Safety and Efficacy Standards: Innovative Approaches to Radical Ideas

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.

Steven

* 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.

Biological Complexity and the Myth of the Low-Hanging Fruit

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.

Steven

* 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.

NIH and Drug Development: Dr. Collins’ New Initiative

Dr. Francis Collins, director of the National Institutes of Health (NIH), wants to create a new National Center for Advancing Translational Sciences (NCATS) at NIH.  The new Center would combine $700 million in existing NIH projects with, perhaps, an additional $300 million from new monies or other NIH programs. NCATS is intended as NIH’s “response” to the biopharmaceutical industry’s failure to produce more new drugs.

FDA Matters doesn’t see the sense of creating a public sector drug development company. Nothing suggests that government has either the requisite knowledge or experience to succeed. Yet, several people I respect are supportive of Dr. Collins’s initiative.

Advocates and critics of NCATS may not be talking about the same thing. NIH describes a very circumscribed process in which NIH quickly passes early research over to industry. NIH will do compound screening, animal studies and sometimes proof of concept human clinical trials. Since NIH already does this without a lot of fanfare, why create a new center rather than just highlighting the work?  

The NIH FAQ also promises that NIH will limit itself to less developed clinical areas where there is not yet commercial interest by industry. The notion that NIH will restrict itself in this way rather than pursue best scientific opportunities…is worth at least a raised eyebrow of skepticism.

Industry is frustrated by the difficulties of developing new medications and is actively searching for ways to do better. Maybe they could use some more help from NIH. Unfortunately, HHS and NIH have taken a less cooperative approach, trying to sell NCATS as a response to industry failures in new drug development, as if they are certain of the cause and know that NIH can do better.

It would be better if government officials focused instead on expanding NIH’s existing role in developing medical knowledge beyond basic research. Congress has shown considerable interest in this over the last few years and, until now, there have been few questions about whether NIH is overstepping its bounds.

NIH implies that NCATS will be a productive goad to an unproductive pharmaceutical industry. Whether this is justified, it would help the discussion if NIH were to be more upfront about its limited expertise in developing products to meet FDA’s standards for approval.

Because of the difference in the two agency’s missions, FDA’s standards are much higher and less forgiving. This is appropriate: we want NIH to advance knowledge; we want FDA to make sure that biopharmaceuticals are safe and effective.

Dr. Collins’ initiative also seems hasty in its desire to re-organize upwards of a billion dollars in NIH’s programs by October 1, 2011. It is seductive to imagine that problems can be solved by redrawing boxes on an organizational chart. Sometimes this works, but more often you get the Department of Homeland Security, an organization that is far less than the sum of its parts.

For the moment, there appears little talk about the possible impact on the rest of NIH if NCATS is created. If $700 million worth of programs is transferred to NCATS and Dr. Collins says he will squeeze more money from other priorities, how can existing institutes and centers not suffer? It would be quite unfortunate if basic research were to be devalued by the rise of translational science.

NIH, as an institution, may not be better off with NCATS.  In any case, new drugs are not going to pour out of NIH, as some seem to believe. 

I’d like to see a lot more public discussion of these issues. Let’s take the time to be sure that the integrity and productivity of NIH are not at risk and that the American people will receive tangible benefits.

Steven

NIH’s FAQ and website on the proposed changes: http://feedback.nih.gov/index.php/faq-ncats/

The interview of Dr. Collins by Gardiner Harris of the NY Times:

http://www.nytimes.com/2011/01/23/health/policy/23drug.html?_r=3&pagewanted=all#

From Pharmaceutical Executive on-line:
NIH Director On the Consortium’s New Remit
As the National Institutes of Health hits the headlines over its remit to help develop new medicines, Director Francis Collins talks about the new initiatives he sees as critical for innovation, industry, and public health.

Hot Town, Summer in the City—2010

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

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

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

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

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

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

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

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

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

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

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

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

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

Steven

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

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

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

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

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

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

FDA Leadership and Challenges: Seven Columns to Re-read for 2010

As a rule, FDA Matters does not cover the day-to-day events at FDA and in Congress. Most readers have multiple sources for news about the agency. I doubt I could do better.

Rather, the goal of this blog is to cover larger themes and provide deeper insights into the world of FDA. I place a premium on exploring FDA's future, as an observer, commentator and instigator. Here are seven columns about FDA leadership and challenges that will help you to better understand the agency in 2010.

