QDIS Blog

As regular readers know, I’ve been following the developments related to Ketek all year. Now, it seems the FDA advisory committee has recommended that Ketek only be used for certain life-threatening indications.

FDA Panel Hits Antibiotic For Bronchitis, Sinusitis - Forbes.com:

Basically, the committee recommended a black box warning on Ketek for its use in community acquired pneumonia which can be potentially life-threatening. The vote on this aspect was 16 to 3 that for community-acquired infections that Ketek should still be available.

They voted 17 to 2 that the the benefits did not outweigh risks for other indications such as sinusitis and bronchitis. These indications are not as serious and can be treated with other drugs. It will be interesting to see if the FDA rescinds the approval of Ketek for these indications. I think that is very likely to happen. For those out there interested in the chemical structure here it is.

Bottom line was that the drug is effective and can be used in certain indications but that physicians and the patient should be aware of the potential problems. Again, I applauded this recommendation; the risks vs reward must be weighed not for the drug itself but based on the exact indication.

Other Resources

FDA Search Results: ketek (sorted by date with most recent at the top)
Aventis Pharmaceuticals -Ketek - June 2006 prescribing information
Patient Information Sheet: Telithromycin (marketed as Ketek) (from FDA.gov)
ketek - Yahoo! Search Results
ketek - Google Searchimage

Technorati Tags: antibiotics, drug safety, FDA, Ketek, Sanofi-Aventis, telithromycin

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As regular readers know, I’ve been following the issues surrounding Ketek (telithromycin) an antibiotic from Sanofi-aventis and reports that it has caused some liver problems.

UPDATE 3-Studies support Sanofi antibiotic, say FDA staff | Reuters.com:

The FDA has had meetings Dec 14-15 on this product as a joint meeting involving both the anti-infective drug advisory committee and the drug safety and risk management advisory committee. It will be interesting to see what comes out of this meeting. We may know later today but most likely early next week.

If you want to know the background as well as key dates in the approval history of Ketek then I recommend the Brief documetn listed below which has a lot of good background material on the product.

Once transcripts are available, i’ll post links to them.

Other Resources
FDA Completes Safety Assessment of Ketek New Safety Information to be Added to Product Labeling (press release of June 29, 2006)
Advisory Committees: CDER 2006 Meeting Documents

BRIEFING DOCUMENT AVAILABLE FOR PUBLIC DISCLOSURE: KETEK® (telithromycin)
Technorati Tags: drug safety, FDA, Ketek, Sanofi, Sanofi-Aventis, telithromycin

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This report again highlights that something is wrong with food safety in this country.

Over 250 sick after eating at Indiana Olive Garden - Yahoo! News

Evidently about 250 people in Indiana have become sickened and three people hospitalized after eating at an Olive Garden in Indianapolis. Interestingly, their is nothing on their website yet in the press release area. Although the exact restaurant has not been identified it is most likely this one on 82nd St in Indianapolis near Castleton Square.

If this is indeed caused by e. coli then I think there is very likely some sort of connection between these seemingly unrelated events. According to the report, it will be about 48 hours before any results are know as to what may be the problem.

It could be that the problems at Taco Bell, Taco Johns and Olive Garden all come from a common source. It would not surprise me if it is all the same ingredient (likely lettuce) and that it came from the same geographic source probably in California. This is all just a guess on my part but I certainly hope there is some sort of coordination in this to hopefully trace it back to it origin.

I think this will just add more impetus to Democrats wanting to reform the food safety part of the FDA. I only hope that it doesn’t involve creating a new government agency combining the food aspects of the FDA with the US Dept. of Agriculture’s inspection of meats. AI better solution that I have expressed in the past is to give an adequate budget to the FDA in order to allow them to do their job properly. It may be that the mission of the food safety group needs to be redefined. I would like to see them beef up their inspection force on the food side.

I lived in Indiana for quite a few years so I was interested in what the local TV stations were reporting on this. I’ve listed their reports below. I may even haven eaten at this restaurant at one time. That’s how I know which restaurant it is. There is really only one located in the northeast side of Indianapolis in the Castleton area.

