Barriers to Clinical Trials-the CT scan

I'm not going to write a book as I did on my last post!

Suffice it to say, some of the barriers to entry of clinical trials are listed on the last post.

I want discuss one real barrier to clinical trial entry that is easily remedied. That is the demand that participants undergo multiple CT scans to track progress (if any) in the trial.

Why is there a barrier? CT scans involve high levels of radiation, and they have definitely been linked to subsequent cancers.

The risk is low, the authorities say. But any increase in cancer risk sort of defeats the search for a cure for CLL, doesn't it? It certainly makes no sense when there is an excellent alternative: MRIs.

Clinical trials are done to look for results. The ultimate hope is a cure, because the drug in tests would be a huge success! Most likely, a more modest goal is envisioned: better results than current drugs.

Determining whether a drug is better than the standard treatment is surprisingly difficult. Drug companies can't wait around for 20 years to see if patients continue to do well (i.e. survive). Instead, they look for 'end points'. These generally include signs of tumor shrinkage or elimination. That is the reason drug companies want to check your nodes. The way most doctors are used to doing this is ordering a CT scan.

Yet we've seen the danger to the patient is real. Given a choice between a trial using an MRI and one demanding multiple CT scans, most people who are aware of the dangers of CT scans will pick the safer one, in other words, the one allowing the use of MRIs.

Why do drug companies deliberately rig their trials so people are less likely to sign up? It's a mystery, with perhaps a partial solution. Several of the drug companies I've talked to are aware of the concerns on the part of patients, and know that an MRI can track lymph node size just as well (or better) than CT scans.

Well, who then is the moving force behind this unfortunate situation? The drug companies blame the CLL researchers themselves! It is the research community that apparently doesn't care about patient safety to the point that they will allow safe alternatives to dangerous radiation exposure to patients.

I've discussed this with a few researchers in light of these claims. Rumor has it that there is a group of CLL researchers who are (pardon the expression) really anal about scans. The Germans.

I suppose we who are not German can recall the reputation the Germans have for meticulous record-keeping and administration. It apparently extends to CLL clinical trials.

Who ever is to blame, it's time the patient community help end the danger. Some of us need clinical trials if we are going to stay alive. We are sacrificing our bodies to advance science. It is incumbent upon researchers to watch out for our health. We are helping them (and the drug companies) when we sign up for a trial. They need to help us avoid doing more damage to our bodies than the investigational drug might cause.

Should you enroll in a clinical trial?

Clinical trials are big business in the United States; indeed, around the world. One group estimates there are 40,000 clinical trials on-going at the present time in the US. Virtually any drug that seeks FDA approval must go through the clinical trial process. This includes already-approved drugs that seek approval for another use; an example of this is our old friend Rituxan, the first monoclonal antibody approved in the US. It is used frequently for CLL, but it was never approved for such a use; instead, it was approved in 1997 for non-Hodgkin's lymphoma. It is undergoing tests now for approval for use in CLL; that's important because any health care 'reform' will limit drug use. It may even make it illegal for Rituxan, or any other drug, to be used off-label.

Any clinical trial needs two things: a new drug or device, and bodies to test them. Cancer, as one can imagine, is chock-full of new drug applications, and clinical trials. Go to the excellent site for the government's clearinghouse for clinical trials (clinicaltrials.gov), and you'll find about (about because it changes every day or so) 23,000 trials in the US and overseas that involve some aspect of cancer.

Some trials seem almost silly. There are, for example, a number of trials examining the value of music to soothe the savage cancer patient's breast. There are some that seek to find the value that art has in calming dying cancer patients.

Mostly, however, clinical trials seek to ascertain the dangers and values of drugs in fighting advanced cancer. (There are some trials, of course, looking at treating patients early in the disease; CLL is a particular hotbed of such studies, since previous research has not uncovered a value in starting treatment early, as opposed as to when it is most definitely needed.

Search clinicaltrials.gov for CLL trials and (as of this moment) 1209 trials show up. The site seems to list trials that only mention CLL in passing; there are far fewer trials that have CLL as the main focus of study. There are probably fewer than 200 that are of serious interest to the CLL patient.

So, should you enroll in a clinical trial? That is a tough question, but, over-all, I'd recommend you seriously consider it. Why? Because every effective drug for CLL has gone through the clinical trial process, and you'd have first (or second, or third) crack at it. When you have run out of options, that is not a small factor.

