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Medscape
January 16, 2014
By Sue Hughes
Several multiple sclerosis (MS) experts who were involved in
the clinical development program for alemtuzumab (Lemtrada, Genzyme) have
voiced their disappointment and frustration over the recent decision by the US
Food and Drug Administration (FDA) not to approve the drug.
the clinical development program for alemtuzumab (Lemtrada, Genzyme) have
voiced their disappointment and frustration over the recent decision by the US
Food and Drug Administration (FDA) not to approve the drug.
Stephen Krieger, MD, from Mount Sinai Medical Center, New
York; Edward Fox, MD, from the Multiple Sclerosis Clinic of Central Texas,
Round Rock; and Jeffrey Cohen, MD, from Cleveland Clinic, Ohio, all told
Medscape Medical News that they strongly disagree with the FDA decision and are
worried about the consequences, which could include patients sourcing the drug
from other countries but not being monitored for the serious safety issues.
York; Edward Fox, MD, from the Multiple Sclerosis Clinic of Central Texas,
Round Rock; and Jeffrey Cohen, MD, from Cleveland Clinic, Ohio, all told
Medscape Medical News that they strongly disagree with the FDA decision and are
worried about the consequences, which could include patients sourcing the drug
from other countries but not being monitored for the serious safety issues.
“It’s a huge enterprise to do these trials,” Dr.
Krieger commented. “A lot of doctors are involved, and we have all seen
patients do extremely well who probably wouldn’t have done so without
alemtuzumab. There is a lot of disappointment among MS specialists.”
Krieger commented. “A lot of doctors are involved, and we have all seen
patients do extremely well who probably wouldn’t have done so without
alemtuzumab. There is a lot of disappointment among MS specialists.”
The company announced that FDA had declined approval for
alemtuzumab on December 27, saying that Genzyme had not submitted evidence from
adequate and well-controlled studies demonstrating that the benefits of
alemtuzumab outweigh its serious adverse effects. The concerns are understood
to relate to the open-label design of the 2 phase 3 Comparison of Alemtuzumab
and Rebif Efficacy in Multiple Sclerosis trials, CARE-MS I and CARE-MS II.
alemtuzumab on December 27, saying that Genzyme had not submitted evidence from
adequate and well-controlled studies demonstrating that the benefits of
alemtuzumab outweigh its serious adverse effects. The concerns are understood
to relate to the open-label design of the 2 phase 3 Comparison of Alemtuzumab
and Rebif Efficacy in Multiple Sclerosis trials, CARE-MS I and CARE-MS II.
The agency has also stated that 1 or more additional active
comparator clinical trials of different design and execution are needed for
approval.
comparator clinical trials of different design and execution are needed for
approval.
“Genzyme strongly disagrees with the FDA’s conclusions
and plans to appeal the agency’s decision,” the company said in a
statement released December 30 after the FDA issued a Complete Response Letter.
and plans to appeal the agency’s decision,” the company said in a
statement released December 30 after the FDA issued a Complete Response Letter.
Prior to that, the drug was the subject of an advisory panel
meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory
Committee, which did not reach a clear consensus. Dr. Krieger told Medscape
Medical News that he thought the advisory panel was in favor of approval.
“The spirit of the panel was that it was approvable,” he said.
meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory
Committee, which did not reach a clear consensus. Dr. Krieger told Medscape
Medical News that he thought the advisory panel was in favor of approval.
“The spirit of the panel was that it was approvable,” he said.
But chair of that advisory committee, Nathan Fountain, MD,
University of Virginia, Charlottesville, defended the FDA’s decision.
University of Virginia, Charlottesville, defended the FDA’s decision.
“It is likely that the FDA did not approve alemtuzumab
for MS because some adverse events that occurred were potentially fatal; in
addition, some of them did not occur for years after administration of the
drug,” Dr. Fountain told Medscape Medical News. “It would be very
difficult to insure that patients would be monitored for these problems for an
adequate duration.”
for MS because some adverse events that occurred were potentially fatal; in
addition, some of them did not occur for years after administration of the
drug,” Dr. Fountain told Medscape Medical News. “It would be very
difficult to insure that patients would be monitored for these problems for an
adequate duration.”
