The Bottleneck for New Drugs is the FDA

Let's face facts: The FDA is a bureaucracy that is still a-glow in the protection of many Americans during the Thalidomide baby birth defect debacle. That protection came, ironically, by a bureaucrat stalling on doing anything in approving the drug. After this woman sat on her hands for months and months, the world learned of the terrible birth defects occasioned by Thalidomide.

The FDA has taken that lesson to heart. Do nothing is the wisest and safest course. If you approve a drug or device, such as Vioxx or breast implants, and there is even the hint of health problems, you will be hounded by lawyers forever. And the drug companies, which put out largely a safe product, will be tarred by the negative publicity surrounding the drug.

As part of the massive deficit spending by this administration, some money is supposed to trickle into cancer research. As the following editorial points out, the last time money was poured into reaseach, it all 'disappeared into a thousand tiny holes.'

The author of the following piece argues that the FDA has to do better this time. Instead of waiting years and years for drug efficacy to be demonstrated by over-all survival, it needs to accept surrogates for effectiveness, such as progression-free survival (PFS) as good enough to move a drug forward.

The Next Front in the War on Cancer
Faster clinical trials are critical if we are to save more lives.

By MARK THORNTON

On Tuesday, President Barack Obama announced a massive initiative against cancer. "Our recovery plan will launch a new effort to conquer a disease that has touched nearly every American, including me," he said in his speech to the nation, "by seeking a cure for cancer in our time."

Specifically, the president was referring to a provision in his stimulus bill that will direct a tranche of funding to the National Cancer Institute (NCI). The money will come from the $10 billion that's being steered to the National Institutes of Health, and it will, for the next two years, match the surge in spending on cancer that occurred between 1999 and 2003.

But despite the lofty goal set by Mr. Obama, it appears that the NCI is not mapping out a specific plan or strategy on how to most effectively use its new money. It is simply going to pour more money into the cancer research community.


In 1998, a new day was dawning in cancer research. The genomic codes of cancer were being broken, and an explosion of new vulnerabilities was being discovered that had the potential to reveal hundreds of new "drugable" targets. The hope then was that this would quickly produce a cure.

The dream was that this dramatic funding increase would break the back of cancer.

It didn't. Now that the money has disappeared, the diagnosis of cancer is no less fearful in 2009 than it was in 1999.

Read the rest at:

http://online.wsj.com/article/SB123569839480689223.html

Our lives depend on doing a better job, folks!

Rituximab Isn't Sugar-Water

Many CLLers use rituximab to treat their CLL. It is preferred to chemotherapy drugs such as fludarabine because it seems by comparison to be relatively non-toxic (except, of course, for the acute infusion reactions).

This paper in Blood points out the chilling fact that rituximab has been linked to a serious brain disease, progressive multifocal leukoencephalopathy (PML).


Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project

Kenneth R. Carson, et al

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment.

We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008.

Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients).

Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

http://tinyurl.com/ofyubj

The other great disease which causes immunosuppression of course is AIDS. These patients can be struck by reactivation of the JC virus. It seems less common in CLL patients, at least it is not described in the literature to any great extent.

You don't want to get PML. It is caused by the JC virus, which is present in almost all adults. It lives in the body, harmlessly, for years. In cases of immunosuppression, occasionally it will attack brain tissue, leading to gross mental deficiencies, and in most cases, death. See the wikipedia article on the JC virus:

http://en.wikipedia.org/wiki/Progressive_multifocal_leukoencephalopathy

It should be noted that since all CLL patients are immunosuppressed, the disease may strike with or without rituximab. However, those using rituximab seem to be at a higher risk of developing the disease. Cases of PML were probably 'hidden' in the general population of immune-deficient patients such as those with CLL, so it was not clear and evident. In those with other diseases who are not immunocompromised, these cases are so atypical as to be suggested to be caused by the rituximab.

"Simply Doomed to Achieve Complete Remission"

I don't know who Vladimir Savostianov is, but he claims to be a hematologist in Minsk, Belarus, and he claims to be able to put up to 60% of CLL patients into prolonged complete remission using old drugs and techniques, regardless of stage (though the patient must be treatment-naive).

