The Great Room
We were in the ‘Great room’ and it was a great room; an impressive room able to seat several hundred people with large screens covering the sides of one wall so that everybody had a clear view of what was going on. With the FDA often following FDA Advisory Committee recommendations this was where many drugs got approved or not and it felt like it.
The meeting starting out with the FDA rep emphasizing that they ‘got it'; that they understood chronic fatigue syndrome is a serious and sometimes devastating disorder that vitally needs treatment options. Announcing that they were both ‘delighted’ and ‘overwhelmed’ by the 750 testimonials from ME/CFS patients, their servers promptly crashed under the weight of the large online crowd watching the proceedings.
One had the feeling they weren’t used to this level of patient participation.
Just two days prior to the hearing, the FDA made public a highly critical 220 page document outlining the FDA’s concerns on the safety and efficacy data. Hemispherx employees, however, appeared confident they could answer the FDA’s queries.
Hemispherx presented first with its President Dr. Carter flashing Dr. Klimas’ famous quote that she’d rather have HIV than chronic fatigue syndrome and emphasizing that ME/CFS can be life-threatening and is as debilitating as multiple sclerosis, rheumatoid arthritis and lupus.
A good part of Dr. Carter’s presentation was focused on safety. The FDA’s background information and questions posted just two days earlier had made it clear safety was going to be a major issue; something that clearly flabbergasted Dr. Carter, who noted at one point, that it was not until this year that substantial safety issues had been raised.
One problem Hemispherx faced was that Ampligen is not just a new drug; it’s (a) a drug that affects the complex and powerful immune system, (b) it’s the first of a new class of immune drugs to get this far at the FDA, and (c)some other drugs in this class have had substantial safety issues. The FDA noted that autopsied rodents given Ampligen possibly indicated signs an overheated inflammatory response and they posed questions about the reliability of the safety data.
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Stating that Hemispherx had ‘irrefutable evidence’ the drug was not sparking a strong inflammatory response , Carter laid out why. The chemical structure of the drug was distinctly different from the other drugs in its class that had safety concerns. In contrast to those drugs Ampligen quickly metabolized into natural molecules indicating it was giving the immune system powerful but transient nudges – hardly the type of activity that would promote a sustained inflammatory response.
Hemispherx argued that Ampligen’s chemical makeup, it’s quick metabolism in the body and years of clinical data indicated that Ampligen was safe.
The rodent data was simply irrelevant ; unlike humans rodents were slow metabolizers of the drug – which meant the drug sat around in their systems for long periods of time – a danger not faced by humans. Only primates, Dr. Carter asserted, were acceptable test animals for this drug.
Plus 95,000 doses of the drug had been given safely since 1997. Whatever issues FDA had with the original study data, dating back 20 years in one case, subsequent use had shown the drug to be safe. Hemispherx’s 174 safety reports indicated the drug was safe, the drug was being safely used outside the country, no evidence of autoimmune illnesses had ever been reported and with some irritation Carter stated the drug’s safety concerns had been dealt with 18 years ago. Carter also tried to allay cancer concerns by noting Ampligen’s anti-cancer effects were currently being studied at academic centers.
Hemispherx’s chief researcher, Dr. Strayer reported that the no evidence of the FDA’s chief concern, an autoimmune response, had ever been reported and then examined the case of one participant with transient liver problems (another FDA concern) who’s health ended up improving greatly on the drug.
Indeed, the study data indicated the drug appeared to be safe with only minor symptoms (eg flu-like issues, nauseas, abdominal issues)appearing significantly more commonly in Ampligen treated compared to placebo treated patients. The FDA, though, was most interested in the outliers; the few patients who reported severe illnesses while on Ampligen even if they couldn’t be statistically traced to Ampligen.
Lecturing a bit, Carter moved on to assert the FDA had not done the proper type of analyses in their background review. He noted that the drug’s five moves from division to division in the FDA, the company been given different instructions from each. Hemispherx would also refute the FDA’s assertion they had not prepared a statistical plan until after a study was done.
Ampligen’s ability to raise endurance levels, one of the other most difficult things to achieve in this disorder, suggested the drug was hitting core features of the disease.
(This will be a central theme for the FDA; researchers are not ‘allowed’ to examine data later and then highlight what works; they are expected to devise a plan of attack and then stick to it. Hemispherx will argue that they did this and the FDA will argue that they didn’t.)
Following close on Dr. Carter’s heels Dr. Lucinda Bateman told the panel her clinic had been involved in some 30 drug trials for chronic fatigue syndrome and fibromyalgia. Emphasizing the community’s needs for good treatment options, she reported that available treatments tended to be poorly tolerated and generally had modest or no benefits. She posted a report from Dr. Lapp, a long time Ampligen provider, that he’d seen from modest to remarkable results in his patients on Ampligen and had seen no serious side effects .
In response to a question,Dr. Batemen noted that the chief endpoint in the trial, increasing endurance, was a particularly difficult thing to achieve in chronic fatigue syndrome as endurance was one of the last things to improve as patients got better.
Dr. Strayer showed that Ampligen increases endurance much more than the five other drugs approved to do that in other diseases had done, that it significantly increases functionality (average Karnofsky score increases from 50-60) and it allows patients to reduce the use of potentially damaging drugs.
Declaring that I am not a statistic, Bob Miller ended Hemispherx’s presentation with a powerful, personal review of the drug’s promise.