Many MS researchers looking at the data to date with this
drug had been hopeful that the dosing schedule of 2 treatments a year apart,
with many patients apparently not requiring any further treatment, might
represent an opportunity to move MS into the category of a controlled chronic
disease. Others had even used the “C” word — cure — in discussions of
its potential impact.
drug had been hopeful that the dosing schedule of 2 treatments a year apart,
with many patients apparently not requiring any further treatment, might
represent an opportunity to move MS into the category of a controlled chronic
disease. Others had even used the “C” word — cure — in discussions of
its potential impact.
“If alemtuzumab were truly curative, then I imagine the
benefits might outweigh the risks,” Dr. Fountain said. “However, the
clinical trials submitted did not allow determination of whether alemtuzumab
altered the natural history of MS. Only through a longer, well-designed,
double-blind, randomized, adequately powered study could it be determined
whether alemtuzumab is curative.
benefits might outweigh the risks,” Dr. Fountain said. “However, the
clinical trials submitted did not allow determination of whether alemtuzumab
altered the natural history of MS. Only through a longer, well-designed,
double-blind, randomized, adequately powered study could it be determined
whether alemtuzumab is curative.
“Although this type of study is not popular among
industry or NIH [National Institutes of Health] sponsors, a curative therapy
for MS would be worth the seemingly high risk of a drug like alemtuzumab and
would represent a foundational breakthrough in MS therapy,” Dr. Fountain
concluded.
industry or NIH [National Institutes of Health] sponsors, a curative therapy
for MS would be worth the seemingly high risk of a drug like alemtuzumab and
would represent a foundational breakthrough in MS therapy,” Dr. Fountain
concluded.
While the advisory panel did not appear to reach a clear
consensus, the assessment of FDA’s own reviewers, released before the meeting,
was more clear, bordering on blunt. In documents provided to the panel in
advance of the meeting, Billy Dunn, MD, acting deputy director of the Division
of Neurology Products, summarizes 3 reports from reviewers: from Evelyn
Mentari, MD, of the drug’s safety; from John Marler, MD, of its clinical
efficacy, and from Sharon Yan, PhD, of the clinical statistics supporting the
supplemental Biologics License Application for alemtuzumab.
consensus, the assessment of FDA’s own reviewers, released before the meeting,
was more clear, bordering on blunt. In documents provided to the panel in
advance of the meeting, Billy Dunn, MD, acting deputy director of the Division
of Neurology Products, summarizes 3 reports from reviewers: from Evelyn
Mentari, MD, of the drug’s safety; from John Marler, MD, of its clinical
efficacy, and from Sharon Yan, PhD, of the clinical statistics supporting the
supplemental Biologics License Application for alemtuzumab.
“As discussed by Drs. Mentari, Marler, and Yan,
significant concerns exist regarding the safety profile of alemtuzumab and the
adequacy of the efficacy data,” Dr. Dunn says in the memo.
significant concerns exist regarding the safety profile of alemtuzumab and the
adequacy of the efficacy data,” Dr. Dunn says in the memo.
Playing Politics?
For his part, Dr. Fox believes the issue is more about
Genzyme not following FDA requests.
Genzyme not following FDA requests.
“I knew the FDA had an issue regarding trial
design,” he said. “There had been a large amount of communication
between Genzyme and the FDA which I thought had been resolved. But it appears
that the FDA wanted a double-dummy design, Genzyme didn’t do it, and now the
FDA is putting its foot down. They appear to be making a point. But I don’t
believe they ever said the drug would not be approved with that trial design.
They allowed it to be filed and fast tracked.”
design,” he said. “There had been a large amount of communication
between Genzyme and the FDA which I thought had been resolved. But it appears
that the FDA wanted a double-dummy design, Genzyme didn’t do it, and now the
FDA is putting its foot down. They appear to be making a point. But I don’t
believe they ever said the drug would not be approved with that trial design.
They allowed it to be filed and fast tracked.”
Dr. Fox says he “isn’t taking no for an answer” at
the moment, and he is organizing an open letter from the alemtuzumab
investigators to the FDA explaining the reasons for the trial design and the
need for the drug. “Individuals from the FDA made this decision, but they
cannot dispute the overriding nature of the results. I want this drug available
for patients with aggressive MS,” he commented.
the moment, and he is organizing an open letter from the alemtuzumab
investigators to the FDA explaining the reasons for the trial design and the
need for the drug. “Individuals from the FDA made this decision, but they
cannot dispute the overriding nature of the results. I want this drug available
for patients with aggressive MS,” he commented.