Public Health Leadership Comes to FDA

FDA leadership–Dr. Hamburg and Dr. Sharfstein– come from an entirely different mold than their predecessors. They have begun an era of public health leadership at the agency. FDA staff and agency stakeholders will eventually come to appreciate that this difference is good for FDA. Read the rest of this entry »

Turning Data into Knowledge

Through statute and directive, FDA has been asked to collect, analyze, interpret and utilize massive amounts of data. The systems are not in place to do this, at least not at the required level of sophistication. Even if they were in place, sifting valuable information from background noise is extraordinarily hard. As a result, FDA needs to manage Congressional and public expectations as to "what is possible and when." Read the rest of this entry »

FDA and NIH: Natural Allies

Tension between CMS and FDA is a fact of life at HHS. This is not surprising because they have fundamentally different missions and world views. An analysis of the FDA-CMS relationship leads to an interesting conclusion: FDA should be doing a lot more with NIH because they have complementary missions and similar world views. They are natural allies. Read the rest of this entry »

In Praise of Predictability

FDA has always found it challenging to make its actions predictable. This problem will worsen while Dr. Hamburg redefines the agency's mission, policies, actions and working assumptions. Once this has been accomplished, the agency will become dramatically more predictable to stakeholders, including Congress. Read the rest of this entry »

To Whom Much is Given, Much is Expected

FDA has received $306 million (15%) more to spend in FY 10. This is the third good year for FDA, after years of bad ones. The agency is still severely underfunded, but progress is finally being made. Now the hard work begins: spending the new money wisely and showing that it has been used to accomplish important public health missions. Read the rest of this entry »

CARS: The Vehicle for FDA's Future

Commissioner Hamburg has spoken a number of times about the importance of regulatory science. She is right. FDA must have the scientific tools and methodologies to be a 21^st century regulatory agency. FDA needs to define regulatory science, develop programs to support it, and package them in a way that will quickly bring recognition and funding. Read the rest of this entry »

Long-term Challenges Need Short-term Attention

FDA Matters has identified seven long-term challenges for FDA. Some of these challenges may take years to accomplish; all need to be started now. Three or four years from now, Commissioner Hamburg will be judged by whether she moved the agency forward in these areas. Read the rest of this entry »

Steven

FDA Should Stay Out of Health Care Reform

When the new NIH director, Dr. Frances Collins, was interviewed by the New England Journal of Medicine, he stated that one of his priorities is to: "put science to work for health care reform." I hope that Dr. Hamburg isn't having similar thoughts about involving FDA in health care reform.

Health care reform is our nation's #1 health priority. It does not lack for attention, participation and debate. Hundreds of billions of dollars will be driven by the outcome. However, our country will not be better off if every health-related agency diverts its attention and finite budgets to the cause.

I have been watching NIH for more than 30 years. All NIH directors have had the same goal: keep NIH and its biomedical research mission out of politics. Some directors have done this by pretending politics doesn't exist. Others have protected the agency by being consummate politicians. Both strategies have been successful at different times and in the hands of different directors.

I do not remember any NIH director openly welcoming politics into the agency.

The NEJM interviewer asked Dr. Collins' whether NIH will become politicized if it takes an active role in health care reform. He responded:

That is always a risk. I am exploring this. I don't know the answer precisely. I do think the idea that NIH's responsibility for trying to influence public health ends at the point of running a clinical trial and publishing the results may be a little narrow for the climate that we are in. While we are a research organization, and that's always going to be our focus, maybe there is more opportunity now….."

"Putting science to work for health care reform" will politicize NIH. This will not be good for biomedical research...or for America's patients who are waiting for treatments and cures. I hope Dr. Collins' comes to this realization quickly and does not let NIH get distracted.

This same point applies equally to FDA. The agency's plate is full with mission-appropriate responsibilities, including implementation of its new authority over tobacco. More work is coming through food safety reform, follow-on biologics and other administrative and legislative initiatives.

The new FDA leadership has made a strong point that science, not politics, should be the basis of FDA decisionmaking. To this, we can all say: bravo! Involving the agency in health care reform guarantees that politics will creep into the agency's activities and conclusions.

Getting involved in health care reform may be trendy….but it will be destructive, if not disastrous, for FDA. The agency needs to stay on mission and out of health care reform.

Steven

Dr. Collins' NEJM interview can be found at: http://healthcarereform.nejm.org/?p=1808&query=TOC.

Dr. Collins Meet Dr. Hamburg

FDA and NIH should be working together more closely and productively. For this to occur, Dr. Hamburg and Dr. Collins need to bless a higher level of cross-agency commitment. The critical next step is a publicly announced meeting of the two to develop and advance a common agenda.

