Posted on Saturday 25 February 2017
In lieu of flowers, Mickey’s family would appreciate it if you would donate to these groups:
- Foundation for Integrity and Responsibility in Medicine – 16 Cutler St, Suite 104, Warren RI 02885
In lieu of flowers, Mickey’s family would appreciate it if you would donate to these groups:
You are all invited to share your memories of my father and his work. I have created a site for such purposes.
Dad died just before midnight last night. Every end-of-life choice made was his, and knowing that gives Mom, Caitlin, and I a lot of peace. The only sadness (not really a regret, since we did all we could to make this happen), was that Dad could not make it back home to die. He was just too sick.
Because Dad was on a trach, he could not speak in the last days of his life, and his hands were too swollen and weak to be able to type. Despite those limitations, we worked out how to communicate surprisingly well. I let Dad know that I would like to turn his blog into a book. He really liked that idea. Given the size of his blog and the amount of quoted information included herein, this will not be a quick project, but it is one to which I am committed. I have already begun to make inquiries. I told Dad that Barney Carroll seemed to me to be a good person to consult with about this project, and he wholeheartedly agreed. I may post here from time to time as I work on this project. I really want to honor him and serve this community to the best of my ability.
You have meant so very much to my Dad. He’s had this whole new career as a retiree, and I thank all of you for that. I know he’s really made a difference in the field, and I am so proud of him. I am the admin for this blog, so if anyone has a burning need to post something here, please let me know, and I can post it as a main topic with the title “Guest Post: John Doe.”
There will be a large memorial gathering in Atlanta soonish. It won’t be immediate because Dad is so beloved by so many people that we expect a large crowd. We would love to have some of you in that crowd if you are able. This is probably several weeks out, but keep that in mind. We want you to know that you are welcome.
Dad was recently working on a Change.org petition. One favor you could do for him and for us is to read and sign it. I have a feeling you will all love it, and Barney says Dad created the graphic of the two ostriches with their heads in the sand.
So much love to all of you. Abby
Abby here. I’m Mickey’s daughter and luckily, I am Dad’s admin, so I’m able to log in and post. My husband and I traveled to Georgia Wednesday afternoon because my father has been admitted to the ICU. He has severe pneumonia, COPD, and renal failure. Yesterday he was intubated and sedated and he remains in that condition. It’s taken me about 36 hours to realize that we haven’t yet contacted the people with whom he communicates the most! There aren’t many updates to give since right now, their primary aim is to treat this pneumonia so he’s sedated (and luckily, stable). I’m willing to take the risk of him being very annoyed with me for “outing” him in this way since I know you all are so engaged with him and will begin to wonder why your very chatty friend has suddenly gone quiet. Dad doesn’t ever like to be special, but as you all have probably worked out by now, he’s pretty amazing. And right now, he’s pretty sick. I can say he’s in very good hands. Mom and I are very impressed with the staff at the hospital.
This will probably embarrass him (frankly, I don’t care), but here’s a photo I took of him a few years ago. Feel free to share your thoughts in the comments. Mom and I will check them later today. Doctors make rounds in the ER between 10 and 12, so we may know more later today.
REGULATORY AFFAIRS PROFESSIONALS SOCIETYBy Zachary Brennan31 January 2017
In a sign of what’s to come for the US Food and Drug Administration [FDA], President Donald Trump told pharmaceutical company CEOs Tuesday that his administration will be “cutting regulations at a level no one has ever seen before.” The comments, which came before the meeting with CEOs from industry group PhRMA, Merck, Novartis, Johnson & Johnson, Celgene and others, Trump said in terms of the drug approval process: “We’re also going to be streamlining the process, so that from your standpoint, when you have a drug you can actually get it approved, instead of waiting for many, many years."
He also called for significantly lower drug prices and again for better negotiations on drug prices between Medicare and companies. “We’re going to get the approval process much faster,” he repeated, noting that “one thing that’s always disturbed me is that you come up with a new drug for a patient that’s terminal and FDA says you can’t have this drug used on this patient and patient will be dead… we don’t know if drug works or doesn’t work, but the patient’s not going to live for more than 4 weeks.”
