An FDA task force has been formed to examine transparency at the Food and Drug Administration (FDA). “President Obama has pledged to strengthen our democracy by creating an unprecedented level of openness and public participation in government, and the FDA looks forward to participating in this process,” said FDA Commissioner Margaret A. Hamburg, M.D. “I have asked the Transparency Task Force to deliver recommendations to me for ways to make more information available and foster better understanding of decision-making.”

One public meeting has been held, and a request for public comments has been posted. C3 provided comments urging FDA to review transparency requirements to ensure that the public is given accurate information both pre- and post-approval.

What does “Transparency at FDA” mean?

In the United States, the Freedom of Information Act (FOIA) was passed after Watergate so that people could ask federal agencies for information about their actions. The agencies, including the FDA, are required to provide the information unless the information is protected by special exemptions. The exemptions are intended to protect individuals, corporate entities and national security. One exemption (Exemption 4) covers:

• Trade secrets such as valuable formulas or processes
• Confidential business information including sales data, technical designs, customer lists, supplier lists, financial data, research data

Generally speaking, discussions between the Food and Drug Administration (FDA) and research sponsors such as drug companies fall under this exemption. In other words, communications between FDA and sponsors are confidential, and thus are not transparent. The assurance of confidentiality allows for free-flowing communication between FDA and the sponsor. Violation of the confidentiality can be considered a criminal offense.

This applies only to non-public information. Once information is made public anywhere, the FDA is no longer required to protect it.

For example …

Here’s a very simple example of what that looks like. When a research sponsor – typically a drug company – has research showing that their treatment helps patients, the sponsor submits the data to the FDA, and asks for approval based on that research. The FDA reviews the application and has several options – they can:

· Approve
· Disapprove
· Refuse to accept the application
· Request additional data

If the application is approved, the research results are summarized in the drug’s label, usually after extensive negotiations between the sponsor and the FDA. In the other situations, the FDA sends a very detailed letter to the sponsor that explains its concerns. The sponsor does not have to release the letter to the public. All communication between the sponsor and FDA is confidential unless the FDA holds a formal public advisory meeting such as an Oncology Drug Advisory Committee (ODAC) meeting, and even then, the FDA can reveal only the information necessary for expert review by the committee. If a drug is disapproved, the public generally does not know why.

Why do both confidentiality and transparency matter?

Bringing a new drug to market takes, on average, over ten years and $800 million - $1.2 billion according to the Tufts Center for the Study of Drug Development. Companies need to protect information that, in the wrong hands, could jeopardize their investment.

At the same time, C3 believes that there are situations where patients should have access to FDA’s perspective, especially if FDA’s perspective differs greatly from the information made public by the research sponsor.

Want to know more?

For additional information about FOIA, see:

• Your Right to Federal Records (2006) This pamphlet is a joint publication of the Department of Justice and the General Services Administration concerning both the FOIA and the Privacy Act
• A Citizen’s Guide to the FOIA (2005) A guide to both the Freedom of Information Act and the Privacy Act prepared by the House Committee on Government Reform
• FDA-specific information about FOIA

FDA’s website has extensive information about drug development.

The Beacham Family In Their Cover Your Butt Shirts at the 2009 Philadelphia Insurance Triathlon

When Brian Beacham decided to run in his second triathlon he knew that this one would have a more significant meaning but he wasn’t able to anticipate what an emotional experience it would become.

On February 13, 2008, Brian’s future brother-in-law, Billy, as family and friends referred to him, was diagnosed with colon cancer that had also spread to his lymph nodes and liver.  After originally deciding to participate in the 2009 Philadelphia Insurance Triathlon for a second time, Brian decided that he also wanted to dedicate his efforts to help raise awareness and money for the fight against colorectal cancer in Billy’s honor. Continue reading…

Pfizer announced yesterday, June 30, 2009, that they are discontinuing a phase III trial comparing FOLFIRI chemotherapy alone to FOLFIRI with added Sutent® (sunitinib).

Based on results so far, the independent Data Monitoring Committee (DMC) determined that a significant reduction in progression-free survival was not statistically possible.  No new safety concerns were identified.

Pfizer was conducting SUN 1122 in a number of countries worldwide.

The primary goal of the trial was to show that Sutent could increase the time it took for cancer to get worse (progression-free survival). Patients in the trial were having their first treatment for advanced colorectal cancer.

Treatment was either FOLFIRI (irinotecan, leucovorin, and continuous infusion 5-FU) alone or FOLFIRI with additional Sutent.

