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Safety and Efficacy Standards: Innovative Approaches to Radical Ideas

Monday, May 7th, 2012

FDA is in the midst of its quinquennial* (five year) review from Congress as part of the user fee reauthorization cycle. Lots of proposals are on the table and FDA Matters agrees with some and disagrees with others. So far though, there doesn’t seem to be anything that would pull FDA apart or create an agency that cannot act with integrity. 

In contrast, two key opinion leaders are talking about potentially radical changes in FDA’s safety and efficacy standards. While neither has seen their specific proposals become part of the Hill debate, there are redeeming qualities to what both of them are suggesting.

User Fee Reauthorization Legislation.  I have been expecting the worst from Congress. Five-years of FDA issues have accumulated and there are tight deadlines for action by summer. The Senate bill just passed subcommittee in late April and the House bill will be marked up starting May 8. So far, House and Senate negotiations have stayed within the bounds of acceptable disagreement and we might see final legislation on schedule.

Of course, there is no guarantee that the reauthorization process wouldn’t yet turn into a mess or that the early start won’t be frittered away in extended debate. However, at least so far, Congress is doing a good job with a tough task.   

Radical thinking, far from Capitol Hill.  In February, former FDA commissioner Andrew von Eschenbach wrote that maybe FDA was being too tough on efficacy in the face of proven safety. Specifically, he wrote:

Instead, after proof of concept and safety testing, the product could be approved for marketing with every eligible patient entered in a registry so the company and the FDA can establish efficacy through post-market studies.

Then, in late April, Dr. Eric Topol** of Scripps Institute and a leader on cardiovascular safety issues, suggested that FDA may be too tough on safety in the face of proven efficacy. Specifically, he said:

The whole concept of having “overwhelming efficacy” of a device, or a drug, or a diagnostic test hasn’t been embraced enough. If we have that, learning about safety could be done on a conditional approval basis…..under a probationary status [with] every single individual…monitored electronically to watch the device, the drug, the test in question.

If the goal was to shock as well as provoke discussion, they both succeeded with me. Each offers a proposal that violates at least two important norms: “all drugs have risks” and “the first obligation of physicians is ‘to do no harm.’”

FDA Matters and, I believe, FDA and most stakeholders believe that substantial evidence of both safety and efficacy are needed before drugs are made available in the marketplace. I imagine the American public would agree.  

Radical Thinking Re-channeled.  I respect both individuals for their intellect and achievements, so I tried to find more conventional ways of looking at their ideas, ways that wouldn’t place tens of thousands of patients at risk. I think I succeeded.

Dr. von Eschenbach’s central point is that we don’t squeeze enough therapeutic potential out of drugs that have been well-tested and have excellent safety profiles. In that case, NIH Director Francis Collins is thinking along the same lines.  

On May 3, he announced  a new initiative, called Discovering New Therapeutic Uses for Existing Molecules. The program “will direct researchers’ attention to [and provide availability for testing] a part of the drug development pipeline traditionally difficult to access: compounds that have cleared several key steps in the development process, including safety testing in humans.”

Dr. Topol’s central point is that seriously-ill patients should have access to therapies that demonstrate impressive efficacy, without delay by inflexible rules about proof of safety. In that case, the Senate is thinking along the same lines.  

As described in a recent column, Proposals to Speed Drug Approvals: Not Created Equal, the Advancing Breakthrough Therapies for Patients Act or the Breakthrough Act (S. 2236) would:

“provide more flexibility when a drug or treatment shows dramatic responses early in development, while still ensuring drug safety and efficacy. For patients, this proposal would allow FDA the ability to move towards more innovative clinical trials, such as minimizing the number of patients enrolled in trials and shortening the duration of trials, when scientifically appropriate.”

S. 2236 is part of the user fee reauthorization bill that passed in the Senate Subcommittee.

Radical ideas met with innovative but conventional solutions. Well done all around.


* Yes, there really is a word that means “once every five years.” http://www.merriam-webster.com/dictionary/quinquennial

** Dr. Eric Topol was recently named the “most influential physician executive in the U.S.” by Modern Healthcare magazine.