The comments on terminal patients seemed to be a reference to what FDA calls compassionate use or expanded access, and as FDA has sped up that process, experts have noted that the difficulty for many of these terminal patients, who have either run out of treatment options or didn’t have any to begin with, is not getting FDA to sign-off on the use of an investigational drug [FDA approves more than 99% of all expanded access requests it receives] but in getting the companies running the clinical trials to allow new patients to enter trials.
“Instead of it being 9,000 pages, it’ll be 100 pages,” Trump said, perhaps in reference to FDA’s rulemakings, guidance and other regulations. He also offered a one-liner about companies not getting their products or their manufacturing plants approved in the US that drew laughter from the group. Between 75% and 80% of all FDA regulations will be eliminated, he added, before commenting on a lack of foreign regulations without any specifics. “It’s very unfair what other countries are doing to us, a lot of that has to do with regulation,” Trump said. “Other countries have no regulation and you go there for that reason.”But as others have noted, no matter where a drug is manufactured, companies have to follow US laws and regulations in order for that drug to enter the US market, which is still the biggest market for pharmaceuticals in the world. As far as his choice for FDA commissioner, Trump said an announcement is coming soon. PhRMA CEO Stephen Ubl called the meeting positive and productive and said Trump’s agenda on taxes, trade and regulation could create 350,000 US jobs over 10 years for the biopharmaceutical industry.
I don’t much like questionnaires. But if required, I prefer yes/no or one word answer questions. And I’ve never designed a questionnaire [before today]. But as I was thinking about post-approval monitoring, I decided I’d give it a shot. I was thinking about what information you might gather post approval in help seeking patients taking the drug. You wouldn’t much care about controls, or statistical medicinal properties. You’d want to know what a clinician would want to know – is it helping? any problems? And how would one gather such information?
There are two points of contact – the drug store and the office/clinic. The pharmaceutical companies have had success with the former. Their drug reps know what doctors are prescribing to inform their sales calls. If a patient filled out a brief questionnaire at the drug store, I think they’d have to give consent to have that information passed on if it were by patient. I don’t know if that would apply by drug alone. But how long the patient took the medication has traditionally been an useful parameter to consider.
"What about the waiting room questionnaires? I’d much rather they ask about the medications the patient is on than being used to screen for depression. It’s really the ongoing data after a drug is in use that clinicians need anyway – more important than the RCT that gets things started…"
I’ll be the first to admit that I’ve been pretty muddled these last several months – since, oh say, around 10:00 PM on November 8th, 2016 to be more precise. I’ve tried out any number of defense mechanisms to tell myself that I’m doing just fine. But to be honest, this election sort of took the wind out of my sails and I expect others of you might have experienced something similar. So I’m now sure that fine isn’t the best word to describe how I’m doing with all of this. I’ve got nothing to say about the election that you haven’t already thought yourself, except to re-emphasize that neither denial nor rationalization are much help on either side of this coin.
I was on an international team that applied for and analyzed an RCT from 2001 [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence]. It was a herculean task – rewarding, but labor intensive and often frustrating [see https://study329.org/]. While I learned a lot, there aren’t going to be too many such studies in its current form because it requires so much effort, time, and expertise. And so full Data Transparency [which I’ve supported on this blog] is a solution for special cases, but not everyday use. It would be infinitely easier if the data were in the public domain, not captive in the remote desktop interface and subject to so many restrictions, but the pharmaceutical companies have buried their heels deep into the pavement. They’re going to any length to hold onto it.
There’s something else. These short term RCTs are done for New Drug Approvals [NDAs] or New Indication Approvals, and that may be fine for that kind of initial testing – maybe the only real way to bring off the FDA’s opener. But like the case of the SSRIs or the COX-2 inhibitors [Vioxx®, Celebrex®], people might take these drugs for months, or even years, rather than just a few weeks. And that’s what got me to thinking about the "prototypical nerd," Linus Tolvold [here’s Linus…]. He didn’t set out to challenge the commercial monopoly, but challenge it he did. And the reason I say it will ultimately come out on top is that the development of Linux is driven by the science of computing, not the profits of the enterprise.
