FDA Matters Mailbag: Hatch-Waxman, Biosimilars, User Fees and More

Over the last month, FDA Matters has covered a wide-range of FDA-related topics: the agency, industry, and Congress, as well as medical innovation, user fee reauthorization legislation, food safety and post-market surveillance. The response has been great: FDA Matters has many new readers and I received a number of interesting questions.

Today’s column touches on biosimilars, Hatch-Waxman, user fees and FDA management. Keep the questions coming!

Is FDA becoming too large for food, drugs and medical devices to be in the same agency?

Last summer, the Commissioner re-organized her office to better manage the growing responsibilities and complexity of the agency’s work. She divided the agency’s work into four parts:

• food and veterinary medicine
• medical products
• global outreach and inspection, and
• administrative matters overseen by a chief operating officer 

The key is that each of these individuals has line authority to manage their part of the agency, rather than being a staff advisor to the Commissioner.  

With specific regard to foods, there are proposals to move the Center for Food Safety and Applied Nutrition (CFSAN) out of FDA. I believe the Center is best served by being part of the public health focus of FDA.

How do Europe and the US compare in their approaches to biosimilars?

Both the European Medicines Agency (EMA) and FDA are acting cautiously, but in different ways. Europe has focused on a limited number of reference products, building their knowledge and experience one therapeutic category at a time.

In contrast, FDA has already met with sponsors to discuss 11 reference products, presumably covering a number of therapeutic categories. Given FDA’s broader approach, proceeding case-by-case with strong scientific requirements is the best way for FDA to acquire knowledge and experience.

A different comparison was also posed to me: an eager EMA versus a reluctant FDA.  In less than two years, FDA has produced multiple policy speeches and articles, three guidances, held multiple sponsor meetings and allowed several sponsors to begin work. I assure you: FDA is fully committed to biosimilars!

As an aside, anyone familiar with the lack of FDA guidance on product-related social media can tell you how FDA behaves when it is reluctant to act. It looks quite different.

If the user fee reauthorization legislation has the potential to be a vehicle for any FDA-related provision, might Congress re-open Hatch-Waxman?

I shudder at the possibility, but can’t rule it out. I asked a knowledgeable friend what he would propose if given the chance to amend Hatch-Waxman. His reply: get FDA out of the patent enforcement business, yet assure generics the equivalent of the 180-day exclusivity if they win in court.

Since this would benefit generics, a trade-off for innovators could be longer exclusivity for new molecular entity (NME) compounds that lack intellectual property (IP) protection. It might be the same 10 years they receive in the EU or the 12 years for biologics. Similarly, a stronger incentive than 5 to 7 years is needed to generate interest in 505 (b)(2) drug applications in the absence of IP protection. 

I’m not suggesting this, but thought it interesting enough to give his ideas some visibility.

Companies are telling me: it’s hard to justify investing in the US biosimilars market because of the resources it will require. Why is FDA Matters so optimistic?

I hear some of this, too. Certainly, the first generation of biosimilar applicants (and there seem to be plenty of them) are going to pay more--and live with more uncertainty for a longer period of time-- than those that start 5 years from now when costs have dropped.

However, those who are successful are going to be rewarded, as I explored more fully in How Biosimilars Will Transform the Marketplace. Put simply:

• If the first biosimilar approvals from FDA are for solid products with good data and fair pricing, then hospital purchasing groups, pharmaceutical benefit managers and formulary committees are going to move significant market share away from the reference products.

• In multi-product categories, the market shift may be even greater because there will be therapeutic substitution, not just substitution of the biosimilar for the reference drug.

 I look forward to more reader questions!

Steven

FDA Guidance on Biosimilars: The Two Minute Version

If you are in the business of developing biosimilar products—or thinking about it—then you have to read all three guidance documents published by FDA on February 9, 2012. They provide essential (but not complete) instructions for how to construct and implement a biosimilar development plan.

For everyone else, FDA Matters is providing the short version. Why take an interest? Because over the next 5 to 15 years, biosimilars are going to dramatically transform the marketplacefor biological products, creating new winners and losers. Also, these new rules are going to lead to new, groundbreaking medicines…and not just less expensive versions of old ones.

Nearly two years ago, Congress passed the “Biologics Price Competition and Innovation Act” (BPCIA) to create an abbreviated approval pathway for biosimilars, which are highly-similar copies of already marketed, complex, large molecule biological products. This is a distinct from making exact copies (generics) of relatively simple, small molecule drug products, whose abbreviated pathway to market was created in 1984 (under the Hatch-Waxman legislation).

Even without FDA formal guidance, companies have begun the process of entering the biosimilars market in the US. Thus far, FDA has received early-stage meeting requests for 35 proposed biosimilars that would relate to 11 reference products (innovator biologic products that are already on the market). About 60% of those meetings have been held and 9 investigational new drug (IND) applications have been received.

The three FDA guidance documents, described in this FDA Fact Sheet, are:

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

As FDA Matters envisioned when the BPCIA was passed, FDA will handle every biosimilar application on a product-specific basis. Two major concepts embody this approach:

• The agency expects sponsors to take a “step-wise approach,” starting with the structural and functional characterization of the biosimilar and reference molecules, then determine “the residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty.” The strength of the analytic proof of similarity and the degree of uncertainty will determine the required amount and type of animal and human testing.
• The agency plans to look at the “totality of the evidence” presented by each sponsor.  Every application must include certain elements--structural and functional characterization of the molecule, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and clinical safety and effectiveness data—but they will be weighed by the overall degree to which they support similarity, rather than by any pre-determined formula.

The law also allows for biosimilars to be deemed “interchangeable” with the reference product. In these guidance documents, FDA has effectively said that sponsors must establish biosimilarity first, and then present additional evidence of interchangeability.

In sum, the guidance documents lay out a daunting, but still feasible pathway for approval of a biosimilar. The first approvals will come slowly over the next 2 or 3 years, and then accelerate after FDA and sponsor companies have more experience.

What about the part where the FDA guidance documents on biosimilars eventually result in new, groundbreaking medicines? The key to approval of a biosimilar is to be able to characterize the structure and function of specific biological molecules and, also, to define the conditions under which the human body is likely to reject a large molecule biologic as a foreign substance (immunogenicity).  

These requirements are forcing companies to invest hundreds of millions of dollars in order to better understand human biology and therapeutic biological products. That knowledge is going to make it possible to find and create wholly new therapies, as well as develop significantly better versions of existing medicines.

We are likely to have biosimilars approved long before this impact hits. However, in about six to ten years, we should see the start of a wave of groundbreaking new medicines that emerge from knowledge that was gained as a by-product of creating biosimilars.   

Steven

For a longer commentary on the new biosimilar guidances, I recommend: First Bio-Similars Guidance Issued by FDA by James Czaban at the Wiley, Rein law firm.

FDA and Industry Relations: A Mix of Frustration and Respect

There is no one answer to the question: what is the state of FDA-industry relations? FDA Matters hears some say: FDA does what industry asks it to do, the agency is a puppet. Others say that FDA is obstinately blocking industries’ path to new, better and innovative products. Yet others say FDA is misguided at points, but well-intentioned and most often right.

The state of FDA-industry relations turns out to be particularly important in 2012. As part of the user fee reauthorization legislation, Congress will be faced with non-user fee amendments affecting every aspect of FDA’s mission, programs and decisions. Industry will be advocating for some; trying to block others, based in part on its relationship with FDA.   

Looking at the situation superficially:

• FDA and the biopharmaceutical industry would appear to be on good terms. Negotiating the language and terms of the Prescription Drug User Fee Act (PDUFA) reauthorization went relatively smoothly and the agreement addresses a number of industry concerns
• FDA and the medical device industry would appear to be on shaky terms, at best. The negotiations on the reauthorization of the Medical Devices User Fee Act (MDUFA) have been extended and contentious. Only in the last few days has there been an agreement in principle on a proposal for MDUFA reauthorization.    
• FDA and the food industry would appear to be on excellent terms. The Food Safety Modernization Act (FSMA) passed in late December 2010. Consumers and most of industry supported the legislation and there has been cooperation by industry on implementation.

In each case, things are more complicated beneath the surface.

Drugs and biologics. Industry is broadly supporting FDA’s proposal for reauthorization of PDUFA, having helped negotiate a number of provisions that will improve the drug development, review and approval model used by the agency. When it comes to the additional amendments to be considered by Congress, the unanimity is already breaking down.  

