I attended the PCNS Drugs Advisory Committee meeting for alemtuzumab, held in Silver Spring, MD on November 13, 2013. As a patient afflicted with multiple sclerosis, I presented my perspective on the safety of alemtuzumab and I have attached that presentation to this letter. I am writing to express my own opinion because after witnessing and participating in the meeting, it is clear to me that the staff reviewers began with a premise that the design of the clinical trials was flawed. And, from the standpoint of the reviewers, if the design was flawed, then by definition, the data is unreliable due to the possibility of pervasive bias. Bias, however, could not be quantified by the reviewers. But, even though bias could not be quantified, the mere suspicion that there was possibly, unquantifiable bias, necessarily forced the reviewers to conclude that the demonstrated superior efficacy of alemtuzumab over rebif could not be trusted. There was no balance, perspective, or middle ground. This was in stark contrast to the CHMP, a consortium of 30 member European countries who, after reviewing the exact same trial data, enthusiastically recommended alemtuzumab for first and second line therapy. Alemtuzumab was, in fact, called a step change in disease modifying therapy. It represents a step change for the Europeans because, for the first time ever, European MS patients will have access to an induction therapy as opposed to the traditional maintenance therapies. And this induction therapy could induce a durable response that might even represent a cure for some patients.
In my opinion, and in the opinion of many physicians in attendance, the staff reviewers refused to recognize the realities of designing a clinical trial for MS. Staff reviewers were insistent that a double masked trial should have been performed in which patients would be forced to take two drug regimens over two years. Those patients randomized to Rebif would also get placebo saline infusions, mimicking alemtuzumab. Those patients randomized to alemtuzumab, would also inject themselves subcutaneously, three times per week for two years with placebo, mimicking rebif.
From personal experience, I can tell you that the interferons are painful to inject and induce flu like symptoms in many patients. It is well known that alemtuzumab induces an infusion reaction in the majority of patients consisting of headaches, chills, fever, etc. The patients would have known immediately which therapy was real and which therapy was a placebo.
Regarding the request for a double dummy design to ensure blinding, Dr. Blumenthal said, "As 92% of patients on alemtuzumab had infusion reactions, patients are going to know what they are being given."
Dr. Rudick, from the Cleveland Clinic, who has been involved in several MS clinical trials, said that the FDA requirement for a double mask design would preclude many studies from going forward. And in testimony given to the panel, he argued, "If issues of bias were applied to Avonex, Betaseron, and Copaxone, we wouldn't have any drugs. And the differences in those studies between active drug and placebo were smaller than alemtuzumab and Rebif here."
Why would the FDA staff reviewers insist that such a trial design is even feasible? There are three possibilities:
- The FDA staff members are unfamiliar with the prevalent side effects of rebif and the class of medications that it represents. If so, they lack critical perspective and cannot perform their jobs effectively.
- The FDA staff members give little or no credit to the intelligence of the MS patient population. If so, they lack critical perspective and cannot perform their jobs effectively.
- The FDA staff members had an agenda that preempted the well being of the MS patient population and were more concerned with enforcing future pharmaceutical obedience to FDA doctrines that strictly define a standard for adequate trial design. If so, they lack critical perspective and cannot perform their jobs effectively.
So, which does one choose? The first two choices imply incompetence. The last choice implies a loss of humanity, empathy, and balance.
Here is what FDA Commissioner Dr. Margaret A. Hamburg said during her commencement speech at the Stanford School of Medicine on 6/16/12:
So never stop learning; never stop asking questions; and never forget that medicine is an art as well as a science practiced by doctors and researchers who bring to the bedside - and to the bench - not only technology and training, but also their humanity, caring, and concern...
But please remember that the more skilled you become, the more specialized you become, and the more dependent on technology you become - the easier it becomes to lose your humanity, forget your compassion, and ignore your instincts.
Genzyme had a choice to compare alemtuzumab to a placebo which would have been unethical, or to compare it to a medication that represented the most widely used class of medications in the world. It chose the latter, electing to keep the raters of disability blinded as well as blinding the neuroradiologists who read the MRI exams. Justin Zivin, MD, professor emeritus, University of California, San Diego, said, "Studies like this can't be blinded, but if raters are blinded that's ok for me." Dr. Blumenthal added: "There was sufficient evidence of efficacy from the MRI data for me. That would not have been biased." And Ying Lu, PhD, Stanford University School of Medicine, California, pointed out that the brain atrophy data also showed a consistent reduction, as well as hospitalizations. "It is hard to be biased on these."
