Post-Market Safety: Getting the Most Out of Inferences That Aren’t Proofs

In the FDA-regulated world, success is often defined as approval of a new product or indication based on two, well-controlled clinical trials. However, the scrutiny doesn’t end there. FDA’s mission includes determining whether already-approved drugs perform safely and effectively when used by large numbers of patients in routine medical practice. 

To understand what happens under these “real world conditions,” FDA has expanded its post-market  efforts, including development of a monitoring system (called Sentinel) that will be able to track drug usage and medical history information on tens of millions of patients. Although such information will be useful, it can only provide post-hoc inferences, not proof of causation. Even with this limitation, FDA Matters thinks developing the system is worthwhile and may provide multiple benefits. 

There are multiple tools for assessing post-approval safety and efficacy that fit loosely under the rubric of pharmacovigilance. When approving medical products, FDA mostly relies on data that comes from pre-specified hypotheses that are tested through randomized, placebo-controlled, double-blind clinical trials. In contrast, the data that comes from pharmacovigilance is inherently less rigorous; indeed it constitutes a form of “data dredging” that FDA abhors. The heart of the problem is that:  

Real world data sets = uncontrolled variables + inconsistent data collection + questionable data accuracy.

When FDA and manufacturers collect adverse events reports, they know there will be underreporting of incidents, as well as limited ability to judge whether problems are drug-related. When FDA looks at the Medicare database, they know that information submitted as part of medical claims is unreliable and subject to systemic bias (e.g. medical coding is designed to support reimbursement, not public health analysis).

The Sentinel database should be superior because it incorporates medical records and patient registry information, along with claims data. Still it provides inferences, not proof.

Active surveillance—continuously monitoring millions of health records---is only worthwhile if these limitations are acknowledged. It can never provide certainty about whether drugs are safe and effective. It can tell you what is worth further examination…but can never tell you the cause of any problem that is identified.

As the FDA mantra goes: association is not causation. No matter how many health records and claims data are reviewed, this is still true.

Clinical trials have limitations, also. Trials don’t tell us how a drug will be used by prescribers. They can never provide complete information about patient outcomes for those individuals with several medical conditions (i.e. multi-morbidity) or who take many medications simultaneously (i.e. poly-pharmacy).

By inference (although not with certainty), pharmacovigilance and active surveillance could bring us closer to addressing potential problems that can’t be resolved by clinical trials. For example, many years ago, I worked on a drug to treat pre-term labor. As I recollect, there were two instances of respiratory problems in a trial of several hundred women. No one could say for sure whether this effect was caused by the drug or occurred at random. A study large enough to find out was infeasible.

Based on the potential respiratory problem, FDA rejected the drug despite the benefits it might have provided to women experiencing pre-term labor. If this same situation were to come up today…maybe FDA would decide differently, knowing it could collect patient outcomes information through pharmacovigilance, particularly active surveillance.

Ideally, FDA would know everything it needs to know about a drug at the time of its approval. Information derived from review of real world data sets can never be as good. But properly understood and carefully analyzed, the inferences derived from pharmacovigilance can add to our understanding about safety, efficacy, drug interactions and side effects.

Instead of just using that capacity to identify post-approval problems, FDA needs to incorporate pharmacovigilance into its thinking about when to approve drugs and with what conditions. FDA’s capacity to do pharmacovigilance and active surveillance should lead to a greater willingness by FDA to approve drugs, particularly those with otherwise solid benefit-risk equations, but burdened by questions that cannot be resolved prospectively or through clinical trials (even in phase 4).

Patients would benefit if FDA made this one of the Sentinel priorities.

Steven

Lies, Damned Lies and Statistics

FDA’s regulations, policies and actions are multi-faceted and complicated. Oftentimes, it is hard to interpret what the agency is doing and why. We all depend on good analysis to understand where the agency has been and where it is headed. Unfortunately, some of what we read about FDA is poorly reasoned or distorted by the media and others.  

Three recent analyses have particularly troubled FDA Matters. They claimed to draw broad and important conclusions about FDA behavior and were uncritically circulated through mainstream and trade press. Yet, the analyses they offer are unremarkable or misleading.

My first example is a recent analysis from a healthcare research firm analyzing the number of FDA refuse-to-file (RTF) letters over the last dozen years. These involve situations where companies file drug and biological applications for approval and the FDA returns them to the company rather than accepting them for evaluation.

There is a methodological problem: FDA does not disclose RTF’s and traditionally companies have not disclosed them. Thus, any analysis of trend data (“more now, fewer a decade ago) is speculative.

