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Recordings from Simmaron’s Roundtable: Scientifically Redefining ME/CFS

Simmaron’s Pre-FDA Workshop Roundtable: Scientifically Redefining ME/CFS, April 25, 2013

Simmaron Scientific Advisor Dr. Daniel Peterson hosted a roundtable discussion in the hours before the FDA’s Drug Development Workshop. He is joined by Dr. Nancy Klimas, Dr. Derek Enlander, Dr. Charles Lapp and Simmaron Researcher Gunnar Gottschalk to discuss state of the art diagnosis and clinical excellence in ME/CFS.

Read Cort Johnson’s Blog, Physicians Roundtable I: Diagnostics

Each of the recordings below is about 30 minutes long (the first is just a recording of the date).

Listen in on the field’s top experts at your own pace!

Scientifically Redefining ME/CFS Recording 1 – Date stamp (1 minute)

 

Scientifically Redefining ME/CFS Recording 2

 

Content:  Dr. Peterson opens the roundtable, discusses improvements in diagnostics and identifies immunological abnormalities that can be tested. He continues with a discussion of Natural Killer Cells and biological measures for treatment and improvement.

 

 Scientifically Redefining ME/CFS Recording 3

 
Content:  Dr. Klimas and Dr. Enlander discuss approaches to diagnosis and evaluation of ME/CFS patients.

 

Scientifically Redefining ME/CFS Recording 4

 

Content:  Drs. Peterson, Klimas, Enlander and Lapp begin an interactive discussion about the needs and approaches to clinical assessment.


 

Scientifically Redefining ME/CFS Recording 5

 

Content:  Drs Peterson, Klimas, Enlander and Lapp discusses biomarkers, treatments, outcome measures and misdiagnoses.

 

 

Scientifically Redefining ME/CFS Recording 6

 

Content:  Simmaron Research Coordinator Gunnar Gottschalk gives Cidofovir results presented at Paris HHV6/7 International Conference

 

 

Scientifically Redefining ME/CFS Recording 7

 

Content: Dr. Peterson and Mr. Gottschalk discuss Simmaron’s research activities for the last two years.

Dr. Peterson Calls for “Therapeutic Strategy” to Develop Drugs for ME/CFS

“We’re Ready”

Dr. Peterson had 2 minutes to get to the point. And he did.

After 30 years of treating approximately 9,000 patients and tired of the ‘therapeutic stagnation’ in this disease, he called on the FDA to ‘execute a therapeutic strategy’ that would pave the way for drug development. No doubt speaking not just to the FDA but to drug company reps listening, he gave them good pragmatic reasons to do so; 1,000,000 sick people in the US, a $9 billion hit to our economy yearly, a market for a diagnostic marker yielding potentially $250 million a year, a drug therapy possibly bringing in billions….PetersonPhoto right

“I implore the esteemed committee to develop a therapeutic strategy for ME/CFS” Dr. Dan Peterson to FDA

Listen to Dr. Peterson at minute 92:00 of this VIDEO.

He didn’t ask the federal government to do it all  on their own. The ME/CFS physician community he asserted is ready to do its part.  They’re already using objective markers such as NK cell functioning, MRI’s, SPECT scans, low VO2 max tests to inform their therapies and they have formed the consortia and networks needed to take on pilot studies and multi-center Phase I, II and III clinical trials.

He was backed up by his longtime colleague, Dr. Nancy Klimas later in the meeting when she said ” much of what is needed to develop drugs for ME/CFS is ‘already in hand'; we have, she said, the ‘clinical trials groups’  who have ‘many, many years of  experience with these…instruments we’ve been talking about’. “There’s really no reason to delay any further”

“There’s  really no reason to delay any further” Dr. Nancy Klimas on targeted clinical trials for ME/CFS at the FDA Stakeholder’s meeting

The key problem is the large heterogeneous population that makes up the ME/CFS community.  Dr. Slagle of the FDA noted that the heterogeneity of the ME/CFS patient population made it necessary for researchers to  define and target specific subsets, but both  Dr. Klimas and Dr. Peterson asserted they’re ready, right now, to bring targeted therapies to bear on just those subsets.

