Interesting article in today’s Wall Street Journal on the use of genetic tools to resuscitate failed compounds.

Here how the story begins:

“As pharmaceutical makers find it increasingly difficult to bring new drugs to market, they are turning to genetic tools to seek uses for medicines that failed to make it out of the development pipeline.

The discovery of new links between genes and diseases can help not only to design new treatments, but to salvage drugs that are shelved when they come up short in clinical trials.”

And here’s the rest of the story:

http://online.wsj.com/article/SB120631682077958247.html?mod=dist_smartbrief

The better understanding of genetic tools (via a robust collaboration of industry, academia, and government) will both expedite failure (which lowers the cost of R&D) and provide a broader spectrum for success (which rewards it).

Sound familiar? Correct – the Critical Path.

Check out today’s house editorial in the Washington Times, “Get out of the FDA's way.”

Some tidbits to tantalize your interest …

In respect to the FDA’s Critical Path program and the Reagan/Udall Foundation:

“A program to establish guidelines on how to use genetic tests called biomarkers to predict who responds best to cancer drugs could be delayed for months as the foundation scrounges for money. Worse, Rosa DeLauro is on record as claiming biomarkers are weak measures of a drug's effectiveness even as the director of the NIH National Human Genome Research Institute, Dr. Francis Collins, hails them as the next revolution in medicine.”

And as to where public opinion falls on this matter:

“Most Americans agree with Dr. Collins. A recent survey released by the Center for Medicine in the Public Interest found that nearly 90 percent of all Americans support the Critical Path Initiative and the development of biomarkers. But the congresswoman's attack on the FDA reflects poorly on both her political and scientific judgment. The FDA cannot meet its responsibilities if it has to protect itself from politicians like Rep. Rosa DeLauro.”

Here’s a link to the complete editorial:

http://www.washingtontimes.com/article/20080207/EDITORIAL/47442621/1013/editorial

It's worth a look.

A new national survey shows that Americans overwhelmingly support the FDA’s Critical Path Initiative. The survey was comprised of a nationally representative sample of 1,049 adults and conducted by Opinion Research Corporation. It was commissioned by the Center for Medicine in the Public Interest and iGuard Inc.

When asked about Critical Path, nine in 10 Americans expressed support. The Critical Path Initiative was launched by the FDA in 2004 to streamline drug development.

The survey also examined attitudes regarding key features of Critical Path. When asked about the FDA's efforts to expand the use of biomarkers to identify which drugs are best for individual patients, 78 percent of those surveyed were supportive.

The survey also found that 77 percent of the public supports partnerships between private companies, the FDA, and academics to create new approaches to drug evaluation and development.

And nearly 80 percent want their member of Congress to support Critical Path.

Survey respondents also expressed support for a voluntary, confidential, online portal where patients could share information about their reactions to different drugs. 87 percent said such a program would boost their confidence in drug safety, and 50 percent said they would take part.

Day in and day out, congressional lawmakers bash the FDA. That may score political points, but the public’s support for this program should send a strong message to Congress: Don’t cut funding from the Critical Path Initiative.

For the full report, click below

http://www.cmpi.org

And then under "Reports" click on "Critical Path National Research Report."

Here’s how the Wall Street Journal story, “FDA Procedures Draw Scrutiny” begins, “Controversies about cholesterol drug Vytorin and diabetes drug Avandia are reigniting debate over what evidence the Food and Drug Administration requires to approve drugs -- and may generate pressure on the agency to raise its bar.”

This is just the latest iteration of politicians and media jumping on the “FDA as tool of industry” bandwagon. And it’s neither true nor accurate. It seems odd that one day the media is writing, pundits and pronouncing and politicians are orating about a parched pipeline and over-zealous regulators while in the next breath about the need for the agency to "raise the bar." Consistency? We don't need no stinking consistency.

And then there’s the bit about proxy markers.

Here’s what the Journal story has to say about that:

“ … proxy markers can be misleading. Sometimes a drug works on a proxy but doesn't deliver the promised benefit for the primary health problem. Or a drug can have side effects that don't surface during initial proxy-marker studies but end up outweighing its benefit.”

What? You mean using markers doesn’t guarantee 100% accuracy! Shocking, just shocking. Here’s the bad news folks – there is no perfect predictor of either risk or benefit. And if we allow ourselves to poo-poo the significant advances that biomarkers deliver than we are heading down the slippery slope of the Precautionary Principle that warns us to “do nothing until we know everything.” Markers aren't magic, nor are they a "perfect" solution. Risk/benefit analysis is an inexact science and safety is a relative concept.

Here’s a link to the complete WSJ story:

http://online.wsj.com/article/SB120122452254515507.html

The best way to help the FDA to “raise the bar” is to accelerate 21st century regulatory science. And that means funding the Reagan/Udall Center. Everything else is just rhetoric.

I took Senator Grassley to task for suggesting that unhappy reviewers and other malcontents air the grievances and differences with FDA division decisions at AdComm meetings a while back. Now from the other side, people and companies who complain about the lack of consistent or guidance from the FDA regarding the reason for holding up an approval also want transparency.