He has posted an interesting protocol on his blog, http://dr-savostianov.blogspot.com/2008/08/chronic-lymphocytic-leukemia-treatment.html

I confess that I find his English to be of the sort of "Borat: Cultural Learnings of America for Make Benefit Glorious Nation of Kazakhstan". However, one needs to accept the premise that his therapy for CLL is interesting and worth a second look, primarily because it is cheap and, if verified, provides a vastly superior complete remission rate than most therapies, with the exception of FCR.

He apparently begins his therapy with prednisone and radiation to the tonsils, spleen, abdominal lymph nodes, and liver. He then administers chlorambucil. He believes that knocking back the pool of CLL with the prednisone and radiation permit the chlorambucil to deal a heavy blow to the CLL. He warns, however, that any departure from his schedule will leave the patient with a case of drug-resistant CLL.

He says this technique is free of immunosupression, and if it does occur, it is a simple matter to remediate.

Make up your own mind, but there is enough sense in this that perhaps there is some merit to it. Certainly it does not depend on expensive drugs such as rituximab, fludarabine, and Campath.

Approval sought for Rituximab in CLL - Why?

Doesn't this sound like the biggest non-news of the month? Rituxan is used routinely to treat CLL, both in combination and alone, though the latter is less frequent.

The following article is important for two reasons. First, it lets the companies advertise rituximab for use in CLL. There are competitors coming, namely Arzerra (HuMax-CD20), which should be approved for CLL this year, as well as several other CD20 drugs.

Secondly, with Obamacare looming, it is likely that off-label drug usage will be curtailed if not eliminated totally. With CLL such an important revenue source for the drug companies, it would behoove the company to have as many applications as possible for the drug already in place.


Here's the press release:

Genentech And Biogen Idec Submit Applications To The FDA For Rituxan For Most Common
Article Date: 22 May 2009 - 4:00 PDT


Genentech, Inc. and Biogen Idec (Nasdaq:BIIB) announced that the companies submitted two supplemental Biologics License Applications (sBLAs) to the U.S. Food and Drug Administration (FDA) for Rituxan® (rituximab) plus standard chemotherapy for people with previously untreated or treated chronic lymphocytic leukemia (CLL). The companies will request a priority review, and if granted, anticipate the FDA will make a decision within six months.

The applications are based on positive results from two of the largest global Phase III clinical trials conducted in patients with CLL. The randomized, comparative studies, known as CLL8 and REACH, showed that Rituxan plus standard chemotherapy for CLL extended the time patients lived without the cancer advancing (progression-free survival or PFS) compared to those receiving chemotherapy alone. In CLL8, previously untreated patients who received Rituxan plus chemotherapy had a 69 percent improvement in PFS (41 percent risk reduction, hazard ratio=0.59; p<0.0001; 95% confidence interval: 0.44,0.72) compared to those who received chemotherapy alone.

Is your Health Care Practitioner Reading Your Blog?

A couple of years ago, I got a huge shock when I went in for some routine blood work in the big, fancy CLL center, and noticed my nurse was acting kind of funny. She mentioned something that I had posted on-line in one of the CLL lists. I had complained about something, and she was defensive about it. I realized that she, or someone else, had been reading my posts about my clinical trial!

For some dumb reason, I thought the only people who would read CLL group messages would be other patients. To be honest, I thought that oncologists and nurses were way too busy to even think about searching on the terms of a trial to see what patients in that trial were saying.

I've known for a long time that financial creeps troll the patient groups, looking for any information they can use to make financial decisions. Although less than honorable, I guess it's something that wouldn't surprise me too much.

But to have my health care practitioner looking for posts on a clinical trial floored me.

I am much more careful now. If I have anything at all even remotely critical to say, I say something like, 'a famous CLL doctor', or a nurse at one of the top CLL centers.' I'll use it every time I didn't want a particular doctor to read what I said about him.

After all, there is no reason at all to get your doctor or nurse mad at you.

The web is a huge party line. (Older folks are at least a bit familiar with the concept of the telephone party line. We used to have one. It was cool, but inconvenient at times.) Be careful what you say!!!

Alternating EGCG and Curcumin - An Update

I decided to experiment a bit on myself, based upon a paper published recently that showed that EGCG and curcumin can have synergy, but only after CLL cells were washed, and the EGCG was given prior to the administration of the curcumin.

Hmmm. Easier to experiment with this than cancer vaccines or ofatumumab (Humax-20). Since I don't have a lab with a newly-minted PhD., I am restricted to trying out substances that are easily available. There are a few out there, and that's why I keep perusing the medical literature, looking for any little angle that might help slow the runaway train that is my CLL.

