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Biosimilars Update: Keys for the Next Year and Beyond

Friday, June 22nd, 2012


The biosimilars market in the U.S. will not grow large overnight. However, over the next 4 to 10 years, a lot of companies are going to become players. During this same period, health plans, pharmacy benefit managers, Medicare, and Medicaid are going to start reaping savings by buying less expensive biosimilars. By a decade from now, sales of biosimilars will be creating new winners and losers in the overall biopharmaceutical marketplace.

In light of this, I was recently asked: what should a developer or investor be looking to achieve over the next year in the area of biosimilars? What should they be looking to achieve in the years after that?

Over the next year: Assuming the U.S. biosimilar law survives the upcoming Supreme Court decision (concerning the constitutionality of the President Obama’s health reform program), then the last roadblock to creating a biosimilar marketplace in the U.S. will have been eliminated.

The key, then, becomes: how quickly can FDA complete the multiple steps  necessary to establishing a viable system for evaluating and approving biosimilars. Here are some key indicators to watch in judging the agency’s progress:

  • the number of investigational new drug applications (IND's) being issued for biosimilars, which would be a “leading indicator” of slowdown or snags in FDA’s initial intake process;
  • publication of draft policy guidances dealing with critical details such as nomenclature, label warnings, unique names, etc. (until these issues are settled, FDA will be reluctant to approve anything);
  • revised estimates of how many fees the FDA expects to collect each year under the new biosimilars user fee program (a rough gauge of FDA’s view of its timeframe for approvals).

For those looking to be active in the biosimilars market, the next year provides an opportunity to build and strengthen relationships with payers (especially purchasing groups). Payers are going to be focused on the strength of clinical, animal and laboratory data comparing the biosimilar to the original biologic product. There will be a need for biosimilars to be offered at a discount to the cost of the original, but high-quality biosimilars with a 15%-20% discount will dominate the market over biosimilars of questionable quality with 30% to 40% discounts.

Similarly, it is not too soon for companies developing biosimilars to start working with practicing physicians—to calm their fears that they will be forced to use inferior biosimilar products that will result in treatment failures. While payers, not physicians, will drive this market—payers will avoid products likely to generate criticisms and resistance from physicians.  

Finally, for those interested in the biosimilars market–stay cool over the next year. Biosimilars are a sure bet for the long-term. However, it will (quite legitimately) take FDA some time to create the new complex approval pathway that is required.

Looking beyond one year. Stay cool is still good advice. Some companies are going to slip behind or drop their investments because of corporate pressures for short-term return on investment (ROI). The biosimilars market is a battle for the long-haul and will belong to those who are prepared to stay the course through the several years it will take for FDA to develop policies and implement them consistently.

Another potential restraint on developers’ and investors’ commitments over the next several years is the persistent allegation that the U.S. biosimilars market will be limited unless FDA makes a determination that a biosimilar is interchangeable with the original product. However, FDA has placed a low priority on establishing a pathway for determining that an approved biosimilar is also interchangeable with the original biologic product.   

This “controversy” is a throwback to the implementation of Hatch-Waxman in the 1980’s. At that time, substituting copies for originals was a new concept, quality was low, purchasing was decentralized, and doctors had no incentive to prescribe generics.  Allowing forced substitution of FDA-approved generic drugs because they were “interchangeable” was an important dynamic in the growth of the generic drug industry.

However, none of these same underlying conditions are present at the beginning of the U.S. biosimilars market—substitution is widely accepted, quality biosimilars will be available, purchasing is far more centralized, and physicians will have incentives to prescribe biosimilars. FDA designation of "interchangeability," key to generic drugs, is almost irrelevant to biosimilars.

As a final thought: the rise of generic drugs made it necessary for innovators to work harder to develop new, patent-protected products that were better than drugs available generically. The same dynamic is going to play out over the next 10 years for biologic products. The biosimilars pathway adds further urgency for innovator companies to be refilling their pipelines with products that are better than ones currently available.  

Spinal Cord Injury—Innovation Measured in Decades, Not Headlines

Monday, June 18th, 2012


We are undergoing a supposed “national crisis” in medical innovation.  Congress, FDA, NIH, and industry are involved in multiple initiatives to “cure” this problem. This is particularly visible now because the user fee reauthorization process is underway, but the state of medical innovation is always relevant because of our headline-driven, crisis-oriented culture. 

To FDA Matters, this approach profoundly distorts medical accomplishment. You can’t use “where are we today” to judge the success or failure of a medical research process that is inherently broad, iterative, uneven, filled with false starts and driven by cumulative success more often than miraculous breakthroughs. As a case in point, I offer efforts to achieve spinal cord regeneration.  

In the mid-to-late 1970’s, I worked for an advocacy group that, among other things, represented the interests of medical research institutions. There was one Congressman on the right committee who was friendly to our cause and with whom we should have had a great relationship.

However, he had two key positions with which we could not agree. He was, simultaneously, the leading Congressional advocate for animal rights and perhaps the only Congressional advocate for spinal cord regeneration. We opposed his position on animal rights because we thought it would hinder medical research.