This is all about one thing; scientifically redefining ME/CFS … wherever that takes us … and as long as it leads to treatments.

Scientifically Redefining ME/CFS SR Facebook logo new

Dr. Peterson’s report of Vistide’s success in a retrospective study of severely ill ME/CFS with herpesvirus infections constituted not just an attempt to provide better treatment options but to redefine this illness using biological variables; in this case a subset of patients with active  cytomegalovirus infections who responded to Vistide.

The Chronic Fatigue Initiative’s Hornig/Lipkin pathogen study will, with the addition of Simmaron’s spinal fluid samples, contribute to this process if they illuminate a distinct subset of patients with active viral infections, as suggested by Madie Hornig in Florida.  (Results are due within the next two months.)

Now comes convincing the pharmaceutical industry that it’s worth their while to invest in this disorder, and that’s where Dr. Peterson’s request for a ‘therapeutic strategy’ that will compel pharma to enter the market comes in.  That therapeutic strategy will involve the FDA  identifying endpoints for subpopulations and study designs that industry will have confidence in.Food_and_Drug_Administratio

Is the FDA ready to do that?

We’ll bring you more of the FDA meeting in coming blogs.

FDA Drug Development Workshop Real Time Tweets

Below are Simmaron Research’s real time tweets from the FDA Drug Development Workshop on April 25th and April 26th last week. They are notes from most of the workshop sessions. While tweets usually have the most recent on top we have swapped this so the tweets here are in chronological order so you can follow the conversation from the beginning. If you are interested in more updates from Simmaron’s Twitter page you can follow us here @RedefiningMECFS.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Join our conversation on Twitter follow us here @RedefiningMECFS.

FDA Advisory Meeting on Ampligen and Chronic Fatigue Syndrome (ME/CFS) Pt I: Dueling Presentations Set the Stage For Critical Vote

Food_and_Drug_Administration

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.

The Meeting

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.

Safety

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.

Sign the Petition to Approve Ampligen Here

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.

The first of a new class of drugs to come under review at the FDA, Ampligen's safety record got special scrutiny.

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.

Efficacy

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 getting at core features of the disease.

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.

FDA Presentation

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.

The FDA's presentation was critical of Hemispherx's safety and efficacy data.

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.

Log Transformation

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

Sign the Petition to Approve Ampligen Here

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.

Discussion Period

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 which often felt hurried did not inspire confidence

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.

Sign the Petition to Approve Ampligen Here  

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.

Harsh FDA Report…Good Committee…Which Way Ampligen?

December 20, 2012

PastFuture

A once in a 20 opportunity for the ME/CFS community presented itself at the FDA hearing on Ampligen

The meeting webcast can be accessed at the following web address:   https://collaboration.fda.gov/aac122012/  At the access page  sign in as a guest. No password is required. For more info click here.

Agenda

  • 8:00 AM EST: Meeting Opens
  • 8:20-9:50 – Hemispherx Presents
  • 10:20-12:00 – FDA Presents
  • 1-2:30 Public Presents
  • 3-5:00 – The Committee answers the FDA’s questions and then votes.

THE FDA

The FDA released its background report and its list of committee members and, if you want to compare the two, the Agency was even-handed; the report was highly critical and the committee members they picked boded well for Ampligen chances..

REPORT

Harshly Critical Analysis

We knew FDA Advisory Meetings can be intense, rough environments. With the FDA background report on Ampligen you can count that as confirmed. This is not going to be easy for Hemispherx..

The FDA analysis of the Ampligen trials, focusing on methodological issues, mistakes and what it believes are inadequate efficacy and safety data does not, on the face of it, appear to bode well for Ampligen and the market agreed with the stock shaving off half its value the day the report was released.

FDA reports do tend to highlight negatives, not positives which makes sense given the way the meetings are set up; the sponsoring drug company presents its data in its best light, then the FDA does its best to poke holes in it, and then the independent review committee decides.

