Pharmalot… Pharmalittle… Good Morning
9 CommentsBy Ed Silverman // July 22nd, 2010 // 6:39 am
Hello, everyone. Nice to see you again. ‘Tis is a lovely morning here on the Pharmalot corporate campus, where the birds are chirping, the dogs are barking and the coffee is brewing. What lies in store today? Meetings and deadlines, no doubt. We have our own, of course. So please join us as we scan the news of the world and confront the future. Dig in and stay in touch…
Vioxx Cases Should Be On The Front Burner (Sydney Morning Herald)
FDA Refuses To Approve NicOx Painkiller (Bloomberg News)
FDA Panel To Vote On REMS For Opioids (MedPage Today)
FDA Urged To Publish All Safety Data From NDAs (PharmaTimes)
Sanofi Asks Court To OK Sex Bias Deal With Reps (Reuters)
US Accelerates Anti-Counterfeiting Drive In East Africa (IPS News)
Lilly Boosts Forecast After Beating Earnings Estimates (Bloomberg News)
Roche Sticks To 2010 Goals Despite Earnings Miss (Reuters)
Only Half Of Payers Support Biosimilar Substitution (Drug Store News)
Some Drugmakers Are Reluctant To Join AIDS Pool (Reuters)
Coffee pix thx to chichcacha flickr creative commons
pharmavet
Let’s not reinvent the wheel here. Summary safety and efficacy data are publically available on the FDA website in the briefing materials made available prior to Advisory Committee Meetings. They are very extensive. If a NDA drug does not go in front of an Advisory Committee, then it’s probably not a New Molecular Entity, and safety data can be found elsewhere. Also, every approved NDA has an extensive review of safety in the FDA Medical Reviewer’s report, which is also publically available. The last thing we need is reduplication of effort. I think that the Pharma Times folks need to do their fact checking a bit better.
es-FDAer
Pharmavet you’re incorrect. While the article is internally inconsistent there are a number of points
1. Comments from the transparency meeting recommends that all safety and efficay information be made available.
2. SBA’s are FDA management summaries of reviews which have much more extensive.
3. Medical reviews often do not include review of safety data from ongoing studies, phase I, or phase II studies. (for example phase I data may push the dose higher or the rate faster or use other routes that give additional information not provided currently)
4. Medical reviews may only give summarized data with cutoffs e.g. > 5% and double placebo.
5. Medical reviews may not provide adequate details, i.e. time course, dose, rate of administration, patient characteristics, or other factors
6. Safety information may be intentionally miscoded resulting in inaccurate information.
7. Safety information may be subdivided in such a way so that the true degree of toxicity is misrepresented, e.g. Liver toxicity, jaundice, individual liver transaminases, LFT’s etc.
8. Case reports with details of deaths and severe toxicities are currently not published
9. Safety data includes data from animal toxicology studies. Yet this may not be included in NDA reviews except by reference to the IND data which isn’t public.
10. The recommendations include supplemental safety data and not just from the initial approval.
11. Recommendations include providing data for drugs that are not approved. Information from these drugs (as well as drugs where development has been stopped) clearly sheds light on safety issues with other drugs in the class. Presently an NDA may be withdrawn if it isn’t going to be approved or even if it isn’t approved the safety data is not releasable unless the sponsor publicly indicates that they are completely dropping any further development.
12. Presently only data from initial approvals are made available yet additional information is collected and available.
The real issue is to make available all safety information that the FDA has access to and not just what FDA summarizes.
pharmavet
Good points, ex Fdaer. But I would argue from the “Big Pharma” perspective that even safety data from studies, especially dose-ranging studies that you yourself cite may well contain proprietary technical information that could be of value to a competitor. Let’s say that my company is searching for a marketing hook in a drug that is equally efficacious to a competitor but at a lower dose. Theoretically the dosing information could be redacted, but that might not really preserve confidentiality, since a sharp competitor who understands pharmacokinetics could reverse engineer the process and estimate the dose with some basic knowledge of bioavailability and studying the plasma time-concentration curves.
Transparency is good, but I don’t think that regulators want to get caught up in a legal thicket over what should be or should not be considered proprietary. Therefore I respectfully submit that this proposal has major potential legal constraints that make it essentially a non-starter.
pharmavet
Sorry, exFdaer. I didn’t read your expanded comment. On Point #6, we all know that coding dictionaries are notoriously imprecise, are internally inconsistent and are externally inconsistent with other dictionaries. Sometimes dictionaries are switched mid-IND at the request of the FDA when a new and improved version comes out. This happened to me in the 1980’s, when major changes to the dictionary formats were undertaken, we had to recode everything and it was a mess. Sometimes when different CRO’s are used for the same IND, especially internationally there may have to be minor or major reconciliations.