Other Resources

WISH-TV - Indianapolis News and Weather - Update: More than 200 Claim Illness from Restaurant
2 Hospitalized, 200 Report Illness After Eating At Restaurant - Local News

Technorati Tags: FDA, food safety, Olive Garden, Taco Bell, Taco Johns

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The FDA earlier this week ordered several companies to stop selling quinine as a treatment for leg cramps. Many of these companies

FDA halts sales of some quinine drugs - Yahoo! News

Quinine is a useful drug for its intended purpose of treating malaria although this has become less useful recently due to the emergence of resistant strains. Mutual Pharmaceutical Company Inc. is approved to sell Qualaquin for the treatment of malaria. What is interesting to me is that this was just approved on Aug 12, 2005.

This drug has serious side effects and its use for malaria is justified since malaria can be life threatening. However, leg cramps are not life-threatening and therefore the benefit does not outweigh its potential down-side in this situation.

Here is the actual release from the FDA

FDA Advances Effort Against Marketed Unapproved Drugs

This touches on a subject I have posted about before that is off-label use. I think it should be left to doctors to decide a drugs use but in some cases such as this, its use really isn’t justified. The problem is quinine has a narrow therapeutic window. This means the difference between an effective dose and a dose that causes serious side effects is quite small.

There are some drugs out there that have been used in medicine prior to some of the current drug regulations and have not been tested to the current standards. The FDA estimates are that several hundred drugs that are un-approved account for about 2% of all prescriptions written each year.

I have tried to find the companies involved as some articles mention as many as eight companies but the only one currently identified are:

Watson Pharmaceuticals
Ivax (now part of Teva)

These companies have 60 days to stop selling quinine. I would be interested if someone else know the other companies involved.

Other Resource

Questions and Answers About FDA’s Enforcement Action Against Quinine Sulfate Drug Products

Final Rules for Drug Products Containing Quinine for Treatment and/or Prevention of Malaria for Over-the-Counter Human Use (pdf)

Technorati Tags: drug safety, unapproved drugs, quinine

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Maybe it is just coincidence but we’ve now had three major outbreaks of e.coli O157:H7 since Sept 2006.

1. Bagged Spinach in western states killed 3 and sickened at least 199
2. Taco Bell on East Coast in NY, NJ, and PA from green onions/scallions: 62 sick, 49 hospitalized
3. John’s Taco in Iowa 14 hospital, 36 sickened and this is still developing

Here are the FDA press releases on the first two incidents:

FDA Statement on Foodborne E. coli O157:H7 Outbreak in Spinach–Update October 4, 2006
FDA Statement on Foodborne E. coli O157:H7 Outbreak in Spinach–Update October 12, 2006
FDA Investigating E. Coli O157 Infections Associated with Taco Bell Restaurants in Northeast
UPDATE: FDA Investigates E. Coli O157 Cases Associated with Taco Bell Restaurants

The most recent is from a Taco Johns (not associated with Taco Bell) in Iowa and the source of the problem has not yet been identified. I would not surprise me though if it ends up being green onions also and maybe from the same source.

14 hospitalized after dining at Iowa restaurant; E. coli suspected - CNN.com

This brings the total to almost 200 sickened and more than 63 hospitalized in the past four months due to e. coli. The CDC states that 61 deaths occur each year due to e coli. I think just about anyone would come to the conclusion that there is likely a problem and some changes need to happen.

I should point out that e. coli is found in the human gut and is normally present and does not normally cause problems. However, this particular strain O157:H7 is particularly virulent and affects people but the worst effects are seen mainly in the elderly or the young. This strain comes primarily from cattle and is found in cattle feces. This can get into water supplies and if that water is used for irrigation, it can lead to contamination. Another problem is that bacteria can form biofilms which are practically impossible to wash off.

There are estimates that tens of thousands of people are sickened each year due to food based illness but the problem is very much under estimated mainly due to sickness not being reported.