Likewise, not knowing which companies received RTF’s means there is no basis to conclude that RTF’s were previously associated with small, inexperienced firms, but now are being received by larger companies. The shift, we are told, might reflect the agency’s enforcement mentality under the new commissioner. And maybe standards have been raised. A commentator (not the author) even suggests that the alleged uptick may be FDA maneuvering to improve its success rate under the user fee program (while, presumably, returning meritorious applications?).

To its credit, the analysis does mention that “the wave of RTF’s” may be related to FDA’s 21^st Century Review Initiative. One aspect of that initiative is for FDA to weed out applications that are likely to be rejected later in the process. This is more efficient for companies, as well as FDA.

Front-loaded reviews are going to create more RTF’s. This seems obvious, if not unassailable. But trying to embellish this with time/trend data and allusions to changing standards raises issues that have no bearing on the question of whether RTF’s are becoming more important in the review process…and whether this is a good trend.

However, the implication picked up by the media was that increased industry interest in orphan drugs was not being met by increased commitment by FDA to get these drugs approved. But is that really the case? I don’t know and, despite appearances, the numbers don’t answer the question.

Showing same-year data for applications, designations and approvals implies that they relate to each. However, any given year’s orphan drug approvals reflect designations that were made 2 to 6 years previously. The meaning of the surge in the number of designations in 2010 cannot be assessed until we see if there are more orphan drugs approved in a few years.

Lastly, there is this week’s headline that: Biopharmaceutical Product Approvals in the U.S. Rose Dramatically in the 2000’s.” As a result of a Tufts University study, we are told that “during the 2000-09 period, 65 biopharmaceutical products received U.S. marketing, approval, up from 39 in the 1990s and 13 in the 1980.” Media seemed to treat this as a revelation. 

However, there was no biotechnology industry to speak of in 1980 and no products. As chronicled in previous columns (link below), the growth of this new industry has occurred over several decades. Is anyone surprised there were more approvals in the 2000’s?  

These three examples are a reminder that those of who write about and critique the FDA have an obligation to be accurate and not misleading. All of us, including myself, will fail sometimes. The media that report on our analyses rarely check to see if our conclusions are valid or make sense. 

Steven

The first analysis is at: http://portal.leerink.com/IRPDocumentViewer/Web/DocumentViewerCache.aspx?docId=4E2F752B612F6B5646706F3D&pad=52384B6E6E74573478656F45317951416D4B6A506E673D3D&userId=52636261346B39577A34343D

The second analysis is at: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2011/01/orphan-drug-designations-and-applications-took-off-in-2010-while-orphan-drug-approvals-tapered-off.html

The third analysis is at: http://csdd.tufts.edu/files/uploads/may-june_2011_ir_report_summary.pdf

Forget the Hype: Change Takes Time     March 21st, 2011

FDA Matters is always impressed by how much FDA does. The everyday tasks are overwhelming: reviewing, approving, monitoring and inspecting the products and facilities responsible for 80% of our food supply and 100% of drugs, biologics, medical devices, vaccines, and animal drugs. Then there are the policy issues, big and small, that must be tended to.

These are largely functional tasks—someone has a job (or several) and does them. Yet, FDA has another life, as the bridge to the future of foods, drugs and devices. This responsibility is vitally important to our nation. It also takes time to bear fruit. Read the rest of this entry

Public Incentives and Drug Development: More is Usually Better

A former colleague often declared: life sciences companies have no alternative to re-investing in developing more drugs, biologics and medical devices. I always thought this naïve because of its implication that life sciences research is self-perpetuating and does not need encouragement.  

Currently, Congress seems primed (through oversight and possibly legislation) to consider the role of companies and government in medical product development. This week, FDA Matters explores the nature and need for incentives to conduct life sciences’ research; last week’s column looked at issues surrounding the pricing of medical products.

The government’s goal in incentivizing certain life sciences research is to stimulate activity that meets or resolves societal needs (e.g. drugs and devices for cancers, therapies for rare diseases, treatments for tropical diseases). Idealistically, the incentives encourage vital, new activity without providing subsidies for research that would have occurred without incentives.  

The reality is different. If the rules (statutory or administrative) for receiving incentives are drawn too tightly, then many research projects will not be undertaken, losing the benefits that society would otherwise receive.

To explain this better, I have identified three broad categories of public incentives for research:

Ordinary research incentives. These are the incentives available for all corporate-supported research. These include the research and development (R&D) tax credit, access to government technology transfer programs and patent protection. For most industries, and even most life sciences research, these seem sufficient to stimulate a high-level of research investment.