While research teams, doctors, and patients on a clinical trial don’t know the results until after the study is complete and analyzed, trials have an independent Data Monitoring Committee that reviews safety and emerging results regularly.  Sometimes DMCs will decide that a trial should be ended early, either because data is so strong for effectiveness that everyone on the trial should have access to the experimental treatment or — as in this case — that continuing it any longer would not prove that the new treatment helped.

Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs for Pfizer’s Oncology Business Unit said,

We are disappointed with this result, but trial successes and failures are an integral part of cancer drug development and contribute to a growing body of knowledge on improving patient care. Pfizer remains committed to developing new agents for colorectal and other GI cancers with ongoing clinical studies evaluating other agents in its pipeline. Investigators will be consulted about the status of sunitinib colorectal studies other than the SUN 1122 trial.

Sutent is currently approved by the FDA to treat gastrointestinal stromal tumor (GIST) and metastatic renal cell cancer.

Disclosure: C3 has accepted funding for projects and educational programs from Pfizer in the form of unrestricted educational grants. C3 has ultimate authority over website content.

At ASCO a number of studies showed the efficacy data of combining 5-FU or Xeloda with oxaliplatin in combination with radiation therapy in patients with rectal cancer.

Based on a German study published a couple of years ago, chemoradiation became the standard therapy for patients with resectable rectal cancer. The rate of sphincter-sparing surgeries and lower toxicities were the reason to prefer chemoradiation prior to surgery instead of adjuvant treatment after surgery.

Over the last couple of years many studies aimed to improve the efficacy of neoadjuvant chemoradiation therapies by intensifying the chemotherapy.  Standard therapy is 5-FU or Xeloda® (capecitabine). By adding oxaliplatin it was hoped that  the success rate of chemoradiation could be increased.

Success of neoadjuvant radiation is measured by a complete pathological response rate (complete disappearance of cancer cells). With 5-FU or Xeloda that can be reached in about 10-15% of the cases. Smaller studies have suggested that the addition of oxaliplatin could double the rate.

However the studies presented at ASCO a couple of weeks ago (ACCORD) did not show any significant difference when oxaliplatin was added. However there was interestingly a lower risk of developing metastases in the patients who received the additional oxaliplatin therapy. These findings may question the ongoing R-04 study which compares 5-FU to 5-FU plus oxaliplatin in combination with radiation therapy.

In the Southwest Oncology Group (SWOG) we have choosen another way. In the study just opened, we started with Xeloda, oxaliplatin and Erbitux (kras wild type), then we continue with the chemo and add radiation to have a both powerful systemic effect and a local effect.

Farrah Fawcett died on Thursday, June 25, 2009 of anal cancer that had spread to her liver.  She was 62.  Anal cancer is much more rare than either colon or rectal cancer, affecting about 5,300 Americans in 2009. 710 will die from it.

In other headlines, the Caterpillar company works with Peoria hospitals and doctors to ensure quality colonoscopy for their employees and a Swiss laboratory will be the first to offer a blood screening test for colorectal cancer.

In research, MRI colonography is useful for patients who can’t have a full colonoscopy before surgery, screening colonoscopies are increasing for Medicare enrollees, and scientists have found factors in tumors that make nerves more sensitive to pain.

Research Reports

• Magnetic resonance colonography was successful before surgery for patients with colon or rectal cancer who hadn’t yet had a complete colonography.  Done either the night before in surgery in the hospital or a week before as an outpatient procedure, it revealed lesions, both cancers and polyps, in 4 out of 47 patients tested, changing the surgical strategy for 3 of them.  One flat adenoma and 5 small polyps were missed and found later on colonoscopy. Although bowel cleansing is necessary, there is no radiation or sedation.  Michael P. Achiam and his team in Copenhagen report on the feasibility and potential benefits of MRC in the July 2009 issue of Academic Radiology.
• Since 1998 when Medicare first began paying for colonoscopy, its use has increased each year for Medicare enrollees, and use of other screening tests including FOBT, flexible sigmoidoscopy, and barium enema has decreased.  Percentage of people on Medicare who have been screened for colorectal cancer has increased each year, but still less than half (47 percent) had been tested in 2005.  Only a third of people 50 to 64 who are covered by Medicare because of a disability had an appropriate screening test.  Anna Schenk in North Carolina and a team at the National Cancer Institute report findings in the American Journal of Prevention Medicine, July 2009.
• Working with mice, German scientists have discovered two substances secreted by tumors that make nerve fibers more sensitive to pain, increase nerve endings in the skin, and cause the growth of tumors.  Blocking the signals of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) may lead to a more effective way of controlling cancer pain.  Matthias Schweizerhof discusses the research in a letter to Nature Medicine published online June 7, 2009. Science Daily had an article about the studies on June 25.