Surprisingly, we were also against his legislation that would stimulate medical research on spinal cord regeneration. We supported groups promoting the fight against cancer or cardiovascular disease because their proposals allowed NIH significant discretion to determine priorities. In contrast, we were against legislation that would require research on narrow and specific topics, such as spinal cord regeneration.

But our objection (and the vehemence of our objection) went well beyond that. The promise of biomedical research was so great, it was wrong to waste research monies on areas that held no promise.

After all, we thought, spinal cord regeneration was the stuff of science fiction. Despite the death and disability from spinal cord injury—an area of genuine unmet need—there was nothing that could be done. People could dream of a future world where medical science could achieve such miracles, but for the foreseeable future it was wasted money and unfairly gave hope to patients to suggest that spinal cord regeneration was possible.

Flash forward 30 plus years and the Congressman looks like a visionary….and the organization I worked for looks like unwitting advocates for the status quo. A rich base of scientific discoveries has improved supportive care, provided mechanisms for limiting the damage from spinal cord injuries and given reasonable hope that spinal cord regeneration is a possibility for humans in the next 10 to 15 years, maybe sooner. 

To gain perspective on this, along with a sense of NIH’s current commitment to this area of research, go to http://www.ninds.nih.gov/disorders/sci/detail_sci.htm and also follow some of the links from that site.

I don’t think we were fools in 1998 because we couldn’t see spinal cord regeneration as a promising research area. Despite the organization’s considerable expertise, we underestimated how far medical research could take us—given enough time, interest, commitment and funding. Also, in retrospect, it is remarkable how willing researchers are to contribute to a process of innovation and discovery for which someone else might eventually gain most of the credit.

Forgive me if I don’t see the crisis of “medical innovation” about which it is so fashionable to complain.

As a result of the user fee reauthorization legislation and other FDA and NIH initiatives, I foresee a more conducive regulatory environment for development and approval of medically-innovative products, particularly orphan drugs. The goal is to allow more flexibility, while maintaining rigor. However, these process enhancements are only valuable if there is a wealth of medical innovation, not a dearth of it.

There is more innovative medical research being done today than at any time in history. But the truly great achievements are usually built on many people’s work undertaken over many decades—and until near the end, they hardly ever rate a headline unless someone is intentionally hyping them. Look beneath the surface and you will find that medical innovation is alive and well and just needs our continued encouragement—via regulatory and funding support.  


PDUFA Reauthorization: Major Upgrades for Orphan Drugs

Wednesday, June 13th, 2012


Congress is to be congratulated on its progress toward passage of user fee reauthorization legislation. House and Senate-passed versions are being reconciled by staff, with a few fairly tough issues yet to be resolved. There is no apparent barrier to a final piece of legislation later this month or during July.  

One of the big winners in this process has been the rare disease/orphan drug (RD/OD) community. Notwithstanding a few remaining (minor) disputes in the RD/OD space (more on this later), the final legislation will contain the strongest set of improvements for the community since the original 1983 Orphan Drug Act.

The RD/OD community had three overriding objectives during the multi-year process of hearings and negotiations that culminated in the House and Senate-passed legislation:

  • FDA flexibility in reviewing orphan drugs
  • Resources  and process improvements for development  of biomarkers/pharmacogenomics
  • Overhaul of the humanitarian device program

The community achieved all three plus a number of additional items that will also be part of the final package.  

The Commissioner’s Commitment Letter. The user fee agreement is only partially contained in the law—much of the detail is in a commitment letter signed by the Commissioner. As part of this, FDA agreed to the Rare Disease Initiative, which includes:

  • increased staffing of the CDER/CBER Rare Disease Programs (RDP) (which provides expertise in orphan drug development to the product review divisions)
  • increased FDA efforts to assure that product reviewers, industry, and patients are working together
  • broadening  research and programming in the areas of non-traditional clinical trial design, endpoints, and statistical analysis associated with orphan drug development
  • enhanced staff training for reviewers with specific regard to approval of drugs for rare diseases
  • better integration of RDP staff into review teams

When the PDUFA legislation becomes law, these will be firm commitments that FDA must carry out for Fiscal Years (FY) 2013 (starts October 1, 2012) through FY 17.

Other RD/OD Priorities.  A number of other proposals, critical to the RD/OD community are in both the House and Senate bills:

  • establishing procedures for faster review and more flexibility for promising therapies for unmet (orphan) medical needs. This will be accomplished by:
    •  updating and codifying FDA’s existing accelerated approval process, and
    •  adding a new process to speed development of drugs demonstrating strong efficacy in the early stages of clinical development (the Breakthrough Act).
  • encouraging greater use of the existing, successful Humanitarian Use Device (HUD) program. The reauthorization legislation expands the scope of HUD (adult and not just children’s devices) and allows companies to make a profit.
  • permitting FDA to use a wider range of experts and to use the government-wide standards for assessing conflicts of interest
  • re-authorizing and improving the Orphan Drug grant program.