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

Monday, April 16th, 2012

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


Proposals to Speed-Up Drug Approvals: Not Created Equal

Tuesday, April 3rd, 2012

An important part of the 2012 user fee reauthorization cycle is Congressional efforts to push FDA toward approving drugs and biologics more rapidly. Most of industry and a large number of patient groups agree. Proposals to speed up FDA are already in play.

Since these proposals have a common purpose, it is easy to think of them as alike. However, most are different from each other—in focus, intent, and likely impact on the agency’s existing decisionmaking process. This is FDA Matters’ analysis of why proposals to speed up drug approvals can’t be lumped together and why FDA may support some, but not others.

Is FDA really too slow? Efforts to speed up drug approvals start with an implicit assumption: FDA is approving drugs too slowly. The conventional wisdom is that FDA’s positioning swings over time like a pendulum. FDA allegedly gets "too easy" with its approvals, but then a few years later is faced with a major product recall over safety issues.

The FDA then hunkers down and the pendulum swings toward being slow and rigid. Finally, the bad experience becomes less immediate in the agency's mind and the pendulum swings back toward “too easy” and the cycle starts again.  

The FDA mindset. FDA hates this metaphor, but secretly fears it might be true. As a result, the agency has been working toward being more consistent….and less prone to the alleged pendulum swing. Among other things, the agency is trying to publish more official guidances and handle perceived blockages proactively (e.g. prospects for obesity drugs seem to have improved since the failure of three such drugs to gain approval in 2010).

Some of this spirit of change is reflected in the agency’s October 2011 white paper, Driving Biomedical Innovation:  Initiatives to Improve Products for Patients. Likewise, as part of the new user fee workplans, FDA and industry agreed to work together, particularly earlier in the development process, so that there are fewer surprises and more approvals. 

Proposals for speeding up drug approvals.  Improving the existing accelerated approval process is the goal of the Faster Access to Specialized Treatments or FAST Act (HR 4132) and section 301 of the Transforming the Regulatory Environment to Accelerate Access to Treatments or TREAT Act (S. 2113).

Accelerated approval allows surrogate endpoints as the basis for demonstrating efficacy. FDA uses this example: “instead of having to wait to learn if a drug actually can extend the survival of cancer patients, the 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.”

The two bills would broaden the means to demonstrate clinical benefit by encouraging use of emerging scientific methods and tools and allowing a wider range of surrogate and clinical endpoints. The bills would explicitly codify the accelerated pathway in law.

A different approach is taken in the Advancing Breakthrough Therapies for Patients Act or the Breakthrough Act (S. 2236).  This bill would “provide more flexibility when a drug or treatment shows dramatic responses early in development, while still ensuring drug safety and efficacy. For patients, this proposal would allow FDA the ability to move towards more innovative clinical trials, such as minimizing the number of patients enrolled in trials and shortening the duration of trials, when scientifically appropriate.”

This reflects a reality: FDA often feels constrained in situations where common sense dictates special handling. An example might be a new melanoma treatment that was approved in August 2012, after receiving significant assistance from FDA to move the drug forward rapidly. However, after reading an earlier NY Times article, it is easy to imagine that FDA might have been even more flexible, but felt constrained.

Finally, some commentators have included former FDA Commissioner Andrew von Eschenbach recent Wall Street Journal article in their discussion of “speeding up FDA approvals.” He advocated “creating FDA pilot programs to bring promising therapies to patients more quickly by allowing them to be approved based on safety, with efficacy to be proven in later trials.”

Speculation on FDA’s position. FDA is certain to oppose Dr. von Eschenbach’s proposal if offered as a legislative amendment. However, FDA is still deciding its position on FAST/TREAT and the Breakthrough Act.

In response to a Congressional question, FDA spoke favorably of the Breakthrough Act.  The key is that FDA is given discretion to provide more rapid and higher level process, but is not directed to change the standard of proof or the meaning of efficacy or safety.

