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Archive for the ‘FDA-NIH Relations’ Category

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.

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.

NIH and Drug Development: Dr. Collins’ New Initiative

Sunday, January 30th, 2011

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. (more…)

Hot Town, Summer in the City—2010

Sunday, July 11th, 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. (more…)

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

Sunday, January 3rd, 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. (more…)

FDA Should Stay Out of Health Care Reform

Wednesday, September 30th, 2009

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. (more…)

Dr. Collins Meet Dr. Hamburg

Tuesday, September 22nd, 2009

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. (more…)

Dr. Hamburg Meet Dr. Collins

Sunday, July 12th, 2009

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. (more…)

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