The Remaining Issues. There are three RD/OD issues that differ between the bills.

The first is in the Senate bill and tries to expand and strengthen the patient voice in FDA discussions. FDA is already doing this. However, the agency has a weak understanding of how much risk some rare disease patients might be willing to bear in order to have even a small possibility of benefit. Patients need to be heard in this debate. I hope the House agrees to this provision.

The second provision is in the House bill. It would revise the accelerated approval process to allow its use when there is little or no data on a rare disease with a particularly small population. I think these represent situations where FDA can best judge each situation themselves rather than being prodded into what might well be an unscientific review process. I hope the Senate does not adopt this provision.

Finally, the House has included a pilot program to encourage development of drugs and biologics for rare pediatric diseases. There are some questions about how this will work, so making it a pilot program makes sense. I hope the Senate agrees to this provision.  


About once a year, I check on progress in bettering the lives of people with rare diseases:

Biosimilars and the U.S. Supreme Court: FDA Program Could Be Nullified

Tuesday, May 29th, 2012


The U.S. Supreme Court will rule on the constitutionality of the Affordable Care Act (ACA) (also known as ObamaCare) no later than early July. One of the possible results is nullification of the entire Act, although FDA Matters thinks this is the least likely outcome.

Nonetheless, the U.S. biosimilars law—passed as a separate section of ACA—could be rendered void if the Supreme Court overturns the entire ACA. Where would that leave FDA? What about those companies that have invested hundreds of millions of dollars to be part of the emerging U.S. biosimilars marketplace?

Controversy over The Affordable Care Act. The ACA, passed in March 2010, creates a comprehensive national approach to the problems of access and affordability of health care.  While not a pure “national health insurance” program that would be recognizable in most of the world, it is more far-reaching than any prior U.S. health legislation since the creation of Medicare (for the over-65 population) and Medicaid (a federal-state program for the poor) in the mid-1960’s. Numerous cost-containment provisions are also included in the ACA.

The ACA nearly didn’t pass Congress at all….and heated opposition has not lessened since its passage. A number of lawsuits have attacked the constitutionality of the law—with the leading case being led by the attorneys general of about 20 states. The US Supreme Court listened to oral arguments earlier this year and will decide the case before it adjourns in early July.

Biosimilars at Risk.   The Supreme Court may uphold the entire law as constitutional. Or they might decide only specific parts of the law are unconstitutional, none of which relate to biosimilars.  In either scenario, FDA will proceed with its current plans to implement the biosimilars law.

However, the Supreme Court might decide that a constitutional problem with one part of the law (e.g. mandating that individuals buy health insurance) is so far-reaching that the entire law is unconstitutional. In this last situation, FDA might be stripped of its authority to implement the biosimilars program enacted into law as part of ACA.

Little Precedent on What Comes Next. The Supreme Court rarely rules that Congressional actions are unconstitutional. When it does so, the Court usually looks for the narrowest Constitutional grounds possible—trying to preserve as much of the legislation as it can. This makes it most likely that biosimilars will survive the Court’s review. It also means there is little precedent as to what would happen to the biosimilars program if the ACA is invalidated in its entirety.  

One possibility is that FDA has innate authority to create and regulate a category of biosimilar drugs and does not need a legislative grant of authority.  This was discussed when Congress was first considering biosimilars legislation seriously in 2007 and 2008. At the time, FDA wisely deferred on the question, stating that it wanted Congressional guidance (meaning legislation). 

Should the law be overturned, the “innate authority” question might be re-raised, allowing FDA to continue with little or no change in its plan. The agency might even argue that Congress has given the agency guidance—treating the language of the 2010 law as a directive rather than a mandate.*

There is no hint as to whether FDA is thinking along these lines. When I asked FDA, I was told: we are confident that the Affordable Care Act is constitutional.

Failing a decision by FDA that it has the innate authority to approve biosimilars, it would fall to Congress to find a way to restore the program by legislation.  According to the trade publication, FDA Week, biosimilars’ leader, Hospira, is gearing up to pursue a legislative re-enactment should the Supreme Court overturn the biosimilars program. The Biotechnology Industry Organization (BIO) and Congress would also want to assure there is a biosimilars pathway.**

The problem: legislative re-enactment might not be so easy. While Congress is generally happy with the current biosimilars law, it was the product of a series of compromises and political maneuvering that left winners and losers. Merely re-adopting current law might prove surprisingly difficult.

Meantime, we all await the Supreme Court’s decision. And it’s safe to say that no one in the bio-pharma community is looking forward to the possibility of a new fight over biosimilars.


* There is no lack of support in Congress for the biosimilars program. Both the House and Senate versions of the user fee reauthorization legislation contain a new user fee to cover part of FDA’s costs for reviewing applications for biosimilar products approvals.

** For those with subscriptions to FDA Week, the article can be found at: http://insidehealthpolicy.com/FDA-Week/FDA-Week-05/11/2012/hospira-to-pursue-biosimilars-bill-if-scotus-strikes-down-health-care-law/menu-id-721.html

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.


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) 


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