Tysabri Waltzes through FDA Advisory Panel by 12-0 Vote

By Steve DiJoseph

The Unanimous Vote Is but the Latest Controversial and Disappointing Action by an ‘Independent’ FDA Advisory Panel

When sales of Tysabri were suspended on February 28, 2005, many critics of the highly controversial MS drug, with potentially fatal side-effects, hoped that would end the saga of a medication that many experts believed should never have been approved in the first place. That, however, was only the beginning of the story.

Almost immediately, efforts began to resurrect the drug since, in the multi-billion dollar world of pharmaceuticals, it has been proven time and time again that there is life after death. All that is needed to begin the rebirth is to have the FDA announce that it is convening an “independent” advisory panel of experts.One would imagine that a panel ofindependent experts would be difficult to convince that a drug that has killed people and will continue to kill people should be allowed on the market. This is especially so when the FDA’s own reviewers and other well-respected scientists have already concluded that a significant number of people will die if the drug is sold to the public.

Surprisingly, however, an FDA advisory panel is often “just what the doctor ordered” when it comes to resurrecting or salvaging a dangerous drug. Consider the following examples:

Even if you: (1) ignore the allegations contained in the 8,000-plus cases involving Vioxx; (2) overlook the evidence that Merck withheld damaging clinical data concerning the safety of the drug and its involvement in additional study-related deaths; (3) discount the numerous (and extremely vocal) condemnations of Vioxx by world-renowned experts as well as the FDA’s own highly respected reviewers (and whistleblowers), and (4) believe everything Merck says about its COX-2 inhibitor, you are left with the following fact; Vioxx was always expected to kill tens of thousands of people.

Bextra (Pfizer) suffered from all of Vioxx’s shortcomings as well as additional extremely dangerous side-effects that made it doubly dangerous to consumers.

Celebrex (Pfizer), the last of the COX-2 triumvirate, has been shown to also present cardiovascular risks similar to those of Vioxx and Bextra albeit to a lesser extent.

In addition, Vioxx (2004) and Bextra (2005) were ultimately pulled from the market by their manufacturers.

Thus, when the FDA convened a special advisory panel to review the three COX-2 inhibitors in February 2005, most of the scientific community believed it was merely to confirm the demise of a class of drugs that was dangerous, overpriced, and no better than cheaper and safer alternatives already on the market. The end was at hand for the failed “super aspirins,” right? Wrong.

If ever there was a perfect opportunity for the FDA to reverse years of accusations and innuendoes concerning its questionable record in protecting the public; that was it. In the past few years, the FDA had been besieged with a number of charges by medical experts, scientists, public watchdog organizations, members of Congress, and even well-respected members of its own research staff that strongly suggested a problematic relationship between the FDA and the very industry it was supposed to be monitoring.

Of the thirty-two government drug advisers who would vote on the issue, ten had consulted for Merck or Pfizer in recent years.

When the votes were tallied, the results were shocking to many but quite predictable if the FDA’s questionable track record in protecting the public was taken into consideration. The committee voted unanimously that all of the drugs significantly increased the risk of heart attack and stroke.

Despite this finding, which could not have been otherwise, Vioxx, a drug pulled from the market by its own manufacturer (Merck) only a few months before, rose from the ashes on the wings of a 17-15 vote. (Without 9 of the 10 “questionable” votes going in favor of the drug, however, the committee would have voted 14-8 to ban Vioxx).

Bextra survived by a margin of 17-13-2 (abstentions). (That vote would have been 12-8 against Bextra without 9 favorable votes from the 10 advisers in question).

Celebrex survived by a 31-1 margin (even though the evidence against it was equally compelling). (The vote still would have been an amazing 21-1 in favor of Celebrex without the 10 “interested” voters).

The panel did recommend all COX-2 inhibitors carry “black box” warnings. Serious? Yes. Fatal? No.

Needless to say, the vote was met with shock and outrage by activists, medical experts, and researchers alike. Several highly reputable news agencies like CBS News, The New York Times, and Forbes, for example, also questioned whether the panel had been “stacked” in favor of the pharmaceutical companies with advisers who had significant “conflicts of interest.”

