By Steven DiJoseph
Normally, the decision as to whether a prescription drug should be approved for marketing is based on scientific evidence and clinical studies. Emotional pleas are simply not part of the usual risk-benefit equation.
In the case of the controversial MS drug Tysabri, however, nothing has ever happened in the normal or usual way.
Thus, as an independent FDA advisory panel in Washington DC grapples with the issue of whether it should recommend the Ã¢â‚¬Å“re-approvalÃ¢â‚¬Â of Tysabri, desperate MS patients, who see the drug as a last resort, and others, who regard its potentially fatal side-effects as too high a price to pay, have stolen the spotlight from the scientific proof.
While victims of MS who have reached the Ã¢â‚¬Å“end of the roadÃ¢â‚¬Â in terms of available therapies want the decision as to whether to take the drug left in their hands, family members of those who may have died as a result of taking the drug have no such desire.
The drug, which won fast-track approval, was pulled from the market in 2005, after only four months, following reports of its involvement in the deaths of at least two people. Rather than being the end of the story, however, it was only the beginning. The effort to have Tysabri re-approved began almost immediately.
The first seed that was planted to Ã¢â‚¬Å“explainÃ¢â‚¬Â 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 (Ã¢â‚¬Å“BiogenÃ¢â‚¬Â) product, <"http://www.yourlawyer.com/topics/overview/avonex">Avonex that led to a build-up and overdose of the active ingredient in the mediation.
It was immediately presumed that this revelation would form a central part of the case made to the FDA for Tysabri’s Ã¢â‚¬Å“relaunchÃ¢â‚¬Â .in 2006.
Elan Corp. PLC (Ã¢â‚¬Å“ElanÃ¢â‚¬Â) 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 <"http://www.yourlawyer.com/topics/overview/tysabri">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 received unexpected support in their efforts from desperate MS victims who viewed the drug as their last hope for treatment and were willing to take the chance that they would not suffer a potentially fatal adverse reaction.
Tysabri, which is designed to suppress the symptoms of multiple sclerosis and CrohnÃ¢â‚¬â„¢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.
Many experts 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.
In the summer of 2005, 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, commenced an action against Biogen and Elan for the wrongful death of Anita Smith, a 46-year-old wife and mother of two.
In February 2000, 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 SmithÃ¢â‚¬â„¢s health was rapidly deteriorating and she was experiencing severe neurological problems, Tysabri gained a coveted Ã¢â‚¬Å“fast-trackÃ¢â‚¬Â 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.
Some of the allegations in the Smith action include:
A second MS drug, Avonex, also manufactured by Biogen was used jointly with Tysabri as an MS treatment during clinical trials. Anita SmithÃ¢â‚¬â„¢s neurologist was already treating her with Avonex since February 2000.
Anita SmithÃ¢â‚¬â„¢s neurologist was paid (as an agent, servant, or employee) by Biogen and Elan as an Ã¢â‚¬Å“InvestigatorÃ¢â‚¬Â 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 (Ã¢â‚¬Å“PMLÃ¢â‚¬Â).
PML is a typically fatal brain disease caused by the immunosuppressive effects of Tysabri or the immunosuppressive effects of Tysabri in combination with Avonex.
SmithÃ¢â‚¬â„¢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, Ã¢â‚¬Å“The Virus That Took Down Tysabri,Ã¢â‚¬Â which described the virusÃ¢â‚¬â„¢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.Ã¢â‚¬Â [Ã¢â‚¬Â¦]
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 patientÃ¢â‚¬â„¢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:
Ã¢â‚¬Å“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 Ã¢â‚¬Ëœunfortunately logicalÃ¢â‚¬â„¢ given that Tysabri works by interfering with the immune system.
Ã¢â‚¬Å“I’m shocked that it happened so soon, but I knew it was going to happen sooner or later,Ã¢â‚¬Â 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.
Ã¢â‚¬Å“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.Ã¢â‚¬Â
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 TysabriÃ¢â‚¬â„¢s long-term effects. That article stated, in relevant part:
Ã¢â‚¬Å“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.
Ã¢â‚¬Å“Nonetheless, the agency’s drug reviewers acknowledged they were unsure about Tysabri’s long-term effects.
Ã¢â‚¬Å“Ã¢â‚¬ËœThe clinical meaningfulness of a decrease in the incidence of relapses at one year is uncertain,Ã¢â‚¬â„¢ the reviewers wrote.
Ã¢â‚¬Å“FDA reviewers found that Tysabri had an acceptable safety profile, though they noted that health risks Ã¢â‚¬Ëœbeyond one year are not known.Ã¢â‚¬â„¢
Ã¢â‚¬Å“Infections, including urinary and respiratory, were seen with Tysabri, but they were Ã¢â‚¬Ëœgenerally routine and did not have a complicated course,Ã¢â‚¬â„¢ the reviewers said.
Ã¢â‚¬Å“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.
Ã¢â‚¬Å“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.