Transparency is the refuge of those who, short of being able to control the outcome, want to at least try to control perception. The FDA needs less transparency and more consistency based on better science. And it needs leadership regarding the question of "Whose life and health care decision is it anyway?" The Critical Path is designed to help shift that decisionmaking to doctors and individuals.

What I'd like to know is, where do the presidential candidates stand on The Critical Path? Do they care? Or are they more interested in making sure there are cheap knock offs of old drugs and faster FDA inspections for UPS shipments of medicines ordered online?
http://www.fool.com/investing/high-growth/2008/01/14/score-one-for-dendreon-and-disclosure.aspx

Appropriations agriculture subcommittee chairwoman Rosa DeLauro has no problem cutting funding to promote the Critical Path initiative. Perhaps it was to make room for about $24.5 million worth of earmarks for her district. That includes about " $400,000 for Connecticut oyster fisheries. DeLauro, who is a member of the Commerce, Justice and Science Subcommittee, received $4.9 million in earmarks in one bill (Agriculture) alone, the "" including $500,000 for the Henry C. Lee Institute of Forensic Science Cold Case Center at the University of New Haven. " That's the same amount and the same bill from which she cut out money for FDA's Critical Path foundation.

Now that's leadership.

View Article

Okay, so it isn't ALL about the money -- only mostly.

Critical Path Trickles Downstream To FDA Reviewers
The Pink Sheet, December 17, 2007

BY: Daniel Poppy (d.poppy@elsevier.com)

A lack of interest from agency review staff impedes progress of FDA's Critical Path Initiative, industry members observe.

"What I have seen in my own personal interactions, both when I was at the agency and when I left the agency, is there is still a lot of difficulty getting this pushed down to the reviewers," AstraZeneca's FDA Liaison Office Executive Director Cathie Schumaker said at a Critical Path briefing conference.

"I do appreciate much more now that I'm on the industry side how important it is to translate this from a visionary approach to a regulatory approach." Schumaker is the former deputy director of FDA's Office of Information Management.

"There is a disconnect between what we hear at the highest levels and what is happening down in the trenches," said Brian Harvey, who is VP of regulatory policy at Sanofi Aventis and a former director of FDA's Division of Gastroenterology Products.

At CDER, reviewers adhere to established regulatory standards despite being exposed to, and often agreeing with, innovative ideas about drug development, Harvey said.

FDA Office of Medical Policy Director Bob Temple suggested that progress is being made but sees hesitancy from both industry and regulators.

"Anything new takes a little while for everybody to get used to it," he said. "These things are spreading, and I see them in action all the time. That doesn't mean everybody is ready to change the thing they are doing right away. Drug companies are very conservative that way too."

Addressing concerns that CDER's staff is not implementing aspects of the Critical Path Initiative, Janet Woodcock, the center's acting director, stressed the agency lacks resources, not interest.

"We now have very enthusiastic buy-in participation at FDA amongst the reviewers, and that's a big success," Woodcock said at the conference, which was co-sponsored by FDAnews and the Center for Medicine in the Public Interest.

"We have gotten a tremendous number of proposals from scientists at FDA about additional projects that could be done to improve the development process. Unfortunately that would dwarf any and all appropriated funds."

Woodcock acknowledged that the direction of the initiative is still largely contingent upon funding. Although the initiative is now being targeted for appropriations, Critical Path activities generally have been directed by the interests of external parties willing to collaborate with FDA (1"The Pink Sheet" Jan. 22, 2007, p. 29). A recent report issued by FDA's Science Board's Subcommittee on Science and Technology outlined the effect the lack of resources is having on FDA's ability to assess developments in emerging sciences (2"The Pink Sheet" Dec. 10, 2007, p. 15).

Given the ad hoc nature of the projects undertaken, Woodcock suggests that many of FDA's efforts to improve the drug development process will take time to bear fruit. "In 10 years you are going to see a very uneven field where some pieces have advanced and moved forward very rapidly and others may require more work or clinical effort won't have matured, and so you're going to see not a coherent science but a patchwork. And it is still going to be very challenging for everyone, but a lot better than it is now," she said.

"I am trying to take a long-term, transformative view. I don't think you can turn an ocean liner around in a year, especially if it involves scientific research and changes in scientific methods," she added.

Echoing many of the speakers at the conference, Harvey praised Woodcock. "The fact that Janet Woodcock is now back as the acting CDER director is probably the best thing that could ever happen for Critical Path. She has an incredible vision. She really is able to inspire people. ... There is a lot of optimism."

Of course, Woodcock's tenure as CDER director is most likely short lived. FDA has launched a candidate search for a permanent center director so Woodcock can return to her position as FDA deputy commissioner and chief medical officer (3"The Pink Sheet" Dec. 10, 2007, In Brief).

Wither the future of 21st century pharmaceuticals?

Consider what Mark McClellen said Thursday at the CMPI/FDA News conference on the Critical Path,

"The future is not going to be like the past."

(A comment that is much more profound the more you think about it.)