Other Headlines

• The Caterpillar company, headquartered in Peoria, IL, provides free cervical, breast, prostate, and colorectal cancer screening to its 45,000 US employees.  To manage costs and ensure quality, they met with hospital and doctors in their area and proposed a program for Caterpillar employees that caps costs for colonoscopy at $1,000 and also grades doctors on how many of eight colonoscopy quality-indicators  they meet. That information is shared with the program doctors.  All doctors who do colonoscopies in the Peoria region are now part of the program.  Health reporter Julie Steenhuysen covers the story for Reuters Health.
• Voillier, a private Swiss testing lab will be the first in Europe to offer a blood test for colorectal cancer based changes in DNA. The test looks for methylation of DNA in the SEPT9 gene which ordinarily keeps tumors from developing.  Cancer cells shed this altered DNA into the bloodstream.  The test was developed by German molecular diagnostics firm Epigenomics, which plans to offer the test in the United States later this year.  Currently a study is underway with 7,500 people who who will have the blood test done before their colonoscopy to find out if changes in blood DNA are reflected in colonoscopy results.

At ASCO 2009 Dr. David Kerr from the United Kingdom presented data on a genetic signature which is associated with tumor recurrence in stage II colon cancer. However these data are not even close to being clinically meaningful.

These data have been discussed by Kate Murphy. However I wanted to follow up with the significance of the data. To increase the risk of recurrence from 12% to 22% is not in any way or form helpful in the clinic, particularly because this outcome is independent of treatment effect.

In other words the technology used by Genomic Health did not result in any clinically meaningful markers which are helpful to decide whether chemotherapy should be given or not.

I was surprised that the data was presented like these are positive data because they have no impact on daily practices. These data need to be improved to make a difference so that they can be used to identify the patients who are at significantly higher risk.

Patients with stage II colon cancer have on average a 15 percent chance of cancer recurring. This is a big challenge! Should we treat everyone and treat many patients with no benefit to make sure we treat everyone who really is at higher risk.?

If we had a genetic marker set which could isolate these patients who are at higher risk, we could spare the ones with very low risk  from chemotherapy for 6 months.

The Genomic Health approach was not successful partly because they did not take advantage of the whole genetic make up. The technology is able to measure 40-50 thousand genes in one test and to figure out what signature would predict recurrence would be the solution.

In breast cancer they have developed a signature to predict recurrence risk and whether chemotherapy should be given.

Although new diagnoses of colon and rectal cancer are decreasing in the United States, the benefit does not reach everyone.

No matter where they lived, incidence of colorectal cancer dropped significantly between 1995 and 2004 for white Americans aged 65 and over, most of whom have Medicare that covers colonoscopy screening.  However, colorectal cancer rates for whites from 50 to 64 did not fall if they lived in rural areas or counties where there was poverty, lack of insurance, or few primary care providers.

African Americans only benefited from reduced incidence if they were over 64 and living in an affluent community.

Researchers from the American Cancer Society in Atlanta reviewed colorectal cancer incidence rates in metropolitan and rural counties across the United States looking at poverty, age, race, and ethnicity. They also measured access to health care by the supply of primary care physicians and amount of insurance coverage.

Medicare made a difference for older people.  Colorectal cancer fell for whites over 64 in all areas, including those with poverty or few primary care physicians.  However, for Hispanics and African Americans eligible for Medicare, only those living in more affluent counties without poverty and with a good supply of primary care saw colorectal cancer rates decrease.

For younger whites from 50 to 64, not covered by Medicare, rates did not decrease if they lived in a county with high poverty, many uninsured, lack of primary care physicians, or in a rural area.

Hispanics and African Americans under 65 saw no reduction in incidence rates in general, no matter where they lived.  If they were 65, rates did not decrease in counties with poverty, lack of insurance, and few primary care physicians.  African Americans also did worse in rural communities.

Colonoscopy screening increased significantly for whites in both age groups.  However, screening with colonoscopy didn’t improve for Hispanics below Medicare age at all, nor for Hispanics over 64 who lived in areas with high poverty.

Likewise African Americans from 50 to 64 saw no increase in colonoscopies if they lived where there were high rates of uninsured.  Colonoscopy screening for African Americans old enough for Medicare didn’t improve where there was poverty or a poor supply of primary care physicians.

