On July 26th, the New York Times posted an editorial relating to the FDA’s decision on the drug Avastin.  Their summary entitled “When a Drug Fails” missed the mark on so many levels that even on vacation, our co-founder Steve Walker felt compelled to respond.

This editorial reflects a typical lack of understanding of why the FDA granted accelerated approval for Avastin as a first-line treatment for breast cancer in the first place. Because there are now multiple approved treatments for metastatic breast cancer, with most women going on to treatment with several of them after their first line treatment stops working, it has become impossible to measure a first line drug’s effect on overall survival (how long a patient lives) after beginning treatment. The first trial of Avastin in this setting (on which its accelerated approval was based) indicated a significant advantage in delaying progression of the disease. The problem is obvious. Given the uneven response of patients to various drugs, and the FDA’s crude clinical trial standards designed only to measure and compare the average response of populations (as opposed to how individual patients benefit or don’t benefit from a drug), the FDA made the right call with Avastin (by approving it) the first time around. Think about it. A patient is treated with Avastin and may, or may not, benefit individually in terms of delayed progression or extended life, because the trials are not designed to try to learn whether the individual patient benefited. The FDA’s statistical trials, by design (a problem that cannot be fixed – it is an inherent limitation of statistics-based trials) cannot measure individual benefit. It can only measure the time to progression and the time to death of an individual, which is then dumped into a pool of those measurements from hundreds of patients in each trial arm, and used to calculate an average time to progression and an average time to death for the two populations (those who got Avastin and those who didn’t). They then compare the average outcomes (actually the average patient in one arm to the average patient in the other arm). Seem simplistic? It is. Each patient then goes on to be treated with multiple other drugs (but each patient’s experience is unique – different drugs in different orders, with very variable outcomes, and mostly outside clinical trials where measurements relevant to the initial trial with Avastin may or may not be accurately measured recorded), then at some point, they die. The patient lives, say, 18 months after being treated with four different drugs. Why did she live that long? Which drugs worked to extend her life, which ones didn’t? The FDA’s statisticians have no idea because the trials they mandate are designed far too simplistically to measure it, and it is the FDA that makes and enforces the expectations for trial designs, despite their frequent assertions to the contrary. The media’s consistently incorrect take on this, including in this editorial, is not surprising only because the media almost always fails to properly explain what happened. The most recent trials of this drug actually confirmed that there is a progression-free survival advantage, just not as much of an advantage as the first trial indicated, which means the drug is having a positive effect – on average, and it is still impossible to statistically measure overall survival for a first-line breast cancer drug. If they ran another trial, the result would show yet another progression-free survival result. The real problem here is not that Avastin doesn’t work – it is that FDA has long refused (actually for about 50 years) to update its clinical trial and regulatory science. Randomized controlled trials and the simplistic statistics that drive them, invented in the 1950′s at the FDA and written into law by Congress in 1962, aren’t working anymore. Just a small amount of progress in a still incurable form of breast cancer makes them unworkable. It is very difficult to make progress against a disease when FDA’s regulation has become so obsolete, we can’t even measure progress. With so much in the balance – more than half a million lives a year in the US alone – can’t we do better? We actually can, but resistance to real change at FDA is so profound, even getting started is proving to be an epic struggle. They are not saints over there. They are government employees following very old rules and policies in very formulaic ways and failing on a grand scale. Maybe you should write an editorial about that.

Steven Walker
Abigail Alliance

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• Access, Compassion, Care, and Ethics for Seriously Ill Patients Act or the ACCESS Act – Amends the Federal Food, Drug, and Cosmetic Act to require the Secretary of Health and Human Services to permit an investigational drug, biological product, or device to be made available for expanded access under a treatment investigational new drug application or treatment investigational device exemption if specified Compassionate Investigational Access requirements are met.
• Gives immunity to the manufacturer, distributor, administrator, sponsor, or physician from suit or liability relating to products approved under this Act. Establishes a procedure for accelerated approval of an investigational drug, biological product, or device that is reasonably likely to predict clinical benefit to a patient suffering from a serious or life-threatening condition.
• Requires the Secretary to establish:
  (1) the Accelerated Approval Advisory Committee;
  (2) a new program to expand access to investigational treatments for individuals with serious or life threatening conditions and diseases; and
  (3) a demonstration project under the Medicare program to pay for drugs, biological, products, and devices approved under this Act.

