I am still working through all the emotions triggered by the highly anticipated December 20, 2012 FDA Arthritis Advisory Committee meeting about the approval of Ampligen, an immune-modulatory drug that has been very successful in treating a sub-group of myalgic encephalomyelitis patients, a devastating disease that has no FDA-approved treatment. The meeting was held at the FDA White Oak Campus in Silver Spring, just outside of Washington, D.C. The purpose of the meeting was to make a recommendation to the FDA regarding whether or not to approve Ampligen. The FDA’s decision is due by February 2, 2013.
Before I dive into giving my impression of the meeting, I should mention that it was often hard to know who on the panel was talking because the meeting room was large and the public was seated at a bit of a distance from the committee. It was also challenging to hear everything that was said at times, as the sound system wasn’t always working that well. Ironically, the members of Hemispherx’s team were frequently admonished for not stating their name before every comment even though they were standing at the podium and everybody could seem them very well. Not so for the members of the committee who were sitting at a u-shaped table (thus hard to make out), but they were not required to state their name before speaking. So, often the public had no idea who was speaking.
After the long and exhausting trip, several very short nights and finding out that a good friend of mine had passed away unexpectedly just hours before the meeting, I didn’t have it in me to take notes. So, this is all from memory, which has been refreshed several times by discussing the meeting with other attendees.
I went to the meting fully aware that the chances for a recommendation to approve Amplgien were maybe better than ever, but probably not particularly good. But I definitely felt like the drug and, thus, the ME community, had a chance here. Maybe the FDA was finally ready to stop the neglect of ME. At least that’s what the agency was claiming, right? After all, there are no FDA-approved treatments for ME and none are on the horizon for years, if not decades.
In light of this huge opportunity, if I wanted to be able to feel like I had done all I could to support the approval of Ampligen, I just had to travel from Incline Village to D.C. to give my three-minute testimony at the meeting in person together with about 30 other patients and their relatives, Kim McCleary of the CAA and Dr. Sidney Wolfe, physician and director of Public Citizen’s Health Research Group.
I have improved so much on Ampligen that I felt I could handle the trip from Incline Village. It wouldn’t be easy and it wasn’t, but when is it ever easy when you are flying United? All three flights I booked on United during the last 2 months were canceled! But consider this: A few months ago, I couldn’t even handle a one-hour flight to the Bay Area to see my family. Now, I was able to tolerate a 27-hour trip to D.C., a day-long meeting and a 12-hour return trip. I have come a long way. All due to Ampligen. And I know in my gut that I am not done improving since I am still relatively early in the treatment.
What I hadn’t accounted for in my attempt to predict the outcome of the meeting was that at least some (maybe many) of the 14 committee members would know close to nothing about either the disease or the drug. I realize that the committee members are probably not paid much for preparing for, and attending, the meeting. These things are mainly a resume builder. But given the stakes for hundreds of thousands of patients plus their families, it boggles the mind that some of those panel members felt comfortable being involved in deciding the future of Ampligen.
Two cases in point: One panel member opined that cognitive-behavioral therapy should be an effective treatment for ME. I am not going to dignify that statement with a comment. Another panel member asked whether Ampligen is available to patients now. What?! I just about fell off my chair when I heard this. This one member (and who knows how many more) was completely unaware of the fact that the only way to get Ampligen right now is to be part of the open-label trial, which means paying for the expensive drug out of pocket and moving to one of the few Ampligen locations and either uprooting one’s family or leaving one’s family behind. The sacrifices patients are making to get access to Ampligen are enormous. How did these guys, who were clearly unqualified to be involved, get on the committee? And why would they want to be on the committee given the unfamiliarity with the disease and the drug? There were two votes right there that we lost. Well, we didn’t lose them. We never had a chance of getting them in the first place. One thing you can’t argue with is ignorance.
What I also hadn’t taken into account was the fact that not everybody on the panel would have a grasp of the magnitude of their responsibility in casting their vote. There was little understanding among many panel members of how immense the suffering is in the ME community, how great the need for hope is among patients, how truly pivotal this decision was and how devastating a “no” vote would be. Quite frankly, I believe that some of the panel members who voted “no” simply have no idea what they have done.