In the meantime be prepared for a difficult hearing. These FDA Advisory hearings have been described as ‘blood baths’ from which few companies and drugs escape unscathed.

Background

Review

A harsh FDA report presented two days before the meeting did not bode well for Ampligen

The  long and rather tattered history of Ampligen at the FDA since 1988 is outlined. The first interagency transfer to a new department occurred in 1992. The long gap between the first proof of concept trial (1990-1991) and the confirmatory trial (1998-2004) probably demonstrated how difficult it was for Hemispherx to raise the money needed to carry out the second trial.

Ampligen’s  New Drug Application (NDA) submitted on Oct, 2007 was refused filing because  it was missing  study reports, ECG and laboratory data, case report forms, ‘dose ranging’, ‘inconsistent statistical plans’, clinical pharmacology data, carcinogenicity data and had database discrepancies.  This was a long list but Hemispherx fixed some of the problems and explained others, and in the first third of 2008 quickly resubmitted the application and it was allowed to move forward.

In Nov 2009, however, citing inadequate effectiveness and safety data, drug-drug interaction data, carcinogenicity data, anti-drug antibody information and inadequate analytical methods the FDA told Hemispherx, among other things,  to conduct a new clinical trial; something which was beyond Hemispherx’s means.

“Your two main studies (AMP-502 and AMP-516) do not provide adequate evidence of effectiveness or safety.”

In 2012, after being moved to another branch of the FDA, Hemispherx requested to be allowed to  re-analyze the data from the second, larger, confirmatory  trial. The agency was leery about this approach stating “It would be unusual for this type of data to provide adequate evidence of efficacy.” but allowed the process to continue forward  stating the efficacy issues would be addressed at the final review..

Two Trials

The FDA will be relying on evidence from two trials; AMP-502 and AMP-516.  (The agency is, unfortunately, not using confirmatory data generated from patients who continued on the drug after the trial because that data was not placebo-controlled.)

First Trial (1990-1991) – The first study (502) involving 92 patients demonstrated significant increases in functioning (Karnofsky Performance Score (KPA)) and ETT (time on treadmill).

Problems had occurred. After finding that the original exercise protocol was too difficult, however, Hemispherx changed the protocol and eliminated the first seven patients from the analysis. ( If those patients are included in the analysis the significantly positive effects disappeared. )

The trial was originally supposed to last for a year but after an interim analysis it was stopped after 24 weeks. The FDA drew attention to the fact  that the statistical analysis plan was written and dated 16 years after the completion of the study and later noted ‘multiple protocol violations’ including patients restarting their other medications during the trial had occurred.

Second Trial (1998-2004) – The second larger trial (516), designed to confirm the first trials results, failed to show significant increases in self-reported  functioning or ETT.  Recently Hemispherx re-analyzed the data using patients with lower disease duration (1-10  years)  and dichotomous branching  techniques and received significantly positive ETT results but still no significant changes in self-reported functionality, daily living, SF-36  or symptom scores.

Hemispherx found that the percent of  patients reaching 25% and 50% increases from baseline was  significantly increased  in patients receiving Ampligen and that patients with lower duration illness (<10 years) were more likely to benefit. Despite reports in the literature that lower duration patients (< 2 years) do tend to respond better  the FDA found ‘no scientific rationale’ for the lower duration analysis and advised caution in interpreting them.

Several issues were reported including using median KPS values  for some patients and minimum median values for others.  Hemispherx also chose to use any response (ie the best response recorded)  during the duration of the trial for its endpoint instead of set responses at the end of the trial.

The re-analysis was helpful but the FDA questioned whether these types of re-analyses are suitable for  determining efficacy  suggesting they  are better suited for ‘hypothesis testing’.

 Due to the nature of analyses conducted after data unblinding, the Agency generally considers post-hoc analyses to be hypothesis generating rather than forming the primary basis of efficacy for an application.