• Amends title XVIII (Medicare) of the Social Security Act to revise the definition of “medically accepted indication” to provide for coverage of a covered Part D drug based on the sponsor’s or organization’s determination that the drug is for a medically accepted indication.
• Requires the Secretary to consider the clinical judgment and risks to the patient from the disease or condition in evaluating the safety and effectiveness of drugs, biological products, and devices that treat serious or life-threatening diseases or conditions, including the evaluation of nonstatistical information.
• Requires any committee evaluating investigational drugs, devices, or biological product applications to have at least two patient representatives as voting members.

The full text of the Compassionate Access Act can be read our site here:

Over at the Ayn Rand Center for Individual Rights, Thomas A. Bowden published a very insightful article related to our struggle.

Bowden says:

Every life-threatening disease presents a health emergency to the individual patient. Morally, you have the right to seek the best treatment you can find. Yet our legal system denies you that right when it comes to private health emergencies.

The important point, as Frank Burroughs relayed in an email praising Bowden, is that tens of thousands of lives could and should be saved each year.

Over the past couple years, there has been a battle raging to help get the drug Provenge approved by the FDA. Many people have brought up conflicts of interests among FDA panelists as reasons that Provenge has not been made available to the public as of yet.

Last week, Jim Edwards who writes the Pharma Analysis blog over at bnet.com wrote a piece titled SEC Probe Into Dendreon Cancer Drug “Conspiracy” Could Put Rumors to Rest. In the post, Jim writes:

The conspiracy theorists believe that the FDA was swayed by a “disparaging letter” about Provenge written by Scher to the FDA commissioner, and that coupled with his conflict of interest this maneuvering unfairly kept Provenge off the market — and doomed many men to die unnecessarily from prostate cancer.

On its face, it does look messy: It’s always bad to have people with conflicts of interest in positions of power.

But a closer look reveals that both Scher and Hussain’s conflicts were disclosed prior to their sitting on the panel, and Scher’s letter contains an entirely reasonable and highly persuasive argument for not approving Provenge at the time — the company didn’t have enough data.

In fact, Dendreon had only presented “secondary endpoint” results, not primary endpoints. In other words, they had cherry-picked their data from two studies in which Provenge failed to meet the primary endpoint goals.

Having read this, Frank Burroughs, President of the Abigail Alliance, felt compelled to respond to Jim in a note which I’ve included below.  The Alliance definitely feels like these issues are real and it is important that people understand this fight.

What your article most certainly should have included was the lopsided FDA Oncologic Drugs Advisory Committee (ODAC) panel’s vote infavor of approving Provenge back in 2008.  The ODAC was convinced prostate cancer patients were being helped by Dendreon’s vaccine.

Sadly your article downplayed Drs.Scher and Hussain’s serious conflict of interest.  You should have been critical of the FDA for allowing them to be part of the Provenge review process in the first place.

Let me make one last note.  Even if the FDA wants more data for Provenge and other drugs and vaccines, what is so vitally needed for patients fighting for their lives, who have run out of options, and like so many cannot get into a clinical trial is early access to drugs and vaccines like Provenge, before the final FDA approval.  This is what the Compassionate Access Act will do that is close to being reintroduced in the U.S. Congress.

I think journalism gets measured by the quality of information it presents, not the drama or the pyrotechnics associated with us.         – Bob Woodward

Please respond in comments if you guys have thoughts on this issue.  We’d love to hear it!

Mason Researchers Launch Innovative Clinical Trial for Colorectal Cancer

George Mason University Published January 19, 2010 By Marjorie Musick

Imagine if treatments for disease could be based not on patients’ diagnoses, but instead on the characteristics of their tissue. By identifying and decoding the cryptic messages hidden deep inside the human proteome, scientists and physicians who study personalized medicine are seeking more effective treatments and disease management for patients.

Lance Liotta and Emanuel Petricoin III, professors of life sciences and co-directors of Mason’s Center for Applied Proteomics and Molecular Medicine (CAPMM), are pioneers in the field of patient-tailored research and personalized medicine. The two study biomarkers (indicators of disease in tissue and bodily fluids) related to cancer, heart disease, liver disease and obesity.

They recently launched a unique clinical trial in partnership with oncologists and co-principal investigators Kirstin Edmiston, medical director of cancer services at Inova Health System, and Alexander I. Spira, director of Fairfax Northern Virginia Hematology Oncology Research Program, to treat patients with late-stage colorectal cancer, a fatal cancer that starts in either the colon or the rectum.

Striking more than 150,000 American men and women each year, colorectal cancer is the nation’s third most commonly diagnosed cancer and third leading cause of cancer death, according to the American Cancer Society.

The three-year trial will accommodate up to 50 men and women who have late-stage colorectal cancer that has spread to the liver.

“Traditionally, all colon cancers have been lumped together and given similar treatments. The novelty about this is that we can, in a very minimally invasive way, start to treat the metastatic tumor based on its unique protein makeup,” says Edmiston.