The Public Testimony
The public testimony of patients was truly moving. More than once did it bring me and others to tears. To hear the details of so much suffering, back to back, was emotionally challenging, but so important.
The public was separated from the committee by a literal red tape and was not allowed to go beyond that line. Only Kim McCleary of the CAA and Dr. Wolfe of Public Citizen’s Health Research Group were allowed to “cross over” that line. Robert Miller’s wife, Courtney, was expressly refused access to the cordoned off area when she tried to speak to committee members after the meeting had ended.
The three-minute time limit per person was strictly enforced. The microphone was turned off at the 3-minute mark. I understand the need to keep a meeting agenda on track. Nothing is more painful than to waste time at an already long meeting. But I would have sworn that the FDA was allowed to go beyond their allotted time slot to make their case against Ampligen. They were not even reminded of the fact that they had gone over. It became very clear who the top dog was at the meeting. It certainly wasn’t the patients.
One big surprise was the testimony of Sidney Wolfe, of Public Citizen’s Health Research Group. Dr. Wolfe was originally slated for an earlier slot during the public testimony, but he somehow managed to change the order of speakers and be the last one—for maximum impact. He read from prepared slides, which all quoted the FDA, trashing Ampligen. I kept wondering what his big “but” would be, as I was sure he was there in the interest of the patients. Naïve, I know. When his three minutes were up, there was no “but.” Dr. Wolfe strongly urged the committee not to recommend approving Ampligen. I was flabbergasted. Dr. Wolfe does not know Ampligen. He does not understand ME. But he clearly believes that he was chosen to protect patients who’ve gone through hell for years and have no other options or prospects for treatment from themselves. Simply astounding!
When it came time to vote on the safety issue, Dr. Buckley, the Acting Chairperson of the AAC, pushed really hard to skip the discussion that was supposed to precede the vote on each question. This was obviously driven by time concerns, as the meeting was running behind schedule and it was getting close to dinner time and to the plane departure times for some committee members. But the patient advocate, Alaine Perry, who did an outstanding job in representing us and really came through for the patient community throughout the meeting, pushed back even harder saying that she felt uncomfortable to have a vote on this important issue without any discussion. I’d like to add that it would also seem highly inappropriate and unusual to skip the discussion, but maybe not so much to somebody who pretty much knew what the outcome of the vote would be—with or without discussion. Reluctantly, Dr. Buckley gave in. The discussion was being had. The vote was “no.”
In the end, the committee overwhelmingly voted to recommend to the FDA not to approve Ampligen by casting a vote on four questions. The vote was “no” on three out of the four questions (9 to 4 and 8 to 5 respectively, so not close). I will list the four questions that were being voted on as well as the names of all committee members at the end of this post. It was abundantly clear to everybody in the room that the whole meeting was just a formality. Members of the committee had their minds made up before they ever entered the meeting room that morning. I understand that there are rules for the FDA on these matters and that an advisory committee meeting is probably required. But seriously, how cruel to put patients through the agony of such arduous travel when the decision was made already!
One member of the committee, Dr. Robert Lahita, was not present for voting. No explanation was given for his absence. The audience was merely told that he had left the room. This seems most unusual for such an important vote, not that it would have changed the outcome even if he had voted “yes.” I presume an emergency was the reason for his leaving, as no other explanation would be acceptable. But what seemed equally as unacceptable was the lack of explanation of his absence.
There is much to say about the meeting, but one of several things that stood out were the distressing votes cast by one of the few ME community’s specialist physicians, Dr. Anthony Kamaroff of Harvard University. Dr. Komaroff voted “no” on all four questions, even on the one question that the majority of the committee voted “yes” on! Throughout the meeting, Dr. Komaroff was hostile and dismissive towards Hemispherx, the sponsor of Ampligen. Still, his vote came as a shock to patients many of whom had pegged him as being on our team. Makes sense, right?! Unlike some of the other committee members who obviously knew nothing about the illness, Dr. Komaroff is familiar with the disease, probably more through his research than through clinical work, but nevertheless. Why would somebody like him sell out the patients he is studying?