Hemispherx was caught in the first study with an exercise protocol that was apparently wiping the participants out. In the second , larger ‘confirmatory’ study Hemispherx had to analyze the results differently to get positive results in the exercise testing but not significantly positive results in self-report tests.  Changes in protocols and analysis are often red flags to reviewers and questions were raised why a protocol and analysis would work in one trial and not the other.

It was rough stuff but a Hemispherx rep appeared unflustered and confident that the company was ready to respond to the FDA’s report.

Tough Subject – With its subsets and its vague definition, ME/CFS is a difficult field to test any drug in, and drugs that practitioners say have positive results in some patients have failed to achieve them in placebo-controlled trials.  If the disorder is larded with subsets then the results of any major trial of a drug that works probably should appear like Hemispherx’s did; that is, it should have weakly significant results because of the patients in the trial who have a different type of disorder altogether.  We should also know of people who had excellent results (we do) and doctors who prescribe the medication to targeted patients should have good results (they do).

Subsets-chronic-fatigue-syndrome-ampligen

Subsets will inevitably complicate matters in any clinical trial for chronic fatigue syndrome (ME/CFS) as its defined now

The FDA must realize that it’s facing an unusual challenge in a disorder that is so poorly defined.  The background report did not take into account the possibility of subsets watering down the study results but the Committee is made of several members who are well aware of this problem. Dr. Unger of the CDC, for instance, has publicly stated she is sure this is true and is engaged in a study that should help ferret them out.

Indeed a recent analysis suggested the subset problem meant Hemispherx started its trial with one of its hands tied behind its back. Throw in the fact that it’s a small company with limited resources and you probably get what we see; midstream changes that attempt to account for new information and re-analyses to target possible subgroups.

One analyst stated:

 

Ampligen’s trials had no way to account for this meta-population problem beyond looking for interesting trends within the data set. And that is what they did… No one seems to know what an appropriate biomarker for the general CFS population is, but the FDA is holding Ampligen up to an unrealistic standard nonetheless. In the end, HEB did find statistical support that Ampligen provides a biologically meaningful impact on the lives of at least some patients with CFS.

The problems facing Ampligen-or any putative therapy for CFS for that matter, is that the underlying cause(s) are unknown. As a result, there are quite possibly distinct sub-groups within any potential CFS study population with markedly distinct pathophysiologies, and hence

Safety

Hemispherx has reported that tens of thousands of doses of Ampligen have been given without issue but the FDA will rely on the results from  ‘only’ 567 patients  of which ‘controlled data’ are available for only 162. The FDA stated that for drugs intended for long-term treatment they would like at least 1,500 people exposed to the drug for short term periods and 100 for over a year.

Here, too, the FDA cited numerous issues including serious adverse events not reported, marked  laboratory abnormalities not reported, miscoding of adverse events and reasons for patient discontinuation of the trial and incomplete/misleading data presentation.  Some serious adverse events  that resulted in hospitalization were not reported. The discrepancies were enough for the FDA to call into question the data from all the trials.

On the other hand, the side effects that showed up more in patients receiving Ampligen  (flu-like symptom, chills, vasodilatation, shortness of breath ) were not particularly significant.  Other more serious side effects did occur but not more significantly in patients receiving Ampligen but the Agency expressed concerns about them.

Overall, the Agency has concerns regarding the reliability of the safety database for Ampligen, based upon lack of appropriate documentation and reporting. While review of the safety database for Ampligen suggests that the drug induces a systemic inflammatory reaction with a number of serious events of concern, the lack of reliable reporting prevents any accurate assessment of frequency. The key safety issue for discussion at the advisory committee meeting is whether conclusions can be drawn from the data as it stands …

Hemispherx will explain why the safety data is sufficient and why oversights, omissions, etc.  occurred and why they shouldn’t bear negatively on the review.

COMMITTEE MAKEUP – the Good News

 

Taking the committee makeup into account one analyst predicted a close but positive vote. At least six people have history with chronic fatigue syndrome and I would be very surprised if Komaroff, Marshall weren’t strong yes votes and the others strongly leaning towards yes. If those six vote yes they’re two votes away from a tie vote and three from a majority vote.  For me, I think Marshall can be very persuasive once he gets going J.

