Tysabri, an MS Drug with Potentially Deadly Side-Effects, Gets FDA Approval for Resumption of Clinical Testing

By Steven DiJoseph

When Mark Twain said, “The reports of my death have been greatly exaggerated,” he could have been writing the opening sentence of an article about Tysabri, the MS drug with potentially deadly side-effects that, like the proverbial Phoenix, has risen from the ashes. Many experts have been left shaking their heads as this modern-day “cat with nine lives” simply refuses to die.    

Although the hastily approved drug was pulled from the market in 2005, after only four months, following reports of its involvement in the deaths of at least two people, the effort to have Tysabri re-approved began almost immediately.

The first seed that was planted to “explain” why Tysabri was not the real culprit in the fatal and near fatal consequences was a report that the adverse reactions may have been due to an interaction with another Biogen Idec (“Biogen”) product, Avonex that led to a build-up and overdose of the active ingredient in the mediation.

An interaction of Tysabri and Avonex, an older MS drug “essentially leads to almost double the intended Tysabri concentration after only 20 weeks,” NCB Stockbrokers analyst Orla Hartford said in a note to investors in July. “Patients on Tysabri alone did not accumulate the drug.”

It was immediately presumed that this revelation would “form a central part of the case made to the FDA for Tysabri’s relaunch,” she said. Hartford, who analyzed data submitted to the U.S. Food and Drug Administration during the approval process, expected the drug to be reintroduced in 2006.

Elan Corp. PLC (“Elan”) and Biogen, the manufacturers, immediately went to work reviewing medical records of patients who had taken the drug in order to find a way to justify seeking re-introduction of the drug from the FDA.

As we previously reported on July 1, 2005, despite the fact that Tysabri had been linked to five cases of a rare and often fatal brain disease, Elan (of Ireland) and Biogen (of Massachusetts) were simply unwilling to give up their quest to bring the drug to market and keep it there.

The two drug makers announced a third-phase trial had produced positive results with respect to the treatment of Crohn’s disease. The trial involved 510 men suffering from Crohn’s and produced a reduction in symptoms within 12 weeks of treatment.

Tysabri, which is designed to suppress the symptoms of multiple sclerosis and Crohn’s disease,

has traveled a very rocky road from the beginning. Shortly after its withdrawal from the market, the FDA was informed by Biogen that a fifth person had developed a rare brain disease known as progressive multifocal leukoencephalopathy (PML) after being treated with the drug.

Biogen and Elan, its development partner, had hoped to return the drug to the market despite three previously confirmed cases of PML (with two deaths) as well as a fourth unconfirmed case. Sales of the drug were suspended on February 28, 2005.

Just before the report of the fifth suspected PML case surfaced in mid-June, Biogen was hinting at a strategy for bringing the drug back to the market that included testing all patients for the virus that causes PML and stop treatment with Tysabri in time to allow the patients to recover.

Many experts, however, remained skeptical about the future of the drug and were not sure at what point additional cases of PML will prove to be an insurmountable obstacle to that plan. The report that a drug interaction, and not Tysabri alone, may have been the problem merely added to the controversy.

By July, Elan’s stock value had suffered repeatedly (since the February 28 withdrawal) and, at one point, its shares were trading at only about 25% of their value before Tysabri was pulled from the U.S. market.

When we interviewed Jerrold S. Parker, a partner in the New York personal injury law firm of Parker & Waichman that represents the estate of one of the patients who died from a confirmed case of PML while taking Tysabri, he stated: “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. This is a drug that simply refuses to die.”

Shortly after that interview, Parker & Waichman commenced an action against Biogen and Elan for the wrongful death of a 46-year-old wife and mother of two.

In February 2000, Anita Smith was diagnosed with multiple sclerosis (MS). By April 2002, she was enrolled in a clinical trial involving the MS drug, Tysabri along with 1,200 other patients.

In November 2004, while Anita Smith’s health was rapidly deteriorating and she was experiencing severe neurological problems, Tysabri gained a coveted “fast-track” approval from the FDA.

Anita Smith took her last IV infusion of Tysabri in January 2005. On February 24, 2005 she died of a rare, and often fatal, brain infection known as PML; the same disease that killed other Tysabri patients.

Four days later, Tysabri sales were halted. Respected scientists and other experts, who had warned of such potential consequences associated with the powerful immunosuppressant, were not surprised.