The authority for foods can be broken down into meat and poultry which is inspected by the US Dept. of Agriculture (USDA) and other foods which fall into the jurisdiction of the Food and Drug Administration (FDA). A major problem is that the FDA not set up to do field testing and monitoring.like the USDA does with meats. For example, the USDA has 7,000 inspectors inspecting 6,000 plants daily whereas the FDA has only 800 for food. Inspections of food processing plants which fall within the FDA’s jurisdiction are inspected only about once every five years!

While I’m focusing on e coli here, but there are other concerns such as salmonela, hepatitis and other food-borne illnesses.

All of this has lead to the call for a new agency. I’m not sure if that is a good idea, but I do think increasing the cooperation between the food and meat/poultry inspectors would be useful. I think again that the problem is not that the FDA does not understand its mission but that they are not funded adequately to do the functions they have been assigned.

Calls for new agency
Chemical & Engineering News: Government & Policy - Food Safety System
ScienceDaily: Calls For A New Food Safety Regulatory Agency Follow Spinach Tragedy

Here is a quote from the Chemical & Engineering News article that supports my position.

According to Michael R. Taylor, an epidemiologist at the University of Maryland School of Medicine, the primary missing element is resources. FDA does not have the resources to do inspections and set up testing systems, nor does it have a mandate “to drive primary prevention at the point of production,” he says. Another problem, he says, is no one—not the head of CDC, FDA, or USDA or California officials—is in charge of preventing the next outbreak of E. coli in spinach or lettuce. When it comes to food, Taylor says, “all play a role, but no one is in charge, and no one fairly can be held accountable.”

If food safety is an issue, then the FDA should be funded adequately in order to bring this expectation into reality.

I would point out though that there other daily risks that are much more hazardous such as driving your car or even death from the flu. However, this does not mean that steps should not be taken to minimize the risks regarding foods.

Other Resources

E. coli infection, disease information, NCID, CDC

Disease Listing, Escherichia coli O157:H7, Gen Info | CDC Bacterial, Mycotic Diseases

The Cincinnati Post - Death by dining: excellent article

US FDA/CFSAN - Nationwide E. Coli O157:H7 Outbreak: Questions and Answers (last updated Oct 20, 2006) only reall covers the spinach incident.
CFSAN Video Library: Dr. X and the Quest for Food Safety (Real Media and Windows Media files)

Recent Science Friday programs on food safety
September 22, 2006, Hour Two: Tracking Food Safety / Solar Energy
November 24, 2006, Hour One: Food

Do our fears add up? - Town Online: good article on everyday risks.

Technorati Tags: e coli, FDA, food safety

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The Senate is going to have a vote on Dr. Andrew von Eschenbach. Here are my thought and notes while watching it on C-SPAN 2.

Ted Kennedy D-MA is up talking about the importance of having a leader at the FDA. Going over the qualifications of Dr. von Eschenbach. Noted he swiftly dealt wit the Plan B over the counter situation.

Mike Enzi R-WY is now talking about the importance of having a confirmed FDA leader. Mentioned the first time having a doctor to head up the FDA in a long time. Mentioned the importance of full authority several times. Mentioned the FDA oversees drugs, food, cosmetics, medical devices, biologics and more. 25% of all American spending is overseen by the FDA.

Bill Frist R-TN is now talking. Mentioned the 100th anniversary of the FDA. Knows Dr. von Eschenbach professionally as doctors and that he is an exceptional leader. Called him the ideal candidate.

Calling the roll…..

Many more yea votes than nay votes and it looks like he will indeed be confirmed.

Andrew von Eschenbach is confirmed 80-11

Votes against were by Santorum, Inhofe, Vitter, Grassley, Talent, Dement, Dewine, Brownback, Bacchus, Voinovich, Snowe,

It is good to see that the FDA will finally have a full confirmed commissioner. Let’s hope it stays that way for a while.