  • Dr. Philip Bautista
  • Dr. Robert Lahita – Rheumatologist – research focus: lupus; latest article – novel treatments for lupus
  • Dr. Tuhina Neogi – Rheumatologist, Epidemiologist – research focus: osteoarthritis and gout
  • Dr. Peter Peduzzi – Biostatistician
  • Dr. Irwin Russell – Rheumatologist associated with Fibromyalgia Research and Consulting in San Antonio, Texas – research focus- fibromyalgia; one study on duloexetine
  • Dr. Larry Borish – NIH grant recipient – allergic reactions in CFS
  • Dr. Lenore Buckley
  • Dr. Ralph D’Agostino (Ph.D)
  • Dr. Jacqueline Gardner (Ph.D)
  • Dr. Anthony Komaroff (MD) – ME/CFS expert
  • Dr. Gailen Marshall (MD, Ph.D) – CFSAC representative
  • Alaine Perry (MPH) – Patient representative – CFSAC representative
  • Dr. Mathew Rudorfer (MD)
  • Dr. Sean Hennessey (Ph.D)
  • Dr. Elizabeth Unger (Ph.D) – Chief of CDC CFS research
  • Dr. James Ware (Ph.D)

Conclusion

The harsh FDA report was produced by statisticians with little knowledge of the disorder but the FDA also produced a committee with a core of members with extensive knowledge of ME/CFS. The Committee vote is the key. Will Hemispherx and the patient advocates be able to convince the committee members to overlook a harsh FDA report? We’ll see.

The vote will come at the end of the day. The committee members will be asked to vote all at once so that the members are not influenced by the others votes.

The FDA will take everything into account and release its decision on Feb 2nd. They could approve the drug outright (not likely to happen), approve it with conditions, ask for more studies or just slam the door on the drug.

Dec 20th: High Noon for Ampligen and Chronic Fatigue Syndrome

December 16, 2012

Decades of hope and work for Ampligen, still the only drug ever produced for CFS, will culminate on Dec 20th.

by Cort Johnson

Ampligen’s time is finally here.  Twenty years of effort and hope  will culminate on the early evening of Dec 20th, when, following an  all-day hearing,  an FDA Advisory committee  will determine  Ampligen’s fate. Palms will be sweating and hearts will be pounding that evening as patients, physicians and their supporters and researchers with decades of work on the line  await what will be a momentous  decision.

Produced by Hemispherx Biopharma, Ampligen is and has been the only drug under development for chronic fatigue syndrome for over twenty years.  No other drugs are waiting in the wings and no other companies appear interested in  putting  years of effort  and millions of dollars into producing or even testing a  drug for this disorder.

It’ll all come down to 6-10 or so independent ‘experts’ opinions on whether this drug is safe, effective and worth putting on the market.

Prior to  the big decision we’ll see presentations from Hemispherx, the FDA and ME/CFS patients.   Dr. Bateman, Dr. Snell and Hemipherx representatives will present for Ampligen.

LOCATION: Open to the Public

Anybody can come and we hope as many people as possible  come and if they wish, give testimony.  Patient Testimony will be given in 3-minute slots  from approximate 1pm to 2:30

December 20, 2012: Arthritis Advisory Committee Meeting Announcement

Center Date Time Location
CDER December 20, 2012 8:00 a.m. to 5:00 p.m. FDA White Oak CampusBuilding 31Great Room (Rm. 1503)White Oak Conference Center10903 New Hampshire Avenue Silver Spring, Maryland

 

For Directions and other Info

Hemispherx is likely to face tough questioning at the FDA Advisory Committee meeting for Ampligen

TOUGH ENVIRONMENT

According to someone who’s been there, FDA Advisory Hearings  tend to be in-your-face type affairs in which tough questions  and a critical attitude are the norm. If Hemispherx  is getting whacked around at the hearing don’t attach too much significance to it;  every pharmaceutical company gets hammered at these hearings – even those that get their drugs approved.