Reagan/Udall Foundation Chairman McClellan also shared this comment,

"Data isn't knowledge."

Now isn't that an apt and memorable motto for the Reagan/Udall Foundation.

Rosa L. DeLauro. The "L" stands fro "Luddite." Consider this press release that just crossed our desk:

Washington, DC – Congresswoman Rosa L. DeLauro (Conn. – 3), as part of an on-going effort to ensure that science – and not industry interests – informs decisions within the Food and Drug Administration, sent a letter to Dr. Andrew von Eschenbach, FDA Commissioner, expressing concern about the Reagan-Udall Foundation and seeking information about its creation.

“While the intended goals of the Reagan-Udall Foundation are worthy, given that it will be funded primarily by pharmaceutical companies, the FDA would be responsible for ensuring that the Foundation does not further increase the industry’s influence within the FDA,” DeLauro wrote. “Although the mission of the foundation is intended to support research that encourages an expedited FDA approval process, I believe the Reagan-Udall Foundation has the potential of endorsing the approval of drugs and devices based on lower standards for safety and efficacy, and without appropriately designed clinical trials.”

We have previously commented on such absurdity on October 15th ("Concerned Scientists") and again on October 17th ("Critical Wrath").

And, yes, this is same Rosa DeLauro who spoke so passionately in favor of H.R. 2693, The Popcorn Workers Lung Disease Prevention Act.

What else can be said?

The Reagan-Udall Foundation was created to promote new tools to accelerate the development a new generation of targeted medicines. The emphasis is on tools, meaning biomarkers, meaning coming up with validated measures and standards at a time when we have a lot of data and information but very little knowledge.

I hope the Foundation focuses on very mundane and important scientific work and provides hub for achieving consensus on measures and markers for qualifying and ap approving drugs based on actual biological differences and mechanisms. And I hope pharma does begin to more money into credible scientific projects that will help change the regulatory paradigm. The scientists in the companies want to do the right thing. I am not always so sure of the marketing types who still cling to the one size fits all blockbuster mentality and who have not yet realized that if drug companies don't get into the business of tracking the safety of their drugs in the post market -- using these tools in research and clinical settings -- they will continue to get clubbed by the likes of Nissen and Graham. If they don't seize the opportunity given to them in Reagan Udall then well....it's their own fault.

Of course, the fact that this might make drug development more efficient years from now (i.e. fewer clinical trials, more subpopulations targeted) and might help drug companies will drive the Marcia Angells, Kassirers, Avorns, etc crazy. Matt Perrone has an excellent piece that captures the knee-jerk "corporations are evil" bleating from the likes of The Union of Conceited Scientists.

Matt Perrone ought to brush up on what a biomarker is however otherwise he will continue to be misled by likes of David Ross who gave him this example:


"For example, Ross, who left the FDA last year over a drug safety dispute, is concerned, as are others, that the FDA might be persuaded to quickly adopt a controversial drug-testing process that uses biological indicators, such as blood pressure and cholesterol levels, to determine a drug's safety.

Drug companies have taken the unusual step of sharing research data on these indicators, called biomarkers, to see if the size and duration of patient drug trails can be reduced. Some critics call their use a high-risk gamble.

"Biomarkers are a bit like dynamite in that they can be extremely useful but they can cause a lot of damage," said Ross.

He cites a biomarker that suggested irregular heart rhythms were a key predictor of fatal heart attacks. Using the assumption, doctors prescribed heart-regulating drugs to millions of patients in the 1980s but abruptly halted the practice in 1989 when a long-term study revealed patients were actually more than twice as likely to die of sudden heart failure."

Note to Perrone and Ross: The reason people died was because the drug was prescribed to patients outside of the clinical trial guideline. Ross is using the "generic" definition of a biomarker, meaning biological measure that is linked to a disease state. A biomarker that captured genetic variations explaining why people more likely to die from the drug is now possible to develop using a blood test. I guess we shouldn't use that. Ditto, all those tests that can now screen to see which people respond to certain cancer drugs and avoid needless chemotherapy or which HIV drugs will work for them.

It should also be noted that Ross was one of the biggest loudmouths about the dangers of SSRIs which have been overhyped to the point that prescriptions are down and suicides are up.

This effort to eliminate measures like cholesterol, glycemic index, bone density, blood pressure as conditions of approval is just an effort to slow down drug approval and move it into the dark ages. It is being engineered by those who believe that the current approach to clinical evaluation is corrupt and corporatized. Supporters offer this more rigid and unreachable methods not because they are based on better science but because they reduce the number of new medicines that companies develop. The attack is political, pure and simple.

The battle lines are already being defined: The opponents of the Foundation and Critical Path oppose both because it might advance industry and industry is evil. (Even though most of the research will be done in collaboration with academia and NIH). Because corporations are involved it is inherently evil and corrupt. WHich allow the other side to distort the mission and the science all they want.


The headline in the WP "New FDA Research Center Rife WIth Risks" tells you that Reagan Udall has already been spun. How sick and sad is that?

http://www.washingtonpost.com/wp-dyn/content/article/2007/10/14/AR2007101400722.html