Comments to the Anesthesiology and Respiratory Therapy Devices Panel at the Food and Drug Administration Regarding the Sedasys® Computer-Assisted Personalized Sedation System

Submitted by Carlea Bauman, President

C3: Colorectal Cancer Coalition

May 28, 2009

These comments are submitted on behalf of C3: Colorectal Cancer Coalition (C3), a non-profit, nonpartisan advocacy organization that is committed to the fight against colon and rectal cancer.

We appreciate the opportunity to comment on the Food and Drug Administration’s (FDA) Anesthesiology and Respiratory Therapy Devices Panel’s (ARTDP) consideration of the Sedasys® Computer-Assisted Personalized Sedation system.

C3 pushes for research to improve screening, diagnosis, and treatment of colorectal cancer; for policy decisions that make the most effective colorectal cancer prevention and treatment available to all; and for increased awareness that colorectal cancer is preventable, treatable, and beatable.  C3 believes in fully disclosing sources of financial support, per our disclosure policy, which can be viewed at www.FightColorectalCancer.org/funding.htm.  C3 has received no funding from Ethicon Endo-Surgery, Inc. or Johnson & Johnson (J&J).  We were briefed on the Sedasys system by company representatives, and have prepared these comments prior to reviewing the FDA briefing information.

Neither these companies nor any of our other corporate supporters have influenced our comments on this issue.

Approximately 1.6 million Americans are screened for colorectal cancer with colonoscopy each year_i.  These people balance the risk of a colonoscopy with the significant benefit of preventing colorectal cancer or finding early-stage, curable disease.  As patient advocates, our first concern is that colonoscopy is as safe as possible.  One risk that colonoscopy patients face comes from sedation.  Our second concern is that people are comfortable during the procedure and are satisfied with their care.

We have reviewed data presented to us by Ethicon Endo-Surgery and J&J, but have not reviewed the briefing documents for this meeting.  We see potential benefits and risks to patients, but at this time, we cannot make a recommendation regarding approval.  Instead, we will share our perspective with you, and ask that you address our questions and comments during your discussion.

Some of the potential benefits to patients that we see with the Sedasys system are:

• For patients undergoing colonoscopy without an anesthetist in the room, the system helps monitor patients in ways that may not be routine now, with the capnometry and an automated response monitor.
• We believe that the continuous infusion of propofol as opposed to a bolus may allow more precise dosing for patients.
• In addition, the safeguards described are reassuring. We think that requiring that propofol be administered with concurrent oxygen and restricting the size of the loading dose will be beneficial to the patient.

At the same time, we have questions about potential risks, which we hope will be discussed by the panel.

In the 1000 person trial, Sedasys was compared to standard colonoscopy sedation.  The primary endpoint was an Area Under the Curve calculation of oxygen de-saturation.  The trial was randomized, but not blinded.  The patient population was carefully selected to reduce risk to patients.

• Control Arm: We are somewhat concerned about the choice of control arm.  Rather than compare propofol delivered via the Sedasys computer assisted personalized sedation automated system to standard sedation with midazolam and an opiate should not the CAPS system have been compared to administration of the same medication (propofol) by an anesthesiologist?  We understand that due to the nature of the trial design, it would have been impossible to conduct as a blinded trial. At the same time, the results of non-blinded trials are more likely to be biased than results from blinded trials.  We would like to understand how FDA and this committee will take this potential bias into account.
• Valid Endpoint: The primary endpoint, area under the curve of oxygen desaturation, seems to make sense intuitively.  We would like to know if this endpoint has been validated to the FDA’s and this committee’s satisfaction.
• Exclusion Criteria: The trial excluded patients at higher risk for problems during sedation.  We would like to understand whether the FDA and this committee believe that these exclusion criteria are sufficient for the product label, or whether additional exclusion criteria should be included.  We are especially concerned that only 50 individuals over 70 were included in the trial, and, if approval is recommended, urge you to consider an upper age limit on the use of the device.
• Real-life, high volume use: The trial tested a complex automated system that made sure the patient was breathing adequately while minimally to moderately sedated and that deep sedation requiring respiratory assistance was avoided.  Sedasys was tested at eight sites, in approximately 500 people, with no serious adverse events.  While the trial was large for a device trial, if Sedasys is used more widely in many different community endoscopy settings with many more patients, there is a greater risk of serious adverse events related to deep sedation or the need for respiratory assistance, as well as quality control issues with the machine itself.  If this committee votes for approval, we would like to understand what steps will be taken by the FDA and the manufacturers of Sedasys to minimize patient risk during launch and early use of the system.