FDA has been more hesitant about FAST/TREAT. Informally, it opposed a prior iteration because, among other things, it lowered standards by not requiring prior validation of a surrogate endpoint.  My understanding is that FDA is considering whether its concerns have been addressed by these later versions of the bills.


FDA Progress “At Risk:” An Update on Funding and a Call to Action

Sunday, March 25th, 2012

FDA MattersState of the FDA—January 2012 identified agency funding as the greatest threat to the FDA’s future. The agency received a very small increase in FY 12 appropriated funding, reflecting the severe budgetary pressure on all U.S. federal agencies. That pressure continues and FDA faces potential cuts in FY 13 (starting October 1, 2012).

Advocacy by the Alliance for a Stronger FDA and other stakeholder groups is critical to sustaining the agency’s appropriated funding and pressing Congress for increases to meet the growing demands on FDA. This column explains the budget situation and calls upon all stakeholders to support increased FDA funding. 

FDA was massively underfunded for two decades. Since 2007, Congress has reversed course and increased the agency from $1.5 billion to $2.5 billion in annual appropriated (non-user fee) funding. The agency is also viewed much more favorably than it was then.

However, the agency received a miniscule $50 million increase in FY 12 appropriated funding. Although this was more than many federal agencies, it is inadequate for FDA’s growing responsibilities. Even still, the agency made good progress on its key objectives in FY 12, mostly by stretching the dollars as best it could.

FY 13 funding could be much worse, while the agency’s responsibilities continue to grow. New Congressional mandates include the Food Safety Modernization Act (FSMA), the Biologics Price Competition and Innovation Act (biosimilars), and bio-defense. In addition, amendments to the user fee reauthorization legislation will impose new requirements (unfunded mandates) on the agency beyond what will be paid for by user fees.

The other sources of growth in FDA’s responsibilities are unrelated to Congress. These include: continuing growth and increased demands of globalization; science’s growing complexity; agency initiatives to promote innovation and regulatory science; and “the unexpected,” whether new foodborne pathogens, drug shortages, or new scientific discoveries that add to the agency’s responsibilities.

FDA must overcome two barriers to obtain more funding. The first relates to how Congress views FDA. Does Congress recognize FDA as providing essential governmental services that must be supported, regardless of budget cuts? Does Congress view FDA as doing a good job with the money it receives? In particular, has it used the increased funding over the last 6 years to improve its effectiveness? Does Congress feel any urgency about funding those FDA activities (e.g. implementation of FSMA) that can only occur if funding is increased in FY 13? 

The second barrier is the overall environment in which budget decisions are being made, especially the aggregate amounts Congress is willing to spend on domestic discretionary programsThe FY 12 appropriations process was driven by pressures to reduce spending. Largely because of lower House spending ceilings, FDA faced the possibility of a $275 million cut under the House-passed bill. FY 13 now looks like it may become a repeat of last year, with the House again choosing lower aggregate spending levels than the Senate. This sets up the possibility (maybe even likelihood) that the House will again vote for a large cut in FDA funding, while the Senate may be barely able to maintain current funding levels.

This is not an acceptable situation. FDA oversees nearly 25% of all consumer spending and touches the lives of every American every day. It’s not just the food, drugs and devices that we commonly think about, but also vaccines, diagnostics, cosmetics, pet food, dietary supplements and so on.

Further, as this blog’s growing global readership  attests….FDA’s decisions affects the lives of hundreds of millions of people outside the U.S. Many countries rely on FDA’s standards of quality and its regulatory decisions. Further, every country in the world is part of the global market in the import and export of FDA-regulated products.

Belonging to the Alliance for a Stronger FDA helps demonstrate support for the FDA. The Alliance’s membership includes all stakeholders —consumer, patient and research advocacy groups, professional societies, companies and trade groups, consulting firms and individuals. A stronger FDA is the only thing they all agree upon…and this carries great weight with Congress. The Alliance’s views on FY 13 FDA funding can be found here. 

For more information about the Alliance, go to www.StrengthenFDA.org or write to me at sgrossman@StrengthenFDA.org.