The Europeans accepted this trial design, acknowledging that the trial design represented a pragmatic approach to these two drugs.
Dr. Billy Dunn, Deputy Director of DNP, was quoted by the Boston Globe as saying, "We indicated our discomfort with the clinical trial as designed", implying that pragmatism has no role in the design of a clinical trial.
On 11/19/13, Dr. Alasdair Coles, one of the lead investigators of the trials, replied on the Barts and the London MS Research Blog, "Several years ago, we discussed the design of the alemtuzumab trials with the FDA at a face-to-face meeting. The FDA approved the trial design then."
As a physician, you know that the majority of MS patients experience many relapses of disease activity over a variable time course and that these relapses are amenable, to some degree, to a variety of medications. You also know that the majority of MS patients then advance into the progressive phase of the disease, for which, there is no treatment. It stands to reason, therefore, that the litany of complications arising from a therapy for any lethal condition such as cancer or a neurodegenerative disease, such as multiple sclerosis are, for the most part, preferable to the ultimate consequence of the disease which, is death.
In the FDA staff review on the safety of alemtuzumab, Dr. Mentari, a nephrologist, highlighted all of the possible adverse complications reported for alemtuzumab. This was not only in the MS patient population but, also in other patient populations such as patients afflicted with chronic lymphocytic leukemia. In her analysis, Dr. Mentari emphasized the incidence of cancer after receiving alemtuzumab. She implied, by referencing the CLL patient population, that the incidence of cancer was much higher in patients on alemtuzumab than in patients on Rebif. Page 118 of the Genzyme briefing document compares the three year incidence of cancer in the patients on Rebif with the patients on alemtuzmab, who received the proposed infusion dose of 12 mg. The rate, per 100 person years, was higher in the Rebif treatment arm (0.289) than in the alemtuzumab treatment arm (0.206).
In listing all adverse events from all patient populations, there was no mention that CLL patients are a sicker patient population that received much higher doses of alemtuzumab in comparison to MS patients. Page 161 of the Genzyme briefing document lists the infusion dose for patients with CLL as 30 mg, given three times per week, for a total duration of 12 weeks. Thus, CLL patients receive a typical dose of 360 mg of alemtuzumab over a duration of 12 weeks. MS patients receive a typical dose of 96 mg over a duration of one year. CLL patients typically receive a dose of alemtuzumab that is four times greater than MS patients in a much shorter course of time.
Was there pervasive bias in her presentation or in the clinical trials? I would also note that page 164 of the Genzyme briefing document indicates that chronic renal failure patients typically receive an infusion dose of 40 mg of alemtuzumab to prevent kidney rejection when undergoing a renal transplant. So, from the perspective of the nephrologist, Dr. Mentari, saving a transplanted kidney is worth the risks associated with the use of alemtuzumab. But saving a brain is not worth the risks associated with alemtuzumab?
Does one size fit all? On 11/20/13, Dr. Shuren announced in FDA Voice that the first of the next generation gene sequencing devices has been approved for marketing. The age of personalized medicine is finally here for patients. In her report, "The Age of Personalized Medicine", Dr. Hamburg commented, "The concept of personalized medicine is not new. Clinicians have long observed that patients with similar symptoms may have different illnesses with different causes. And similarly, that medical interventions may work well in some patients with a disease but not in others with apparently the same disease." Is it here only for cancer patients or can patients with neurodegenerative diseases take advantage of personalized care?
Regarding over-restrictive policies and the need for speed, Dr. Richard Pazdur, director of the Office of Oncology and Hematology Products was quoted as saying, "When patients know there is an active drug, two months make a big difference, because they're dying of a disease. It's like holding a glass of water in front of a person dying of thirst and saying, no, you can't drink."
There is no CURE for MS. Lemtrada is the closest thing to a cure that we have. Yet, if you have cancer, you can be treated with chemotherapy and radiation, both of which are harmful in so many other ways, if not kill you as well. But, it's okay, as long as there is a chance to put the cancer in remission, patients and physicians choose the therapy with its complications over the more likely consequence of death.