Technorati Tags: FDA Commissioner, von Eschenbach

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Just recently the Senate voted 89 to 6 to end debate on Dr. Andrew von Eshenbach for FDA Commissioner. This sets up a vote for later today (Dec 7, 2006)

ABC News: Senate moves ahead on Bush pick to lead FDA:

I look at this as good news! It seems that some of the holds have been overcome and there should be a vote today. THis is indeed good news and I look forward to him being confirmed. THe FDA has been leaderless for far too much of the time in the past few years.

Technorati Tags: FDA

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This past week thee were two interesting hearings on the safety of both food and drugs.

PharmaLive: Sen. Enzi Holds Hearings on Food and Drug Safety

Given the number of instances lately that have received media attention (Vioxx and the e coli 0157 problems with spinach) I think this is timely. What follows are my thoughts, comments and interesting points on the drug safety hearing made while watching it.

Ms Burke of Institute of Medicine
• General feeling of the need giving the FDA more authority to ensure safety
• Need for new tools to predict safety.
• Central clearing house for clinical trials information
• S 3807 closely parallels many of the suggestions in the Institute of Medicine Report released in Sept.
• FDA scientists may have been pressured to change recommendation based on politcal views according to Senator Ted Kennedy
• $6 per year for every American is what the FDA budget comes to even though they oversee about 25% of the GNP
• A life-cycle approach to drugs should be taken including post-marketing studies
• The CEDR organizational structure is sometimes dysfunctional.
• A major need for leadership and stability.
• Recommendation to make the FDA Commissioner a fixed 6 year appointment.
• Recommend entirely funding from congressional budget and curtailing use of PUDFA.

This is interesting since this model is being proposed for reviewing ads for approved drugs.

• IOM committee did not think breaking up CEDR into one for approval and one for safety made sense. Did want to get post marketing folks involved earlier in the process.
• Legislation will NOT force cultural change. This is why leadership is critical.
• IOM had many recommendations especially with regard to ways to possibly integration various divisions and to change the culture.
• FDA ability to unilaterally change labeling was discussed.
• Appropriations should be primarily but PUDFA funds are needed these should also be made available for post-marketing
• IOM did not want to comment on biogenerics. Senator Hatch pursued this quite extensively.
• Senator Patty Murray brought up concern of politicalization of scientific information within the FDA.
• Statues need to be given to the FDA to unilaterally make changes to labeling. This came up several times.
• DTC ads were discussed and are needed but need to be informative to the consumer. They should be easily understood.
• Senator Clinton asked about comparative effectiveness studies. Nothing was really offered in this regard.

2nd segment; five people testified
• Clinical trial registries were discussed by several people giving testimony.
• Better funding was mentioned by almost all.
• In this part, sometimes questions asked and answered led to more questions in my mind but the Senators never seemed to follow up on what the people testifying really meant. There should be more follow-up questions in my opinion. Sometimes it seemed the clock was more important than the content of the meeting.
• No one was in favor of separating safety from approval within the FDA.

One last comment. I truly believe all government hearing should be easily available online in video as well as pdf version of the statements.

Other Resources

• Full Committee Hearing Hearing - Hearing on Building a 21st Century FDA: Proposals to Improve Drug Safety and Innovation (includes links to pdf files of witness testimony)

• Video of hearing (Real Player: begins at 35:04: ~1 h 54 min in length)

• Full Committee Hearing on Food Safety: Current Challenges and New Ideas to Safeguard Consumers (includes links to pdf files of witness testimony)

• Video of hearing (Real Player: begins at 17:47: ~x h y min)

• Ted Kennedy | S. 3807, The Enhancing Drug Safety and Innovation Act of 2006

Technorati Tags: drug safety, FDA, food safety

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A recent UPI report focused on the number of FDA approvals.

United Press International - Health Business - Analysis: FDA approving more drugs:

The report states that September and October were strong and there have been 83 approvals putting it in line with 2004 results. However, this may be temporary and not a long term trend. I think the lack of a lead and the possibility of even more legislation regarding drug safety will likely slow down the process.

