

June 2nd, 2010

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

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 »

Orphan Drugs and Bio-Similars: Is 12 Better than 7?

In the new bio-similars legislation, orphan drugs were granted protection for the longer of 12 years of data exclusivity or 7 years of market exclusivity. Since both are triggered by the date of approval, many people have assumed that 12 years protection is always better than 7 years protection.

FDA Matters says: not so. Other than patent protection, the Orphan Drug Act's grant of market exclusivity to orphan drugs is still the best friend of an innovator company.

The new bio-similars law creates a regulatory pathway by which biologics similar to ones already on the market can get approved more quickly and with less original data. In a prior column, FDA Matters pointed out that the data exclusivity provisions were both more and less beneficial to originators than it seemed:

• More because no bio-similar can use the abbreviated approval pathway if the reference (originator) drug was approved less than 12 years before. This "pathway exclusivity" includes data exclusivity, but is more far-reaching. Even if a bio-similar has its own data, it still can't use the new pathway to approval.
  
• Less because the new law protects reference (originator) products against bio-similars for 12 years, but only if the bio-similar seeks to use the new abbreviated approval process. Many of the companies planning bio-similars are going to use the full BLA approval process instead, where the 12-year pathway/data exclusivity doesn't apply.
  

When this is applied to orphan drugs, two different situations emerge:

• If the bio-similar wants to use the abbreviated pathway, then the 12 years of pathway/data exclusivity protects the original orphan product. In this case, the 12 years is better for the originator than 7 years of market exclusivity.
  
• If the bio-similar wants to use the regular BLA pathway, then the 7 years of market exclusivity protects the original orphan product. The 12 years of pathway/data exclusivity doesn't apply at all.
  

What comes next depends heavily on FDA. The law is new and lacks clarity on many key points; the patent provisions border on the unworkable. The new pathway may not turn out to be usable.

Nonetheless, the new law clearly empowers FDA to find ways to get more bio-similar products on the market. Since, at best, this can only be partially achieved through the abbreviated pathway, I believe the agency will be looking for ways to make the BLA process friendlier for bio-similar and bio-better products.

This suggests that bio-similars of orphan products are going to use the BLA process a lot. Seven years of market exclusivity will still be the core protection that all orphan companies will want for their products.

For innovators of orphan drugs, the message is: prepare for competition. Don't assume that you will have more time because of problems with the new pathway or the protections it grants. Seven years of market exclusivity is all you can really count on.

For those planning bio-similars of orphan drugs, the message is: don't violate the originator's patent(s) and get your own data to support a BLA filing. Also, prepare to discount in order to get market share. It will never be like the generic drug market, but with biologics costing upwards of $300,000 per year….offering a 20% discount is serious money that will be welcomed by health plans and patients.

A final thought: costs to enter the bio-similar market are going to come down over the next 5 to 8 years. This means that orphan products with less than $1 billion in annual revenue are going to see competition much sooner than many predict.

Steven

My earlier column:

Data Exclusivity and Bio-Similars: Both More and Less Than It Seems
May 2nd, 2010

FDA Matters has been very upbeat about the prospects for the bio-similar marketplace. "Smart money" (i.e. companies currently making billions from their ability to discover or license new bio-pharmaceuticals and market them) decided to play before they knew the ground rules on exclusivity and patents. We can only conclude that there must be substantial amounts of money to be made, regardless of the specifics.

With this in mind, FDA Matters explores why there is a persistent belief that the bio-pharmaceutical industry got something better than data exclusivity. I also explore whether data exclusivity will really provide valuable protection for original reference biologic products. Read the rest of this entry » or go to: www.fdamatters.com/?p=921.

Data Exclusivity and Bio-Similars: Both More and Less Than It Seems

FDA Matters has been very upbeat about the prospects for the bio-similar marketplace. "Smart money" (i.e. companies currently making billions from their ability to discover or license new bio-pharmaceuticals and market them) decided to play before they knew the ground rules on exclusivity and patents. We can only conclude that there must be substantial amounts of money to be made, regardless of the specifics.

With this in mind, FDA Matters explores why there is a persistent belief that the bio-pharmaceutical industry got something better than data exclusivity. I also explore whether data exclusivity will really provide valuable protection for original reference biologic products.

Those who keep referring to market exclusivity under the new law point to the fact that FDA can't approve a bio-similar under the abbreviated bio-similar pathway until 12 years after the original, reference drug was first approved. That sounds like market exclusivity.

My understanding of the BIO interpretation: it doesn't prevent another company from going and generating its own data and getting its own approval through the existing BLA approval pathway. Hence, all that is protected is the company's data.

The new law "protects" the reference product from competitors….by denying competitors the benefits of the new approval pathway for 12 years. It is not market exclusivity because there are other ways to get a bio-similar approved. It is more than just data exclusivity because the competitive product can have its own data and still not be able to use the new abbreviated pathway for approval.

What has been granted to the reference product is "pathway exclusivity" for 12 years.

This suggests that the market is going to divide. Those who wish to market bio-similars of drugs that were approved more than 12 years ago will have a choice between the abbreviated pathway and filing a full BLA application for approval. For those who wish to market bio-similars of drugs that were first approved less than 12 years ago, the choices are: wait or go the full BLA route.

Many companies—even those with the opportunity to take the abbreviated pathway-- are going to decide that the advantages of a full BLA exceed the cost of collecting additional data. Some will take the data from their European bio-similar approvals and talk with FDA about which pathway will work best. Others will work toward approval of BLAs for so-called "bio-betters." These are new products that are bio-similar to an existing product, but are safer, more effective or easier to use.

What comes next depends in part on FDA. The new law clearly empowers FDA to find ways to get more bio-similar products on the market. Since this can only be partially achieved through the abbreviated pathway, I believe the agency will be looking for ways to make the BLA process friendlier for bio-similar and bio-better products.

FDA approval of a bio-similar will not assure a marketplace unless other changes occur. I envision health plans, insurers and government programs shifting toward "therapeutic substitution," where lower-priced bio-similar products will be put on formularies in place of the original reference product.

This has already occurred in the statin market, where an increasing percentage of prescriptions are filled with a generic statin, regardless of whether the doctor wants the patient to have a brand product. Right now, it seems like a stretch for bio-similars to be subject to therapeutic substitution, but FDA approvals of bio-similars and bio-betters will open up this possibility. Insurers needing to save money (and companies willing to lower prices to gain market share) will do the rest.

This brings me back to my other point: that the bio-pharmaceutical industry will find that the benefits of data exclusivity (and pathway exclusivity) will prove to be much less valuable than they seem now. BLAs are going to get easier, the marketplace will start substituting therapeutically, and all that "smart money" will prove to have been well-invested.

What do you think? Post a comment.

Steven

For those readers who want to familiarize themselves with what the new law says, it is pages 686 to 703 at: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills&docid=f:h3590enr.txt.pdf

More on bio-betters: "Pfizer Pushes on New Biotech Drugs"

http://online.wsj.com/article/SB10001424052748704464704575208580328253618.html?mod=dist_smartbrief#articleTabs%3Darticle

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 »

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 »

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

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 »

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

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 »