I am sure that Dr. Komaroff has rationalized his decision. The data isn’t there. The drug’s efficacy hasn’t been proven. The drug’s safety hasn’t been proven. Hemispherx is not trustworthy. The problem with that line of arguing is that the data is open to interpretation. And that is exactly how some, though not enough, other committee members voted “yes.” Also, if one enters into the equation the fact that there is no other approved treatment for ME patients as a result of a scandalous neglect and abuse of this patient group by medical and scientific professionals and the government as well as the fact that the suffering is seemingly never-ending, I find it simply impossible to comprehend how somebody who knows this disease and understands the great suffering would reject Ampligen, a drug that has been given to patients for 24 years with no fatality and no serious side effects that can be definitively traced back to Ampligen.
I understand physicians who decide that they are not comfortable with providing Ampligen to their patients. The drug’s mechanism is not totally understood. The administrative burden that comes with prescribing it, as part of Hemispherx’s open-label trial, is a nightmare. The guidelines for shipping and storing the drug have to be meticulously followed. Infusion reactions do happen, including infiltrations, which are painful and potentially dangerous, although—based on patient reports—maybe less so than originally thought. Not wanting to get involved with Ampligen, even as an “ME doctor,” is a reasonable decision. But why torpedo the drug by keeping it out of the hands of those who are willing to help those who are suffering and therefore keeping it from patients altogether?
If “our” specialists do not help us, we are doomed. If I had to take a guess, I would bet that Dr. Komaroff didn’t bother to pick up the phone and call those physicians who, unlike him, actually know the drug: first and foremost Dr. Peterson, but also Dr. Bateman, Dr. Lapp, Dr. Klimas, Dr. Enlander. I would also bet that he never talked to a patient about his or her experience with Ampligen. Wouldn’t want to risk having to revise one’s opinion once made up. The dangers of the academic ivory tower!
After the meeting was over, Dr. Komaroff was chatting with Dr. Wolfe; two kindred souls who were clearly pleased with themselves. Dr. Komaroff had a huge smile on his face until I started taking pictures of him. It might have occurred to him that that was a bit inappropriate, as patients were crying and utterly devastated. Better not to provide any lasting evidence of such insensitivity to the patients.
Patient advocate, Anita Patton, approached Dr. Komaroff to remind him of his Hippocratic Oath and to let him know that he had done some real harm to patients with his vote. Dr. Komaroff’s response was, “I have a plane to catch.” He then moved away from Ms. Patton who, as a member of the public, wasn’t allowed behind the red tape and he proceeded to chat with somebody else in the area off-limits for patients.
Blowing off Ms. Patton that way was so undignified and he was, by his own admission, more concerned about catching his plane than the consequences of his actions. So, I couldn’t stop my self from saying, “I hope you’ll miss your flight.” I regret saying that. That wasn’t professional of me. And it was pointless, as I am sure Dr. Komaroff slept very well that night.
Dr. Unger of the CDC voted “no” on three out of the four questions. Mindy Kitei summed up very well, in her piece, “The Oxford Definition, It’s Baaack,” how many patients feel about that. Mindy said, “In my view, Beth Unger—who should know the suffering that millions experience with ME better than most FDA committee members—would vote for Ampligen approval when pigs fly.” I have nothing to add.
I haven’t always gotten a good vibe from Dr. Gailen Marshall at the CFSAC meetings. For example, his reaction at the last CFSAC meeting after a patient testified about the consideration of suicide seemed totally inadequate and inappropriate. To suggest, as he did, that only patients who are not informed about all the exciting research being conducted (yeah, right!) would commit suicide was so off the mark. It can be more depressing to know about the research projects underway right now (not many!) than to be blissfully unaware of how neglected this illness still is and how small the chances are that there will be a treatment in one’s lifetime. But I must say that Dr. Marshall was as true champion for the ME community at the AAC meeting. He voted “yes” on all four questions. I wanted to give him a really big hug after the meeting. That’s how grateful I felt to him and still do. But I wasn’t going to risk getting arrested for breaking through the red tape.