As of now, with the current maintenance therapies, people with MS have no chance of every saying or thinking that they are free of disease. The patient representative on the panel, Cynthia Sitcov, urged the FDA to consider the "the incredibly moving testimony from patients." She noted that numerous letters from patients and advocacy groups have been sent to the FDA. "They are remarkable. Every single one describes this drug as life changing."
If so, why would physicians somehow conclude that an induction therapy, capable of inducing a "life change", should only be reserved for the sickest of MS patients? Induction of a durable response in the relapsing phase of the disease could delay or prevent transition into the progressive phase of the disease, for which, there is no treatment. In arguing that alemtuzumab is too risky for mild disease and should only be reserved for severe disease, relegating the induction therapy to such a late phase of the disease, may be too little too late for the MS patients.
So, here we are in the US with alemtuzumab, the first legitimate induction therapy ever, capable of transforming the lives of so many MS patients, waiting in the wings and ready to go. And the US regulators tell us that the medication is too dangerous for us? While the European regulators embrace it?
Can you please explain the dichotomy that exists between the Office of Oncology/Hematology Products, with its willingness to accept risks in the face of death, and the pedantic approach of the Division of Neurologic Products which chooses to stand in the way of a transformational medication due to concerns of non-lethal complications such as a life long risk of hypothyroidism and ITP? Could it be that there is a total lack of leadership and perspective from the likes of Dr. Eric Bastings and Dr. Billy Dunn? Or could it be something more subtle, such as gender bias, that prevents men in a leadership position form having the requisite empathy for the majority of MS patients who happen to be women?
It angers me beyond words! This is my life and so many other people's lives that they are discussing in such a self-righteous, pompous way! You can bet that if someone on that committee or on the staff had MS, or someone near and dear to them had MS, they would have argued tooth and nail to make it available for first and second line use.
There are choices to be made. "Induction therapy vs. maintenance therapy" and "Escalate therapy slowly as disease worsens vs. treat disease at the earliest presentation with the most effective therapy".
A decision that restricts Lemtrada to those patients who fail all other therapies sets us up for failure. It is well known that the risks of PML increase dramatically with the use of prior immunosuppressive medications. Biogen and physicians chose to define the immunosupressives as chemotherapeutic agents. But we know that all the disease modifying therapies are in essence, immunosuppressives.
And what about a woman with MS who is desirous of becoming pregnant? She could take this medication two years prior to conception and not have to worry about the toxic effects that maintenance therapy could have on her pregnancy. But this option will be unavailable to her if the medication is restricted to second line use. So, again, I ask you whether or not there is gender bias from male physicians in leadership positions at the Division of Neurologic Products? Or is it just pervasive bias and arrogance on the part of physicians that they know what is best for the MS patient population?
Dr. Blumenthal said, "I could not interpose myself between the patient and their neurologist. It is for them to decide whether it is the right choice."
After witnessing and listening to the FDA staff presenters, one is left with the impression that the FDA regards the MS patient population as a herd of sheep that needs shepherding. The FDA will tend the herd and coerce patients to stay on maintenance therapy so that the pharmaceutical companies can utilize this multibillion dollar annuity to fund development of other billion dollar annuities. And when we advance into the incurable, progressive phase of the disease, we are set adrift to die by ourselves. The FDA, by portraying alemtuzumab as a therapy that is too dangerous for the majority of patients, enables this scenario.
Complex decisions regarding novel therapies, such as alemtuzumab, belong in the domain of the physician patient relationship and should not be restricted by regulators who have no vested interest in the disease. After application of a risk management strategy, and comparing the risks of Lemtrada to Tysabri, a reasonable person would conclude that Lemtrada is safer than Tysabri. The latter has resulted in over 400 cases of PML and 88 deaths. Patients, such as myself, who have had no other alternative than to stay on Tysabri, after failing all other therapies, deserve an alternative therapy, such as alemtuzumab, to escape the risk of PML.
We, as patients, and I stress that all MS patients, deserve the right to choose our own therapy in conjunction with our neurologists. The majority of the members of the PCNS Advisory Committee voted that alemtuzumab is effective in the treatment of the relapsing, remitting phase of MS. The overwhelming majority of members voted that safety concerns should not preclude marketing approval. Alemtuzumab, therefore, should be approved with a risk mitigation strategy for first and second line therapy.