Despite the fact that every news outlet had been forecasting the end of the COX-2 era in its reports up to February 19, everything changed on February 20. Now, the very same journalists were actually writing articles about the possible “comeback” of Vioxx, Merck’s salvation with respect to the litigation against it, how Celebrex could recover its “luster,” and how the FDA vote immediately translated into stock increases of 6% for Pfizer and 12% for Merck.

Next, consider what happened only last October. A story was carried by hundreds of news outlets, including newsinferno.com, of an eagerly awaited diabetes drug, nearing final approval by the FDA, which significantly increases the risk of heart attacks, strokes, or death, as reported by researchers in a study published in the Journal of the American Medical Association (JAMA).

Muraglitazar, which would be marketed as Pargluva by Merck and Bristol-Myers Squib, was recommended for approval in September 2005 by an 8-1 FDA advisory committee vote.

Using the very same data the FDA panel and staff examined, however, the JAMA study researchers identified several extremely serious health concerns about the drug including almost a threefold greater risk of heart failure, heart attack, stroke, and death.

“Ten of 1,000 patients would die, have a heart attack or a stroke,” said lead author Steven Nissen of the Cleveland Clinic. “Those are serious irrevocable events.”

“These findings are particularly concerning because the significant excess of adverse events was observed after only limited drug exposure ranging from 24 to 104 weeks,” Nissen, and colleagues reported. “Real-world exposure would likely substantially amplify the risk. Taken as a whole, these data demonstrate that [Pargluva], if approved by the FDA, would constitute an unacceptable patient hazard.”

One must wonder; how then did the FDA advisory committee that recommended the drug for approval by a vote of 8-1 ignore both the indisputable clinical data as well as the FDA’s own analysts who had themselves identified evidence of cardiac risk?

Bristol-Meyers Squibb was forced to pull back Pargluva but only because the JAMA study data could not be ignored by the FDA which requested additional assurances in an “approvable letter” sent to the company in late October 2005. The drug is now in limbo and may never reach market.

With this track record of questionable advisory panel votes, skeptics of the FDA drug approval process had little doubt that Tysabri would sail through a similar “test” this week, warts and all.

As Yogi Berra would say; “This is like deja vu all over again.”

Much had been written about Tysabri before the panel met this week and most of that was negative. In fact, the claims contained in law suits, medical journal articles, and collateral research since 1991 indicated (quite strongly) that the drug should probably have never been approved.

Moreover, the allegations of possible wrongdoing with respect to the clinical trial that include claims of improper enrollment of subjects, who did not meet the threshold criteria for the test, and the withholding of critical medical information in the form of pre-enrollment MRI films raised a number of red flags for the panel to consider before it heard any testimony at all.

Once the panel convened, however, the evidence against Tysabri only became more pronounced and unequivocal. The drug will kill people if it is returned to the market.

To be sure, there are many MS victims and parents of children with the disease who desperately want the drug returned to the market since they believe it is a last resort. They believe it is their right to decide if they wish to risk a potentially fatal brain infection in order to have access to the drug.

Many of these people appeared before the panel to offer extremely emotional testimony in favor of returning Tysabri to the market. In addition, there was testimony from experts that the drug does work.

These issues, however, were never seriously questioned. The real issue is, and has always been; how many lives are the FDA, Biogen, and Elan willing to sacrifice simply to market a drug that works. This would mean ignoring the emotional pleas associated with the re-launch effort and taking a much harder look at the risk/benefit analysis for the drug.

In terms of the potentially fatal adverse reactions that many experts (in and out of the FDA) believe are inevitable, the question seems to be; what do you tell the public and MS patients once people start dying?

Pre-panel the following data existed:

While taking Tysabri and Avonex in the clinical trial, a number of test subjects 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.

One subject, Anita Smith, who, it turned out, was admitted to the trial despite the fact that she did not have MS, 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 might never make it back on the market, many experts in the field of pharmaceutical development regarded 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.

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 had 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 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.”

In response to the question: “ Will Tysabri be available to all patients?” the FDA wrote: “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 were 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 were already predicting that the drug would survive the advisory panel review and receive a favorable recommendation with respect to its being re-released on the market. They were absolutely correct.