“If we’re going to be successful in treating the metastatic disease, which is what kills people, then we need to focus on using therapies targeted toward the individuality of a patient’s disease state. This clinical trial is the first step toward doing that.”

Trial participants will be treated with standard metastatic colon cancer therapy and will test the addition of Gleevec, a medicine that is typically prescribed for certain forms of leukemia and gastrointestinal tumors. Gleevec targets disease pathways in tumor cells that previous CAPMM research revealed were among those found in typically fatal liver metastasis in colorectal cancer patients.
Because the primary tumors in the colon are removed in most colorectal cancer patients as soon as they are diagnosed, this study will focus on treating the often fatal secondary tumors or metastatic lesions that appear when the disease spreads to the liver, causing death through destruction of that organ.
To sample these lesions, CAPMM’s scientists developed a new drug target mapping technology called “reverse phase protein microarray.” This allows the researchers to create a unique molecular profile or “fingerprint” that shows which protein pathways or drug targets are activated in the lesion. This process will allow the researchers to determine whether specific drugs such as Gleevec might be an effective treatment for a particular patient before it is even administered.

By monitoring the drug target activity in trial participants’ tumors and basing their treatment on those characteristics, the researchers are hopeful that the clinical trial will lead to more effective and individualized treatment for patients suffering from this devastating disease.

“The exciting aspect of this trial is that an established drug is being considered for a new indication, and that’s one of the promises of personalized therapy — that a patient’s molecular portrait would be considered as the rationale for choice of therapy rather than based on the site or the kind of cancer alone,” says Petricoin.

“Until now, the most cutting-edge clinical trials utilize genomic profiling of the tumor to select patients. This is the first trial that uses a direct proteomic approach that maps the drug target activation networks that are in use in each patients’ tumor — just technologically being able to do this in a real clinical trial is a first.”

Patients interested in participating in the clinical trial should contact Stacey Banks, Inova’s clinical research coordinator, at 703-776-3565.
Financial support for the study is being provided by Novartis, which developed and manufactures Gleevec.

Over at Experimental Drug Therapies Blog there was some great discussion around the Abigail Alliance’s mission. When we caught wind of it, Frank stopped by and added his own thoughts. Click here to to read it all. Below are Frank’s comments:

This is great that there is such an excellent discussion going here on this blog. Let me add and clarify a few things from the extensive comments.

As regards safety, what the Abigail Alliance and the bill in Congress, Access, Compassion, Care, and Ethics for Seriously Ill Patients Act (ACCESS Act S.3046 H.R.6270), are talking about are drugs and vaccines for cancer and other serious life-threatening illnesses that are showing significant efficacy in clinical trials. Also it is important to keep in mind that drugs and vaccines in clinical trials are very closely monitored for safety. Another important point is that the decision to take an investigational drug by a person who has run out of FDA approved options and cannot get into a clinical trial, should be the patient’s in consultation with their doctor.

Here is what is profound (from www.abigail-alliance.org):
“Every drug for cancer and other serious life-threatening illnesses that the Abigail Alliance has pushed for earlier access to in our eight-year history is now approved by the FDA! There is not one drug that we pushed for earlier access to that did not make it through the clinical trial process. Many lives could have been saved or extended, if there had been earlier access to these drugs!”

As of early 2009 the count is 16 drugs! EVEN the FDA’s own Science and Technology Board in their late 2007 report recommended there be a provisional approval mechanism for promising developmental drugs.

Speaking of the FDA Science and Technology Board, they and for a long time the Critical Path Initiative (www.c-path.org) have been pushing the FDA to use more modern scientific and statistical tools in clinical trial design, drug data, drug review, and approval. The ACCESS Act covers many early access issues, including jump starting the FDA using more modern tools.

By the FDA using more modern scientific and statistical tools, the use of placeboes would be greatly reduced. There are a significant number of patients who opt not to enroll in clinical trials, because they don’t want to take the risk of getting a placebo. Therefore the ACCESS Act would actually help speed up clinical trial enrollment.

One last note for now is that data outside a clinical trial can add to the knowledge about a new therapy.

Thank you all for your input.

Frank Burroughs, Abigail Alliance

If you guys haven’t noticed, we launched our new site design on October 24th in time for our fall fundraising drive.  If you run into any bugs please leave comments here.

As always, thank you for your support; it’s what keeps us going.

-Jason

Thanks for joining us in the fight to provide better access to developmental drugs.  We will be using this blog to discuss the latest in our battles with the FDA as well as highlight the work of others who share our goal of saving lives.