Writing in Cancer Causes and Control, Yong Ping Hao and colleagues concluded,

Individuals residing in poorer communities with lower access to medical care have not experienced the reduction in colorectal cancer incidence rates that have benefited more affluent communities, and that this is likely explained in part by lower utilization of colorectal endoscopic screening even in older populations with coverage through Medicare. Further research is needed on factors that explain the disparities and potential interventions to address them.

Colorectal cancer patients whose cancer had spread to their livers benefited from surgery during which heated chemotherapy was pumped directly to their livers. Isolated hepatic perfusion (IHP) shrank tumors and increased survival time.  It may be a hopeful new approach to treating colorectal cancer that is widespread in the liver.

Median survival time after the treatment was a little over 17 months.  A third of patients lived two years or more.

A clinical trial of a similar hepatic perfusion technique without open surgery is currently available at the NIH Clinical Center in Bethesda, Maryland.

During an abdominal operation, surgeons placed tubes in major blood vessels in the liver.  Heated chemotherapy was then pumped for about sixty minutes through the liver.  This technique allows stronger chemo to be delivered directly liver tissue and avoids the side effects of chemotherapy that goes throughout the body.

Two drugs were used in the reported studies:  melphalan and tumor necrosis factor (TNF).  Some patients received only melphalan, some only TNF, and some both.  In addition, some patients had a pump placed in their abdomen to infuse chemotherapy into their liver through the hepatic artery after the surgical treatment.

There were 120 patients who had some form of hepatic perfusion treatment, 114 available to be evaluated for this report.

• 69 patients had either complete (2) or partial (67) tumor shrinkage (61 percent)
• Median time until cancer recurred in the liver was 7 months
• There was no clinically meaningful tumor reduction in the 10 patients who received TNF alone
• Median time to cancer progression in the liver for TNF alone group was 3 months.
• Patients who didn’t receive additional hepatic arterial infusion (HAI) after surgery had 57 percent response and a median time to liver progression of 5.8 months.
• HAI improved both response rate to 65 percent and time to liver progression to 13 months.

Response rate was not affected by the amount of tumor in the liver, by previous chemotherapy, age, or gender.

Serious side effects of treatment included changes in liver function tests after surgery that returned to normal, very low blood pressure in some patients, bleeding, and infection.  Five patients died, although these deaths occurred in early phase I trials of TNF when finding a tolerable dose was the goal.

In reflecting on the results of their studies, researchers at the University of Maryland Medical School in Baltimore and the National Cancer Institute in Bethesda led by H. Richard Alexander, Jr. M.D. wrote,

Regional therapy eliminates unnecessary systemic toxicity and when used as second-line therapy can be used selectively for those who may benefit most, that is, those with disease that has remained confined to liver by serial imaging over time.

They concluded,

Isolated hepatic perfusion results in marked tumor regression and prolonged survival in patients with colorectal cancer liver metatases. Continued development of IHP in this clinical setting is warranted.

SOURCE: Alexander et al., Annals of Surgical Oncology, Volume 16, Number 7, July 2009.

In studies reported this week  fewer specialists managing colorectal cancer were found in US counties with large African American populations, older adults with cancer had significantly worse physical and mental health, and palliative sedation at the end of life did not hasten death.

In other headlines, colorectal cancer screening for the uninsured will begin on July 1 in Minnesota, and if screening reveals cancer, treatment will be covered under the Minnesota Medical Assistance program.  The FDA warned consumers not to use Zicam nasal gel or swabs to avoid loss of smell, and doctors advised patients on long-term Xeloda therapy to carry a letter from their oncologist explaining possible loss of fingerprints if they travel internationally.

Research Reports

• Communities with large percentages of African Americans have less access to the doctors critical to colon and rectal cancer care. Analyzing data from the HHS Area Resource File, researchers discovered that as the percentage of African Americans in individual US counties increases, the numbers of gastroenterologists, radiation oncologists, and colorectal cancer surgeons decreases.  Awori J. Hayanga, MD wrote in the June 2009 Archives of Surgery, “Increasing numbers of minority patients in counties is accompanied by a differential access to specialists. This may affect the likelihood of a patient to receive appropriate care.”
• Measuring health-related quality of life, older adults with most cancers, except melanoma and endometrial cancer, have poorer physical health than matched over 65 controls.  However, only older cancer patients with lung, colorectal, and prostate cancer had significant reductions in mental health.  Bruce Reeve and his team linked data from the Medicare Health Outcomes Survey (MHOS) and NCI SEER cancer registry to determine how a cancer diagnosis affects both physical and mental health and quality of life. They reported their results online June 9, 2009 in the Journal of the National Cancer Institute. A JNCI Memo to the Media has more information about the study.
• Palliative sedation given to manage severe symptoms at the end of life does not reduce survival time when compared to patients treated with standard hospice protocols, according to a study in the July Annals of Oncology. The study resolves some ethical questions of using sedation for unmanageble end-of-life pain even if it might hasten death.  Dr. M. Martoni wrote, “Palliative sedation therapy does not shorten life when used to relieve refractory symptoms and does not need the doctrine of double effect to justify its use from an ethical point of view.”