Well, I alternated the two drugs, changing them every 24 hours. I didn't 'wash' my cells, but I did remain hydrated, which doesn't wash cells but is important to all of us, anyway.

The results have been less than spectacular. My counts are pretty low after my four cycles of FCR, ending early because of persistent neutropenia. (The famous doctor at MD Anderson who said he could give me three years with FCR was off by about 2.8 years...)

My main gauge of success/failure of any treatment is, number one, the WBC count, and two, the size of my massive abdominal nodes. Since my counts are fairly low, I really only have my abdominal node size to go by. I sort of can tell whether things are shrinking or not by how tight my pants are.

I used to be a not-very-svelte 36 inch waist size (there was a time when a 32 waist was loose on me; I think that was the Nixon administration though). After I developed the 11q deletion after my HDMP+Rituximab (high dose steroids with high dose rituximab), my waistline started to morph out of control. After the 36 inch pants became too tight, I opted for the 38, then the 40, and then the 42. So in one year, I gained six inches in waist size without gaining an ounce of over-all weight.

Bummer!!!

Sad to say, even after about three weeks of the EGCG-curcumin-EGCG shuffle, my pants weren't a bit looser. So, I deem the effort a failure.

However, I did feel pretty good during the time, no night sweats, no hot flashes, no increase in fatigue, and my counts didn't suffer.

Why didn't I see better results? Two reasons, I think. First, I have very advanced, stage IV CLL. I've been fighting poor-prognosis CLL for over 10 years now, and I've developed, I'm sure, lots of bad chromosomal changes and increase chemo-resistance.

The second reason, probably much less important, but important nevertheless, is the abysmal bioavailability of both EGCG and curcumin. It's one thing to dump a teaspoon of pretty curcumin in a witch's brew of CLL cells; it's another to achieve an equivalent level of curcumin in one's bloodstream.

The usual trick is to take curcumin with bioperine. One must be careful not to overdo this compound. Too much apparently isn't good for you. The other thing is to dissolve the yellow, highly-stainable curcumin into warm or hot coconut milk. The high fat content of the coconut milk definitely does dissolve this spice. I also add a little bit of alcohol to help dissolve the product, usually amaretto. The latter adds a nice flavor to the concoction. Margaret swears by the C3 complex that comes from Sabinsa corporation. A number of companies use that product to make their offerings that are available retail.

The EGCG I usually use is Teavigo. This is available from a variety of suppliers; I purchase mine from The Vitamin Shoppe, which has a reasonable price for the product, and sometimes offers free shipping for a certain dollar amount of purchased product. I add another EGCG extract with a different formulation just to cover all my bases.

Both are supposedly best taken on an empty stomach. I will tell you that the EGCG is very rough on my stomach, so I do eat something perhaps fifteen minutes after swallowing the pills. It will make me throw up if I wait any longer.

My 'guru' on curcumin is Margaret, who posts on her own Multiple Myeloma blog. She's an older hand at the curcumin business, and has really benefited by using the spice. Her blog, 'Margaret's Corner', is one of the blogs listed on the right side of this blog post. She is a wealth of information on curcumin, including a section on how to get rid of curcumin stains, which I will attest gives anything you touch after you've pulled apart the capsules a very bright, vivid yellow, which will not wash out.

I was taking to wearing an old, ratty robe while making the curcumin mess. My wife gave this robe a pretty pink color after washing the formally white terry cloth with some red shirts. Now this pink robe has several splotches of screamingly yellow curcumin stains on it, that defy all attempts to remove them.

I suppose my entire digestive tract from top to bottom is now fluorescent yellow in color. I wonder if that would show up on an MRI?

Cutting healthcare costs

My antenna go up when I hear this phrase. It reminds me of the 'NICE' organization in the UK. This is the group that 'evaluates' drugs to see if they are 'cost effective'. Obviously, when health care is just another budget item, competing with schools, defense, and welfare expenditures, there is great pressure to hold down costs.

The track record of NICE when it comes to cancer drugs is poor. UK residents just don't have the panoply of therapies available in other countries, including the United States.

Everyone is in favor of cost-effectiveness, right? Well, if you are, remember that CLL patients are a very small lobbying group, and drugs such as Rituxan and Campath are very expensive.

If you are concerned about the treatments you will be getting in the future, pay very close attention to the details. It's one thing to say you are going to cut health care costs; it's another when the savings comes from denying care to you.