Upgraded incentives.  Ordinary research incentives are sometimes not enough to stimulate life science research that will benefit society. As a result, Congress has created a number of upgraded incentives for medical product development.

For example, Congress has provided partial patent term restoration for drug companies experiencing particularly long delays in receiving marketing approval. This has led to increased research investment (as well as boosting the generic drug market as part of the same legislation).  

Also, Congress created the Orphan Drug Act to provide incentives for research on drugs for rare diseases/small populations. This law incorporated a number of incentives, notably up to seven years market exclusivity for any new orphan indication on a drug.  

FDA also provides a number of upgraded incentives for particular types of research through its expanded access and accelerated approvals programs. User fee waivers granted to first products from new companies also stimulates research investment.  

Extraordinary incentives.  Sometimes even upgraded incentives aren’t enough to stimulate vitally important research. In those cases, Congress may consider incentives designed to dramatically alter the normal risk/reward/certainty calculation that usually precedes research investments.

Thus far, I can think of only one instance of extraordinary incentives. In 2007, Congress enacted a program that awards a “priority review voucher” for successful development of a new treatment for a neglected tropical disease. Owning a voucher entitles a company to ask for a priority review (6 months) by FDA of an unrelated product that would otherwise be granted a normal review (10 months). Currently, Congress is looking at legislation (S. 606) that would extend this voucher program to developers of products to treat pediatric rare diseases.

It is up to Congress to decide whether to encourage particular life sciences research beyond the ordinary incentives. When upgraded or extraordinary incentives are under consideration, the goal is stimulating substantial additional research....and the development of many new drugs that are particularly beneficial to society.   

In all such situations, there is a risk that incentives will be provided to research that would have occurred anyway. My own experiences suggest that overly tight restrictions on program eligibility result in understimulatoin of needed research. When creating incentives and, also, assessing their impact later, Congress needs to take the broad view of the societal good that can be achieved by upgraded and extraordinary incentives for research.

Steven

Drug Product Pricing 101                 March 26th, 2011

A thousand good deeds of the pharmaceutical and biotechnology industries have been washed away by the decision of K-V Pharmaceuticals to charge $1500 per dose for Makena, a drug that reduces the risk of pre-term delivery in pregnant women. There is an easy comparator: the same therapy has been compounded in pharmacies for years at a cost of $10 to $30 per dose. Congressional and public reaction has, quite understandably, been one of outrage.

No one knows the right price for this drug, but there are ways to find out. In conversations this week, FDA Matters discovered that many knowledgeable people don’t know that there are tools to rationally evaluate and guide product pricing decisions. Read the rest of this entry

FDA Is Fighting on Two Fronts

FDA is still a 20th century agency. It lacks the databases, technologies and tools to do its work. It does not have the depth of manpower to be experts in all the increasingly complex sciences associated with medical products and foods. It lacks the confidence to consistently make decisions based on risk-benefit analysis, rather than leaning toward the highly restrictive Precautionary Principle.

FDA Matters can’t see any downside to the FDA gaining the technology, the manpower and the confidence to transform itself into the 21st century FDA that our nation needs. Yet, Commissioner Hamburg has to fight on two fronts to preserve her ability to make the necessary changes.

The new Congress has a different set of priorities than the previous two. Deficit cutting and government accountability are on everyone’s mind.

Under a House-passed bill that would fund the federal government in Fiscal Year (FY) 11, the FDA would be allotted $241 million below the level at which it was funded in FY 10. Were this to become law, the agency would need to cut new programs, abandon initiatives and probably lay off staff. To reach agreement with the House, the Senate will also have to cut the federal budget, although perhaps not the funds for FDA.

A 21st century FDA requires capacity to meet new challenges. This won’t occur if the FDA’s budget is being cut.

At the same time, Congress is increasing its oversight/investigative activities. Oversight of FDA needs to occur, but it comes at a price. Investigative hearings are a potent reminder to FDA that cautious, risk-adverse decisions are the ones Congress won’t question. Thus, FDA is reinforced in being a 20th Century agency, rather than encouraged to modernize and think more broadly about problem-solving in the 21st century.

Also, there is an ongoing shift from public funding of FDA to industry funding. User fees pay for very specific tasks. Over-reliance on them reduces the flexibility that FDA leadership needs to handle public health challenges, especially modernizing and strengthening the agency.

Prevailing with Congress won’t be easy and must be considered Commissioner Hamburg’s top priority. At the same time, she must deal with growing unhappiness among FDA-regulated medical product companies.