Thus, even though the panel and the FDA itself recognized that the evidence shows the drug will kill some of the very patients it was designed to help, Tysabri stood an excellent chance of being re-marketed albeit with tighter prescribing rules, long-term monitoring, and more stringent “black box” warnings.

According to Dr. Russell Katz, director of the FDA’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.

“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,” Katz told the FDA’s Peripheral and Central Nervous System Drugs advisory committee panel.

In a letter from Anita Smith’s husband, which was read to the panel by the dead woman’s daughter Beth Ann, Walter Smith stated: “We were never told Tysabri would result in Anita’s death. If we had known that, we would have happily stayed away from the trial”

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.

There is also the strong incentive for Biogen to save this drug that will undoubtedly reach “blockbuster” within one to two years if returned to the market. Even conservative estimates predict annual sales for Tysabri will ultimately top $1 billion; an easy target when you consider the $23,000-plus cost for one year of treatments. Biogen can also calculate that, even without inflation and price increases, 30 years of Tysabri will cost only one MS patient almost $700,000).

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 and the “rubberstamp” reputation of the independent advisory panels.

Only two weeks ago, Anita Smith’s attorney, 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, 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 were alleged by Smith’s attorneys.

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 (local counsel on the case) 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.”

Significantly, the critical MRI films in issue were not provided to the NEJM for its July 2005 article. As it turns out, those films would have significantly impacted on that article since they indicate Anita Smith failed to meet the “McDonald criteria.”

“In April, 2001, an international panel in association with the NMSS of America recommended revised diagnostic criteria for multiple sclerosis. These new criteria have become known as the McDonald criteria after their lead author. They make use of advances in MRI imaging techniques and are intended to replace the Poser Criteria and the older Schumacher Criteria.” ( http://www.mult-sclerosis.org/McDonaldcriteria.html)

Moreover, Dr. Gregory Shoukimas, who reviewed Anita Smiths medical records after her death, said she had not met the definition of an MS patient. The decision to include her in a trial for a drug that led to her death raises ”serious concerns that Biogen Idec is incapable of proceeding in a safe manner with future clinical trials,” he said.

A discussion with Jason Mark (an attorney with Parker & Waichman), who has been closely following the hearing before the advisory panel, indicated to us that the following matters (among other things) were discussed yesterday before the 12-0 vote (that was taken before debate – and before the non-voting member of the panel made numerous damaging remarks about the drug) to recommend the approval of Tysabri for return to the market.

* Other MS drugs don’t have a fatality rate associated with them. Only Tysabri has a fatality rate, which the committee chair referred to as 1:1000, while noting that a range up to 3:1000 has been presented and that different sources suggest different statistics. Other MS drugs have side
effects and there are statistics for infection rates, however, there are no death statistics for those drugs.

* Biogen is not seeking approval for any pediatric use of Tysabri.

* Extensive discussions were had concerning the “Tysabri registry” that will be created. Patient enrollment in the registry will be mandatory, and information will include deaths, PML, other infections, serious adverse events, and (possible) use of concomitant immunomudolators. The purpose of the registry is to track information, and learn more about, the Tysabri-PML issue. No resolution on how often the registry will be updated. The discussion revolved around once every six months, but there was no finality on that. There was also no finality as to what the basis of the information must be. There was an issue as to whether the treating physician would be able to provide information and have the registry updated based on a mere telephone with the patient, or if it would require an in-person physical examination. Biogen was proposing the more flexible option, and didn’t want to define how the physician must or must not obtain patient information to send in to the registry. The committee chair was the one who raised the in-person examination. No vote taken on this. It will be something the FDA will have to decide.

* No one believed there should be anything to preclude re-entry into a Tysabri study (other than PML). The concern over hyper-sensitivity reactions can be addressed through early antibody screening.

* The majority of the committee believed that the risk of PML does exist even in monotherapy (without Avonex). There was some discussion of the Crohn’s patient who was on Tysabri monotherapy for the last 8 months of his life. Prior to that, he had used other immunosuppressive agents. The proposal is only for use as a monotherapy at this point. Someone later commented”we’re terrified” in response to the chair’s statement that no one was discussing/suggesting concomitant use with other immunosuppressives.

* No studies need to be conducted prior to permitting the “re-marketing” of Tysabri. “Re-marketing” in this context means use under strict controls.