I personally think the low-lying fruit has been picked over throughly and now there needs to be more validation of potential drug targets in order to facilitate research and allow for more potential drugs to be developed. Until more valid targets are discovered, I think the rate of drug development will continue to be sluggish.

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If you are a regular reader you know I’ve posted several times about the antibiotic Ketek (telithromycin). It seems that Senator Charles Grassley (D) Iowa has asked for information from the FDA on this and that the FDA has not responded appropriately.

PharmaLive: Grassley Makes Available Responses from FDA Nominee :

Here are the three aspects that are pertinent .

1. Written answers from von Eschenbach to confirmation hearing questions from Grassley (pdf)
2. Letter from Grassley to the Senate Majority Leader placing a hold on the von Eschenbach nomination
3. Letters from Grassley to the Secretary of Health and Human Services regarding agency responses to congressional inquiries.

The third point is the one I want to more fully discuss.

I fully agree with the need for any agency including the FDA to respond to congressional inquiry. The third letter is interesting in that it states in no uncertain terms that Grassley feels the FDA has not been forthcoming with information and may be withholding information. Here is a portion:

In recent weeks, my Committee staff interviewed a number of FDA officials who
referred to extremely relevant documents, which have been withheld from the Committee
to date. Further, the Committee is aware that at least three FDA officials, who played
integral roles in the FDA’s review of Ketek, were never asked to review their files and
turn over relevant documents in their possession to the Office of Legislation. For
example, most recently, my Committee staff was to interview the Regulatory Project
Manager (RPM) for Ketek, pursuant to my request letter, dated October 5, 2006. Last
Wednesday, more than six months since the Committee subpoenaed Ketek documents,
FDA notified my Committee staff that during interview preparation it was discovered that
the RPM was never directed to produce documents responsive to the Committee’s
subpoenas. It is simply dumbfounding that someone as centrally involved as the RPM in
the review of a drug was not directed to produce documents pursuant to the Committee’s
subpoenas. This latest “oversight” is but one of many that shows the inability of
HHS/FDA to comply with the Committee’s subpoenas in good faith.

While it may not be deliberate, it certainly is disturbing that there my be this sort of lack of communication.

The original subpoenas were issued May 19, 2006 and as of Nov. 21, 2006 the response still had problems according to Grassley especially with regard to redacted information where no notation was made as to why the information was redacted.

I know that Grassley has a reputation of being tough on the FDA and some have come out against this hold. See (Eye on FDA: Hold It). I think that if the FDA indeed has not appropriately replied to the subpoena then it might be justified. I personally don’t think it help the situation in the long run but I do know that congressional oversight has been lacking and that that situation may be changing starting next year now that the Democrats control Congress.

This has also been covered in the following article from the Washington post.

FDA, Lawmaker Clash Over Antibiotic - washingtonpost.com:

What is interesting is this reply to Grassley from Dr. von Eschenbach

Von Eschenbach wrote that “the disclosure of information that might relate to any open investigation in response to congressional inquiries poses an inherent threat to the integrity of the executive branch’s enforcement and litigation functions.”

This sounds like what I’m sure we will here a lot of in the coming year; executive powers.

I personally think there are ways to handle this where the enforcement and litigation can be handled without causing problems and feel this sort of reply from Dr. von Eschbach certainly doe not bode well with regard to working with Congress. If I were up for a position of any sort, this certainly would not be the tone of my rply to an important group I knew I would have to work with closely in the future.

Here was Senator Grasley’s response.

“The actions and words of this nominee display a misunderstanding of congressional oversight of the executive branch of government,” Grassley said.

I think we are going to hear much more of this sort of exchange between the executive branch and the legislative branch for the next two years. I think it could lead to some ugly confrontations and eventually the judicial branch may be involved. It will be interesting to see how this develops.

This appears to me to be setting up a showdown and it looks like it could go on for sometime. In the meantime, consumers lose because again, the FDA has no permanent leadership.

Technorati Tags: drug safety, FDA, Grassley, Ketek, telithromycin

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