The FDA presentation consisted of a complete destruction of Ampligen. In all fairness, Hemispherx didn’t have all their ducks in a row and that was very unfortunate, but we have no other approved treatment, no prospect of one in the foreseeable future and no hope whatsoever. That didn’t seem to enter the equation for the FDA at all. Nor did the fact that Hemishpherx is a small drug company and, unlike the big pharma hitters, doesn’t have unlimited financial resources to conduct another 300 patient placebo-controlled, double-blind, randomized study, as the FDA wants them to do.
The FDA struggled hugely to distinguish side effects of the drug from typical symptoms of the disease. Seriously, abdominal pain? Show me an ME patient who doesn’t have that symptom as a result of having ME! And infections? Infections are one of the hallmark features of ME. Flu-like symptoms, headaches, fevers, pain, chills, diarrhea, depression, suicides, suicide attempts: all part of everyday living of an ME patient not on Ampligen.
Like a physician friend of mine pointed out to me: Could it be that there was a patient on Ampligen who had deep vein thrombosis because ME patients just can’t move much because they are too ill? And counting an incident of cancer as a side effect of the drug despite the fact that the cancer had been a pre-existing condition prior to starting Ampligen treatment, as had been determined after the cancer was detected, really makes you wonder.
Interestingly, the FDA didn’t consider the data of the ongoing open-label trial in terms of efficacy, which would have been a slam dunk in favor of the drug, but they did hold the side effects experienced by patients in that trial against the drug. I call that cherry picking.
Hemispherx was denied the opportunity for a rebuttal on the side-effects issue by Dr. Buckley, the AAC acting chairperson.
Another point the FDA kept making was that they were not convinced that Ampligen provides sustained relief, i.e., is a cure. In that spirit, I think the FDA should consider pulling insulin off the market, as it requires ongoing injections to treat diabetes. How about blood pressure medications, thyroid medications, cholesterol medications, etc.?
The FDA has approved more dangerous drugs for conditions less serious than ME, a serious and life-threatening disease, more than once.
There is no doubt in my mind that Ampligen would have received a favorable recommendation had it been developed by big pharma or if it were a treatment for most other diseases, even those less serious that ME. It would have received such recommendation even if it had more serious side effects. There is a clear bias against ME and against Hemispherx, the drug maker. Maybe the bigger problem is the complete lack of understanding of how serious this disease is. Without that, the risk-benefit analysis is bound to be completely off.
I had a short conversation with Dr. Michele, Clinical Team leader of the FDA, after the meeting. Dr. Michele, whom I found very personable, said that the FDA has yet to vote on the application. In other words, not all is lost. The reality is that the agency does not usually, if ever, approve a drug that has been recommended for denial. That conversation just added insult to injury and I couldn’t resist remarking that my growing up in East Germany has not bestowed a high level of confidence in me that a government would do the right thing.
But I have to hand it to the FDA in one respect: They have become excellent at paying lip service. Several times during the meeting were we assured that the agency is aware of the seriousness of the disease. A “sincere” appreciation of the large number of patients taking an interest in the matter was expressed numerous times. There was obviously some good public-relations briefing before the meeting.
The FDA received about 750 written patient comments before the meeting and that seemed to have left an impression on the agency, which remarked that they hadn’t seen so many written comments and so many patients in attendance in a long time at a meeting. They are starting to get the idea that we are not going to let up. They are starting to feel the heat. It may too late for patients my age and older. But we will still fight for the generations that come after us.
