FDA approval process under fire: PML-Lethal Side-Effect of Tysabri--Multiple Scl

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[sSRI-Research] FDA approval process under fire: PML-Lethal

Side-Effect of Tysabri--Multiple Sclerosis Drug

 

 

 

 

FDA approval process under fire: PML-Lethal Side-Effect of

Tysabri--Multiple Sclerosis DrugALLIANCE FOR HUMAN RESEARCH PROTECTION

(AHRP)

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

 

 

FYI

 

" When Anita Louise Smith enrolled in an experimental drug trial in

2002 in Colorado, she had a diagnosis of multiple sclerosis but no

symptoms and was looking to reduce the chances of being ravaged by the

disease. Last year, she died at the age of 46 from an infection linked

to the drug. "

 

Biogen and Elan, the manufacturers of the drug, Tysabri, refused to

release her medical records and imaging scans. Inferno News reports:

" Since the MRIs and any supporting records could establish the fact

that Anita Smith never had MS, they may very well expose Biogen and

Elan to a significant possibility of being found liable for her

conscious pain and suffering and untimely death. "

 

 

On March 1, 2005, The New York Times published an article in which a

leading expert on Tysabri, who participated in its original

development in animal tests, stated that no one should have been

surprised that patients being treated with Tysabri would contract PML

(progressive multifocal leukoencephalopathy), a rare, but lethal brain

infection.

 

As far back as 1992, based on animal studies and other in vitro

experiments, scientists who developed Tysabri had concluded that it

was far too dangerous to use in humans. By suppressing the immune

system, Tysabri allows the JC virus, ordinarily latent in a patient's

kidney, to travel to the brain via the bloodstream, where it begins

uncontrolled replication.

 

Respected scientists and other experts, who had warned of such

potential consequences associated with the powerful immunosuppressant,

were not surprised. The complaint filed is extensive--64-pages with 14

separate causes of action reveals number of interesting facts and

allegations:

 

Based on all of the available data, many experts believe the

manufacturers (Biogen and Elan) should have conducted long-term

studies before ever testing Tysabri on human subjects. News Inferno

reports: " It is alleged that at no time did either company disclose to

the participants in the clinical trials of Tysabri that literature in

professional journals questioned the use and/or safety of the drug in

humans. "

 

An article in The Lancet discusses the pitfalls of current clinical

trial selection criteria in which relatively healthy (asymptomatic)

patients who are not disabled by a chronic degenerative disease like

multiple sclerosis-are enrolled as test subjects of drugs that often

are found to be highly toxic.

 

" Lawrence Steinman, a professor of neurology and head of immunology at

Stanford, said the F.D.A. should not have approved the drug on the

basis of only one year's data. He said the risk of serious infections

like P.M.L. was 'unfortunately logical' given that

 

Tysabri works by interfering with the immune system. "

 

There appears to have been ample evidence in the form of test data and

opinions from highly qualified and credible experts that this drug

posed a serious risk of the very injuries (and deaths) that ultimately

occurred. " Certainly, PML was always a possible risk due to the

immunosuppressive quality of the drug. "

 

There is disagreement about whether the drug should have ever have

been approved. Within 3 months Tysabri was withdrawn from market.

" Despite serious concerns of many critics of the FDA's (over 50%

industry-funded) fast-track approval process in general, and the hasty

approval of Tysabri in particular, the FDA announced, only last month,

that it had decided to grant permission for the clinical studies of

the drug to continue. "

 

Meanwhile, Biogen's unconscionable concealment of the data outraged a

Massachusetts judge who issued a Court order requiring the company to

release the medical records: " Anita Smith was a human being and not a

laboratory animal that belonged to Biogen. Thus, her records cannot be

withheld at the company's direction. To have argued otherwise was

unconscionable. "

 

 

Jerold Parker, attorney for Anita Parker's estate, assessment,

unfortunately is not isolated-it describes the culture within the

pharmaceutical industry: " It is simply amazing to watch Biogen and

Elan insist on placing profits above safety. Clearly, they will do

anything possible to recover their investment and turn a profit on

this questionable drug. "

 

That immoral culture has infected academia and the highest ranking

government oversight agency staff. FDA policies have contributed in a

major way to the erosion of concern for public safety. The FDA,

therefore, cannot be looked upon for a solution.