Based on some recent FDA decisions (e.g. on three weight-loss therapies), many in industry believe FDA is erecting an insurmountable wall of trial design and safety requirements, all intended to slow or deny approval for large-population drugs. Yet, the blockbuster drug (rather than personalized medicine) will remain the industry’s primary business model for at least the next 10 years. Further, Americans still need safe and effective drugs that can treat hundreds of thousands of patients.

Similarly, there have been a number of skirmishes about review standards for medical devices. FDA has moved slowly, listened hard and made compromises. However, with some justification, industry still fears that proposed new standards and procedures will be expensive and delay approval of safe and effective medical devices in the US. FDA also finds itself being compared to the European system, where medical devices are approved far more quickly.

Current industry unhappiness might not be such a challenge for the Commissioner, except for its likely impact on user fee negotiations, agency funding, Congressional oversight and the national debate over how to stem the flow of American jobs and capital to Europe and Asia.  

Ultimately, the FDA’s “fight” with Congress and “fight” with industry come down to one issue: the creation of a 21st century FDA.

It won’t happen if Congress doesn’t fund modernization, tears FDA apart with investigations or relies too heavily on user fees. It also won’t happen if industry—which is the natural advocate for a more modern FDA—can’t work with the FDA to synchronize public health and safety concerns…with efficient and effective ways to review and approve new therapies.

 Steven

FDA and Congress: FY 11 Deficit Reduction Could Cut Deep   February 13th, 2011

Based on budget-cutting actions in the House of Representatives, the FDA is now vulnerable to substantial cuts in its current-year programs. This column analyzes the House situation for FY 11, based on analysis I have done for the Alliance for a Stronger FDA, which is the leading voice for increased appropriations for FDA. Read the rest of this entry

Will the New Congress Be Good for FDA-Regulated Industries?     December 19th, 2010

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. 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. Read the rest of this entry

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

The return of a Republican majority in the House of Representatives means an increase in Congressional oversight and investigations. This mirrors 2006, when the Democrats took back Congress and immediately started investigating the Bush administration. Once again, 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

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.

FDA: An Honest Broker on the Slow Path to Biosimilars

FDA Matters' enthusiasm for biosimilars is a matter of public record. The market will build slowly, but 10 years from now the new law will be seen as ushering in a new age of biopharmaceutical product development. FDA will present the next glimpse of the future on November 2 and 3, 2010, when it holds hearings on implementing the new approval pathway.

The key to the future will be the FDA's strong commitment to expanding prescriber and patient choice among biological products. FDA will be satisfied (and successful) if the new law stimulates biosimilars, bio-betters, and innovative new biological products, along with a dramatic increase in knowledge about the nature and characterization of biologic products.

Misunderstandings abound about the new law and how it is likely to reshape the biopharmaceutical landscape. Experts keep saying that innovator (reference) products have been granted 12 years of market exclusivity. Reading the sentences carefully, data exclusivity prevents biosimilar products from being approved through the new abbreviated biosimilars pathway for 12 years. It does not prevent approval of a biosimilar through a traditional biological license application (BLA).

There is also the perception that the biosimilars market will be limited to billion-dollar products and a few companies that have the capital to enter the marketplace. Despite this view, there are at least five or six companies ready to advance biosimilar and bio-better products over the next few years. More will come.

Over time, innovation will bring costs down and significantly lower barriers to market entry. Competition will bring prices down to competitive levels. Discounts may not be as low as those in the generic drug market, but significant savings will result from 20% to 30% discounts on drugs costing $50,000 per year and more.

We are told many things about the agency: it is going to lower standards, be extremely cautious, fail to develop adequate guidance for industry or proceed with no ground rules, etc. Passage of Hatch-Waxman 26 years ago elicited similar concerns. A quarter century later, that law has resulted in 70% of US prescriptions being filled with generic drugs.

The path to a more vigorous biopharmaceuticals market will not be easy. The law is not well-written and the patent provisions seem an additional barrier. FDA will be very cautious about the new approval pathway, but it may look favorably on biosimilars submitted as BLA's. Although I don't agree, it has been suggested that even a single serious safety problem for an approved biosimilar will kill the market. Also, at least one reimbursement expert has told me that a biosimilars market may never emerge because doctors lack financial incentives to use these products.

The Federal Register notice for next week's FDA hearings lists a careful series of questions upon which the agency wants comment. At the hearings, expect little, if any, feedback from FDA. They won't ask many questions either. At the risk of leaving everyone guessing, the agency will keep its own counsel, determined to be an honest broker among competing interests.

Guidances and regulations take years to develop and publish. FDA will proceed carefully and consistent with its public responsibilities. The impact will not be measured by how many products come through the new abbreviated pathway (perhaps not many) or how many products are deemed "interchangeable" (maybe none).

FDA's ultimate success will be the broad expansion of biopharmaceutical products. This will happen eventually, but patience will be required.

Steven

Background on the FDA hearing on biosimilars:

http://edocket.access.gpo.gov/2010/pdf/2010-24853.pdf

Information if you want to attend the hearing or watch the webcast:

http://www.fda.gov/Drugs/NewsEvents/ucm221688.htm

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. With this in mind, this column 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 »

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

March 21st, 2010

The long fight is over for follow-on biologic (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

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. FDA Matters believes there has been a lot of fuzzy thinking about what type of companies will be players and how they will position themselves. The Federal Trade Commission report, released last week, is just the latest illustration. Read the rest of this entry »

FDA and Quran Burning: Trouble Can Start With a Tweet

Bravo! Florida Pastor Terry Jones has decided not to burn a copy of the Quran. The next danger is that the Pastor's "success" will be seen narrowly as the unique confluence of 9/11, the Ground Zero mosque, and the readiness of millions to take to the streets at signs of American intolerance toward Muslims.

FDA Matters thinks the lessons are larger and urges FDA to pay attention to how this reflects changes in the way crises develop and decisions are made.

According to the Washington Post, on July 12 the Pastor sent a simple message on Twitter: "9/11/2010 Int Burn a Koran Day." From that beginning, he became the focus of international concern and one of the most watched people on the planet. All news sources—print, television and internet—were filled with stories about his intended actions. The situation most resembled a dramatic, high-stakes hostage negotiation. In a sense, it was, with Pastor Jones'copy of the Quran as hostage.

If we are imaginative, there is much more to concern us than Pastor Jones. We now know that one man's temper tantrum (or cause?)—distributed via Internet, Twitter, YouTube, 24/7 news outlets, etc.—can leave the world's leaders pleading for a favorable outcome. The power to capture the public eye, move public sentiment and galvanize the world...now belongs to all us. As Pastor Jones demonstrated, not everyone has the restraint to use that power responsibly.

In the late 1980's, AIDS activists staged a large demonstration that caused a multi-day lock-down situation at FDA. Patients and their friends were expressing their desperate need for access to drugs in development. It was a scary time at the FDA. No one wanted to create the precedent that FDA "would bend to a mob," but there also was a lot of sympathy for the plight of HIV patients.

Soon thereafter and over the next few years, FDA made a number of significant changes to the drug approval process. For example, the demonstrations eventually led to an accelerated approval process and "fast-tracking" of certain new drug applications. FDA began to treat surrogate endpoints seriously (e.g. CD4 viral load count rather than HIV disease progression). Most of these changes have been judged "good" with the passage of time, but there was a lot of uncertainty at the time.

With all the new avenues for communication, this scenario could easily repeat itself today on behalf of any number of diseases that are life-threatening or crippling. Could a group of parents with dying children try to force FDA to grant compassionate use access to a drug in pre-clinical (animal) testing? To make their point, the parents could create a vigil for the children with countdown clocks, while posting daily video showing their deterioration.

Yet another scenario might blend the skills of the Tylenol poisoner with the long-term persistence of the Unabomber. Every three months, anonymous videos might be posted that show gloved hands adulterating some additional batches of a food, drug or device. This would be a corporate nightmare that would also bring all FDA-regulated products under suspicion. FDA would be at the center of an enormous public health crisis.

I know I have not reflected the depth or breadth of challenges FDA could face. Hopefully, these few make the point that FDA is increasingly vulnerable as an agency. It must prepare for risks well beyond those faced by most federal agencies.

Commissioner Hamburg ought to meet soon with senior staff to review, extend, and refresh FDA's crisis plans. Even if they met two weeks ago, they should do it again because Pastor Jones has proven that the world has changed.

And while senior staff is having this discussion, they should also plan some simulations and practice drills. A crisis plan is only as good as the ability to implement it.

Steven

The Washington Post story describing the escalation after the tweet is at: http://www.washingtonpost.com/wp-dyn/content/article/2010/09/10/AR2010091007033.html?hpid=topnews

FDA’s “Summer of Safety Concerns”

One of industry's great fears is that FDA will become obsessed by theoretical or miniscule safety concerns and ignore the difficult realities of providing consumers with a varied and plentiful food supply and providing patients with effective medical therapies.

It is even possible to think this has occurred. It has been a long summer of media and Congressional attention to safety: whether drug manufacturing, medical products already on the market or Salmonella contaminated eggs. A closer look suggests to FDA Matters that theoretical safety risks and inappropriate FDA concerns about safety are not the issue.

As laid out in more detail in "Safe": Many Meanings Complicate FDA Policymaking, there is a strong tendency to think of FDA's safety mission as if it were one type of activity. There are at least six different meanings of "safe" that are relevant to FDA.

For example, we want our food to be "inherently safe," "safe from intentional and negligent contamination" and "safe from unintentional contamination." Much of FDA's attention to food safety this summer has been about unintentional contamination (seafood in the Gulf and eggs with Salmonella).

The agency needs more resources for food inspections and, in the case of eggs, it should benefit from implementation of new standards that were already being phased in. New food safety legislation should also help, but only if Congress appropriates the funds for it to work properly. Whatever substantive or political barriers exist to passage of this legislation, there does not appear to be widespread disagreement about FDA's role or the standards it applies in assuring food safety.

We want medical products (drugs, biologics and devices) to be "safe as tested pre-approval,""safe as used post-approval" and "safe as manufactured and distributed." None of this summer's medical product safety issues appear to be about nuances of safety or shifts in FDA's approach to balancing risk and benefits in these three areas of safety concern.

Concern over potential cardiovascular risks from the diabetes drug Avandia existed before its approval. I do not see this as an issue of FDA standards or focus—but rather conflict over the proper interpretation of studies and data. Policymakers and industry should be wary of drawing any larger meaning from this about FDA's policies on safety.

Much of the rest of the summer's medical product safety issues were about "safe as manufactured and distributed." There seems to be consensus—even among those with problems-- that real lapses occurred and were violations of reasonable safety policies. As described in prior columns, this requires CEO's to take manufacturing and distribution seriously, rather than for FDA to re-think its existing safety policies.

While this may have been FDA's "summer of safety concerns," there doesn't seem to have been any change in how the agency balances competing demands involving safety. As the FY 11 appropriations process comes to a conclusion this Fall, there is good reason to put more funding into safety analysis and enforcement. Drawing any larger conclusions is, at best, premature and probably unwarranted.

Steven

Since before Memorial Day, FDA Matters has blogged extensively about FDA and safety issues, although this was not planned. Here is a sampling of columns:

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

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

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

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

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 »

FDA to Industry: Contractors R U June 17th, 2010

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. Read the rest of this entry »

Hot Town, Summer in the City—2010 July 11th, 2010

For the news media, the only FDA story this coming week will be the two-day advisory committee meeting reviewing the diabetes drug, Avandia. Missing from public dialogue is the extraordinary (perhaps unprecedented) number of large, consequential projects that FDA will be working on this summer. Every part of FDA is involved in some initiative that could become a "game-changer" for the agency. Read the rest of this entry »

Benefit, Risk and the Coming Age of REMS August 8th, 2010

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

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

FDA’s Pivotal Role Fighting Bioterrorism and Emerging Infectious Diseases

With Congress out of session until September 13, the Executive Branch has the opportunity to gain extra column inches and media bandwidth. Thus, last week's report on medical countermeasures (MCM), released by HHS Secretary Sebelius, drew a lot of interest and a minimum of Congressional comment.

The Secretary released the findings and recommendations from a top-to-bottom review of the Department's efforts with regard to the development of MCM. In the view of FDA Matters, the report thrusts FDA back into its rightful place as a key agency deserving more resources and respect for its national security responsibilities.

MCM are products that will decrease morbidity and mortality from a bioterror attack or from naturally occurring emerging infectious diseases. Think anthrax or radioactivity from an improvised nuclear device for the first, think H1N1 influenza for the second.

Scientifically and medically, these are difficult products to discover and develop. Financially, they won't ever be developed without:

• federal assistance to promising research; and
  
• a strategic national stockpile and government contracts that will buy proven MCM's.
  

As with the larger promise of moving medical therapies from "bench to bedside," there is no progress without FDA. The agency encourages companies by helping them to define appropriate safety and efficacy endpoints for their particular MCM and works with them to resolve questions of animal models, lab standards, statistical plans, quality manufacturing, etc.  

Then, the agency evaluates the testing results and determines whether to approve the product. This work has an additional wrinkle. With most MCM's (maybe all) it is unethical to do human efficacy trials (e.g. intentionally expose a human being to anthrax to see if the MCM works). Instead, the agency (and the company) must make the difficult evaluation as to whether efficacy in animals is a sufficient surrogate for efficacy in humans.

The Secretary (and the underlying report) found that FDA's efforts in this area are insufficiently funded. Perhaps for the first time, there was a more global recognition of FDA's central role in making us safer from bioterrorism and naturally occurring emerging infectious diseases. The Secretary also recognized that FDA needs resources above its current level to do this job well.