My understanding is that there will be two presentations; the FDA will present its interpretation of the data and Hermispherx  with Dr. Bateman, Dr. Snell and its own raft of professionals will present its case. The FDA Advisory Board, made up mostly of rheumatologists  will pepper each group with questions and come to a decision on three questions.

      • Does  Ampligen work ( efficacy)?
      • Is Ampligen safe?
      • Do Ampligen’s benefits outweigh its risks?

Each member will answer each of these questions live and we’ll get  their decision in public  that day. From there the FDA will take their reports into account and submit their final ruling on Feb 3rd, 2013. They almost always follow the decisions of the Advisory Board.

Still Some Unknowns

There’s still quite a bit about this meeting that we don’t know and that the FDA probably won’t share until 2 days before the meeting. Take no offense at this – this, for some reason,  is standard FDA procedure. (The FDA states they will provide the information at least two day before the meeting, which everybody is taking to mean it will happen two days prior. )

At Least Two Days Before the Meeting..We Will Know

      • Panel Makeup – The final makeup of the panel.  We do  know that the panel will be made up of persons from the Arthritis Advisory Committee and perhaps others but we’re not sure who.  The FDA website states the  committee is made up of 12 slots, six of which are vacant (including the Chair :) ). Of the six persons  listed on the website one of them, Dr. Irwin Russell, is director of the Fibromyalgia Research and Consulting Clinical Research Section of South Texas. Another is an immunologist; none of the others, at first glance, have any indirect connections with CFS or FM.
      • Patient Advocate – the identity of the ‘Patient Advocate’, who presents the needs of the patient community to the panel will be listed.
      • Discussion Points/Questions – Hemispherx will want to rest up beforehand because the FDA may list a series of questions  they want information on just  two days before the epochal hearing takes place. Hemispherx may  be cramming all the way up to the hearing..
      • Webcast Link – We’ll  get the link for the webcast.

The information will be available here or maybe here; it’s not entirely clear from the notice..

STAR ALIGNING? 

Ampligen has been under review of one sort or the other since the nineties, but after  a surprisingly good year for Ampligen there is  good  reason to hope for a successful outcome.   In July the FDA reversed a devastating 2009 decision requiring Hemispherx to produce new  expensive studies which  appeared to  put Ampligen out of reach for good.  With chronic fatigue syndrome gaining more prominence, though, and with  the FDA being given a  new mandate to give  serious, underserved  illnesses a foot up,  Ampligen was  back in the mix in 2012.

Key Legislation Provides An Opening

The 2012 FDA Safety and Innovation Act (FDASIA) passed in July appears to  have played a key role in reversing Ampligen’s fate. The FDASIA encouraged the FDA to use a process called ‘accelerated approval’ which allows the Agency to conditionally approve drugs  for ‘serious and life-threatening illnesses’ while  drug companies worked on proving efficacy. This is a perfect mechanism for small drug companies like Hemispherx which would be allowed to market the drug and use the profits to fund further studies it couldn’t otherwise undertake.

Have the pieces come together for Ampligen and Hemispherx?

Coming just two days after the passage of FDASIA, the FDA turnaround  on Ampligen might indicate the FDA  is using the drug to make a statement regarding its willingness to follow FDASIA guidelines.  Indeed, Sue Sutter, a noted business/pharmaceutical journalist suggested  the FDA’s change of direction on Ampligen may have been directly  influenced by the  FDASIA.

More groundwork was laid on Sept 13th when FDA Deputy Director, Sandra Kweder, M.D. publicly stated on an ME/CFS Teleconference that the  FDA considers ME/CFS to be a “serious and life threatening disorder”.  An FDA notice for the meeting  that specifically mentioned ‘accelerated approval’ and ‘unmet medical needs’ with regard to drugs for ME/CFS indicated that the FDA, again, was specifically drawing attention to FDASIA guidelines.