I'm reserving judgment until more is known about the president's plan. I will be seeing if health care will be changed for the worse.

(In my opinion, the best thing would be to increase spending and make a serious move to start curing cancers. Imagine how much more money cancer patients would be saving the health care system, and paying into the entire economy, if they could be free from the illness and pain of cancer!)

Kanzius Cancer Machine is Effective Against CLL Cells

Former broadcast engineer and radio station owner John Kanzius devoted his final years to the development of a 'cancer-killing machine.' Mr. Kanzius' technical background in radio, along with an accidental exposure to radio waves that heated up the coins in his pocket, wondered if the power of the radio waves could be harnessed to kill cancer cells. He says that he was motivated to do something to help cancer patients fight their cancers, after getting off on a pediatric cancer floor in a visit to MD Anderson, and witnessing first hand the suffering that cancer inflicts on young patients.

He was visiting the renowned cancer facility in order to undergo treatments for his own cancer, chronic lymphocytic leukemia (CLL). Although originally believing the cancer-killing properties of radio waves would be limited to solid tumors, Mr. Kanzius couldn't help but wonder if it could help cure his own cancer. Unfortunately, he passed away in February, 2009, as preliminary testing of his invention was underway. He always knew that it was a long-shot, but he reserved hope that he might benefit from the machine he created.

Meanwhile, research on the Kanzius invention continues. Doctors at MD Anderson, who were initially intrigued by the possibilities of marrying radio waves and nanoparticles, have made progress. The latest news released on May 8, 2009, demonstrates that the Kanzius machine can indeed kill CLL cells.
Reported by David Bruce and published on GoErie.com, the external radiofrequency generator can kill CLL cells while not significantly damaging normal cells, an important finding.

This finding was ascertained in December, 2008, using the cancerous cells of 19 CLL patients. However, the results are only a tantalizing hint at the possibilities of the machine. Dr. Steven Curly of MD Anderson, who has been spearheading the research effort, said that the CLL killing was probably due to the heating of the cells, which are tagged with gold nanoparticles, attached to a monoclonal antibody that attaches to CLL cells.

So, another step forward. According to the article, the percentage of CLL cells killed was not enumerated, so I can't tell how effective the treatment was, nor can I tell from the article how long the duration of the RF field exposure was, what antibody was used (I'm assuming a rituximab-like MoAB), or any other parameter that would be vital to know.

I've read elsewhere that theis RF generator can heat cells up to 600 degrees or so, plenty warm to kill them. Of course, non-CLL B lymphocytes express the CD20 marker, so it would seem that the machine could potentially kill every cell that carried sufficient gold nanoparticles.

Ideally, this would work as a 'super-rituximab' that, as long as a cell expressed the CD20 marker in sufficient quantities, it could be killed by the machine.

For the full news article, go to http://www.goerie.com/apps/pbcs.dll/article?AID=/20090508/NEWS02/305089932/-1/NEWS02

For more information about the Kanzius Cancer Machine, go to http://www.kanziuscancerresearch.com/

Cholesterol and CLL-How's it Going?

My one reader will remember that I've decided to postpone killing CLL cells by dying. One thing to do this is to deny the cells the means with which to grow. Cholesterol levels are dysregulated by CLL, possibly because the rapid growth of the clone (that is, the CLL cells) require cholesterol to form the cells themselves. That is one theory, at least.

Believing that reducing cholesterol in my diet and reducing it further by adding a bit of fiber to my diet probably won't hurt me, I embarked about a month ago on a fiber-added diet. I must report that the results of my little experiment is inconclusive at best.

One of the 'problems' is that, at the present time, my WBC is quite low, below even the normal range due to my recent bad experience with FCR (fludarabine, cyclophosphamide, and rituximab) for my CLL. So I can't report a huge drop in the WBC numbers. I can look at the ratio of neutrophils to lymphocytes (the two largest components of the white blood count). It has bounced around, but still shows too many lymphocytes. The ratio has not changed for the better.

So, I am not bouyed by these results. I will continue to add a teaspoon a day to my diet, because I probably don't get enough fiber as it is, and adding a bit won't hurt. Didn't seem to help, don't think will hurt.

I'm thinking on embarking on a different CLL journey in the near future; alternating EGCG with curcumin. A recent paper shows that the combination seems to work better than either does alone.

More later.