 

Below reports in Forbes and Business Wire discuss the points raised by

The Lancet article.

 

An in-depth review of Anita Parker's case and the evidence cited in

the complaint filed with the court, see:LEGAL NEWS

In Major Ruling, Massachusetts Court Orders Biogen to Produce 'All

Medical Records' of Woman Who Died During Tysabri Clinical Test

'Immediately'

 

Date Published: Saturday, February 25th, 2006 By Steven DiJoseph

http://www.newsinferno.com/archives/890#more-890 and

http://www.ahrp.org/cms/content/view/92/28/

 

 

 

Contact: Vera Hassner Sharav

212-595-8974

veracare

 

 

 

http://home.businesswire.com/portal/site/google/index.jsp?ndmViewId==news_view & n\

ewsId=

060302005234 & newsLang==en

Stanford Doctors Spotlight Fatal Flaw in Multiple Sclerosis Drug Trial

Business Wire March 2, 2006

 

When Anita Louise Smith enrolled in an experimental drug trial in 2002

in Colorado, she had a diagnosis of multiple sclerosis but no symptoms

and was looking to reduce the chances of being ravaged by the disease.

Last year, she died at the age of 46 from an infection linked to the drug.

 

This tragedy -- recounted in an article in the March 4 issue of The

Lancet by two Stanford University School of Medicine neurologists --

serves as a telling case study of what can go wrong in clinical

trials. In their article, Annette Langer-Gould, MD, and Lawrence

Steinman, MD, warn of the pitfalls of testing a drug with unknown side

effects in patients who would do fine without the drug.

 

The drug in question is natalizumab, which has the brand name of

Tysabri. In November 2004, the U.S. Food and Drug Administration

fast-tracked its approval for use in multiple sclerosis patients

following promising results seen early in two clinical trials. But

within months of the approval, some patients taking the drug had

developed a rare infection -- progressive multifocal

leukoencephalopathy, or PML -- and Smith and one other patient had died.

Langer-Gould, a clinical instructor in neurology, treated a patient

who was part of the clinical trial and developed PML after taking

Tysabri; the patient survived. But that experience, coupled with an

examination of Smith's case, prompted Langer-Gould to approach

Steinman about writing an article that would examine the

appropriateness of testing a drug on people with no evidence of the

disease and who are not disabled at the time of the trial.

" We are arguing that people with no disability should probably not

enter into a clinical trial or be recruited into clinical trials,

because where is the potential benefit to them if nothing is wrong? "

said Steinman, professor of neurology and neurological sciences and of

pediatrics.

" This situation represents a systemic problem, " said Langer-Gould. " It

is not just one company being a rogue, doing something out in left field. "

 

Langer-Gould and Steinman argue that if a drug has a known risk of

death, it should only be used on patients who are likely to suffer

severe disability from the targeted disease -- and for whom there are

no other options. In other words, those who have tried all the other

available therapies. That is almost the reverse of what happened in

the Tysabri trial, which excluded the most severely affected patients.

 

" A big mistake was made in these trials that, in my opinion, is easily

preventable, " said Langer-Gould. " All they need to do is tighten up

entry criteria into multiple sclerosis clinical trials and we could

avoid similar types of problems in other trials. "

Multiple sclerosis results when the immune system attacks the

protective myelin sheath surrounding nerve cells, causing them to

misfire and leading to loss of motor control and possibly paralysis.

Tysabri appeared to block this effect and, after the first year of the

two-year clinical trials, did not appear to cause more infections.

 

Steinman was involved early on in the development of the drug,

publishing on its effects in 1992. Even then, he had suspicions that

the drug's mechanism of action -- blocking the entry of immune cells

into the nervous system -- might also make patients more vulnerable to

infections. Indeed, PML is an infection that usually affects people

whose immune systems are compromised.

" It was a shocking development that a drug that had so much promise

and so many potential benefits ended up causing two deaths and one

very serious injury, " said Steinman. " It is kind of a cruel Greek

drama, something that may be more beneficial than anything yet

developed for multiple sclerosis, but yet may be far more dangerous

than those other approved drugs. "

 

The FDA withdrew Tysabri only three months after its approval. The FDA

is now considering re-approving the drug. On March 7 and 8, an FDA

advisory panel is meeting about the possibility of bringing back

Tysabri as a single therapy (in the trials, it was combined with

another drug).

" I predict it will come back with really hellacious warnings, " said

Steinman. " I think the right course would be to have it undergo more

testing, but I don't think that is practical or fair to patients; they

ought to have the opportunity to decide with their physicians if they

are willing to take the one in a thousand risk of dying. "

 

But Steinman and Langer-Gould expressed reservations about the drug

returning to the market. They noted that its effects, while

impressive, are in general not much better than what is seen with

other available drugs: The risk of relapse dropped from an average of

two relapses every three years using other approved multiple sclerosis

drugs to one every three years with Tysabri.

" Do you want to expose someone to the risk of death for eliminating

one relapse every three years? " said Steinman. " I say no. "

" I'm not sure if it is wise to re-approve it, " added Langer-Gould.

" The question is, will the FDA rise to the occasion and admit their

mistake and try to prevent future mistakes or are they going to ignore

it? "

 

Stanford University Medical Center integrates research, medical

education and patient care at its three institutions -- Stanford

University School of Medicine, Stanford Hospital & Clinics and Lucile

Packard Children's Hospital at Stanford. For more information, please

visit the Web site of the medical center's Office of Communication &

Public Affairs at http://mednews.stanford.edu.

 

~~~~~~~~~~~~~~~~~~~~

 

http://www.forbes.com/lifestyle/health/feeds/hscout/2006/03/03/hscout531359.html

FORBES

Controversial MS Drug Trial Flawed, Experts Say

03.03.06, 12:00 AM ET

FRIDAY, March 3 (HealthDay News) -- Two experts are questioning

whether a woman who died of a rare infection after participating in a

trial for the multiple sclerosis (MS) drug Tysabri should have been

included in the study in the first place.

 

The patient was suspected of having MS but showed no symptoms, and was

later found not to have had MS. Now, a commentary in the March 4 issue

of The Lancet paints a cautionary tale of what went wrong, and asks

whether the woman should have received Tysabri at all, when other safe

and effective agents were at hand.

 

The piece, penned by Stanford University neurologists Dr. Annette

Langer-Gould and Dr. Lawrence Steinman, adds fuel to the debate over

Tysabri (natalizumab), which has been linked to three cases of a rare,

dangerous infection called progressive multifocal leukoencephalopathy

(PML). Two of those cases proved fatal.

 

Researchers quickly halted the trial last February after the PML cases

emerged. At the same time, Biogen Idec and Elan Corp., the drug's

makers, heeded a U.S. Food and Drug Administration advisory and

withdrew Tysabri from the market, just three months after its

fast-track approval for cases of especially tough-to-treat MS.

 

However, research published this week in the New England Journal of

Medicine found the drug to be safe and effective, at least for the

short term. And after a yearlong investigation, an FDA advisory

committee recently announced that it will meet Tuesday and Wednesday

to consider the company's request to return the drug to the market.

 

In the Lancet commentary, Steinman and Langer-Gould criticize how the

original trial was conducted.

" When you test a drug that is potentially dangerous and, in this case,

carries a risk of one per 1,000 of fatality or serious injury, one

ought to be careful that the subjects in the study have a fair

risk-benefit balance, " explained Steinman, a professor of neurobiology

and neurological sciences who helped develop Tysabri.

 

In fact, the woman who died, Anita Louise Smith, had been diagnosed

with MS, even though she had no symptoms. In the end, it was

determined that Smith did not have MS. " But that can happen, " Steinman

said. " MS is a notoriously difficult disease to diagnose. "

 

However, whether or not an asymptomatic patient such as Smith should

have been included in the trial to begin with points to the crux of

the problem, according to Steinman.

 

" One needs to reexamine the justifications for putting someone on an

experimental MS drug when they have no disability, " he said, adding

that the criteria for including patients in such a trial needs to be

re-evaluated.

 

Steinman does believe the FDA should let Tysabri go back on sale. " If

I were the FDA commissioner, I would let it back -- with warnings

about the risk, " he said. " I would leave it up to physicians and their

patients to make the decision. "

 

However, Steinman believes the drug will -- and should -- be used

mainly for patients who are not doing well, and not for patients in

the early phases of MS.

 

" It's hard to justify looking a person in the eye and saying that 'You

have all these approved drugs that are safe -- or [you have] this

drug, which might be more effective. However, it carries a chance that

you can die from it or have a really serious neurologic injury,' " he said.

 

Langer-Gould, who treated the MS patient who survived PML, believes

the risk of developing the infection while receiving Tysabri is

greater than reported. But, she explained, " all you need to have is

three more cases, and the estimate becomes one in 500. "

 

In addition, Langer-Gould doesn't think Tysabri is significantly more

effective than other, safer MS drugs. " This drug does nothing more

than [add] a 4 percent reduction in disability, which is nothing, " she

said.

 

However, Langer-Gould said she, too, would like to see Tysabri back on

the market. " I'd like to have this drug as an option for patients who

are sicker, " she said. " But I'd have to tell them that I have no data

to support the use of the drug, because most of the patients at risk

for disability were excluded from the trial. "

 

" We have so little for these patients, " she noted. If nothing else is

working, Tysabri might be worth a try, she reasoned: " At that point in

their disease, there is nothing to lose. "

 

Langer-Gould is concerned, however, that if Tysabri returns to

pharmacy shelves, there is a high risk of it being wrongly prescribed.

" There are still many clinicians out there saying that they are going

to use it as first-line treatment, " she said. " They have a

misunderstanding of both the efficacy and the safety of the drug. "

 

" Physicians have to be willing and ready to accept the fact that it

may kill or permanently disable their patients if they are going to

use this drug, " Langer-Gould said. " They need to ask themselves if

that's a decision they are going to be willing to live with. "

 

One expert thinks the ongoing Tysabri controversy distracts from other

promising work in MS treatment.

" Steinman and Langer-Gould make some interesting points, " said

Nicholas LaRocca, the director of Health Care Delivery and Policy

Research at the National Multiple Sclerosis Society. " Over the years,

the whole science of clinical trials in MS has been evolving, " LaRocca

said. " We are way ahead of where we were 20 years ago. This is not a

field that is standing still. " He added that there's always been

controversy as to whether or not doctors should actively treat

patients who appear to be doing well. " If you talk to a number of

neurologists, you will get differing opinions, " LaRocca said.

 

One neurologist who took issue with the Lancet commentary illustrates

that point.

" The accusation that this lady was put at risk inappropriately is

specious, callous and vicious in its condemnation of standard of

practice for clinical neurology research, " said Dr. Norm Kachuck, an

associate professor of neurology at the University of Southern

California Keck School of Medicine. " It is sad and tragic that anyone

is injured in medical care, in medical research. With the best of

intentions, the most careful physician can do harm with the two-edged

swords of our armamentarium. "

 

" There is no reason except the obvious -- that research is a search

into the unknown, with only roughly estimated risks -- that this

woman, and all of the other courageous folks who contribute their

bodies and souls to medical research, would not have been made a

subject in this and other trials which we do to help understand and

cure human disease, " Kachuck said.

 

The amount of attention Tysabri has gotten is striking, LaRocca added.

" It sort of obscures the broader picture of MS research, and some of

the other exciting things that are happening in MS research, " he said.

" We hope that we can get back to focusing people's attention on some

of the exciting things that are happening in the MS field. "

 

More information For more on MS, head to the National Multiple

Sclerosis Society.

 

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of

which has not always been specifically authorized by the copyright

owner. Such material is made available for educational purposes, to

advance understanding of human rights, democracy, scientific, moral,

ethical, and social justice issues, etc. It is believed that this

constitutes a 'fair use' of any such copyrighted material as provided

for in Title 17 U.S.C. section 107 of the US Copyright Law. This

material is distributed without profit.

 

 

 

Contact: Vera Hassner Sharav

212-595-8974

veracare

 

 

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of

which has not always been specifically authorized by the copyright

owner. Such material is made available for educational purposes, to

advance understanding of human rights, democracy, scientific, moral,

ethical, and social justice issues, etc. It is believed that this

constitutes a 'fair use' of any such copyrighted material as provided

for in Title 17 U.S.C. section 107 of the US Copyright Law. This

material is distributed without profit.