People undergoing screening colonoscopy are trying to prevent disease; therefore, we must minimize the risk of colonoscopy.  Our overriding concern is that people undergoing screening colonoscopy are safe and comfortable.

We greatly appreciate the opportunity to comment on the critical issues in front of you today, and look forward to listening to your discussion.  Thank you very much for your consideration of our comments.

_iVijan S, et al. “Projections of demand and capacity for colonoscopy related to increasing rates of colorectal cancer screening in the United States” Aliment Pharmacol Ther. 2004 Sep 1;20(5):507-15. http://www.medscape.com/viewarticle/488909

This week we have research reports about risk of complications after hand-assisted laparoscopic colectomies, the benefit of music therapy during hospice treatment, and a gene that predicts better response to cetuximab.

In other headlines, we found an excellent overview of the progress made in colorectal cancer treatment with data and references.  In addition, there is information about management of colonoscopy sedation in HIV patients receiving antiretroviral medicines and a lifting of the FDA ban on concentrated liquid morphine for terminally ill patients until an acceptable substitute can be found.

Research Reports

• Hand-assisted laparoscopic colectomies didn’t have any more serious longterm complications than more limited laparoscopic surgery.  In hand-assisted laparoscopic surgery (HALS) a slightly longer incision is made to allow the surgeon to insert a hand into the abdomen and work with laparoscopic instruments.  Comparing over 500 patients, half of whom had standard laparoscopic colectomies and half whose laparoscopic surgery was hand-assisted, researchers found no differences in rates of incisional hernias, small bowel obstruction, or wound infections.  About 2 percent of patients had to have the laparoscopic surgery converted to an open operation, and incisional hernias were considerably higher in this group (25 percent compared to 5 percent who didn’t need conversion.)  Surgeon Dr. Toyooki Sonoda from Weill Medical College of Cornell University writes about the study in the January 2009 issue of the Journal of the American College of Surgeons.
• Music therapy during hospice care for patients and their families helps caregivers after the patient’s death.  They have memories of joy and empowerment rather than pain and distress.  They report feeling stronger having contributed to their loved one’s comfort through music.  Lucanne McGill from University of Winsor School of Music interviewed caregivers after family members who had participated in music therapy died.  She writes about her research in Palliative and Supportive Care, March 2009.
• Mutations in the TP53 gene predicted better outcomes from treatment with Erbitux® (cetuximab) in a French study.  In a group of 64 colorectal cancer patients treated with Erbitux, 41 had mutations in the TP53 gene and, as a group, had better disease control with their tumors either shrinking or remaining stable.  Median time before the cancer got worse (time to progression) was 20 weeks in patients with a TP53 mutation versus 12 weeks in those without mutation.  Writing in the British Journal of Cancer, Rouen scientist A. Oden-Gangloff said, “This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based chemotherapy.”

Other Headlines

• Certified physician assistants Maura Polansky and Alicia Ross have written an excellent overview of progress in screening and treating colorectal cancer in the Journal of the American Academy of Physician Assistants. They include data for colorectal cancer incidence and survival and information about progress in treatment from 5-FU through recent targeted therapies.  Five year survival for all patients improved from 49.39 percent in 1975 to 65.5 percent in 1999.  Screening rates doubled between 1987 and 2000, but still remain below 50 percent.  New drugs have improved median survival and increased liver resectability for patients with metastatic colorectal cancer.  A very good review of what we know about colorectal cancer today with a list of key references.
• Patients who are being treated with some antiretroviral regimens may need special consideration with sedation for colonoscopy. Because antiviral drugs block a critical enzyme necessary to metabolize the usual drugs used for sedation, dangerously high doses can build up. Not giving the antiviral medicine for a day or so is not sufficient to reduce this effect. Two expert pharmacists and a gastroenterologist discuss how to manage sedation safely in an article in Journal Watch. Beginning with low doses of sedative and pain medicines and carefully increasing them to keep colonoscopy patients comfortable is suggested by all three.  HIV patients can have colonoscopies, but need special care.  Read detailed discussions of the pharmacology interactions of antivirals and sedation in Journal Watch from the New England Journal of Medicine.
• On April 3, News in Brief reported an FDA warning to manufacturers of some opiate drugs to stop making and distributing them because they were not approved.  The warning included high concentrate 20 mg/ml morphine sulfate oral solution which is widely used to help with pain in terminally ill patients.  The palliative care community told FDA that there was no other product on the market to meet the patient need, and FDA has lifted the ban until a suitable alternative can be developed.  FDA said, “The FDA appreciates the help we received from the palliative care community about how this drug is being used today to help patients. We want to continue to talk to them as we move forward on this difficult issue.”