A careful review of the extensive 64-page (315-paragraph) complaint with 14 separate causes of action revealed a number of interesting facts and allegations:

A second MS drug, Avonex, also manufactured by Biogen was used jointly with Tysabri as an MS treatment during clinical trials. Anita Smith’s neurologist was already treating her with Avonex since February 2000.

Anita Smith’s neurologist was paid (as an agent, servant, or employee) by Biogen and Elan as an “Investigator” in their clinical trial of Tysabri.

While taking Tysabri and Avonex in the clinical trial, Anita Smith and others developed opportunistic infections including Progressive Multifocal Leukoencephalopathy (“PML”).

PML is a typically fatal brain disease caused by the immunosuppressive effects of Tysabri or the immunosuppressive effects of Tysabri in combination with Avonex.

Smith’s treatment was comprised of 30 IV infusions beginning on April 12, 2002 and ending in January 2005. Tysabri had received fast-track FDA approval in November 2004, the same month Smith began to suffer severe neurological problems.

She was hospitalized on February 12, 2005 and diagnosed with PML. Smith died on February 24, 2005. Tysabri sales were suspended by defendants on February 28, 2005. An autopsy (participated in by defendants) confirmed that Anita Smith died of PML.

An explanation of the mechanism of the infection is set forth in detail as follows:
On March 2, 2005, Forbes published an article about PML under the headline, “The Virus That Took Down Tysabri,” which described the virus’s latent virulence as follows:

The JC virus, discovered in 1971 and named with the initials of the patient in whom it was found,  is present in almost everyone but only destroys the brain when somethings damages the immune system and allows the virus to run rampant.” […]

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.

Based on all of the available data, many experts believe Biogen and Elan should have conducted long-term studies before ever testing Tysabri on human subjects. 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.

On March 1, 2005, The New York Times published an article in which a leading expert on Tysabri who participated in its original development stated that no one should have been surprised that patients being treated with Tysabri would contract PML. In this regard,the article stated, in relevant part:

“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.

“I’m shocked that it happened so soon, but I knew it was going to happen sooner or later,” said Professor Steinman, who participated in an early animal study that led to the development of Tysabri. Dr. Steinman is a co-founder and director of Bayhill Therapeutics, a company developing competing drugs for multiple sclerosis.

“Dr. Steinman said he had expressed his apprehensions about the drug in speeches and in an article in the journal Science in July and had been asked by Biogen executives to tone down criticism of the drug.”

On March 9, 2004, the Los Angeles Times published an article providing specifics with respect to the infection rate and adding that FDA officials lacked sufficient information about  Tysabri’s long-term effects.  That article stated, in relevant part:

“In hundreds of pages of documents that offered the first detailed look at the FDA’s handling of the drug, reviewers noted that Tysabri appeared more effective than existing drugs, reducing relapses in patients by 66%, based on one year’s data. The reviewers said it was “reasonably likely” that the drug would provide long-term benefits.

“Nonetheless, the agency’s drug reviewers acknowledged they were unsure about Tysabri’s long-term effects.

“‘The clinical meaningfulness of a decrease in the incidence of relapses at one year is uncertain,’ the reviewers wrote.

“FDA reviewers found that Tysabri had an acceptable safety profile, though they noted that health risks ‘beyond one year are not known.’

“Infections, including urinary and respiratory, were seen with Tysabri, but they were ‘generally routine and did not have a complicated course,’ the reviewers said.

“Stanford University professor Dr. Lawrence Steinman, an MS specialist, had warned there was a clear risk of infection for patients taking such drugs, because they tend to suppress the body’s immune system.

“Steinman had helped discover the active agents in the drug, but later became concerned about potential side effects, and is working on a competing drug. He noted that the infection rate of Tysabri patients in one trial was 2.1%, compared with 1.3% in the placebo group.

“‘There were hints of an increase in the infection rate,’ said Steinman. ‘The FDA should have dug deeper.’”

While MS patients and parents of children with MS were concerned that what appeared to be a promising medication may never make it back on the market, many experts in the field of pharmaceutical development regard Tysabri as a dangerous drug that never should have been approved by the FDA in the first place.

There is also the claim that Tysabri should not have been used in human trials before thorough long-term studies were conducted.

Most of all, however, 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. This factor made the combination therapy of two such drugs (Tysabri and Avonex) problematic and worthy of serious consideration (and appropriate warnings) before it was routinely prescribed to patients in the clinical trial.

For several years now there has been a growing concern among independent experts that the pre-approval process used to determine the suitability of a new drug for marketing is getting worse instead of better.

Since the late 1990s, there has been a dramatic increase in the number of drugs which have had to be withdrawn from the market. The institution of an industry-funded a “fast track” drug approval process has lead to inadequately tested drugs being rushed to market and the need for more and more serious (“black box”) warnings.

Many drugs which have caused widespread injuries or deaths have been unceremoniously pulled from the market not long after their release. Some of the more recent “failures” in the longevity department are: Tysabri – 4 months; Lotronex – 9 months; Duract – 11 months; Posicor – 12 months; Redux – 17 months ; Raplon – 19 months; Raxar – 23 months; Baycol – 27 months; Rezulin – 38 months; and Baycol – 50 months.

One in five new drugs has serious side effects that do not show up until well after FDA approval. This often results from what many experts see as two serious flaws in the current “fast track” or “accelerated” approval process, namely, the lack of longitudinal (long-term) testing and the use of test groups which are far too small to represent an accurate sampling of the true range of patients who are likely to take the drugs being tested.

Significantly, in a high percentage of situations, problems develop either; (1) after patients have taken a drug for greater periods of time than the test groups, or (2) in segments of the population which were never included in the test groups at all or, at least not in a sufficient representative sample size.

Moreover, today’s drugs are being marketed without dosing charts or information with respect to the well-known fact that each person will metabolize a drug differently.

The pharmaceutical industry has also largely ignored the developing science with respect to “pharmacogenetics” which is the branch of genetics that studies the variations in responses to drugs based on individual genes.

These genetically determined differences in reactions to a given drug cannot be properly studied or determined when small test groups are exposed to a drug for a very short test period.

The Food and Drug Administration (FDA) has also placed itself in a compromising position by accepting huge sums of money from the pharmaceutical industry to fund the agency’s Office of New Drugs which is now expected to “fast-track” drugs to market.

The pharmaceutical industry now funds more than 50% of the FDA’s fast-track approval process for branded drugs, and overall, there are some 2,500 employees assigned to review an average of about 150 New Drug Applications (NDA) a year. The new drug evaluation and monitoring budget was about $400 million last year.

No such funding is given to the FDA for post-approval monitoring of adverse reactions and side-effects by the Office of Drug Safety which only has about 112 employees.

Fast-track approvals, which are usually based on short-term testing of small test groups, have had disastrous results when used for drugs which are specifically designed for long-term or lifetime use by large segments of the population.

Experts fear the pre-approval lack of long-term studies and the use of relatively small test groups can only lead to significant post-approval problems when less common or delayed side-effects become apparent.

At this time, however, it appears that the FDA is unwilling to admit it may have a problem when it comes to approving drugs based on insufficient clinical tests.

According to the director of the FDA’s Office of New Drugs, Dr. John Jenkins, the agency has no plans to act on suggestions from several experts that it request drug manufacturers to conduct larger clinical studies in the pre-approval process in order to detect serious, but less common, side-effects.

Jenkins claimed there might be “unintended consequences to what sounds like an easy, good idea.” One example would be to delay access to new therapies.

Many critics of the current process disagree. If a new drug makes it to market through fast-track approval only to be pulled from the market almost immediately due to the emergence of side-effects that were not detected because of inadequacies in the clinical study process, what purpose was served by rushing the approval in the first place?

Despite all of the concern over the fast-track approval process in general and the approval of Tysabri in particular, the FDA has announced that it has granted permission for the clinical studies of the drug to continue.

In its announcement, the FDA stated that it had “removed the clinical hold” on studies of Tysabri. “This will allow clinical trials to go forward.”

“In February 2005 Biogen-IDEC had announced suspension of marketing and clinical trials after three patients developed progressive multifocal leukoencephalopathy (PML), a frequently fatal infection of the brain, two following treatment with natalizumab for MS, and one patient being treated for Crohn’s Disease. Two of these cases were fatal.”

The removal of the clinical hold allows patients with MS who were previously treated with the drug under an investigational (IND) study to resume treatment “in an IND study following discussion with their physicians about the potential risks and potential benefits of treatment.”

Remarkably, the FDA stated that, “Although this treatment has been shown to have benefit in patients with relapsing-remitting MS, concern about the risk of PML associated with use of Tysabri remains.”

While the “drug is not being placed back on the market at this time,” the FDA has scheduled an Advisory Committee Meeting on March 7 and 8, 2006 to discuss an application for Tysabri for use in treating patients with relapsing forms of multiple sclerosis. “Aspects for discussion include the risks associated with the drug, its efficacy in the treatment of multiple sclerosis relapses and disability, its possible return to the marketplace, and its proposed risk management plan(s).”

In a Q & A with respect to the lifting of the “clinical hold,” the FDA stated that it was taking this action because an “extensive re-examination that Biogen and Elan undertook on all patients who had received natalizumab in clinical studies” revealed, “No additional cases of PML.” In addition, “Biogen has proposed a resumption of natalizumab administration under an IND study with very specific plans for close monitoring of patients.”

Although not mentioned in the body of the FDA release, the following statement was included at the end of the answer to the question: “Will Tysabri be available to all patients?” “Biogen has not proposed to administer the drug to anyone who had not previously been receiving it under an IND study. Biogen has submitted an application to FDA to resume marketing the drug for more widespread use. That application has a due date for a decision by FDA in late March 2006.”

To further justify what many experts see as an imprudent decision by the FDA, the agency stated that, while it “remains very concerned about the potential for PML associated with natalizumab use” the currently available information is “not adequate to clearly define the level of risk or the exact circumstances when this risk occurs.”

In addition, the FDA stated that “the existing efficacy data with natalizumab indicate this is a very effective product and multiple sclerosis is a devastating neurologic disease.”

Although the logic behind further testing makes sense to some experts, there are some that believe the drug should never have been approved in the first place.

As reported in HealthDay News (2/17):  “A multiple sclerosis drug pulled from the market early last year due to safety concerns was initially approved too quickly and probably should not go back on the market, at least not without more data, according to an expert writing in this week’s British Medical Journal.”

The author believes Tysabri was approved too quickly in the first place. According to Dr. Abhijit Chaudhuri, a consultant neurologist for the Essex Centre for Neurological Sciences at Oldchurch Hospital, Romford, Essex, in England: “The rate at which Tysabri was first tracked is absolutely unacceptable for a condition like multiple sclerosis, which can last for 30 years. They did not even look into the side effects and this is unbelievable. It’s a major failing.”

Dr. Chaudhuri agrees with the need for further study: “If a study is being conducted with ethical approval and physicians and participants are well aware of the risks, I have nothing to disagree about. Any scientific study where use of new product is closely monitored should go ahead.”

He was quick to point out, however, that he disapproves of the initial approval process for the drug.

“According to Chaudhuri, the FDA approved Tysabri only on the basis of short-term results from two unpublished trials, and before final data were available.” (HealthDay News 2/17)

“Based on what we’ve seen so far, there is no evidence to suggest that this is very effective for MS,” he said. “We’re talking about a condition that affects young people fairly early in life and which lasts for 30 to 40 years, so it’s a lifelong disease. Before you start using that, you must have convincing and compelling evidence that long-term disability is significantly reduced, at no cost for side effects. And I don’t think we have that kind of information.”

While there are still significant hurdles for Tysabri to overcome before gaining approval for re-introduction to the market, critics of the FDA drug approval process and of the agency’s close ties to the pharmaceutical industry are already predicting that the drug could survive the advisory panel review in March and be the subject of a new application for approval in the not too distant future.

When we asked several litigation attorneys familiar with pharmaceutical products to comment on the Tysabri saga, they were unanimous in their skepticism concerning the FDA’s ability to protect the public from harmful drugs given the current state of the approval process. Jerrold Parker summed it up like this: “I certainly wouldn’t bet against Tysabri making it back to the market. If the FDA’s track record over the past several years tells us anything, it tells us that, with respect to the drug approval process, the bottom line usually wins out over concerns for the health and safety of the public.”

(Sources: FDA Press Release and Q & A; British Medical Journal; HealthDay News; The New York Times, Los Angeles Times; Complaint in Smith v. Biogen, et al.; and Newsinferno.com Archives)

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