The FDA’s decision to hold an  ME/CFS  advocacy teleconference and use ME/CFS  to produce it’s first Stakeholders Meeting for  a disorder in decades next year  also suggests a positive stance by the FDA.  (One FDASIA provision calls for more patient involvement.)  Sue Sutter  called these efforts “a major step in the FDA’s efforts to raise the profile of CFS as a drug development target”.

Finally a Jan 2011 decision to consolidate, after being bumped around to six divisions,  oversight of CFS treatments in the Division of Pulmonary, Allergy and Rheumatology Products, suggested the Agency was trying, finally, to get its arms around this disease and its challenges.

THE PLUS’S

The Drug

  • Ampligen out-performed a placebo in exercise trials
  • Patients on the drug were able to reduce their use of other medications, some of which can  be harmful
  • Over 1,000 patients have been administered over 90,000 doses of the drug safely
  • Even long term use of Ampligen appears to be safe (ie does not cause disease)
  • Significant buy-in from physicians who have administered the drug and patients who have taken it.  (See Dr. Peterson talking about Ampligen in the past   Read Kelvin Lords experiences on Ampligen here).

The Disorder

  • Chronic fatigue syndrome is a relatively common disorder with no FDA approved drugs (and no other drugs in sight) which presents high economic costs to people who have it and to the  nation as a whole
  • CDC figures suggest that chronic fatigue syndrome is functionally as disabling as multiple sclerosis and 10 times as common
  • Other disorders with few FDA approved drugs have been given more latitude with regard to drug efficacy at the FDA; ie if no other treatments are available the FDA is willing to relax its efficacy requirements.
  • FDASIA passage supports accelerated approval in cases where serious unmet needs are present and the drug is safe.

The MINUSES

  •  The biggest hurdle Hemispherx has to deal with is the age and number  of its studies.  In 2009 the FDA wanted a brand spanking new study with lots of bells and whistles.  The FDA relinquished that stance earlier this year but Hemispherx could be penalized for not being a billion dollar pharmaceutical company with resources to burn. Hemispherx’s re-analysis of its original data had Ampligen performing better. Will that be good enough?
  • Controversial Disease – with a poor definition. Will the disorders negatives trump its positives and the community’s needs? No federal agency has ever made the CFS communities needs a priority. Will the FDA be the first?

DECISION TIME

Taking Responsibility – The FDA rarely does not follow the decisions of its independent reviewers but the responsibility for the final decision is theirs.  They, of course, contributed to Hemispherx’s dilemma by moving the drug around to six regulatory teams.  Frustrated with these kind of bureaucratic bottlenecks and the slow pace of drug approvals, Congress acted in 2012 to make the FDA work more effectively for chronically ill people in the U.S.

It’s hard to see what the FDA has to lose by giving Ampligen Accelerated Approval status. They know the disorder is serious, they realize the community has huge unmet needs, they have proof of efficacy and most of all, they know the drug is safe.

POTENTIAL GAME CHANGER

Ampligen approval would change how ME/CFS is viewed leading to more respect and more funding

If approval occurs patients will get access to a drug that’s worked well for many, doctors will view ME/CFS as more of a treatable disorder and immune research will heat up.  Future studies examining Ampligen’s effects could very well pave the way for a biomarker and uncover subsets.

FDA approval would also give pharmaceutical companies the message the FDA is serious about finding ways to get drugs to this community and that it will work with them where it can to do. A thumbs down could suggest the opposite.

Maybe the biggest change, though, would be a change in context for ME’/CFS.  If you can change the context in which a thing occurs opportunities that were denied to it come naturally. An FDA approval would make this disorder more real as a disorder thus giving it more access to the opportunities other ‘real’ disorders have. The FDA does not approve drugs for figments of the imagination; it approves drugs for HIV, pneumonia and cancer.  Ampligen approval would begin to thrust chronic fatigue syndrome into that realm and  disorders like that  get respect, they get interest and they get funding.

The final decision for Ampligen will come on Feb 2nd.