For purposes of disclosure: I am one of the founders and serve as Deputy Executive Director of the Alliance for a Stronger FDA.


My duties with the Alliance are in addition to, and apart from, the work of my policy and regulatory consulting firm, HPS Group, LLC., which is the publisher of FDA Matters.  The views expressed in FDA Matters are my own, and those of HPS Group, and are not the views or positions of the Alliance.

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

Monday, March 19th, 2012

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

Biological Complexity and the Myth of the Low-Hanging Fruit

Monday, March 12th, 2012

Two events persuaded FDA Matters to write another column on biological complexity and its implications for medical research, drug discovery, and personalized medicine. First was the release of a remarkable study on gene mutations in cancer tumors. It is a stellar and sobering example of how biological complexity confounds our expectations that rapid advances in science will quickly lead to cures. 

Second was the multiple comments from readers of last week’s columnsuggesting that drug discovery (and biomedical advances generally) are so hard because “the low-hanging fruit has been picked.” This is a persistent and dangerous myth that devalues past breakthroughs and distorts the challenges bio-medicine faces over the next decade. 

This past week’s New England Journal of Medicine contained an original article on cancer tumor heterogeneity. According to Reuters, the study showed:

 “about two-thirds of genetic mutations in samples from primary tumors of kidney cancer patients were different from one another, even if they were taken from the same tumor…Researchers also found even more genetic differentiation in biopsies of secondary tumors. The findings suggest that using samples from a primary tumor as a basis for treatment decisions may not be good enough, researchers said.”

An accompanying NEJM editorial, as well as a Wall Street Journal article and comments,  both pointed to this as a setback for matching treatments to the genetic make-up of a person’s tumors (i.e. personalized medicine). Their comments didn’t surprise me.

Over 2 ½ years ago, I put personalized medicine in perspectiveby comparing it to the long history of biotechnology. I didn't predict the cancer gene mutation discovery. I just pointed out what history tells us: biological complexity is greater than we imagine, making promising areas of discovery appear closer to maturity than they really are. The truth of this was on prominent display in these new research results on cancer tumors.

This provides a near-perfect context to respond to those who thought the answer to last week’s column, “Why is Drug Discovery So Hard (and Expensive)?is “because the low-hanging fruit has been taken.” They suggested: what remains to be accomplished in human biology and drug discovery is incredibly difficult because all the easy questions have been answered and the easy drugs and biologics have already been developed.*

As near as I can tell, a great many very smart people believe this. And they could not be more wrong. The challenges ahead are, indeed, quite difficult….but so were yesterday’s challenges before we solved them.

The “low-hanging fruit theory” is truly insulting to a generation of bioscientists whose record of accomplishments over the last 50 years was achieved by their hard work and dedication, as well as their brilliance. If anything, they might argue that it is easier now—given the new knowledge and the new tools that researchers have to work with.

Beyond that, the view of the past as low-hanging fruit–“easy and less expensive”–distorts our view of the future…that somehow we face challenges greater than other people have faced before us. We don’t.

Human biology is complex and biomedical research is slow and time-consuming. Most new knowledge raises as many questions as it answers (as is certainly true with the new cancer tumor research). None of this is new.  And it is true no matter where you stand in the continuum of biological knowledge, whether you are Pasteur or one of today’s biotechnology “rock stars”.

I am not pessimistic or discouraged about biomedical discovery or opposed to personalized medicine, just concerned we see them in a realistic light. I conclude that:

·         More biological knowledge is always better than less.

·         Having more knowledge doesn’t tell you whether the next task is easier or harder (and often it is both).

·         Having more knowledge doesn’t tell you whether success is near or far.


These three observations are controlling principles in biomedical research’s quest to lessen the burden of disease and provide all of us with a higher quality of life.


Since this is FDA Matters blog, how does FDA fit in? The agency works closely with companies developing drugs and devices and is one of the final arbiters in whether biological knowledge has, indeed, been turned into benefit for mankind.


The agency needs the tools, the resources and the top scientific minds to stay ahead of the ongoing flood of new biomedical knowledge. It needs to be ready to stimulate, then evaluate, what we hope will be a torrent of new, ground-breaking drugs and devices that will, over time, arrive.