* Only people with higher levels of disability should get the drug. Only people who meet the MRI criteria for MS should get to use the drug.

* The disease needs to be substantiated before someone gets to use the drug. One of the committee members stated that, given the risk of PML, we have to be sure of the diagnosis, and this requires a diagnostic MRI. Another member stated that we should use the most stringent criteria.

* There was some discussion regarding whether Tysabri should be a first-line of treatment. At least one member noted that we’re still unclear about what the risk is. Another member noted that whatever is put in place now may change based on what is learned. Another person commented that it should not be a first line of defense because of medical-legal implications. There was a vote on this — 7 to 5 in favor of it being used as a first-line treatment (with the non-voting member voting no).

* No one at the hearing ever disputed the fact that people are going to die if Tysabri is re-introduced to the market.

* There was a vote on whether there should be a lower limit on the EDSS disability score in order for someone to receive the drug. The vote was 10-1 against there being a lower limit with one abstention.

* The vote was 12-0 in favor of returning Tysabri to the market for at least “some patients, taking into account the preceding discussion of specific populations.” Biogen’s representatives were openly elated in their reaction to the vote.

* There was a lengthy discussion of exactly what information to track in the registry and the mechanics of how it should work.

* There was also a long discussion regarding the observational cohort study proposed by Biogen — a 5- year study to evaluate the long term safety of Tysabri in the clinical practice setting — and what observations/findings must be made before receiving Tysabri. One of the committee members, pre-warning that her statement was going to be met with objection, suggested that there be a baseline CSF examination to have something to compare subsequent CSF samples against if necessary. There was strong objection to that suggestion.

* The panel spent considerable time discussing what the risk management plan “checklist” should look like. Any indication of an exacerbation of symptoms will be treated as if it is PML and evaluated. The FDA will need to determine what that additional evaluation will entail. There was discussion as to submitting the checklist monthly, in advance of each patient’s infusion -reported to a central location – and, if it doesn’t arrive, a red-flag goes up for that patient. One committee member was concerned that it would be difficult, if not impossible to “recognize PML and to differentiate from MS based on a checklist.

* There was a long discussion on how frequently to monitor patients with MRI studies, and doing scans in the absence of clinical symptoms for monitoring purposes. Biogen’s position was that there was no data to indicate that screening MRI’s will detect PML in the absence of clinical symptoms, since all the MRI’s that diagnosed PML in the three known patients were taken subsequent to the onset of clinical symptoms. One committee member noted that there may be an issue regarding insurance companies paying for the MRI in the absence of a clear
instruction on the issue from the FDA.

* There was some discussion regarding combination therapy, which should be evaluated in clinical trials only after the risk of PML or other infections in monotherapy is better quantified.

* A question was raised concerning how many adverse events it will take to pull the drug off the market again. Another member stated that he believed the 1:1000 risk to be fairly accurate, and if it becomes higher, we may be back here. The chair openly stated that it is likely there will be cases of PML and it is likely that death will occur. What we do here today incorporates that fact.

* A committee member asked what the “emergency plan” was if someone develops PML, which someone will. What will we tell them? How will we treat them? Anti viral therapy? Biogen’s representative said that Tysabri would immediately be suspended and that they’re investigating whether plasma exchange would be beneficial. Members openly conceded there is no clear therapy for PML.

The totality of the research, studies, testimony (emotional and scientific), articles, legal filings, and all other available information to this point regarding Tysabri boils down to a rather simple proposition and that is: A very expensive drug that works (at least in the short-run) with respect to a seriously debilitating disease will inevitably (and concededly) kill some of the very people it is supposed to help.

Does that notion satisfy the risk/benefit equation for market approval by the FDA? Many experts, researchers, and Anita Smith’s family say no. The cash register, however, says yes, and in today’s world, that makes all the difference. Expect to see Tysabri approved by the full FDA for return to the market before the end of the month; deaths to follow sometime thereafter.

(Sources: FDA Press Release and Q & A; British Medical Journal; HealthDay News; The New York Times, Los Angeles Times; Reuters; Forbes.com; Boston Herald; CNN.com; The Wall Street Journal; Associated Press; Complaint and other court filings in Smith v. Biogen, et al.; and Newsinferno.com Archives)

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