The FDA And Special Protocol Assessments
11 CommentsBy Ed Silverman // February 10th, 2010 // 11:08 am
Earlier this week, shares in Cell Therapeutics plunged when FDA documents revealed serious concerns about the safety and effectiveness of the biotech’s pixantrone med for non-Hodgkin’s lymphoma. The documents were posted online in advance of a meeting that was scheduled for today, although postponed due to the latest snowstorm.
The FDA noted the drug was associated with potentially fatal cardiac side effects, including heart failure, and the agency questioned the strength of a Phase III trial, which enrolled far fewer patients than originally planned - 140 instead of 320 (click here and go to briefing documents). Yet the company had continually maintained it was operating under a Special Protocol Assessment, or SPA.
What is an SPA? This is an agreement between a drugmaker and the FDA that says the design and endpoints of a phase III clinical trial are sufficient for approval. However, an SPA is considered proprietary, so the FDA never releases such agreements, although a company can do so. As TheStreet.com noted last week, Cell Therapeutics claimed to have an SPA for its pixantrone study in press releases as well as public statements made by execs, but was never mentioned in filings with the Securities and Exchange Commission, raising questions about whether an SPA was still in effect.
Lo and behold, the FDA documents this week revealed that an SPA was no longer in place, because agreed-upon procedures hadn’t been followed in March 2008: “The study was not stopped at a planned interim analysis and early study stopping invalidated the applicant’s Special Protocol Assessment.” Meanwhile, the company had continued to reference the SPA in subsequent press releases, such as this one from April 2009. This explains the stock plunge - investors lost confidence. This may not have happened if SPAs were released publicly. As Forbes notes, a change is in order - the FDA should be required to disclose all SPAs.
UPDATE: A clarification: earlier, we wrote that an SEC filing mentioned an SPA, but wasn’t disclosed. In fact, there was no mention.
George
I felt blindsided by the FDA revelations on Monday and their effect on the Cell Therapeutic stock price. Information on both The Cell Therapeutic web site and webcasts over the past several months indicated heart problems only at excessive doses and touted only the increase in remission/prolonged life. Is a class-action lawsuit being considered?
Condor
Hello George –
This is an easy case of securities fraud — the company knew it was material, and false — yet continued to repeat it.
There are sure to be sharks in the water, by now.
Namaste
Condor
I would say that the FDA was reasonable it its assumption that SEC rules would take care of public disclosure requirements — and that the company would follow the SEC rules.
That is to say — I don’t think we need an FDA rule on disclosure here, JMHO.
Most public companies take the SEC rule obligations pretty seriously.
Namaste
Salmon
Condor,
While I agree that FDA was reasonable in assuming the SEC requirements were adequate I disagree that FDA could reasonably assume companies would follow them. Having seen many drugs go through development and then be marketed I believe it’s fairly standard practice in the industry not to reveal material information.
Salmon
Vic
Just a thought here: why is it that anything that involves drug development and potential changes to the rules in favor of a company seem to be “proprietary” and protected under 21 CFR 10 while comments to dockets and such other documents are not?
Seems like that FDA needs to reconsider the position that they have taken to allow for so much “proprietary” documentation. For example, try to get a 483 or Warning Letter from FDA. You can’t read what it is that they are talking about because of all of the “(b)(4)” notations [for those not aware, this is part of 21 CFR 10 which allows for deletion of "proprietary" information during the FOIA process]. I wonder if any of the subjects in the trial were actually made aware of the “SPA” that was (or wasn’t or might have been or might not have been, etc) in effect for the study since 21 CFR 50 and 58 require that the subject be aware of these changes especially if they have already signed informed consent documents. I also wonder if the new “risk” information was provided. But then we probably will never know because all of this is typically considered (b)(4) fodder by the agency.
Skeptical
Before we get carried away blaming Cell Therapeutics, while I do agree they violated the terms of the SPA, it could very well be that they are just too inexperienced to know or care that the FDA would consider the SPA null and void. Unless there is documented evidence that Cell held specific discussions with the FDA after they changed enrollment and the FDA clearly stated that the SPA was now null and void (eg during a pre NDA meeting), its tough to pin blame on them. It could have been a case of the FDA discovering the change and making the point after the submission had been filed. Oftentimes, small companies fear the consequences of proactively contacting FDA to discuss changes to their development program or issues so they just avoid it altogether. Pay me now or pay me later.
pharmavet
I agree with Skeptical about the inexperience of the company. However, as we all know, ignorance is not an excuse. FDA takes interim analyses and all they entail extremely seriously. Any deviation from an agreed upon planned interim analysis is considered as about as major a protocol violation as there is, and should relieve FDA of any responsibility under an SPA. I agree about the need for confidentiality. Why give a competitor an edge when the originator has done all of the heavy lifting to at least get to the point of an SPA.
Robert
Is it just me or does the FDA seem understaffed–or inept?
David
As an oncologist, I would regret it and feel sorry for Cell Therapeutics if Pixantrone is not approved. However, I do see that it will be difficult for it to be approved.
And my ultimate feelings towards Pixantrone will depend up information that I don’t know about, that is, how cardiotoxic is it (hopefully not too much) and just how effective is it.
We can deal with neutropenia,… that is not the problem. Thrombocytopenia, if it happens can be a really annoyance.
The problem is that the drug is being tested for low grade lymphomas. Almost everything works for low grade lymphomas and because of this, every new antilymphoma drug gets tested for low grade lymphomas.
But what about high grade lymphomas? What about high grade lymphomas in patients with diminished cardiac output? We would normally use an aggressive treatment with Cytoxan, Doxorubicin, Vincristine and Prednisone combined with Rituximab. But with a poor heart, we have to eliminate the best drug… that is, the Doxorubicin. If Pixantrone were as effective as Doxorubicin but less cardiotoxic, it might be a reasonable substitute.
But let’s face it, Cell Therapeutics would never test it in that setting… hard to do a study because it would be unethical to test it against Doxorubicin (which would be contraindicated in patient with left ventricular dysfunction). And furthermore, there just are not enough patients.
So a drug that could be a very useful medicine in a small number of patients will not be approved and eventually discarded (anyone remember piraxantrone? Losaxantrone? and other aza-drugs from the early 90’s?). Cell Therapeutics has not intention of getting such a drug approved for a very small population and the FDA has no insight what-so-ever on what other uses such a drug could have and where nich products could come in handy. And the inability of allowing similar drugs to be available at lower than usual costs for rare indications has put a real damper on inovation and drug development in this country.
ex-FDA
David, I have to disagree that FDA has no insight. Plus companies bring their own outside experts to FDA to explain if they feel it’s important for FDA to understand. FDA may even reach out on their own talking to people at NIH and elsewhere. As for inability of allowing drugs to be available at lower costs that’s untrue. Cancer drugs do not go through nearly as rigorous testing and development as other drug classes so development is cheaper. Even then there’s the Fast-track development and approval process which eliminates the highest costs of drug development prior to approval http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/SpeedingAccesstoImportantNewTherapies/ucm128291.htm.
Skeptical
Robert, I’m in industry but I have to say that there are many passionate and dedidated scientists within the agency that are being asked to make tough decisions on vast amounts of data in a finite period of time. They strive to balance the regulations with protecting and enhancing public health. The problem is Congressional oversight and committees that don’t have a clue about anything to do with science, disease, patient care or drug development.