For example, during 2011, The Biotechnology Industry Association (BIO) released a series of proposals for improving FDA. FDA Matters praised BIO for putting forth a bold agenda, while seeing its centerpiece proposal, a new “progressive approval” pathway, as only a starting point for discussion. In a tacit acknowledgement of FDA opposition (not publicly expressed by FDA) and industry dissension, BIO has recently started advocating instead for changes in the existing FDA accelerated approval process.

Medical devices. The difficult relationship between FDA and the medical device industry is long-standing. Both sides have been able to talk, often quite productively, but ultimately the device industry returns to its default position that the FDA needs to be held accountable for its inconsistent guidance and lack of timeliness in its reviews.

The just-released MDUFA reauthorization agreement in principle (in the form of FDA meeting notes) looks like it can bridge the gap that has divided FDA and the medical device industry…or at least that’s my interpretation of industry and FDA press statements.  However, Congress may yet amend the proposal if industry proves divided  in its support.  As to non-user fee amendments in the medical device area, it is to be assumed (given the history) that they will tend toward contentious, with FDA on the defensive.

Food.  Public discussion of the user fee reauthorization legislation has focused on drug and medical device issues, but nothing prevents food from becoming part of the mix. Any issues or amendments left over from the FSMA debate are fair game, as would anything that went into the final legislation despite objection from FDA or some interest group.  

One of the most prominent “leftover” issues is the extent of fees collected from the food industry to support FDA activities (merely calling them “user fees” is enough to generate a heated discussion). While the issue may come up regardless, there is a strong chance that the President’s budget request will contain legislative proposals for new food fees, starting in FY 13.

Conclusion. As the user fee reauthorization legislation moves forward, it may be too much to ask for fair debate, FDA-industry harmony, and quick resolution of outstanding issues. Time is of the essence—the real deadline is closer to July 1 than September 30

It would also be wonderful if all parties (including Congress and industry) would stick with the issues and refrain from bashing FDA. 

Steven

User Fee Reauthorization: FDA Is In Trouble If 2007 Repeats Itself

Starting this week, the House will hold hearings on reauthorizing the drug and medical device user fee programs that fund one-fourth of the agency. While user fees have become largely non-controversial, this “must-pass” legislation is Congress’ opportunity to consider dozens of other FDA issues, some controversial and many time-consuming.

During the last user fee reauthorization in 2007, multiple non-user fee issues delayed enactment of a new law until September 27, just a few days before the start of the new fiscal year. In FDA Matters’ view, FDA is in serious trouble in 2012 if it once again takes until September to complete the user fee reauthorization legislation.  

There are two user fee programs up for reauthorization this year: the Prescription Drug User Fee Act (PDUFA) and the Medical Device User Fee Act (MDUFA). In addition, two new user fee programs have been proposed by FDA. One covers generic drugs and the other biosimilars and interchangeable biologics.

If only these four user fees were at stake (two renewals, two new), Congress could conceivably be finished by July 1, 2012. This would be optimum for giving FDA enough time to invoice and collect the user fees for the coming fiscal year (FY 13). It would also give FDA time to start making new hires and to work on any additional requirements in the new law. A lot of things could be in place by the start of the fiscal year on October 1, 2012.

However, almost no FDA legislation has passed since the last reauthorization five years ago. Pent-up demand for FDA amendments is enormous and delays are to be expected. July 1 does not look like a realistic target to complete legislation.

What happened in 2007 is beyond instructive, it is frightening. As a general precaution, FDA left many staff positions vacant during 2007, just in case the user fee monies were not renewed. As required by law, FDA compiled lists of employees it could not pay if user fee monies were not available on October 1, 2007. The agency narrowly avoided actually having to send out RIF (lay-off) notices to individual employees. While the RIF process was a formality, this created a great deal of distraction within the agency. 

Simultaneously, the timing for invoicing companies and collecting fees was disrupted and fee revenue was not collected, as it usually is, by October 1. While FDA was dealing with this (which required delays in hiring), it faced the harsh reality that many provisions of the new law became effective immediately and had to be addressed with existing staff.

Memories seem to vary about the impact in 2007. I remember significant problems; others have told me the disruption was not consequential. In fact, there is direct evidence of the impact.

Below is a slide from a December 2011 presentation given by Dr. John Jenkins, head of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER). His intent was not to focus on 2007 or to draw comparisons, but the point seems quite clear.

The chart shows the number of pending drug applications on which FDA was behind schedule (as judged by the timeframes established in the user fee law). The green bars represent the most important applications, those involving new molecular entities (NMEs). The light blue bars represent other drug and biologics applications, while the violet bars represent applications for additional efficacy indications.

A backlog started to form in the second half of 2007. It increased significantly and lasted for more than 24 months. There may well have been other factors at work, but it seems more than a coincidence that the problems started at the same time as the disruption caused by the new law.

If 2012 becomes a repeat of 2007, then FDA will find itself under withering criticism later this year for not reviewing innovative drug applications in a timely fashion. Medical device are likely to be similarly impacted. FDA will be unhappy, companies with pending applications will be outraged, and patients will be short-changed as potential new therapies are delayed.

Congress needs to commit to speed up the process, minimize amendments, and make new provisions effective six months or a year after enactment. What is possible by July 1 is a House-Senate agreement on a very limited piece of non-controversial legislation that addresses user fees and perhaps one or two other items.

It is a disservice to FDA and the public health for Congress to do otherwise.

Steven

The State of the FDA—January 2012

FDA is the only federal agency that touches the lives of every American several times every day. Its remarkably broad mandate includes all medical products and 80% of the nation’s food supply, plus countless other products. Despite this, when the President delivers his State of the Union (SOTU) address to Congress this week, it is unlikely that FDA will rate a mention.

FDA Matters will instead provide its second annual “State of the FDA.” As reflected in last week’s column, FDA did well in 2011, but one year’s progress does not change the continued precarious state of the FDA. Here is our analysis:

Strengths: FDA’s most important strength is the dedication of the agency’s staff  and the leadership of Commissioner Hamburg’s team. In the current environment, their efforts are invisible to the public they serve and largely unappreciated. If safe foods and safe and effective medications are important to you, say “thank you” to the FDA staff that make it possible.

The agency’s independence is another key strength of the FDA. At the moment, many FDA observers don’t see it that way, viewing the HHS Secretary’s decision to overrule FDA on Plan B as evidence that the agency is weak and dependent. However, Plan B is a ‘one-of-a –kind” controversy, presenting uniquely difficult and combustible issues that aren't present in 99.9 percent of FDA's decisions. If you look at the totality of FDA actions, the agency is remarkably independent from HHS and the White House. Rather than a weakness, this is one of the agency’s strengths.

Weaknesses: Despite a number of recent, laudable efforts at improvement, the FDA is still disorganized and largely ineffective in communicating its messages to the public, media, stakeholders and Congress. Notably, an analysis published in the journal, Medical Care, last week concluded that: although some [FDA] communication efforts had a strong and immediate effect, many had little or no impact on drug use or health behaviors and several had unintended consequences.

FDA’s information technology (IT) systems continue to be grossly inadequate for an agency with such large, far-flung and complex responsibilities. Some progress has been made with analytic data bases, such as the Sentinel program to track post-market safety, and with data bases that improve the flow of information within the agency and between field and headquarters. The October 2011 appointment of a new chief information officer with industry experience is a hopeful sign.

Opportunities: The promise of science has never been brighter. And Dr. Hamburg, to her credit, has made it a priority to improve the agency’s scientific bench strength—better credentials, better training and better tools.

This provides FDA and the medical products industries with the opportunity to forge a new “social contract” with regard to scientific standards and product approvals. FDA must commit to becoming less formalistic and bureaucratic in its dealings with companies. It must demonstrate (not just accept) that advancing medical innovation is an integral part of the FDA’s role in promoting public health. In turn, industry needs to accept that “science, fairly evaluated within predictable guidelines,” is an appropriate expectation as opposed to a system based on short-cuts to market and ill-defined, “leap of faith” assumptions about safety and efficacy. In addition, industry bashing of FDA needs to end. It is counterproductive to everyone’s interests.

Equally promising is the opportunity to significantly upgrade the safety of the American food supply. Even with the devotion of FDA staff to this cause, we are lucky that the reported levels of foodborne disease and product adulteration are not higher. The year-old Food Safety Modernization Act (FSMA) is, by general agreement, a blueprint for moving to a new level, one where a safer food supply reflects smart decisions.

Threats: The largest threat to FDA is inadequate funding. As science has become more complex, industry more global and information more integral to every human interaction, FDA oversees a rapidly expanding portfolio of products and responsibilities. Even without the threat of budget cuts facing all federal agencies, it would be hard to grow the FDA budget enough to stay ahead.

A related threat is the potential for massive expansion of FDA’s unfunded mandates during Congressional reauthorization of the drug and medical device user fee programs. FDA is almost certain to be given new (and needed) authority for drug import inspections and drug shortages. In addition, Congress will consider and most likely pass a dozen or more other new programs or significant changes in FDA regulation. FDA will almost certainly have to implement these new requirements without additional appropriations. 

Steven

For those who may be interested, here is a link to “The State of the FDA—January 2011” http://www.fdamatters.com/?p=1240.

Medical Innovation, Food Safety, and Imports: Did FDA Have A Good Year in 2011?

 Before turning to 2012, FDA Matters wanted to take one more look at FDA’s performance in 2011. So much happens at FDA that it’s easy to lose perspective. And no matter what the agency does, somebody will be unhappy. So, should Commissioner Hamburg feel good about the last 12 months?

FDA Matters thinks it comes down to how well FDA handled the three most important challenges it faced:

• improving the medical product review process, including stimulating innovation;
• implementing the Food Safety Modernization Act; and
• advancing the agency’s ability to assure the safety of imports.

Before exploring these particulars, FDA Matters feels FDA staff and Dr. Hamburg should be applauded just for surviving the daily grinding pressure of the agency’s workload. As I have noted previously, FDA’s greatest strength is its people.

Medical Product Review Processes. Was it a good year? The approval process for drugs, biologics and medical devices elicited widespread criticism that FDA was too slow, too risk-averse, underweighted patient benefit, and was demanding certainty where none was possible. The unhappiness was constant and palpable from medical device stakeholders; more muted, but still quite strong among bio-pharmaceutical stakeholders.

As the year went on, this critique of the agency increasingly coalesced under the rubric of innovation. Specifically, FDA was accused of creating processes and making decisions that stifle American innovation and cost American jobs.

FDA formulated its response in several ways:

• Integrated innovation-oriented benchmarks and goals as core components of both prescription drug and medical device user fee negotiations,
• Outlined innovation initiatives in February 2011, CDRH Innovation Initiative, and October 2011, Driving Biomedical Innovation: Initiatives to Improve Products for Patients,
• Appointed Stephen P. Spielberg, MD., PhD, an academician and industry veteran as Deputy Commissioner for Medical Products with the intent that he would focus his efforts on promoting medical product innovation, and
• Focused public attention that 35 new innovative medicines were approved during fiscal year 2011, a notable increase over the prior year.

Optimistically, I believe these actions are the start of a turning point for the agency. The largest barrier is not agency leadership’s willingness to promote innovation…rather it is that combining public health and innovation requires a new identity for the agency, something that can't happen overnight.

Food Safety. Was it a good year? At the very end of 2010, Congress passed the Food Safety Modernization Act (FSMA), which creates a sophisticated risk-based food safety system that stretches from the farm to our tables. The new law created or enhanced FDA authority in the following areas: prevention, inspection and compliance, response to problems, imports, and enhanced partnerships with other food safety agencies.

Implementing the new law is a complex multi-faceted task that has been made even more difficult by inadequate funding. Further, many of the new law’s mandates became effective quickly, leaving little opportunity for manpower and IT resources to be mustered to the tasks.

The agency just released its one-year progress report and there seems to be general consensus that the agency has done a tough job well. Year two (2012) will be at least as challenging, but we are definitely one-year closer to a safer food supply.

Imports. Was it a good year? The third major challenge to FDA in 2011 was continuous rapid globalization of the world markets for food, drugs, and medical devices. Almost every country in the world produces raw materials, ingredients or finished goods that become part of imported products regulated by the FDA.  

In July 2011, the FDA issued a special report, Pathway to Global Product Safety and Quality, which describes the enormous impact of globalization on FDA-regulated products. FDA is responding through:

• closer partnerships with its foreign counterparts and public-and private-sector third parties,
• development of global data information systems,
• continued expansion of its capabilities in intelligence gathering, and
• allocation of agency resources based on the risk of a food safety problem.

During 2011, the agency further expanded its network of overseas offices and reorganized its headquarters oversight. The latter was accomplished by appointing Deborah Autor as the new Deputy Commissioner for Global Regulatory Operations and Policy.   

Conclusions. In upcoming columns, we will be detailing the challenges facing FDA in 2012. Meantime, we urge Dr. Hamburg and all of FDA to take a moment to think back with pride to 2011. You had a good year.

Steven

Post-Market Safety: Can Sentinel Do Some of the Heavy Lifting?

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

This column first appeared on June 21, 2011. It is one of my favorites from last year.

Understanding FDA—Its Strength Is Its People

Science is essential and rules and regulations must be followed…but ultimately it is the people of FDA who determine whether the agency functions well and acts in the best interests of the American people.  For that reason, a recurrent theme in FDA Matters is the importance of FDA employees. Their jobs are much more difficult than most of us imagine.

Consider the oft-expressed paradigm: FDA is committed to science-based decisionmaking. Yet, science doesn’t exist in a pure, understandable, easily accessible and unassailable form. Neither do laws and regulations. While law and science are fundamental to FDA decisions, only people can actually make the decisions.

During 2011, FDA Matters explicitly looked at the role of staff three times.

The first column asked: Will the Real FDA Please Stand Up?  It was in response to a widely circulated e-mail appealing for public support to prevent the firing of “courageous, honest FDA scientists who risked their careers to save lives by informing Congress about serious safety concerns involving dangerous, FDA-approved drugs and medical devices.”

Whistle-blowing is sometimes necessary. However, the image of a corrupt, politicized FDA cynically suppressing dissent and putting the American people at risk is inconsistent with the FDA that I have known and followed for over 30 years. Yet, I acknowledged that the claims made in the e-mail are persistent and come from many sources.

Exploring this in the column, I concluded that FDA is making progress in handling dissent and in encouraging managers to be more open-minded. While FDA makes mistakes, there is no conspiracy. The agency is fully committed to serving the American people. 

My second column, People, Not Science, Make Decisions, looked at why decisions take so long, especially product approvals. When asked about bottlenecks at FDA, I had to admit that people slow the process down. I pointed to three factors that cause delays:

• FDA lacks sufficient resources.  FDA has been dramatically understaffed for decades, although better funding in recent years has improved the situation. Even still, new demands on FDA are increasing faster than staff can be added.
• FDA’s culture promotes intensive scientific discussion.  Objective science-based decisionmaking is a goal, not a reality. People arrive at decisions with a bundle of perceptions and experiences that render their judgment subjective. Yet, they wouldn’t have much to contribute without those experiences.
• Science has become more complex and results often unpredictable. Life sciences’ products are increasingly based on cutting edge discoveries. It takes more time, more thought and more knowledge on FDA’s part to make a good decision about them. 

Finally, I devoted a third column, FDA and Things that Might Go Bump in the Night, to exploring what happens when FDA staff has to decide the fate of breakthrough technology that could bring great benefit or great sorrow to humankind. In the current context, I had nanotechnology, genetically-engineered (GE) animals, and synthetic biology in mind.

Thirty years ago, FDA gave a cautious “yes” to the first biotechnology studies that eventually became important medical products to treat cancer, arthritis, MS and many other diseases. The world is a better place as a result.

In retrospect, the decision was right, but at the time, this wasn’t clear. Scary visions of mad scientists and technology run amok were powerful forces in the early days of biotechnology. In response, FDA staff took great care in setting up an appropriate regulatory environment.

Conclusion: Based on my experiences working with FDA and as expressed in these three columns, I believe that FDA staff--the people contributing to and making the decisions at FDA--are its strength. While they are human and make mistakes, FDA’s employees are smart, conscientious and committed.   

Steven

FDA and Congress: Prospects for 2012

Barely more than a year ago, the US experienced a “wave” election—sweeping a Republic majority into the House of Representatives and reducing the Democratic majority in the Senate. As a result, FDA faced a Congress in 2011 that contained fewer friends and less support than previously.

The consequences, thus far, have been small. Congress became so absorbed with deficit reduction that it accomplished little else this year and spent almost no time on FDA issues. Circumstances will change this in 2012 and, fortunately, we have strong clues about Congressional attitudes and priorities.

At the end of 2010, FDA Matters devoted six blog columns to examining the impact of the election on FDA and its regulated industries. As predicted, Congress was more interested in deficit reduction in 2011 than any other topic. This shows no sign of abating.

For FDA, this means constant pressure from Congress on funding, particularly from sequestration and other threats of across-the-board cuts in federal spending. FDA’s best position is always to have its needs evaluated on an individual agency basis—rather than being part of a larger funding action.

Congress chose not to address FDA’s FY 11 appropriation in the post-election session. Instead, it addressed this in April of 2011 on fairly favorable terms to the agency.

Similarly, FY 12 appropriations demonstrated that Congress was still receptive to partially meeting FDA’s growing resource needs, but it became clearer that future funding increases will be even harder to get. Arguments for FDA being an exception to deficit reduction will be made often next year by agency supporters within Congress and by outside advocates.

In general, very little legislation passed Congress in 2011 and virtually none without bi-partisan support. FDA Matters pointed out that achieving such consensus was possible on FDA issues when Democrats from technology-oriented regions joined with Republicans on positions that could enjoy industry/patient or industry/consumer support. This approach did not produce any legislation in 2011.

However, technology-oriented Democrats are likely to join Republicans in shaping the user fee reauthorization legislation, which Congress “must-pass” in 2012. It seems certain that the bi-partisan pathways will produce most of the legislation, including new authority for drug import inspections, incentives for development of antibiotics and provisions to address drug shortages.

I expected a substantial ramp-up of Congressional oversight and investigations of FDA and regulated industries, which never materialized. There were a few hearings, but never the vehemence or persistence that would have represented a major change from the previous Congress.  I still believe there will be an uptick in these activities, but most likely it will be deferred until late 2012 or 2013, after Congress adopts the user fee reauthorization legislation.

A final column last year asked the provocative question: will the new Congress be good for FDA-regulated industries? Republicans generally want federal regulations and regulatory agencies trimmed back significantly. In contrast, FDA-regulated industries generally want more flexible regulatory requirements and greater certainty in their implementation, but are not interested in eliminating FDA’s regulatory responsibilities or limiting its ability to assure public health and safety.

So far, this Congress has not come to a firm conclusion about FDA. It has not embraced FDA as an essential government service—like national defense and air-traffic controllers—but neither has it marked FDA as a particular target to starve, roll-back, harass or marginalize.

The deciding factor may be how FDA responds to Congress’ insistence that FDA be a positive force in the advancement of American innovation and a contributor to US competitiveness. This is precipitating an identity crisis at FDA, which the agency is working hard to resolve.

If FDA succeeds in integrating innovation into its mission, priorities and processes, then Congress will be able to see FDA (and the support it enjoys) as being essentially different than other regulatory agencies that do not have widespread public support.  This is the optimum position for FDA in its relationship with Congress.

Steven

Beyond Plan B: Scientific Integrity and a Possible Third Class of Drugs

Patient access to the emergency hormonal contraceptive “Plan B One-Step” has been one of the most combustible issues ever faced by FDA. It received more attention last week when FDA approved expanded access for adolescents under 17 and HHS Secretary Katherine Sebelius promptly overruled the agency because she found inadequate scientific support for the decision. (For my readers outside the US, here is a New York Times article that provides background).

FDA Matters wonders: has FDA’s scientific decisionmaking authority been thwarted in some lasting way, as some have claimed? Is it time to reconsider proposals for a new category of drugs for which pharmacists are the gatekeeper?

Under the Federal Food, Drug and Cosmetic Act and other laws, the Secretary of HHS has the legal authority to make virtually all decisions within the Department’s jurisdiction. Most of this authority has been delegated to subordinates, including the FDA Commissioner, although the delegation can be withdrawn at any time. No one remembers an instance in which the Secretary explicitly overruled FDA.

Was there a lapse in communications between FDA and HHS? Normally, the Secretary and the Commissioner (or their staffs) discuss controversial decisions before they are made and a compromise reached. Had this occurred, FDA would have announced that compromise as the agency’s decision and taken the heat for ignoring its advisors and staff.  

The alternative explanation, which I hope is true, is that there was an understanding that FDA’s voice should be heard and its integrity preserved, while the Secretary would take the heat for the decision by overruling the agency. This would be consistent with an approach that Commissioner Hamburg has championed: that government should be more honest and transparent about disagreements, as long as everyone understands that someone with decisionmaking authority will actually make a decision.

Either way, it is important to recognize that Plan B has proven to be a “one-of-a-kind” controversy, presenting uniquely difficult issues that aren’t present in 99.9% of FDA’s decisions. I see no reason for commentators to be writing, as one did:  “FDA’s medical and scientific integrity has been forever blighted by these frankly political decisions.”

Secretary Sebelius is not going to make a habit of questioning the scientific support for FDA’s decisions. Nor have we any reason to fear the death of FDA’s integrity or to conclude that it can no longer be a scientifically-driven regulatory agency.

Leaving aside the merits of either FDA or HHS’s position, the Plan B controversy provides an impetus to consider whether there should be a third class of drugs that are neither prescription-only (Rx) nor over-the-counter (OTC). The day after the HHS decision, John Jenkins, director of FDA’s Office of New Drugs, suggested just such a connection between Plan B and a potential third class of drugs known as “behind the counter” drugs (BTC).   

BTC, which has been discussed for decades, relies upon pharmacists to dispense these drugs without a prescription and independent of a physician-office visit. Pharmacists are the most widely distributed of all health care professionals, as well as the most readily accessible. BTC would empower them to provide additional education, monitor appropriate use and discourage misuse for a wide variety of drugs. 

Currently, OTC products containing pseudoephedrine are handled as BTC because of their potential use in making methamphetamine. According to Dr. Jenkins, statins are potential candidates for BTC status, as might other drug classes where petitions for Rx to OTC switches have been denied but there is still potential for safe patient self-treatment without a physician office visit.

In sum, accessibility to the emergency contraceptive Plan B continues to be a disruptive and controversial issue for FDA. However, this is a unique issue and there should be no continuing damage to FDA because the agency was overruled by HHS. A third class of drugs could evolve out of this that might be beneficial to patients across a number of diseases and drug classes, including hormonal contraceptives.

 Steven

Bold Discussions: Possible New Approval Pathways for Breakthrough Drugs

For discussion purposes, let’s assume that there is a broad consensus that patients would benefit if new drugs and devices could get to the US market sooner. Current market barriers can be fearsome: long timeframes, high cost and regulatory uncertainty.  How can we fix this problem? What costs and risks are involved in getting products to patients faster?

These are old questions, renewed this year by the Biotechnology Industry Organization’s (BIO) proposal to create a “progressive approval” process. This is controversial, but also worthy of widespread discussion. FDA Matters finds itself interested and open-minded about ways to permit earlier market-access if patients will benefit and the safety risk minimized.

Currently, FDA has several mechanisms for helping drugs move faster through the approval process, but only one might be said to be an alternative pathway. FDA describes it as follows:

ACCELERATED APPROVAL:  [I]n 1992 FDA instituted the Accelerated Approval regulation, allowing earlier approval of drugs to treat serious diseases, and that fill an unmet medical need based on a surrogate endpoint….For example…FDA might now approve a drug based on evidence that the drug shrinks tumors because tumor shrinkage is considered reasonably likely to predict a real clinical benefit [e.g. prolonged survival].

Since creation of the program, FDA has granted an average of about four accelerated approvals to drugs each year, sometimes for more than one clinical indication. More than half of these indications have been shown subsequently to have clinical benefit and FDA has converted the approval from accelerated to regular. Others accelerated approval drugs are still being studied and a few have been withdrawn.  

FDA has itself shown interest in moving beyond accelerated approval. Early this fall, FDA released a report, Driving Biomedical Innovation: Initiatives to Improve Products for Patients. In a section entitled “Expedited Drug Development Pathway,” the agency observes:

Sometimes during the development of a new drug to treat a serious or life-threatening disease that has few therapeutic options, the new treatment performs much better than standard-of-care in the early trials. While there is general agreement that such a drug should be developed quickly, there is not a common understanding of how to appropriately speed up development while simultaneously gathering adequate evidence about the performance of the product.

FDA envisions a series of meeting with stakeholders to develop this concept and answer a number of difficult questions about the nature of a new pathway and how it could be implemented.

Consistent with this, BIO had already been talking about transforming the FDA approval process by permitting a “progressive approval” and market access for innovative products that:

• treat an unmet medical need,
• significantly advance the standard of care, or
• are highly targeted therapies for distinct sub-populations.

The November 11, 2011 BioCentury reported that Senator Kay Hagan (D-NC) will be circulating draft legislation to create two new FDA approval pathways, presumably beginning the process of providing details for BIO’s concept. Here are the new approaches:

• Progressive approval would require data "reasonably likely" to predict clinical benefit, the standard currently used for accelerated approval. Unlike accelerated approval, drugs could receive progressive approval without data from a surrogate endpoint.
• Exceptional approval could be granted when the data necessary to satisfy the standard for approval "cannot ethically, feasibly or practicably be generated."

Much more needs to be said about how these would be implemented. In particular, it is not uncommon for a drug to produce solid safety data and/or startlingly good efficacy data in phase 2 (preliminary human trials), then fail in phase 3 (clinical trials to support approval).

Even after we see the bill text, the BIO/Hagan effort must still be seen as a conversation starter. But it is a discussion well worth having.

Steven

Of possible interest to readers:

While the accelerated approval approach has been successful, it also raises a host of methodological questions. One of the best critiques is Professor Tom Fleming’s Surrogate Endpoints And FDA’s Accelerated Approval Process (Health Affairs, 2005).

By Whose Standards: FDA’s Identity Crisis and the Level Playing Field

FDA advances public health, protects consumers, regulates products and is an important force in our national economy. Now, FDA is being challenged by Congress and the President to justify itself as a positive force in the advancement of American innovation and as a contributor to US competitiveness.

This is precipitating an identity crisis at FDA. The agency is constantly establishing new standards (and revising old ones) that will protect consumers and bring new therapies to patients. Now it must also consider whether it is unduly impeding American industry.  As this forces FDA to rethink who it is and what it stands for, FDA Matters believes a different FDA will emerge.

The Need for Standards.  Most of FDA’s authority has been granted by Congress in response to marketplace abuses that had led to harmful products becoming commonplace. In each case, FDA has used that authority to set standards that all products must meet, creating a level playing field for industry. As a result, producers of quality products are assured that their competitors will also have to meet standards. 

How important is this effect? A manufacturer in a highly-competitive, FDA- regulated industry once told me: to survive as a business, our upper boundary is limited by what our most foolish competitor offers for sale. FDA standards (and enforcement of those standards) are what assures that both the well-intended and the foolish deliver products that are at or above a defined level of quality and surety.

We mostly take the benefits of a level playing field for granted. Yet, greed, carelessness and malevolence are always at work behind the scenes trying to create a profitable advantage out of substandard products (e.g. counterfeiting, ingredient substitution).  

Abuses aren’t limited to product manufacturing and distribution. Unsafe and ineffective products also result if standards aren’t created and enforced for clinical trial management, proof of efficacy, acceptable clinical trial designs, food additives, data reporting integrity, post-market surveillance and so on. Having these standards also assures fair competition among companies.

The Standards Crisis. By creating, applying and enforcing the highest standards, FDA wants to be seen as the primary force in assuring that Americans have the safest food supply and the safest and most effective therapies anywhere in the world. The agency aspires to always be “the gold standard” for the world.

Two sets of circumstances are forcing the FDA to rethink this particular sense of purpose and self-image. As a result, an identity crisis is slowly building within the agency. 

First, the “highest” standard is rarely the best way to stimulate innovation. If FDA had chosen the toughest, most protective and most restrictive standards in the late 1970’s and early 1980’s, the biotechnology industry might not exist today. (see FDA and Things that Might Go Bump in the Night).

The agency faces this same challenge in creating the highest standards that nonetheless help advance nanotechnology, open new vistas in diagnostics and genomics, and encourage breakthroughs in drugs or medical devices. The tension between the “highest standards” and “reasonable and appropriate standards” is a visible and palpable part of the current controversy over revising medical device categories and approval standards. (see Medical Device Melodrama: A Great Story With a New Plot Twist)

Second, there is no global force that levels the playing field among each nation’s regulatory agencies…the way FDA levels the playing field for companies and products in the US market. Efforts at international harmonization of regulatory standards have stretched into decades. Without global standards, there are differences in requirements and even greater differences in interpretation in each national marketplace.

FDA knows that setting standards substantially higher than other nations creates the risk that other countries will introduce new products first. It also makes it more likely those countries can attract more industry, capital and jobs in the global economy. Apart from the issue of bragging rights over whether a drug or device was approved first in the US, considerations of international competition (versus cooperation) have been peripheral, at best, to FDA’s identity.

Conclusion. Right now, FDA is struggling to show that it can be all these things: the gold standard, the toughest, the best, the stimulator of innovation and the advocate for companies and products that meet American standards.

Ultimately, FDA will reconcile these roles because it has no choice. The resulting FDA will not necessarily be better or worse. The change may be dramatic or subtle. The only certainty is FDA’s identity will be different.  

Steven

In Praise of Predictability: A Virtue Revisited

More than two years ago, FDA Matters suggested that one of FDA Commissioner Hamburg’s goals would be making it easier for stakeholders to anticipate agency actions. I was looking beyond transparency (see what FDA is doing and has done). I hoped the agency would focus on the larger virtue of predictability (being able to anticipate FDA’s standards and actions).

The task has proven larger than I imagined and the volume of issues facing the agency has made progress hard. However, the agency has taken many steps forward, even as it has been pushed backward on a number of occasions. Is the glass half empty or half full?

I believed that, after the initial stage of setting new policies and assembling her team, one of Dr. Hamburg’s priorities would be to provide more guidance (published and spoken), explain more actions, and rationalize and coordinate more regulatory processes. With regard to this goal of predictable, science-based regulation, progress has definitely been made.

Once completed and enacted, the 2012 round of user fee legislation will further contribute a degree of predictability. The five-year renewal cycle allows industry and FDA to re-work ground rules for the product review process (note: these negotiations are intended to change process, not standards).  

So why doesn’t it feel like FDA is making more progress in becoming predictable and science-based in its regulatory decisionsmaking?

First, a degree of uncertainty is inherent in the nature of FDA’s work. I’ve explored this theme in two recent columns. One discussed the role of FDA staff and the necessity that People, Not Science, Make Decisions. The other examined the biological complexity that makes it impossible to provide guidance that anticipates all situations and outcomes (FDA Approvals and the Failure of the “Human Body as Machine” Metaphor).

Second, certain well-publicized areas of conflict between FDA and industry have tended to exaggerate the overall degree of unpredictability. For example, FDA faced a decision last year on three weight-loss drugs—and approved none, despite credible claims that the drugs met FDA standards.  The agency’s reasons satisfied some observers, but not others. This particular situation became something of a poster-child for critics who say that FDA is unpredictable in its decisionmaking.

The ongoing struggle between FDA and the medical device industry has also focused attention on claims that FDA’s regulatory decisions are not predictable. I have chronicled the often-heated debate in a number of columns, most recently Medical Device Melodrama: A Great Story With a New Plot Twist.

Medical devices were a conflict waiting to happen. It is not because FDA is disinterested in improving predictability in this area. Rather, the approval process is uniquely adapted to the nature of medical devices (wide range of risks, short innovation cycle for product improvements) and almost impossible to explain to someone not already familiar with medical device regulation. Ironically, the two years spent (thus far) on improving the medical device process began with FDA unexpectedly approving a device based on irregular agency procedures.  

Increasing predictability and science-based decisionmaking are still hallmarks of Dr. Hamburg’s agenda. A recent example is FDA’s new initiative to spur biomedical innovation and improve the health of Americans. Streamlining and reforming FDA regulation is one of the initiative’s goals. 

If FDA has not become more predictable in your area of interest, keep encouraging FDA to make it so. The agency is listening and making progress. They need feedback on where processes have broken down or do not produce predictable decisionmaking. In the quest to achieve this goal, I believe the glass is half-full.

Steven

Should Money Have a Seat at the FDA Table?

FDA’s traditional stakeholders are patients, consumers, health professionals, and industry.  Add Congress, media and other government agencies and you have the full set of FDA audiences. What they all have in common: a commitment to the public and individual health of Americans.

While FDA’s focus is health and safety, almost every decision has economic consequences.  Money is never far from the surface. Yet, to my knowledge, Wall Street has never been treated as a stakeholder or an audience of FDA. Now a variant has emerged: organized efforts by venture capitalists (VC) to affect how FDA evaluates drugs, biologics and devices.

Why do VCs care about FDA? Venture capital is financial capital provided to early-stage, high-potential, high risk, growth companies, usually start-ups. Such funding plays a critical role in a large number of medical products that FDA reviews for market approval.

If FDA is more open to innovation and new technology, venture capital firms are more likely to invest in medical product companies in the United States. Conversely, a hesitant, overly cautious FDA makes it more likely that venture capital monies will be used to fund information technology, telecommunications and software companies, rather than life-sciences companies.

What is the VC community doing now about FDA?  Last week, the Medical Innovation and Competitiveness Coalition held a press event, releasing a survey they had conducted in partnership with the National Venture Capital Association. www.nvca.org/vital_signs_data_slides.pdf

In attendance were Senators Michael Bennet (D-Colo.) and Richard Burr (R-North Carolina), both members of the Senate Committee with jurisdiction over FDA. The Senators’ interest is the prominent role that small companies and venture capital play in economic growth and job formation.

The survey of venture capital firms found a significant decreased commitment to investment in life sciences over the past 3 years, with more dollars aimed at overseas projects. According to the Wall Street Journal:

The chief reason [for decreased investment], according to most of the 156 venture firms surveyed, is dysfunction at the Food and Drug Administration, an agency investors say is so unpredictable and risk-averse that young companies are now inclined to merely give up on trying to get on the market in the U.S.

This is definitely attention-getting, but needs to be seen in context. VCs are the FDA’s natural critics. Having invested millions of dollars (and sometimes hundreds of millions of dollars) in a company’s science and product pipeline, VCs are more likely to see product failures as a result of FDA deficiencies than their own failures to back successful products.  

However, the survey may still have a point….and VCs can be a powerful voice for a stronger, more predictable, science-based FDA.

How has FDA responded?  The Obama Administration has emphasized the importance of innovation in building the US economy. There is some question about the effectiveness of that effort overall, but it has been a serious theme at FDA under Commissioner Hamburg.

Last week, Commissioner Hamburg unveiled FDA’s new initiatives to spur biomedical innovation and improve the health of Americans. According to FDA’s press release, this is FDA’s blueprint for addressing “concerns about the sustainability of the medical product development pipeline, which is slowing down despite record investments in research and development.”

Should “money” have a seat at the table among FDA stakeholders?  Companies and individuals seeking “return-on-investment” are significant contributors to making medical progress possible. VCs are the natural allies of an FDA that wants to be a strong, science-based agency and is willing to admit that its process and judgments can always be made better.

FDA needs to carefully consider the critique being offered by the VC community. FDA Matters supports FDA in its willingness to do so.   

Steven

Why is it so hard for investors to pick winners? Why is it so hard for FDA to be flexible?    

Complexity, Uncertainty, Unpredictability: Not Necessarily Bars to FDA Approvals   July 17th, 2011

In most discussions of science and medicine, there is an implicit assumption that the human body is a machine—complex and biological, but still a machine. “The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients.  Read the rest of this entry

FDA Should Consider Cost in Some Decisions

FDA decides whether drugs, biologics and medical devices are safe and effective and can be marketed legally in the United States. The agency analyzes risk-benefit, but never cost. In contrast, public and private insurers, along with physicians and pharmacists, have the responsibility for cost-benefit decisionmaking.

FDA Matters has always felt quite strongly that this was the right way to allocate roles. Safety and efficacy determinations are difficult enough without weighing cost, so keeping a barrier between them makes sense. Two events this past week have left me wondering whether there are certain limited circumstances when FDA should be able to take product cost into consideration.

On September 26, 2011, The Oncology Commission of the British medical journal, Lancet, released a report entitled: “Delivering Affordable Cancer Care in High-Income Countries.” The 40-page report is wide-ranging, but its conclusion straightforward: as cancer care grows more expensive (and it is doing so at a rapid pace), affordability, accessibility and value are issues that need to be confronted aggressively.

Medicare, Medicaid and private payers are undoubtedly looking at this report, hoping to glean insights on cost containment strategies that can mesh with improved cancer care. They may also be looking for support and better rationales for tough decisions they may need to make in the near future.  

FDA also has a stake in affordable cancer care. The growing problem of drug shortages in the United States is heavily skewed toward oncology drugs (mostly generic injectable products). Patients suffer, research is delayed, and more expensive drugs are often substituted (or patients do without).

While ingredient shortages and manufacturing problems play a role, there are also economic drivers. In many cases, it is not sufficiently profitable for manufacturers to produce older oncology drugs. FDA cannot hope to  improve the shortage situation without considering cost—and may need to find ways to favor less effective or riskier products only because they can be made available at a market-driven price.

FDA also plays a role (however unintentionally) in exacerbating the crisis in affordable cancer care. Oncology is one of the hottest areas at FDA, with a large number of new products added to the market over the last few years. More are coming. Increasingly, they are being priced at about $100,000 per cycle. Some patients may need multiple cycles or multiple expensive drugs, all of which contribute to further cost escalation.

This brings us to the second event that occurred last week. I was asked the seemingly naïve question, what would FDA do if a drug was only 90% as good as the safest and most effective therapy on the market (the standard of care), but would be available for only 10% of the cost? I gave the stock answer: FDA only approves therapies that are as good as or better than the existing standard of care. The cost aspect is irrelevant and would never be considered or even discussed.

But then I thought about the Lancet Oncology Commission report. Wouldn’t patients benefit if FDA had some room to consider standards of care, risk-benefit and comparative cost? It scares me to write this….the whole notion of FDA putting cost on the table seems like an abandonment of principles, as well as fraught with potential misuse. Certainly, FDA should not be rejecting therapies because they would be expensive.

In a sense, there are already two possible exceptions. To demonstrate bio-equivalence, generic drugs must have a bio-availability profile within the range of 80% to 125% of the innovator drug. For potentially expensive new products, there is the possibility of approval based on clinical trials that show the product is “non-inferior” to the best therapy on the market. It is possible that a product could be approved as non-inferior with a 10% margin of error, setting up a “90% as good” paradigm. 

But neither of these situations gives FDA explicit permission to say: we are approving a drug, biologic or device that is not quite as effective or safe because it will make care more affordable and accessible. I am not yet an advocate for this….but I think it is one of the possibilities that we need to be discussing. 

Steven

The Lancet Oncology Commission Report is available only as a reprint from Lancet, which charges for it. http://www.thelancet.com/commission/delivering-affordable-cancer-care-in-high-income-countries. If any reader knows of a site where it is available without charge, please let me know.   

US press coverage of the Lancet Oncology Commission Report was thin. Here is the Reuter’s story: http://www.reuters.com/article/2011/09/26/us-cancer-costs-idUSTRE78P26B20110926

A prior column with some relevance:

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 and Things that Might Go Bump in the Night

FDA’s everyday business requires balancing risk and benefit as these might apply to a particular medical product or a new food.  Occasionally, FDA is faced with a much larger responsibility: judging a breakthrough technology that could bring great benefit or great sorrow to humankind. Who can confidently know in advance which it will be?

Still, FDA must decide.  If they say “yes,” whole new industries and benefit may be created for patients and consumers. Or, the world and humankind may be subject to devastation. Today, the agency is faced with just such challenges in dealing with nanotechnology, genetically-engineered (GE) animals, and synthetic biology.   

Thirty years ago, FDA gave a cautious “yes” to the first biotechnology studies that eventually became important medical products to treat cancer, arthritis, MS and many other diseases. The world is a better place as a result.

In retrospect, the decision was right, but at the time, it wasn’t clear. Scary visions of mad scientists and technology run amok were powerful forces in the early days of biotechnology. In response, FDA took great care in setting up an appropriate regulatory environment.[1]

Not surprisingly then, FDA proceeds carefully when new areas of science and technology have great potential, but could also be the source of great harm.  

One such area is nanotechnology, “the science involving manipulation of materials on an atomic or molecular scale.” The agency is concerned because: “materials at the nanoscale can have different chemical, physical, or biological properties compared to their conventionally-scaled counterparts.” What we consider safe may not be safe if made from nano-particles.[2]

FDA responded in 2006 by forming a Nanotechnology Task Force, which still exists. It released an assessment and recommendations in 2007 that have guided FDA’s subsequent actions. These include the first draft guidance on nanotechnology in regulated products, published earlier this year. More extensive guidance is expected in the future.[3]

Yet another science with great potential for benefit, but also possible risks, is genetically-engineered (GE) animals. FDA has been monitoring this field for two decades and accelerated its efforts over the last 5 years as GE animal products have gotten closer to filing for approval.[4]

Currently, the agency is working (slowly and carefully) on GE Atlantic salmon that have been modified to grow faster.[5] If approved, it would also be the first GE animal to become part of our food supply. Opponents call it “Franken-fish” and allege that it will be dangerous to humans and the environment.

The agency has held hearings, sought feedback from advisory committees and tried to solicit all viewpoints. When it finally decides, it wants to be certain that the result will be beneficial and not harmful to our society.

While nanotechnology and GE salmon are well-along in the decisionmaking process, the FDA is only just beginning a similar cycle regarding “synthetic biology.” While “synthetic biology” can be defined a number of ways, it is generally considered to be “the use of molecular biological techniques and chemical synthesis to mimic and even redesign natural biological systems.”[6]

Synthetic biology raises the specter of artificial life (more mad scientists running amok?). The Presidential Commission for the Study of Bioethical Issues released a report in December 2010[7] and NIH is also deeply involved. FDA is watching, adding staff with appropriate backgrounds and planning carefully, knowing that product-specific questions about synthetic biology are coming its way.

As with biotechnology thirty years ago, FDA continues to make tough decisions about dramatic new technologies that can alter our way of life—for good or bad. Some fear will always be with us, if only because a wrong decision might be catastrophic. Past experience shows us the agency will be appropriately deliberative before coming to a conclusion.

Steven

 [1] http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm081964.htm

 [2] “There is a virtual consensus among scientists that the toxicology of engineered nanomaterials is largely unknown, and that toxicity data cannot be extrapolated from existing toxicology studies conducted on larger-scale materials.” http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/NanotechnologyTaskForce/ucm118910.htm

[3] http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258377.htm

[4] http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/GeneticallyEngineeredAnimals/default.htm

[5] For more information on GE salmon: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/ucm222635.htm

[6] Testimony of Dr. Anthony Fauci on synthetic biology: http://www.hhs.gov/asl/testify/2010/05/t20100527a.html

[7] http://www.scribd.com/doc/47350129/NEW-Directions-the-Ethics-of-Synthetic-Biology-and-Emerging-Technologies

FDA’s Busy Summer of 2011

Once upon a time, Washington slowed a little over the summer. Those days are long gone…and this was a particularly busy summer. Congress went down to the deadline on the debt limit/deficit reduction legislation, then left town for August. There was a continuous stream of FDA headlines in June, July and August.

FDA Matters focused on a number of the most pressing issues: post-market safety and surveillance; barriers and opportunities for increased drug discovery and approvals; the rising tide of imports; prospects for biosimilars and medical devices; FDA funding; and various crises facing the agency.

Here is a recap of the summer’s stories:

FAQ: How Biosimilars Will Transform the Marketplace      August 21st, 2011

Biosimilars will be a huge success--used by most prescribers at least some of the time. Much of the current negativity about the market for biosimilars is fed by a mismatch of expectations: the Biologics Price Competition and Innovation Act (BPCIA) is barely 18 months old, while the transformation of the marketplace will take a decade or longer. FDA Matters explores the likely evolution of the marketplace in a set of FAQs.  Read the rest of this entry

FDA Funding Prospects Altered by the Budget Control Act     August 14th, 2011

The Budget Control Act of 2011 (BCA) will have a heavy impact on FDA’s future. Under this new law, most discretionary spending programs will shrink—not merely cease to grow. Yet, FDA’s growing responsibilities and resource needs are not diminished because federal spending is being reduced. Our nation is less safe and less healthy if FDA cannot excel at its mission. Read the rest of this entry

People, Not Science, Make Decisions  August 8th, 2011

To FDA Matters, the people making the decisions at FDA are its strength. They are smart, conscientious and committed. Yet, when asked about bottlenecks at FDA, I have to admit that people slow the process down. There are good reasons why this is so. Read the rest of this entry

Medical Device Melodrama: A Great Story With a New Plot Twist  August 1st, 2011

Two years ago, FDA Matters urged FDA and Congress to review the 510(k) approval process for moderate-risk medical devices and predicted meaningful changes that would work for FDA, industry and consumers. FDA and industry have been proceeding along these lines (albeit with some tough negotiating and lots of rhetoric)…until the Institute of Medicine (IOM) declared that the current system is so flawed that a new regulatory framework is needed.  Read the rest of this entry

FDA, Reorganization and the Four Crises    July 24th, 2011

Dr. Hamburg’s reorganization plan addresses four crises that beset the agency: industry discontent with the medical product review process; public concern about import safety; implementation of the Food Safety Modernization Act; and Congressional concerns that the agency is inefficient in its use of resources. The new structure should drive better decisonmaking and greater productivity…. at a time when the agency is struggling to fulfill its growing mission and faces the potential for budget cuts.  Read the rest of this entry

Complexity, Uncertainty, Unpredictability: Not Necessarily Bars to FDA Approvals      July 17th, 2011

In most discussions of science and medicine, there is an implicit assumption that the human body is a complex biological machine. “The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients. Read the rest of this entry

Should FDA Have an Independence Day?     July 4th, 2011

FDA Matters thinks that making FDA an independent agency will not make FDA more effective or more efficient. Although the idea is not truly harmful, proposing independent agency status is a seductive distraction from the tough job of improving FDA. Read the rest of this entry

Imports: FDA Issues a Cry for Help   June 26th, 2011

 No challenge to FDA’s mission looms larger than the rapid globalization of the world markets for food, drugs, medical devices and other FDA-regulated products. By way of making this point, the FDA released a special report, entitled “Pathway to Global Product Safety and Quality.”  FDA Matters read the report carefully and heard a cry for help, if not an actual primal scream. Read the rest of this entry

Post-Market Safety: Getting the Most Out of Inferences That Aren’t Proofs   June 21st, 2011

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.  Read the rest of this entry
Steven

FAQ: How Biosimilars Will Transform the Marketplace

FDA Matters thinks biosimilars will be a huge success. FDA-approved products similar to off-patent biologics (“biosimilars”) will be available in the US by 2014 or 2015, with more added each year. There will eventually be price competition in the range of 20% to 40% discounts. Biosimilars will be used in most health care settings with most prescribers using them at least some of the time.

Much of the current negativity about biosimilars is fed by a mismatch of expectations: the Biologics Price Competition and Innovation Act (BPCIA) is barely 18 months old, while the transformation of the marketplace will take a decade or longer.

Will the biosimilar market be similar to the generic drug market? Over the last 25 years, generic drugs have grown from 12% of all prescriptions to nearly 75%. Discounts can be as great as 80% off the original innovator price. Because of their greater complexity and higher production costs, biosimilars will never achieve similar market penetration nor sell at such a steep discount.

However, generic drugs and biosimilars share a common premise: the willingness of physicians and pharmacists to use alternative products (generic and biosimilars) instead of the innovator (or reference) product with which they are most familiar. As generic drugs have become accepted by prescribers, so too will biosimilars.

Will biosimilars fail if they don’t generate substantial discounts?  Biological products are more expensive than drugs and at the extreme end may cost $100,000 to $300,000 in a year. In order to gain market share, biosimilar manufacturers will have to provide discounts to purchasing groups, wholesalers and benefits managers of at least 20% off the originator’s prices. Deeper discounts are likely if there is more than one biosimilar competing for sales. To payers and purchasers, saving $20,000 on a $100,000 medication is both substantial and significant.  

If physicians and pharmacists don’t accept biosimilars, how will the market grow? It took more than 25 years for generic drugs to reach 75% of all prescriptions. As with generics, physicians will gain experience with biosimilars as they become available. Meantime, powerful forces of change--led by payers, purchasing groups and formulary committees--will start to narrow the choice of products easily available to physicians and pharmacists. This will become evident by 2015, although it may take as long as a decade for the pace of new biosimilars to transform the marketplace.

Why is therapeutic substitution important in understanding the market for biosimilars?  Increasingly, payers and purchasing groups have treated drugs within a therapeutic class (e.g. statins) as interchangeable and insisted on use of the least expensive one or two. Similarly, biosimilars are eventually going to be judged in the marketplace by safety and efficacy within a therapeutic class, rather than the degree of similarity to the reference product. FDA will create the basis for this approach by looking at the totality of the evidence before deciding the testing requirements for a biosimilar….but has already made clear that some clinical trials (i.e. more concrete proof of safety and efficacy) will be needed as part of the first generation of biosimilar applications.

Why does the success of biosimilars seem so certain to FDA Matters, even in the face of their slow evolution and the many unanswered questions about details? Knowing that it may be months before the first guidance is issued, key FDA leaders are making clear that they are active and serious. Agency leaders recently authored a “perspectives” article, published in the New England Journal of Medicine, that explains their approach.  In June 2011, the head of CDER’s Office of New Drugs indicated that FDA had already held 15 drug development meetings with representatives of 21 companies interested in nine different biosimilar products.