(There is also the altruistic nature of trials as well. By joining, you will help future CLL patients have access to proven drugs. But studies have shown that most participant hope to have some benefit as well).

Let's say you've decided to at least look at clinical trials. Are they all created equally? No, of course not. Unless Bach or Picasso really rocks you, you might just say no to music and art clinical trials. You are not going to get cured by such a trial. But what should you look at?

I'll give you my thoughts on the subject, but remember that I'm 'only' a CLL patient, one who has (thank the Lord) outlived his projected lifespan by a number of years, and who is hanging in there as I write.

First of all, you have to decide what drug to look at. This takes research, even if it is just talking to your oncologist. I relied on a CLL expert to guide me in my choice of clinical trials, up to a point. I must admit that, while I am an expert on my own body and how I feel, the CLL expert has seen hundreds of cases, and is more of an expert on how my disease will, in general, progress.

I thought long and hard about my first trial I undertook in 2006. I researched everything the CLL doc told me were my options (and the field is pretty wide open when you are untreated). Yes, I was drowning in green tea back then, but I was still progressing, so my doc and I agreed that I needed something stronger to knock the CLL back.

I also looked at the trials his institution offered. I asked about each of them. I then searched on the top five or six that seemed as though they might be good for me. I printed out study after study, and, using a highlighter, I marked the response rate, the side effects, the burden of treatment (would I have to stay in the hospital) and so on. I then went to clinicaltrials.gov and looked at everything that seemed familiar, and a few that didn't. I had been tracking and thinking about clinical trials since I had been diagnosed some eight years before, so I wasn't unfamiliar to the terrain.

Next, I needed to make a decision about what phase trial to look into. A refresher: a phase one trial is a dosing safety trial, meaning they ramp up the drug until unacceptable toxicities are found. A phase two trial is an efficacy trial, that is, does the drug show any activity in the disease. The phase three trial compares the new drug with the standard treatment. (Placebos are never used now in lieu of treatment; it is considered unethical to withhold at a minimum the 'gold standard' treatment, though that hasn't always been the case, in the old, bad days.)

The problem with phase one trials is poetically described in another way to look at these trials: First-in-Man trials. (Many drugs have been used elsewhere, but the name tells a lot.) The phase one trial is given over a range. The first patient usually gets a dose that is far too small to do anything at all. The subsequent patients are given higher and higher doses, until bad things start popping up. Pre-clinical trials give a hint of activity in humans, since they use human cells in culture, as well as the ubiquitous mouse and rat studies.

I have undergone a phase one trial, but I try to avoid them for the reasons outlined above. If you press the trial coordinator, he or she will generally tell you what the other patients in the phase one trial have experienced. But that isn't a foolproof guide. In my phase one trial, the trial coordinator told me to expect flu-like symptoms. (This is such a common description of side effects, it's a little like telling a diner that mongoose or arctic wombat 'tastes like chicken'.) To say I had 'flu-like symptoms' was something like saying the Titanic had a little problem with an iceberg.

I puked my guts out! It was horrible. Yes, I experienced projectile vomit! It was even green, something like the Exorcist (I had a huge helping of spinach quiche the night before.) I've never had such a terrible flu, or if I had, I've blocked it from my memory to protect me from insanity. (Because of my, and others, experience, they now give anti-emetics, or drugs to quell nausea. Thanks, guys, what took you so long?

I prefer the phase two trial. Generally, in a phase two trial you are guaranteed to get the drug (not so in the phase three trial, which is, after all, a comparison trial). The maximum tolerated dose has been established. Anti-nausea drugs have been prescribed. Dosing schedules may been worked out, more or less. Results have been published on the experiences of the first trial (yes, my experience is now part of the record...). You have a better idea of the risks and benefits of the trial.

The phase three trial, as I mentioned above, has the huge disadvantage of not giving the investigational drug to all comers. This is very important in a serious and fatal cancer such as CLL. Why, you could get the standard treatment without going through the qualification process, all of the scanning, all of the prep work, and so on. Some trials do try to 'sweeten the pot' by offering the new drug to 2/3 of participants, instead of a 50/50 split. This is much better for the patient, but this isn't a common practice, for some reason. The best option of all is to give the drug to everyone, and compare their results with historical controls. Hardly any researcher likes this option, which is too bad for the patient community.

My next post will deal with the very real barriers to patient's signing up for trials. It seems to me that not enough researchers are concerned with how we feel about the clinical trial process.

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!!!