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Archive for the ‘Drug Approval and Access’ Category

Bold Discussions: Possible New Approval Pathways for Breakthrough Drugs

Monday, November 14th, 2011

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 Others accelerated approval drugs are still being studied and a few have been withdrawn.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.


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

Monday, November 7th, 2011


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.  



In Praise of Predictability: A Virtue Revisited

Monday, October 24th, 2011

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.


Should Money Have a Seat at the FDA Table?

Tuesday, October 11th, 2011

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.   


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

Monday, October 3rd, 2011

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. 


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

Sunday, September 18th, 2011


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.



 [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


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

FDA’s Busy Summer of 2011

Tuesday, September 6th, 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




FAQ: How Biosimilars Will Transform the Marketplace

Sunday, August 21st, 2011

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.  


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

Monday, August 8th, 2011


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.




*   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?

Sunday, 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.


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.




* 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

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