Hemispherx felt the treadmill endurance test results would be both pivotal to their case and difficult for the panel to understand and brought along an expert, Dr. Chris Snell of the Pacific Fatigue Lab, to answer questions. The panel, however, got swept up in other issues.
The FDA presentation was unremittingly critical. Using chart after chart, they pointed out irregularities in the data and noted that several times the company changed course in midstream. At one point, for instance, Hemispherx stopped its 1991 trial at 24 weeks instead of continuing it for a year as they’d promised. Another time the company started a trial, recognized that the exercise protocols were too harsh and wiping out the patients, then revised it and eliminated the first 7 patients from the final data set. That seemed to make sense, but every change bothered the FDA and considerable discussion ensued about the significance of those 7 patients.
Hemispherx evoked surprise at the FDA’s recent emphasis on safety data. The Agency was highly critical of what they felt were lapses in the data.
The FDA said that 41% of the people listed as responders no longer could be categorized as such as they continued on the drug in the post-trial cost-recovery period. (Most of the original participants in the trial continued on with the drug after the trial was over – itself a strong commendation for the drug. ). They stated that most of the statistical significance came from just a few patients who improved remarkably on the drug and from patients on placebo who fell apart.
Safety turned out to be a huge issue and the FDA brought up numerous small irregularities; an lupus flare reported for a patient although people with lupus were supposed to be excluded from study, abnormal liver tests in the raw data that didn’t show up in the final report, different numbers for patients who discontinued the study…
The FDA clearly took great affront at these irregularities; it wasn’t necessarily that they altered the results…it was that they were there in the first place. There was no doubt that this was a data set with problems and if you were watching Hemispherx’s stock you would have seen it rise after Hemispherx’s presentation and then plummet after the FDA’s. Hemispherx would have to answer for them in the discussion period to follow. After lunch they appeared ready to do so.
In the end few disagreed that the data indicated that Ampligen was effective at least a subset of patients. The disagreement was whether Hemispherx should be allowed to move forward at that point or whether new studies should be done to target that subset.
To “log transform” or not to was one of the major issues the FDA raised in their background report; the fact that log untransformed data had shown that Ampligen had a significantly positive benefit while log transformed data indicated the drug (almost did but) didn’t have that effect.
This technical question would dog Hemispherx throughout the hearing; and they would ultimately answer it but one had the feel that it was too late…that the damage had been done. Hemispherx’s statistician, with years of FDA experience under his belt, showed instructions from the FDA stating that log transformation should not be used unless necessary because it could skew the data, and then
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The FDA officials were focused on something else, though, when and why Hemispherx decided to log transform or not the data. The big question was whether Hemispherx saw the data before it decided whether or not to transform the data. The statistician appeared to argue that Hemispherx had to check the variance to determine if transformation was warranted but in the end stated the biostatistician who prepared the data was no longer with the company and they didn’t know. That was a huge blow…
Never mind that Hemispherx had demonstrated that the log transformation data was not warranted or that non transformed data was appropriate …the FDA was mostly interested in whether the biostatistician had ‘followed the rules’. It was a bizarre thing as a patient to watch a drug that could help ill people be held up on procedural issues but there it was.
This is how the FDA approves drugs? More impromptu debate than rigorous analysis the discussion session kind of flowed along from topic to topic with a pro-FDA moderator calling the shots. In fact, an actual debate, with each side arguing pro’s and con’s of each issue would have been much better.
The FDA’s sloppy and rather ad hoc process often felt hurried and did not inspire confidence
Instead of issues being drawn up, presented on the screens and then discussed in an organized manner with each side given equal time, the conversation lurched from topic to topic with the Hemispherx reps being frustrated spectators too many times.
After lunch, Hemispherx had appeared confident even after the morning pummeling they’d taken from the FDA team. They felt they had answers to the FDA’s concerns but after the meeting, several members of the team felt they simply were not provided the opportunity to produce them. The moderator did call on Hemispherx several times but, for the most part, the FDA personnel to held the floor.
The short early discussion period clearly left many questions hanging at a time when the issues were fresh in the reviewers minds but the later discussion period felt hurried as well.
Given the ad hoc nature of the discussion period drugs companies must shake in their boots and investors must tremble when they approach these meetings. Then again, this is an FDA that gives companies 220 pages of background materials and a list of questions to be answered two days before the meeting. The FDA team clearly has the upper hand in these hearings and that’s apparently how they want it.
Process vs Result
The hearing was largely a contest between those focused on process and those focused on the results. The FDA stated months ago that changes in protocols as studies were underway meant the study was now a hypothesis gathering expedition not a validation study. If Hemispherx found out their exercise protocols were too harsh they should have stopped the study , redo their protocols, cleared them with the FDA, enrolled another group of patients and then redo the study. That’s not a process a small drug company will find easy to accomplish.
Hemispherx acknowledged that yes, at times, we had to change things – but when we did, that data showed this drug helps ME/CFS patients. Given the needs of this community we think that should be enough.
Indeed, the needs of the community loomed large in the minds of several panel members who stated that, however irregular the study follow through, they felt Hemispherx showed that the drug helps patients and that was the paramount issue for them.
Several of those who voted against the drug also agreed that Hemispherx did show efficacy at least for a subset of patients but they wanted standard protocols followed and felt there were too many irregularities with the data. They encouraged Hemispherx to do another study.