Ã¢â‚¬Å“Ã¢â‚¬ËœThere were hints of an increase in the infection rate,Ã¢â‚¬â„¢ said Steinman. Ã¢â‚¬ËœThe FDA should have dug deeper.Ã¢â‚¬â„¢Ã¢â‚¬Â
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.
The Food and Drug Administration (FDA) has placed itself in a compromising position by accepting huge sums of money from the pharmaceutical industry to fund the agencyÃ¢â‚¬â„¢s Office of New Drugs which is now expected to Ã¢â‚¬Å“fast-trackÃ¢â‚¬Â drugs to market.
The pharmaceutical industry now funds more than 50% of the FDAÃ¢â‚¬â„¢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.
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 numbers of people. MS certainly falls into that category.
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.
Many critics of the current process argue that 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 Ã¢â‚¬Å“removed the clinical holdÃ¢â‚¬Â on studies of Tysabri. Ã¢â‚¬Å“This will allow clinical trials to go forward.Ã¢â‚¬Â
Ã¢â‚¬Å“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.Ã¢â‚¬Â
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 Ã¢â‚¬Å“in an IND study following discussion with their physicians about the potential risks and potential benefits of treatment.Ã¢â‚¬Â
Remarkably, the FDA stated that, Ã¢â‚¬Å“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.Ã¢â‚¬Â
While the Ã¢â‚¬Å“drug is not being placed back on the market at this time,Ã¢â‚¬Â 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. Ã¢â‚¬Å“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).Ã¢â‚¬Â
In a Q & A with respect to the lifting of the Ã¢â‚¬Å“clinical hold,Ã¢â‚¬Â the FDA stated that it was taking this action because an Ã¢â‚¬Å“extensive re-examination that Biogen and Elan undertook on all patients who had received natalizumab in clinical studiesÃ¢â‚¬Â revealed, Ã¢â‚¬Å“No additional cases of PML.Ã¢â‚¬Â In addition, Ã¢â‚¬Å“Biogen has proposed a resumption of natalizumab administration under an IND study with very specific plans for close monitoring of patients.Ã¢â‚¬Â
In response to the question: Ã¢â‚¬Å“Will Tysabri be available to all patients?Ã¢â‚¬Â the FDA wrote: Ã¢â‚¬Å“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.Ã¢â‚¬Â
To further justify what many experts see as an imprudent decision by the FDA, the agency stated that, while it Ã¢â‚¬Å“remains very concerned about the potential for PML associated with natalizumab useÃ¢â‚¬Â the currently available information is Ã¢â‚¬Å“not adequate to clearly define the level of risk or the exact circumstances when this risk occurs.Ã¢â‚¬Â
In addition, the FDA stated that Ã¢â‚¬Å“the existing efficacy data with natalizumab indicate this is a very effective product and multiple sclerosis is a devastating neurologic disease.Ã¢â‚¬Â
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): Ã¢â‚¬Å“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.Ã¢â‚¬Â
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.
Ã¢â‚¬Å“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.Ã¢â‚¬Â (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 agencyÃ¢â‚¬â„¢s close ties to the pharmaceutical industry are already predicting that the drug will survive the advisory panel review and receive a favorable recommendation with respect to its being re-released on the market.
Thus, even though the panel and the FDA itself recognize that the evidence shows the drug will kill additional patients it was designed to help, Tysabri stands a very good chance of being re-marketed albeit with tighter prescribing rules, long-term monitoring, and more stringent Ã¢â‚¬Å“black boxÃ¢â‚¬Â warnings.
According to Dr. Russell Katz, director of the FDAÃ¢â‚¬â„¢s Division of Neurology Products, it is possible that possibly one in every 1,000 patients will get the JC virus believed to cause PML.
Ã¢â‚¬Å“There will be additional cases of PML, and perhaps many cases, and there will likely be considerable mortality associated with use of the drug, and this is a fact that is not likely to change,Ã¢â‚¬Â Katz told the FDA’s Peripheral and Central Nervous System Drugs advisory committee panel.
In a letter from Anita SmithÃ¢â‚¬â„¢s husband, which was read to the panel by the dead womanÃ¢â‚¬â„¢s daughter Beth Ann, Walter Smith stated: Ã¢â‚¬Å“We were never told Tysabri would result in AnitaÃ¢â‚¬â„¢s death. If we had known that, we would have happily stayed away from the trialÃ¢â‚¬Â
While Biogen and Elan claim that the drug can be marketed safely if carefully monitored, critics do not agree since there is doubt that doctors will be able to differentiate between MS symptoms and those of early onset PML.
The FDA reviewers themselves recognized this significant problem. Moreover, patients fearful that the drug would be pulled from the market forever might be reluctant to report symptoms and be willing to risk the JC virus and PML too.
A decision by the panel is expected as early as today or tomorrow.
(Sources: FDA Press Release and Q & A; British Medical Journal; HealthDay News; The New York Times, Los Angeles Times; Associated Press; Complaint in Smith v. Biogen, et al.; and Newsinferno.com Archives)Ã‚Â Ã‚Â Ã‚Â