In Major Ruling, Massachusetts Court Orders Biogen to Produce ‘All Medical Records’ of Woman Who Died During Tysabri Clinical Test ‘Immediately’

By Steven DiJoseph

Anita Smith died from a rare, and often fatal, brain disease while participating in a late-stage clinical trial of the MS medication, Tysabri. As it turned out, a number of other patients being treated with the drug also contracted the same disease.

Although she had been diagnosed with multiple sclerosis, an autopsy revealed that Smith never had MS, thereby making her enrollment in the trial problematic at best. Moreover, the unusually high incidence of the brain disease in Tysabri patients raised a serious question as to the drug’s safety.

Although the potentially deadly side-effect caused the hastily approved drug to be pulled from the market on February 28, 2005, after only four months, the effort to have Tysabri re-approved began almost immediately.

Elan Corp. PLC (“Elan”) and Biogen Idec (“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.

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 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.

Just before the report of the fifth suspected PML case surfaced in mid-June 2005, 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.

When we interviewed Jerrold S. Parker, a partner in the New York personal injury law firm of Parker & Waichman that represents the estate of Anita Smith, 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 a wrongful death action against Biogen and Elan on behalf of the estate of the 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 PML. 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 review of the extensive 64-page (315-paragraph) complaint with 14 separate causes of action reveals 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.

Significantly, Anita Smith’s treating 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) quite problematic and worthy of serious consideration (and appropriate warnings) before it was routinely prescribed to patients in the clinical trial.

Despite the 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.

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 fast 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.”

Specifically, with respect to Anita Smith, Dr. Chaudhuri stated: ”Because the pathology did not support the clinical diagnosis of multiple sclerosis in the fatal case, the diagnosis is questionable, and the decision to enroll an atypical patient is debatable.”

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.

Only two weeks ago, 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.”

Then, much to the surprise of Parker& Waichman (attorneys for the Smith estate) and Anita Smith’s husband Walter, who has become an outspoken critic of the drug and who intends to testify at the upcoming FDA hearing in March, it was learned that MRI films (and possibly other medical records) of Anita Smith existed and were in the possession of Colorado Springs Imaging.

The MRIs (taken on March 21, 2002, April 16, 2003, and April 21, 2004) and the records and reports relating thereto were not among the materials turned over in discovery by Dr. Fodor (Smith’s treating neurologist) or any other healthcare professional that had treated Smith.

Since these reports (if any), and especially the MRI films, could be extremely significant with respect to the misdiagnosis of Smith (as having MS) and the improvident decision to enroll her in the Tysabri clinical trial, Parker & Waichman sought production of the records.

In an “emergency” motion to obtain these MRI films and any accompanying records, a number of unusual circumstances are alleged by Smith’s attorneys, Parker & Waichman (Jerrold Parker and Jason Mark) and their Boston-based counsel Robinson & Cole (Alex H. MacDonald, Michael D. Lurie, and Kimberly A. Dougherty).

When they became aware of the existence of these important and possibly pivotal records, Smith’s attorneys contacted Colorado Springs Imaging (CSI), an independent diagnostic center, and requested a copy of the MRI films and any other materials relating to them.

Under the law of every jurisdiction in the U.S., a patient is always entitled to a copy of their own medical record and once a properly executed authorization is delivered, a medical provider must release those records as directed by the patient or the patient’s legal representative.

Here, Smith’s attorneys advised CSI that an authorization executed by Walter Smith, as administrator of the estate of Anita Smith, would be sent to them to permit the release of the records in question.

After initially agreeing to the release, CSI apparently contacted Biogen (or Biogen’s attorneys) and, as a result, reversed itself and refused to release the MRIs or any other records it had with respect to Anita Smith. CSI claimed Biogen’s consent was necessary before any exchange could take place.

Although Smith’s attorneys strongly protested to CSI and Biogen’s attorneys, Biogen remained adamant that it could deny the release because the records belonged to the drug company and not to Anita Smith or her estate.

The emergency motion to compel Biogen to authorize the release of the MRIs and other records in CSI’s possession was submitted on extensive papers from both Parker & Waichman and Robinson & Cole and argued before Middlesex Superior Court Judge Julian T. Houston.

After a contentious hearing at which Biogen’s attorneys took a position that Judge Houston openly regarded as legally unsupportable, the court issued the following order:

“Motion # 14 allowed after hearing. Defendant Biogen- IDEC, Inc. is ordered to immediately direct the Custodian of films and medical records of the late Anita Smith, Colorado Springs Imaging is to release any and all medical records in its possession to the Plaintiff, Walter Smith, see General Laws chapter 112, section 12cc. The aforementioned records are to be released forthwith.”

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.

When reached for comment at a legal conference in Hawaii, Jerrold Parker expressed his appreciation for the prompt and definitive ruling by Judge Houston. Mr. Parker stated that it was “incredible” that any medical provider or law firm “could have taken the position that diagnostic tests like MRIs and any reports related to them could not be obtained by the patient. 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.”

(Sources: FDA Press Release and Q & A; British Medical Journal; HealthDay News; The New York Times achieves, Los Angeles Times achieves; Complaint, motion papers, and court documents in Smith v. Biogen, et ano., Civil Action 2005-02527 – Middlesex Superior Court; and Archives)

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