Individuals from the FDA made this decision, but they
cannot dispute the overriding nature of the results. I want this drug available
for patients with aggressive MS.
cannot dispute the overriding nature of the results. I want this drug available
for patients with aggressive MS.
Dr. Fox was a member of the international steering committee
for the development program for alemtuzumab and an investigator in the phase 2
and both phase 3 trials of the drug. He says the steering committee included
specialists from many different countries, and there was international
consensus on the study design.
for the development program for alemtuzumab and an investigator in the phase 2
and both phase 3 trials of the drug. He says the steering committee included
specialists from many different countries, and there was international
consensus on the study design.
Dr. Krieger, who was a site principal investigator for the
CARE-MS 2 trial, takes a similar view. “The FDA did request several times
that Genzyme conduct the studies with a double-dummy design, but Genzyme set a
higher bar of efficacy by using an active comparator and that in itself made a
double-dummy design difficult. But why then did the FDA let them go ahead and
give them fast track status for the drug approval process?”
CARE-MS 2 trial, takes a similar view. “The FDA did request several times
that Genzyme conduct the studies with a double-dummy design, but Genzyme set a
higher bar of efficacy by using an active comparator and that in itself made a
double-dummy design difficult. But why then did the FDA let them go ahead and
give them fast track status for the drug approval process?”
The FDA concerns revolve around the fact that the patients
were not blinded, Dr. Krieger explains. But he maintains this was accounted for
by other factors. “There were blinded evaluators and there were regular
assessments to make sure the evaluators remained blinded.”
were not blinded, Dr. Krieger explains. But he maintains this was accounted for
by other factors. “There were blinded evaluators and there were regular
assessments to make sure the evaluators remained blinded.”
Dr. Cohen echoes these opinions. “The open design of
the study was very vigorously discussed on the steering committee of the
CARE-MS program, of which I was a member. The hypothetical concerns about bias
are well known,” he said.
the study was very vigorously discussed on the steering committee of the
CARE-MS program, of which I was a member. The hypothetical concerns about bias
are well known,” he said.
“I have 2 disagreements with the FDA,” Dr. Cohen
added. “I don’t think the double-dummy design would have been feasible as
patients would know which drug they were on because of the side effects. And
there was enough evidence presented to assuage the concerns about bias.”
added. “I don’t think the double-dummy design would have been feasible as
patients would know which drug they were on because of the side effects. And
there was enough evidence presented to assuage the concerns about bias.”
Dr. Krieger made the point that alemtuzumab is given as an
infusion over a few days, whereas interferon β-1a (Rebif, EMD Serono/Pfizer) is
administered as an injection 3 times a week, so a double-dummy trial would
involve patients being given sham injections 3 times a week for the 2-year
trial period or undergoing a sham infusion for several days, which he said was
“impractical and unethical.”
infusion over a few days, whereas interferon β-1a (Rebif, EMD Serono/Pfizer) is
administered as an injection 3 times a week, so a double-dummy trial would
involve patients being given sham injections 3 times a week for the 2-year
trial period or undergoing a sham infusion for several days, which he said was
“impractical and unethical.”
“Every single person knows what drug they are on, even
with a double dummy,” Dr. Fox agreed. “With all the effort involved
to make a double dummy happen, it would have been a sham.”
with a double dummy,” Dr. Fox agreed. “With all the effort involved
to make a double dummy happen, it would have been a sham.”
He further pointed out that most other MS drugs have been
tested against placebo, which makes blinding easier. “Because of safety
concerns with alemtuzumab, it was felt that the only way to justify its use was
to compare with an active drug routinely used for MS. This is a higher standard
than applied to any other MS drug, but it is this that has caused them problems
because of the lack of blinding. But alemtuzumab is very clearly more effective
than Rebif on reducing relapses, slowing disability, and reducing MS lesions on
MRI.”
tested against placebo, which makes blinding easier. “Because of safety
concerns with alemtuzumab, it was felt that the only way to justify its use was
to compare with an active drug routinely used for MS. This is a higher standard
than applied to any other MS drug, but it is this that has caused them problems
because of the lack of blinding. But alemtuzumab is very clearly more effective
than Rebif on reducing relapses, slowing disability, and reducing MS lesions on
MRI.”