When Dr. Bernard Carroll comments here, he often uses the term "hand waving" when describing some of the tricky maneuvers used in the clinical trial reports to smooth over shaky logic or rationalize absurdities. It’s a great term, I think originating in the world of stage magicians who use exaggerated gesticulations to distract your attention. My wife’s a figure skating fan, and there it’s called "hand dancing" – dramatic arm and hand gestures to cover up sloppy skating. After reading so many jury-rigged clinical trial reports, I’ve almost come to see the whole narrative as organized around a verbal version of these attempts at artifice, and find myself jotting down the essential pieces in a hastily sketched table on the back of a nearby envelope or piece of scrap-paper. So the basic efficacy table isn’t just a concept or a proposal. It’s an outgrowth of my experience. I guess the formula goes:
article narrative – bullshit = basic efficacy table
One thing the ghost-writers seem to count on is that most doctors look at the abstract, scan the graphs and tables, and move on. I used to see that as virtue – getting through so much material on a regular basis. In my doctor youth, I could do that. But no longer. If a Clinical Trial report or a review article is there to be read, it’s there to be read closely, pencil and envelope back at the ready. At least that’s true of the industry funded clinical trials of psychiatric drugs that I find myself reading these days.
When I drew this diagram, it’s not how things are. It’s how I wish they would be. Step one is the approval of the study Protocol by the Institutional Review Board. At that point, by my reckoning, the trial should be registered [on ClinicalTrials.gov]. There’s no reason at all that the Protocol couldn’t be published at that point. It has been written down for the IRB. Why not make it a part of the registration process. That would mean that a bona fide copy of the a priori declarations would be available from the outset.
adapted from Table 1A inby Deborah A. Zarin, Tony Tse, Rebecca J. Williams, and Sarah CarrNew England Journal of Medicine. 2016 375:1998-2004.
|When does information need to be submitted to or posted on ClinicalTrials.gov?|
|Submission: Within 21 days after enrollment of the first trial participant|
|Posting: Generally, within 30 days after submission. For ACTs of unapproved or uncleared devices, no earlier than FDA approval or clearance and not later than 30 days after FDA approval or clearance (i.e., “delayed posting”), unless a responsible party authorizes posting of submitted information prior to FDA approval or clearance|
|Descriptive information about the trial: e.g., brief title, study design, primary outcome measure information, studies an FDA-regulated device product, device product not approved or cleared by the FDA, post prior to FDA approval or clearance, and study completion date|
|Recruitment information: e.g., eligibility criteria, overall recruitment status,|
|Location and contact information: e.g., name of sponsor, facility information|
|Administrative data: e.g., secondary ID, human-subjects protection review board status|
|Results information reporting|
|When does information need to be submitted to or posted on ClinicalTrials.gov?|
|Standard deadline: Within 12 months after the date of final data collection for the prespecified primary outcome measures (primary completion date)|
|Delayed submission with certification: May be delayed for up to 2 additional years (i.e., up to 3 years total after the primary completion date) for trials certified to be undergoing commercial product development for initial FDA marketing approval or clearance or approval or clearance for a new use|
|Submitting partial results: Deadlines are established for submitting results information for a secondary outcome measure or additional adverse information that has not been collected by the primary completion date|
|Extension request: After receiving and reviewing requests, NIH may extend deadlines for “good cause”|
|Posting: Within 30 days after submission|
|Participant flow: Information about the progress of participants through the trial by treatment group, including the number who started and completed the trial|
|Demographic and baseline characteristics: Demographic and baseline characteristics collected by treatment group or comparison group and for the entire population of participants in the trial, including age, sex and gender, race or ethnicity, and other measures that were assessed at baseline and are used in the analysis of the primary outcome measures|
|Outcomes and statistical analyses: Outcomes and statistical analyses for each primary and secondary outcome measure by treatment group or comparison group, including results of scientifically appropriate statistical analyses performed on these outcomes, if any.|
|Adverse event information: Tables of all anticipated and unanticipated serious adverse events and other adverse events that exceed a 5% frequency threshold within any group, including time frame (or specific period over which adverse event information was collected), adverse-event reporting description (if the adverse-event information collected in the clinical trial is collected on the basis of a different definition of adverse event or serious adverse event from that used in the final rule), collection approach (used for adverse events during the study: systematic or nonsystematic), table with the number and frequency of deaths due to any cause by treatment group or comparison group|
|Protocol and statistical analysis: Protocol and statistical analysis plan to be submitted at time of results information reporting (may optionally be submitted earlier)|
|Administrative data: Administrative information, including a point of contact to obtain more information about the posted summary results information|
First off, anything they do is a step forward. They’ve had the machinery available for two decades, and have done little with it. So they’re finally requiring registration for all the studies, and they pledge to keep up with it. An excellent start.