Bio-pharmaceutical companies are not just asking for meetings with FDA. Large sums of money are being invested in the belief that a substantial and profitable biosimilars market will evolve. For example, a large pharmaceutical company recently closed a deal worth up to $720 million for the rights to a biosimilar version of another company’s blockbuster biologic product.

Biosimilars will transform the drug marketplace. We are just in the early stages, which makes it hard for some to see the degree of change that is coming.  

Steven

The FDA’s August 3, 2011 article on biosimilars in the New England Journal of Medicine is at: http://www.nejm.org/doi/full/10.1056/NEJMp1107285.

People, Not Science, Make Decisions

People constantly make decisions. We choose vanilla instead of chocolate or a job in DC instead of a job in Texas. Can’t decide? Then, maybe, flip a coin.

Yet, the most important decisions—such as FDA approvals--can’t be treated so cavalierly. While scientific evidence and good judgment are necessary to make these choices, people make the decisions.

To FDA Matters, the people making the decisions at FDA are its strength. They are smart, conscientious and committed. Yet, when asked about bottlenecks at FDA, I have to admit that people slow the process down. There are good reasons why this is so.  

FDA lacks sufficient resources.  FDA has been dramatically understaffed for decades. Better funding in recent years has improved the situation, but not nearly enough. Also, it seems like new demands on FDA are increasing faster than staff can be added.

Many FDA employees have overwhelming workloads and inadequate time to refresh their scientific knowledge or broaden their thinking. As a result, higher levels of evidence and “certainty” become necessary to reach decisions. Getting to “yes,” particularly for product approvals, often consumes a great deal more time than telling a sponsor “no” or asking for more information. Hiring more staff would reduce or at least stabilize workloads*.

FDA’s culture promotes intensive scientific discussion.  Objective science-based decisionmaking is a goal, not a reality. People arrive at decisions with a bundle of perceptions and experiences that render their judgment subjective. On the flip side, they probably wouldn’t have much to contribute to the decisionmaking process without those experiences.

This is true for FDA, where agency staff—all with subjective views--interact and struggle to come to a clear decision.  If six or seven well-trained, highly-disciplined FDA scientists examine a pre-clinical or clinical trial, there are certain to be multiple views about the meaning of the data It is a slow path to a consensus, if one can be forged at all.   

Delay can increase further if the agency—as it has in the past—expects a single conclusion to emerge from such staff engagement. One of Commissioner Hamburg notable efforts has been to manage dissent (and let it be expressed in public), rather than always force consensus decision-making.

Science has become more complex and results often unpredictable. Life sciences’ products are increasingly based on cutting edge discoveries. It takes more time, more thought and more knowledge on FDA’s part to make a good decision about them. No sponsor feels good when FDA doesn’t know the science behind their product. Delays are inevitable while FDA catches up.

Medical and scientific information is rarely simple. Sometimes a protocol has a sound hypothesis, great supporting science, and logical inferences from similar studies, etc. It feels like running the clinical trials is merely a formality. …and yet the product ultimately turns out to have little efficacy or unexpected safety problems. Every FDA reviewer knows: assumptions based on early data can often be wrong. Biological complexity can, indeed, lead to surprises.

Conclusion. There is much that can be done to improve the FDA regulatory pathways, particularly for approvals, even though bottlenecks are inevitable.

FDA staff makes the decisions, which is how it should be. As individuals, their decisions cannot be isolated from workload, culture or complexity. Faster is possible, but it is important that people slow the process enough to be sure that decisions are both scientific and sound.

Steven

*   Adding new staff eventually helps. However, it can take upwards of two years for new hires to be trained, integrated, knowledgeable and experienced enough to lessen the workloads of others.

Complexity, Uncertainty, Unpredictability: Not Necessarily Bars to FDA Approvals        July 17th, 2011

In most discussions of science and medicine, there is an implicit assumption that the human body is a machine—complex and biological, but still a machine. If we could only understand all the mechanisms, processes and parts of that machine, then we could prevent and cure disease. Yet, the further we travel into the biology of life, the more complexity we find and the less certainty and predictability.

“The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients.  Read the rest of this entry

The State of the FDA—January 2011      January 16th, 2011

FDA’s touches the lives of every American at least 6 to 10 times each day. The agency oversees 80% of the nation’s food supply, all of human/animal medical products and cosmetics, and almost all radiation-emitting devices. Altogether, the agency is responsible for about 20% of all consumer dollars spent in the United States.

With the President set to deliver his State of the Union address to Congress in 10 days, it seemed a good time for FDA Matters to provide its view of the “State of the FDA.” At the beginning of 2011, the agency is doing well, but has a lot of catching-up to do and faces a number of threats. Read the rest of this entry

Is the Human Body Just An Exquisitely Intricate Machine?

In most discussions of science and medicine, there is an implicit assumption that the human body is a machine—complex and biological, but still a machine. If we could only understand all the mechanisms, processes and parts of that machine, then we could prevent and cure disease.  Yet, the further we travel into the biology of life, the more complexity we find and the less certainty and predictability.

“The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients.

Medical progress is the direct result of basic and clinical research conducted according to rules of scientific evidence and proof that have been refined over several decades. Our knowledge grows and our methods of discovery improve through our nation’s support for medical research at NIH and regulatory science at FDA, as well as billions invested by industry. 

Even still, we can’t consistently or logically explain why good scientific hypotheses tested in well-controlled trials often produce unimpressive clinical outcomes. Or why some medical products are clearly helpful for some patients in a clinical trial, but of no benefit to other patients who appear indistinguishable in baseline characteristics.  

Researchers, medical products companies and FDA would love to know the answers to these questions. Until we do, we are powerless to explain, predict or prevent the persistent and expensive discovery failures that are frustrating patients (and investors) who are desperate for medical successes.

We imagine the failures come from the imperfection of our knowledge. This is certainly true, but not a complete answer.

For several hundred years, physicists assumed the world was a machine, a so-called clock-work universe. This was logical and worked remarkably well to explain and predict physical phenomena. Then quantum mechanics demonstrated unpredictable, random, counterintuitive outcomes in the physical world. Ultimately, quantum mechanics increased our knowledge of the physical world, but only after its uncertainty and inconstancy became part of the calculations.

Similarly, there is no clock-work biology just waiting for us to discover all the mechanisms, processes and parts. Some complex biological responses may prove to be “explainable” only through unpredictable, random, counterintuitive activity.*

This may be true of individual responses, as well. If each of us has a unique fingerprint and a unique personality, why should it be hard to imagine that we each have our own biology that can never be fully defined or predicted, even if we could identify all the unique machine-like (e.g. genetic) elements?

If the metaphor (man as machine) is incomplete--and some degree of biological response is inherently unpredictable, uncertain, unknowable, as well as individualized—then FDA’s current standards of evidence and proof are not optimum for stimulating medical discovery. Many products that would benefit patients may not reach the market.

FDA Matters believes the FDA understands this is a problem, at least at the senior management level. However, the agency currently lacks the culture or impetus to incorporate complexity, uncertainty and unpredictability into its approaches to approving medical products. Admittedly, it also operates in an environment where it is gently praised for approvals when they occur….and harshly vilified later if an unresolved or unexpected issue (i.e. uncertainty) is a source of clinical problems.

Patients, physicians, researchers and medical products companies want an environment where a higher level of patient benefit can be achieved, even at the cost of a slightly larger degree of uncertainty and unpredictability. FDA needs to accept and act on this challenge or face rising discord with those stakeholders.

Steven

* Note: there is some work specifically on how quantum mechanics may explain certain biological processes, such as photosynthesis, but the analogy here is only that random, unpredictable biological responses play a very large confounding role in biological discovery, even greater than commonly attributed. See also: “Biology faces a quantum leap into the incomprehensible” http://www.guardian.co.uk/science/blog/2010/nov/12/biology-quantum-leap

Earlier columns from FDA Matters that are related:

Post-Market Safety: Getting the Most Out of Inferences That Aren’t Proofs  June 21st, 2011

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. Read the rest of this entry

Scientific Reductionism and the End of Medicine      December 27th, 2009

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

Have you ever heard someone accused of “reductionist thinking?” You probably will in 2010 because scientific reductionism is a critical, but rarely articulated, foundation of personalized medicine.   Read the rest of this entry