* Dr. John LaMattina, former President of Pfizer R&D, examines this same question in his recent column in Forbes. We agree that “low-hanging fruit” is a myth, but articulate the reasons differently. His perspective complements my own and I recommend reading it along with this column.

Why is Drug Discovery So Hard (and Expensive)?

Monday, March 5th, 2012

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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


Quality and Safety “Just Don’t Get No Respect”

Monday, February 27th, 2012

In every successful company, the glittery careers and the recognizable names belong to people who develop new products that meet consumer and patient needs. Innovation in new products (and careful husbanding of intellectual property and market share) is what brings in the revenue and determines corporate success.

By comparison, there is little recognition and often sparse resources for the people devoted to making sure those products (new and old) are safe and of high-quality. The best product ever developed is worthless, and possibly harmful, if standards are not maintained and manufacture and supply carefully monitored. The stakes are so much higher for FDA-regulated products.

FDA Matters has previously analyzed how “safe” has many meanings. My focus in this column is the safety of processing, manufacturing and distribution of FDA-regulated products. Is the milk we drink safe from adulteration (either intentional or unintentional)? Are medical devices manufactured with sufficient precision?

Does every batch of a biological product deliver consistently safe results? Are sterile conditions maintained when drugs are manufactured? The list of questions is endless because there are a limitless number of ways in which products can be unsafe.   

When FDA Matters has covered quality and safety issues in the past, we have almost always mentioned our suspicion that CEO’s and others in the corporate suites are not concerned enough.  It is reflected in the recalls, the extended plant closings, the drug shortages caused by suppliers unable to produce quality products, and the number of inspection reports (483’s) that contain substantive and non-trivial problems.

We assume that CEO’s want to produce safe and high-quality products. After all, it is bad for business to do otherwise. Yet, we suspect too many corporate executives are overly focused on new product development, marketing and sales and worry too little about the quality and safety of what they already produce.

Close accountability and adequate resources are the necessary ingredients of quality and safety. Too often, the opposite appears to be the case in corporations: inattention, underfunding, delegation to distant subordinates and overreliance on vendor guarantees.

FDA won’t back down from its vigilance. Commissioner Hamburg’s reorganization of the agency was, in part, to consolidate authority over quality and safety and put it in the hands of an immediate subordinate. Dr. Hamburg did what I hope every corporation would do—insist on closer accountability to the CEO with regard to production of safe, high-quality products. This becomes more urgent as the scope of this responsibility becomes global, more complex and harder to manage.

The foundation of the Food, Drug and Cosmetic Act was enacted so long ago and generally has been so successful, it is easy to forget that FDA was created and built for the specific purpose of protecting consumers and the public health from dangerous products. It is the FDA that cleaned up the market in tonics and patent medicines, ensured there were serious consequences for companies that adulterated food and drug products, and created a basic public trust in the foods, medicines, devices and cosmetics that we use daily.

Quality and safety of FDA-regulated products is also on the mind of Congress. A little more than a year ago, it passed the Food Safety Modernization Act, a thorough overhaul of our nation’s approach to assuring Americans have a safe food supply in a global environment.

This year, as part of the reauthorization of user fee legislation, Congress is probably going to adopt additional provisions addressing the safety of drug imports, the need to eliminate drug shortages, and the necessity of supply chain integrity. Also in that legislation will be the Generic Drug User Fee Act, which funds a significant expansion of FDA’s efforts to inspect generic drug facilities.

Industry, Congress and FDA need to continue their focus on innovation and new products. This is the path that will bring better lives to Americans and allow our nation to better compete in the global economy.

While doing so, they must also pay sufficient attention and provide adequate resources to the fundamental, but less glamorous, job of assuring the processing, manufacturing and distribution of safe, high-quality FDA-regulated products. We must insist on this standard in the American marketplace.


FDA Guidance on Biosimilars: The Two Minute Version

Sunday, February 12th, 2012

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.   



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

Monday, February 6th, 2012

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. 


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