The Administration placed a price tag--$170 million in funds to be available until expended--on the size and scope of the monies needed to upgrade FDA's efforts in this area.  The monies will come from dollars previously appropriated to HHS to combat pandemic flu. HHS and OMB have agreed that the monies can be transferred administratively as long as they retain their original purpose of helping to deal with pandemic flu.

However, the Secretary's recommendation is for the transferred funds to also be used for non-pandemic medical countermeasures. This requires a budget amendment to be sent to Congress to broaden the permitted uses of these funds. How likely is Congress to approve this? We probably won't know until after September 13.

What we do know for sure is that FDA can use the additional resources and America will ultimately be safer as a result.

Steven

FDA Matters' most recent (and still accurate) assessment of FDA and the FY 2011 appropriations process:

Update on FDA's Appropriation for FY 11 July 18th, 2010

On July 1, the House Appropriations Agriculture/FDA Subcommittee marked up it FY 11 bill. The bottomline was good for FDA: $2.571 billion, a $214 million increase over FY 10, about 9%. No further details will be released until the full committee marks up.

On July 15, the Senate Appropriations Committee marked up its version of the Agriculture/FDA funding bill. The good news is that the Senate agreed that FDA needs better funding….and provided $2.516 billion, a $158 million in new monies. This is a bit more than 6%. Here is FDA Matters' analysis of this critical budget battle. Read the rest of this entry »

For Those Who Don’t Work With Patients: A Reality Check

Guest Column: Summer, Camp, Kids, Cancer

By Margaret Anderson, Executive Director, FasterCures

While we focus on improving the efficiencies of the system that discovers treatments and cures for disease, there are untold numbers of people taking a medical treatment journey right now. For the kids partaking in the 28th year of Camp Fantastic in Virginia this week, they get to focus more on the fun, and less on the challenges of coping with a cancer diagnosis and with treatment. Camp Fantastic is a program of a nonprofit called Special Love that gives cancer families support.

I learned of this amazing place from Kathy Russell, who has been involved since its beginning and who also runs the Children's Inn at NIH. The NIH Children's Inn helps families with kids in treatment at the NIH Clinical Center to get a bit of normalcy in their lives by providing a warm atmosphere for them to stay in versus an isolating hotel room. The overriding philosophy is that families make a key difference in the lives of their sick children. The work they do represents the full spectrum of NIH investment – from bench to bedside.

By the end of my chat with Kathy, after I dabbed my eyes, I was ready to pack my bags and tell everyone I knew to come with me to help prepare Camp Fantastic and allow kids there to take a break from cancer and be just kids. This year there will be nearly 100 kids at Camp Fantastic between ages 7-17. Usually one-half of them are in active treatment and there are upwards of 60 medical professionals (in addition to countless other folks) who volunteer their time before and during the camp. They literally set up a mini-hospital on-site because it's in a remote location and far from a hospital with specialized pediatric oncology services. She told me of how kids get their bloodwork done in the am, and a van takes the samples into NIH to do labs and then turns back around with results and medication.

Every year, at least one child is usually transported from the camp in an ambulance or a helicopter to a hospital for further treatment, requiring diligent attention to medical details as well as a carefully thought through psychosocial plan of action to share that news with the other campers. Families are communicated with each day, and as you'd imagine many are nervous and excited about their kids being there. Some children participate while in their final stages of life.

Their families make the ultimate sacrifice by being selfless enough to share their children with others, so that their kids can live out their final hopes and dreams – the same dreams we all have. To do the things we dream of doing, especially those seemingly simple things associated with summertime.

Stories like this remind me of the passion and dedication of the medical research community, of the care providing community, and of the volunteer community. It's a reality check for me, and for those of us who work on policy-related issues. These kids and their families point out the obvious – that time is of the essence in all we are doing to get to faster cures.

It can be hard to make the FasterCures message personal at times as we deal with mostly macro-level issues, but hearing about Camp Fantastic reminded me why we do what we do. Because it's summer vacation time, and every kid (and for that matter, every grown-up) deserves a shot at creating their own lazy crazy hazy days of summer memories.

www.fastercures.org

With thanks to Margaret and Faster Cures for allowing me to reprint this from their blog.

Steven

One of my earlier columns for FDA Matters:

Patients Come First

November 11th, 2009

Most seriously-ill patients wake each morning wondering how they will surmount the day's challenges. They are concerned about the health of all Americans, but can't help being focused upon their own medical situation. Most of the people I know in the medical products industry wake each morning with the hope that their day's efforts can contribute to improving the health of all Americans, as well as provide specific benefits to seriously-ill patients.