Thus there could be myriad reasons for coding inconsistencies that are not the result of intentional miscodings. We all know about Glaxo’s misdeeds in this arena, but I don’t think that we should consider coding errors to be “Glaxo violations” everytime we suspect them to occur.
ex-FDAer
One of the reasons that the information is not made available currently is because of the argument you presented about it being proprietary. This was discussed at the transparency meetings and the argument was essentially rejected. Dose ranging etc still needs to be done and comparative data for different drugs in a class is useful information for clinicians.
As for miscoding I agree with you about coding dictionaries changing and didn’t mean to imply that all or even many cases are intentional. I have however seen clearly intentional misrepresentations of information. The example I was giving was one of them. There were separate categories for increased LFTs, increased SGOT, increased SGPT, increased transaminases, etc. yet they weren’t combined to indicate the total incidence of hepatotoxicity. What was troubling was this was in a pediatric study for a supplemental application and there had already been several deaths due to liver failure in children who had received the drug off label. Plus the drug had caused several deaths due to liver failure in adults during the original development. The information about pediatric safety was presented at an advisory committee meeting however as it was for a supplemental application it didn’t come out in an SBA when the pediatric indication was approved. So if you didn’t attend the AC meeting and pay attention tough.
pharmavet
Agreed. One of my problems with the dictionaries to which you allude is that they don’t easily allow for natural groupings of symptoms that comprise a disease state, as you allude to with hepatotoxicity. For example it would be more instructive to be able to group “cough, fever, and chest pain” into a single diagnosis of “pneumonia” when it is appropriate. Otherwise you have these cases of “chest pain” which alarm the regulators, which would be perfectly explainable if you could just code it as pneumonia. What happens then, in real life, for example, is that six years and three clinical monitors later, you are running around trying to pick up the pieces in trying to explain away all of these cases of “chest pain”.
The above scenario actually happened to me during a study that I ran during a particularly severe winter when there was an outbreak of influenza and post-influenzal pneumonia.
pharmavet
Ex FDAer, do you have a published reference to the Transparency Meetings that you discussed?
Thanks.
pharmavet
Never mind, found it. I agree that if transparency is in the interest of public health in a compelling way then that’s good. However, I don’t see, for example why FDA needs to publish the Complete Response Letter for the 12th heartburn med or the 36th ACE inhibitor when the safety characteristics of these classes are well known. Also publishing CRL’s or even the supporting reasons for them is tantamount to giving your competitors a Mapquest on how to proceed in their own programs, and would therefore directly or indirectly influence the compettive balance. Therte is no need to do that if Public Health is not at stake.
The other reason that I think that transparency will ultimately be limited is that it is in the FDA’s interest to do so. For otherwise, the unintended consequence of transparency will be to open up the agency to second-guessers and armchair quarterbacks of all stripes.
Not publishing all of tyhis minutia would also be a good example with compliance with the Paperwork Reduction Act of 1995.
ex-FDAer
While you make interesting points which have been raised many times before by others. I think that the evidence indicates that they aren’t necessarily valid. Look at the antipsychotics and antidepressants . How many are on the marketor even Avandia. Yet public info recently released by the FDA for the last few drugs approved indicate that there may be class effects as well as effects with the latest drugs that may not have been appreciated previously or that may be significantly worse. As for giving a roadmap to competitors that isn’t necessarily bad if it provides them with information to address safety issues early or that leads them to drop compounds that are significantly more dangerous with regards to class effects especially if there are numerous alternatives already available. Or even if it provides an incentive to perform studies whereby they can document a new treatment as safer. As for public health well you can’t know unless the information is published in the first place otherwise it’s just buying into someone else’s claims to trust them. (Remember Bernie Madoff.) As for second guessers and armchair quarterbacks there will always be some but in general most people are not going to go through 1000’s of pages of scientific documents or have the expertise to critique them effectively, and even if they do unless they can get a large credible organization to review their materials and get behind them, such as Public Citizen or Consumer’s Reports they’re not going to get any traction. In fact I can point to examples where transparency has been a total bust even though the released documents reveal major problems.
I doubt that publishing information already collected, analyzed, collated and published internally by the FDA comes under the paperwork reduction act for where does it require any new paperwork by citizens?