In an earlier column, I concluded that FDA and NIH are natural allies, with closely-related purposes as public health agencies. They share a similar worldview that medical and scientific knowledge should be derived from random clinical trials.

Subsequently, I wrote a column about the cultural and organizational barriers to a closer working relationship between NIH and FDA. I urged Commissioner Hamburg to meet with Dr. Collins to start breaking down those barriers.

Dr. Collins was interviewed in last week's New England Journal of Medicine and stated his five priorities:

• integrating new technologies to make basic research more productive;
  
• translating basic research into clinical applications;
  
• science in support of health care reform, notably comparative effectiveness;
  
• global health; and
  
• reinvigorating the NIH-oriented research community through support for more young researchers, more innovation-oriented grant review panels, and a stable and predictable funding trajectory for biomedical research.
  

These are appropriate priorities for NIH, but not reassuring to me as an FDA advocate.

Dr. Collins knows that most NIH-driven medical advances can't go "from bench to bedside" except through FDA. Yet, he only mentions FDA once in the interview—to observe that the FDA has put the only clinical trial involving stem cells on hold. Although cooperation on this trial is a good thing, NIH and FDA need a broader, deeper and longer-lasting set of activities and goals.

Undoubtedly, NIH and FDA representatives are discussing how their new bosses can work together within the new Administration. This is necessary and useful, but not sufficient to dramatically improve the relationship between the agencies.

I am clamoring for something that is more public than emissaries feeling each other out.

The two agencies working together are powerfully synergistic….and boundless in the benefits they could bring to the American people by joining forces. The involvement of NIH Institute Directors and FDA Center Directors is essential to building a better, more productive relationship. But it will never happen if it requires them to overcome cultural and tribal impediments that keep resource-maximizing organizations from fully sharing responsibilities, decisions and monies.

Unless Drs. Collins and Hamburg personally create the expectation of cooperation at the highest levels, there will be little movement at the center/institute level. Only Dr. Hamburg and Dr. Collins can set the proper tone, provide guidance and break down the barriers. I previously asked Dr. Hamburg to meet with Dr. Collins.

Now, I urge Dr. Collins to meet with Dr. Hamburg. Please.

Steven

Dr. Collins' NEJM interview can be found at: http://healthcarereform.nejm.org/?p=1808&query=TOC

My two earlier columns on this topic:

FDA and NIH: Natural Allies
June 12th, 2009 http://www.fdamatters.com/?p=299.

Dr. Hamburg Meet Dr. Collins
July 12th, 2009 http://www.fdamatters.com/?p=366.

Dr. Hamburg Meet Dr. Collins

FDA and NIH are natural allies, with closely-related purposes as public health agencies. They share a similar worldview that "medical and scientific knowledge derived from random clinical trials" is superior to all other sources. I explored this in an earlier column at: http://www.fdamatters.com/?p=299.

Last week's announcement of Dr. Francis Collins to be NIH director provides a unique opportunity for FDA. Dr. Hamburg needs to meet Dr. Collins….and create a shared vision.

Government agencies are no different than corporate divisions: they crave positive attention, fight to accumulate bigger budgets and more personnel, and resist any attempts to lessen their autonomy. Tribal rules apply. Outsiders---no matter how well-meaning—cannot be assumed to have your organization's best interests at heart.

One could ask: why should FDA and NIH be different than this grim picture of organizational behavior? The answer is: they aren't. Except in rare cases, having a noble organizational purpose does not suspend the accumulative and suspicious culture that is inherent in any group.

There are countless joint initiatives and working groups that link FDA and NIH. Common purposes and a similar world view often push them together…but I am told that many of these meetings are productive only in a very narrow sense. Although the work gets done, the spirit of common purpose is often weak. Enthusiasm for power-sharing is low. Extending projects to related areas is sometimes never discussed. But opportunity is everywhere.

FDA and CMS relate in a different way. As described in my earlier article, the agencies do not have common purpose and do not have a shared view of what knowledge is important. Because of these fundamental differences, opportunities for shared initiative are limited and relations will always be strained. For FDA and CMS, good will and occasional joint successes can never overcome the distance between them.

Not so FDA and NIH. The two agencies working together are powerfully synergistic….and boundless in the benefits it could bring to Americans. The interest of NIH Institute and FDA Center directors is essential to building a better, more productive relationship. But it will never happen if it rests on their ability to overcome the cultural and tribal impediments.

Only Dr. Hamburg and Dr. Collins can set the proper tone, provide guidance and break down the barriers. Dr. Hamburg, meet Dr. Collins. Please.

Steven