The world-views of patients and industry are not dissimilar. They can share a dream (and an action plan)…if it is built on an unwavering commitment to patients coming first. Read the rest of this entry »

Late Friday Afternoon: FDA, Politics, and Scientific Integrity

When my Smartphone delivered an e-mail at 5:12 p.m. on Friday: "FDA approv…," I knew that FDA had just announced something controversial. All public relations people (including those at FDA) have been taught that late Friday is the time to release stories you don't want to receive much attention.

Indeed, it was the 5-day emergency contraceptive pill, Ella, that was approved. So far, FDA seems to have achieved its goal of less coverage. But I was left wondering if the announcement required that treatment and why it led one advocate to describe the decision as "further evidence that the FDA is committed to restoring scientific integrity in its decisions."

Abortion is, of course, one of the so-called "third rails" in American politics. For politicians, this means: if you touch it, you will get burned politically. It has never been easy for FDA either. For many years, they were caught in the middle of Congressional and societal fights over the abortifacient, RU-486.

As I have written before (link below), FDA has been a master of little-noticed decisions that create or re-position a disease category. With the new approval, they seem on relatively safe ground in deciding it is an emergency contraceptive. Apparently, there is a nuance as to whether the drug's mechanism of actions solely delays ovulation or also makes the womb less receptive to implantation. There may be a theological difference, but I don't see any practical difference.

Ella's approval doesn't seem to have been a hard decision and I can't imagine FDA found it particularly difficult. By announcing the decision late on Friday afternoon, they probably made it seem more consequential and controversial than if they had sent out a more complete press release at a time more conducive to news coverage.

That brings me back to whether this approval is really about "restoring scientific integrity" in FDA decisions. The comparison is being made to the controversy over Plan B, an emergency contraceptive with a much shorter window of efficacy than Ella.

The main issues for FDA regarding Plan B were: should the drug be available over-the-counter (OTC) without the input of a prescribing physician and whether it should be available OTC for women under 18. In my opinion, these were not primarily scientific issues, but social and societal ones. It is completely unlike the current approval of Ella, which will be dispensed only by prescription and doesn't raise the same societal issues or maybe doesn't raise any at all.

I am not defending the Bush administration's handling of Plan B. They could not have done a worse job and they deserve the criticisms they received. But the administration was probably right that the issues were not primarily scientific ones and required input from politically-accountable levels of the government and elected officials—people who have responsibility for public policy that impacts social and societal interests. The Bush Administration should have been more honest about that, rather than pushing the decision down to FDA officials.

Apart from a couple of decisions like Plan B, which are rare, controversial and were badly mishandled, I don't see that the agency made scientific decisions during those years that lacked integrity. There are always controversies about application of "safe" and "effective" standards….and accusations that science is being ignored. Ella is science-based decisionmaking and business as usual for FDA, not some restoration of agency integrity.

Steven

The FDA press release and the WP and NYT coverage:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm222428.htm

http://www.washingtonpost.com/wp-dyn/content/article/2010/08/13/AR2010081305098.html

http://www.nytimes.com/2010/08/14/health/policy/14pill.html?scp=1&sq=ella%20contraceptive&st=cse

An earlier column that is relevant. It includes a brief comment on FDA and pregnancy.

FDA: Invisible Arbiter of What Constitutes Disease

November 19th, 2009

According to Wikipedia, "disease" refers to any condition that causes pain, dysfunction, distress and social problems. What constitutes disease is more varied and changeable than this definition might suggest.

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

Benefit, Risk and the Coming Age of REMS

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

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

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

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

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

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

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

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

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

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

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

Steven

Some earlier related columns:

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

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

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

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

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

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

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

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

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

For Twenty-Five Million Zebras: New Hope for Therapies

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

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

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

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

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

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

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

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

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

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

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

Steven

When Abbreviated May Not Mean Faster or Easier

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

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

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

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

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

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

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

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

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

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

Steven

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

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

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

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

Hot Town, Summer in the City—2010

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

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

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

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

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

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

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

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

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

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

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

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

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

Steven

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

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

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

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

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

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

FDA, 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

Is the New FDA Different than the Old FDA?

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

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

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

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

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

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

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

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

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

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

Steven

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

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

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

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

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

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

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.

Dissent and Efficiency: Difficult Trade-offs for FDA

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

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

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

FDA Matters sees three needed changes at FDA:

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

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

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

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

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

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

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

Steven

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

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

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