Alemtuzumab is already approved in the European Union,
Canada, and Australia, and additional marketing applications are under review
by other regulatory agencies.
Canada, and Australia, and additional marketing applications are under review
by other regulatory agencies.
All 3 experts were also uncomfortable about the situation
that may now arise, with alemtuzumab being available in Canada and Europe but
not in the United States. They point out that this could lead to unsupervised
use and big safety concerns.
that may now arise, with alemtuzumab being available in Canada and Europe but
not in the United States. They point out that this could lead to unsupervised
use and big safety concerns.
Dr. Krieger commented: “It is highly likely that some
patients will travel to Canada to get it. It is relatively easy to undergo the
2 single administrations 1 year apart in a different country, but the problem
is that there won’t be any safety programs set up in the US to monitor
patients. This drug has some dangerous side effects. Patients need to be
monitored closely. This won’t happen if they get the drug abroad. This is a
very risky situation.”
patients will travel to Canada to get it. It is relatively easy to undergo the
2 single administrations 1 year apart in a different country, but the problem
is that there won’t be any safety programs set up in the US to monitor
patients. This drug has some dangerous side effects. Patients need to be
monitored closely. This won’t happen if they get the drug abroad. This is a
very risky situation.”
“This was never going to be a medicine for everyone but
it is a powerful product for those with the most active form of MS,” he
added. “And there is a big unmet need here. But these are not the patients
I would choose to send to another country for treatment. These are the patients
I would want to keep close.”
it is a powerful product for those with the most active form of MS,” he
added. “And there is a big unmet need here. But these are not the patients
I would choose to send to another country for treatment. These are the patients
I would want to keep close.”
Recent experience with the use of angioplasty to address
chronic cerebrospinal venous insufficiency (CCSVI) in MS shows without a doubt
that knowledgeable, motivated patients with MS have been known to take matters
into their own hands. After the first studies relating to a possible link
between CCSVI and MS came out, hundreds of patients used their own resources to
fly to centers, sometimes in different countries, to obtain treatment despite
the lack of data to support efficacy or safety, and issues with follow-up care
once they returned.
chronic cerebrospinal venous insufficiency (CCSVI) in MS shows without a doubt
that knowledgeable, motivated patients with MS have been known to take matters
into their own hands. After the first studies relating to a possible link
between CCSVI and MS came out, hundreds of patients used their own resources to
fly to centers, sometimes in different countries, to obtain treatment despite
the lack of data to support efficacy or safety, and issues with follow-up care
once they returned.
One possible scenario now would be that MS centers in the
United States may collaborate with hospitals in Canada or Europe and together
offer a program under which, if a patient obtains alemtuzumab treatment in a
country where it is available, they will undergo monitoring back home at the US
hospital.
United States may collaborate with hospitals in Canada or Europe and together
offer a program under which, if a patient obtains alemtuzumab treatment in a
country where it is available, they will undergo monitoring back home at the US
hospital.
Dr. Cohen says he has discussed this very possibility.
“That is not an ideal situation but it would be feasible if it is the only
option,” he added.
“That is not an ideal situation but it would be feasible if it is the only
option,” he added.
The National Multiple Sclerosis Society, which describes
itself as a “collective of passionate individuals who want to do something
about MS now,” testified before the FDA advisory committee on alemtuzumab,
addressing “the need for more therapeutic options for people with MS and
the importance of empowering people with MS to make their own informed
treatment decisions,” the society notes in a statement reacting to the
FDA’s decision not to approve alemtuzumab.
itself as a “collective of passionate individuals who want to do something
about MS now,” testified before the FDA advisory committee on alemtuzumab,
addressing “the need for more therapeutic options for people with MS and
the importance of empowering people with MS to make their own informed
treatment decisions,” the society notes in a statement reacting to the
FDA’s decision not to approve alemtuzumab.
“This is disappointing news, given the need for more
therapeutic options for people with MS living in the United States,”
Timothy Coetzee, PhD, chief advocacy, services and research officer at the
National Multiple Sclerosis Society, said in the statement.
therapeutic options for people with MS living in the United States,”
Timothy Coetzee, PhD, chief advocacy, services and research officer at the
National Multiple Sclerosis Society, said in the statement.
“The Society will continue to monitor this process and
update its constituents of any news,” the release concludes.
update its constituents of any news,” the release concludes.
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