The timing of the meeting, right before the holiday weekend, was disastrous for patients in attendance. Here is one example: One patient from Reno flew from Washington, D.C., to San Francisco where her plane to Reno was delayed by 6 hours only to be canceled after that. (You guessed it: United). She was unable to book another flight until after the holidays despite trying all airlines servicing Reno from the Bay Area because, well, it’s the holidays! So after getting up at 4 am Eastern on Friday, she rented a car at the San Francisco airport and drove, though a heavy rain storm for 6 hours, all the way to Incline Village that night, arriving at 2 am Pacific on Saturday (25 hours after getting up the prior morning) to stay there with a friend to receive her Ampligen infusion—which she would have normally gotten on Thursday had the meeting not been scheduled on that infusion day—at Dr. Peterson’s office later that day. She then got stuck in Incline Village until Sunday afternoon because of a heavy snowstorm affecting Mt. Rose highway, the road between Incline Village and Reno. Her kids who were home from college and whom she doesn’t see that often had been waiting for her in Reno since Friday afternoon when she was scheduled to arrive at home.
Scheduling the meeting right before the holidays also meant that patients had to pay higher airfare, were mostly unable to upgrade their tickets using miles to have a less painful flight and will be less functional throughout the holidays, as they recover from their trip. I myself have been stuck in Incline Village because of the heavy snow. I had planned on going home on Saturday to be with my 2-year old daughter and my husband for Christmas. I will attempt to fly out on Monday now. In case it’s still snowing too much then, I have a back-up ticket for midday Tuesday, Christmas Day!
Many patients have complained that the live streaming of the meeting was basically not working. They lost connection as soon as they had logged on. Some said that the webcast problem forced them to continually reboot their computers in addition to having to keep signing back on to the meeting. Many patients were not able to follow the meeting because of these technical issues. Some set up Skype meetings with fellow patients who were successful in logging on, but missed a good part of the meeting because of the technical issues.
I found these reports extremely surprising. The building the meeting was held in seemed to be very new and the technology looked state of the art. There were lots of cameras built in the high the walls. There was also a camera set up in the back of the room specifically for the meeting with a live cameraman.
The degree of disability and/or resulting poverty of many patients made it impossible for them to attend in person. The sub-par quality of the webcast also prevented them from attending via the Internet.
It seems that this was no isolated incident and that the FDA is well aware of its technical issues. The meeting notice contained this disclaimer regarding the webcast: “While CDER is working to make webcasts available to the public for all advisory committee meetings held at the White Oak campus, there are instances where the webcast transmission is not successful; staff will work to re-establish the transmission as soon as possible.”
In the year 2012, I can think of no excuse not to provide a quality live streaming of an event that is expected to create a lot of interest in people who are too sick to attend in person.
Here are the 14 members of the AAC:
Larry Borish, MD
Lenore Buckley, MD, MPH
Ralph B. D’Agostino, Sr., PhD
Jacqueline Gardner, MPH, PhD
Lisa Gualtieri, PhD, ScM
Sean Hennessy, PhamD, PhD
Anthony Komaroff, MD, MA
Robert Lahita, MD, PhD
Gailenn Marshall, Jr., MD, PhD
Alaine Perry, MPH
Matthew Rudorfer, MD
Irwin J. Russel, MD, PhD
Elizabeth Unger, PhD, MD
James H. Ware, PhD
The Four Questions
1. Considering the totality of the data, is there substantial evidence of efficacy for Ampligen for the treatment of patients with chronic fatigue syndrome (CFS)?
Yes: 4 (Borish, Marshall, Perry, Rudorfer)
Not Voting: 1
2. Has the safety of Ampligen been adequately assessed and characterized for the treatment of chronic fatigue syndrome (CFS)?
Yes: 4 (Marshall, Perry, Rudorfer, Perry)
Not Voting: 1
3. Is the safety profile of Ampigen adequate for approval for the treatment of CFS?
Yes: 8 (Borish, Gardner, Hennessy, Marshall, Perry, Rudorfer, Russel, Unger)
Not Voting: 1
I admit to being confused by the difference between question 3 and 4. I think, but don’t know for sure, that question #3 was a vote on whether the committee thinks that Hemispherx was being truthful when it provided the safety information regarding the two Ampligen trials.
4. Based on the information included in the briefing materials and presentations, has the applicant provided sufficient efficacy and safety data to support marketing of Ampligen for the treatment of chronic fatigue syndrome (CFS)?
Yes: 5 (Borish, Hennessy, Marshall, Perry, Rudorfer)
Not Voting: 1