Other Headlines

• On July 1, 2009, with funds from an increased tobacco tax, the Minnesota Colorectal Cancer Prevention Act will provide screening for uninsured and underinsured residents of Minnesota. Program participants must have family incomes less than 250 percent of poverty and be over 50 or at high risk of colon cancer.  If cancer is found during screening, patients will be covered by Medical Assistance for their treatment. The American Cancer Society recognized state representative Maria Ruud, a nurse practitioner, as Legislator of the Year for her leadership in writing the legislation and getting it passed.
• On June 16, 2009 the FDA warned consumers to stop using and throw away intranasal Zicam Cold Remedy Nasal Gel and Zicam Cold Remedy Swabs. The zinc-containing  products have been linked to a loss of the sense of smell, for many people with the first use.  Zicam Cold Remedy Swabs, Kid Size has been discontinued, but the FDA is concerned that some people may still have it in their homes.  Because children may not report loss of a sense of smell, the FDA is particularly concerned with the use of zinc in the noses of children.  The FDA has sent a warning letter to Matrixx Initiatives telling them that these products cannot be marketed without FDA approval.
• Hand-foot syndrome side effects from Xeloda® (capecitabine) may cause loss of fingerprints with long-term use.  The July 2009 Annals of Oncology reports on a case of a man with head and neck cancer who took oral Xeloda for over three years as maintenance therapy.  He was detained trying to enter the United States because his fingerprints could not be detected.  In a letter to the editor of Annals, doctors say that patients on long-term capecitabine therapy should be warned about the possibility of fingerprint loss and carry a letter from their oncologist explaining the situation.  They point out that it is unclear how soon fingerprint loss may occur.

Throw out that refrigerated Nestles TOLL HOUSE Cookie Dough!  And don’t eat it raw or bake it.

The Food and Drug Administration has announced a voluntary recall of all varieties of Nestle® TOLL HOUSE® refrigerator cookie dough.  While no e. coli bacteria have been actually found in the dough, there have been a number of reports of consumers becoming ill after eating the raw dough.

Baking the cookies may not eliminate the risk of contamination because cooks may get bacteria on their hands or on other kitchen surfaces.

Nestle and the FDA emphasize that people should never eat raw cookie dough or other foods that are intended to be baked or cooked before eating.

The products involved in the voluntary recall include all varieties of Nestlé TOLL HOUSE refrigerated Cookie Bar Dough, Cookie Dough Tub; Cookie Dough Tube; Limited Edition Cookie Dough items; Seasonal Cookie Dough and Ultimates Cookie Bar Dough. A complete list is available from Nestle. It includes all varieties, not just chocolate chip.

The FDA and CDC are working with Nestle on a study of e. coli illness that may be related to raw cookie dough.  Since March 66 people have reported being sick in 28 different states. Twenty-five persons were hospitalized; 7 with a severe complication called Hemolytic Uremic Syndrome (HUS). No one has died.

The e. coli strain (E. coli O157:H7)  causes abdominal cramping, vomiting, and diarrhea, which may be bloody.  Young children and the elderly are at the highest risk of develooing  HUS which can lead to serious kidney damage and even death.

If you have had these symptoms after eating raw cookie dough, the FDA says to contact your doctor or health care provider right away.  All such illnesses should be reported to local or state health departments.

More information is available from Nestle by calling 1-800-559-5025 or by going to their website. Nestle says that consumers who have recalled cookie dough can return it to the place where they bought it for a full refund.

Note: If you make cookies at home from your own ingredients, be careful about tasting the dough or offering your kids the spoon to lick.  Raw eggs used in cookies may contain salmonella bacteria.  This is not the same bug as the e.coli involved in the Nestle recall, but can be as dangerous for you, your children, or a sick or elderly family members. Kate