Initial Registration: They say that they want the submission of the trial registration within three weeks of the initial subject’s enrollment and posting on-line within the 30 days after submission. Of course I’d prefer our "before the study starts" timing, but within the first two months will do. The point is to get it registered before they can look at the results and modify the Protocol – and two months is early enough for me. As for what’s to be posted, they don’t require posting the whole Protocol. That’s a disappointment. I’d prefer anchoring the outcome parameter at the beginning. But at least they do require declaration of the Primary Outcome Variables with registration.
Posting the Results: This has traditionally been the most ignored requirement. They say: "Outcomes and statistical analyses for each primary and secondary outcome measure by treatment group or comparison group, including results of scientifically appropriate statistical analyses performed on these outcomes, if any" and add in "Protocol and statistical analysis plan to be submitted at time of results information reporting (may optionally be submitted earlier)." And I say A+! With that information, I could fill out my entire basic efficacy table, The only thing they left out was the Effect Size and there would be ample information to do that calculation.
And for timing on the Results? I’d have to say "barely passing," if that. "Within 12 months after the date of final data collection for the prespecified primary outcome measures (primary completion date)" and "May be delayed for up to 2 additional years (i.e., up to 3 years total after the primary completion date) for trials certified to be undergoing commercial product development for initial FDA marketing approval or clearance or approval or clearance for a new use." That’s a disappointment, and I can’t see any reason for it. The results are just what they are – they’re the results of the prespecified variables analyzed in the prespecified way. Who needs time for that? But I’ll have to admit that if they were to actually to follow these standards, the improvement would still be dramatic, probably satisfy most of us. With new drugs or new indications, they’d still be early in the drug’s patent life.
I don’t know if my musings about the Linux story worked, but what I was trying to talk about was the computer community’s struggles with the secrecy of the commercial developers – a problem similar to ours with Clinical Trials and their sponsors. Watching those computer code struggles happen from the sidelines, things took of when Linux came around and they had a new own platform [operating system]. Linus’s problem with "UI" [user interface] has held them back [see Ted talk – in here’s Linus…], but others are beginning to make it easier to use now. My point was rather than trying to gain access to the systems of others, they came into their own when they had their own system.
For many reasons, I think that something similar is ultimately the only real solution to the problem of industry’s control of drug trial and reportings. RCTs may be appropriate for drug approval purposes, the and FDA usually bases the approval on making the a priori declared primary outcome variables. But they aren’t so appropriate for deciding about actual usage of the drugs, particularly when presented in the journal articles we call experimercials – often distorted by a variety of tricky moves. Medicine is going to have to find some non-commercially driven way to test drugs that will give us reliable ongoing clinical information – our own Open Source platform.
But in the meantime, I’ve been thinking about data transparency – having access to all of the raw data from clinical trials. I certainly think that’s the way it should be. Medicine is almost by definition an open science. The majority of clinical education is apprenticeship, freely given. No secret potions, no wizards allowed. Secret data just doesn’t fit. But the business end of industry isn’t medicine. I frankly doubt that we’ll get access to all the data free and clear any time soon. It’ll probably always long be a fight like it was for us with Paxil Study 329. The marketeers see that data as part of their commodity and hold on to it at any cost. So they’ll stick with their restrictive data sharing meme as long as possible; jump on any legality they can find along the way; play havoc with the EMA’s or anyone else’s data release plan; etc. [and they can afford a lot of havoc!].
So, whether we have access to the raw data or not, we should be able to fill out this Basic Efficacy Table [or something close] for every Clinical Trial. The reasons we can’t are mixed up with non-compliance and non-enforcement, not non-consensus or non-requirenent: