what to do? sign the petition!!!…

Posted on Friday 7 October 2016

Perhaps, rather than talk about what the NIH and FDA propose doing about it, we should frame the problem that needs fixing. Because of the PHARMA Sponsors’ keeping clinical trial data secret [proprietary, intellectual property] and the FDA, the only entity with access, we are only privy to the published journal articles for our information about clinical trials. And it is increasingly apparent that there has been widespread corruption in the public reporting – leaning towards exaggerated efficacy and minimization of harms. While it’s hard to prove because it happens behind closed doors, a common tool of distortion involves outcome switching – changing reported outcome parameters to fit the results. For this and other more scientific reasons, the outcome parameters and methods of analysis must be declared before the trial begins.

If the outcome parameters and methods are clearly declared a priori [in the Registration process on ClinicalTrials.gov] AND the results of these preregistered parameters are posted in the ClinicalTrials.gov RESULTS database as soon as they are available when the trial ends…
  • … the reader can be assured that the outcome parameters weren’t changed based on the data itself [Hypothesis After Results Known – HARK]
  • … then the reader sees the RESULTS of those prespecified variables directly
  • … so there’s no question about the outcome of the trial.
In other words, there is another mechanism beside just the published article available to the reader to evaluate the study. There is no reason that the Protocol and Statistical Analytic Plan can’t be submitted at the time of Registration – it’s at hand as part of the Institutional Review. There’s no reason that the results can’t be posted at the time a trial is submitted to the FDA or to a journal. The results are at hand as part of either kind of submission.

How could we be sure that the a priori declaration of parameters and methods is accurate? Ask the FDA to certify their accuracy. In most cases, they already have the documents as part of an FDA registration. How could we know that the resulrs posted are accurate? Ask the FDA to certify that they match those submitted to the FDA. They are the only agency with access to the data itself, and have evaluated it as part of their approval process.

But that’s not what the NIH/ClinicalTrials.gov/FDA did [see what to do? the final rule?…]. The NIH and ClinicalTrials.gov wrote the final rule, which is essentially what was in place before except they clarified a few ambiguities and promised to enforce it this time around. The FDA was supportive but changed nothing. It’s going to take direct legislation to get changes like the ones suggested above in place – mandated by Congress. Those are the exact changes that are in our petition [Stop False Reporting of Drug Benefits & Harms by Making FDA & NIH Work Together]. Please take a look and sign it. 

It’s time for the NIH/ClinicalTrials.gov/FDA to give clinicians and patients a mechanism to see clinical trial results in their true light, rather than through a haze of marketing hype in distorted journal articles…
Mickey @ 8:00 AM


Posted on Friday 7 October 2016

Mickey @ 7:49 AM

what to do? the final rule?…

Posted on Thursday 6 October 2016

Recently, FDA/NIH/clinicaltrials.gov issued their long awaited reforms with something of a media blitz:
  1. Toward a New Era of Trust and Transparency in Clinical Trials
  2. Trial Reporting in ClinicalTrials.gov — The Final Rule
  3. New federal rules target woeful public reporting of clinical trial results
  4. HHS Issues New Rules To Open Up Data From Clinical Trials
I’m impressed that the N.I.H. and its ClinicalTrials.gov registry under the respective direction of Francis Collins [NIH Director] and Deborah Zarin [ClinicalTrials.gov Director] have done a good job of identifying the problems and clarifying loopholes. Dr. Collins focuses on the government funded studies and Zarin on ClinicalTrials.gov procedures. While I have something to say about their solutions [below], they’ve definitely taken a long look at the sins of the fathers and sent down some credible commandments. However, I can’t say that I was at all reassured by the FDA’s response. If they had a Press Release, I couldn’t find it. It wasn’t mentioned on their FDA blog. Here are the quotes from Robert Califf from the articles above:
  • Federal officials said last year that they wouldn’t penalize offenders before clarifying the reporting rules. Now that this is happening, “I’m expecting a flood of trials to get registered,” FDA Commissioner Robert Califf told reporters during a conference call. “It would be pretty hard to hide that you are doing a clinical trial or hide the result. … I’m very optimistic about this.”
  • Yet not a single researcher or trial sponsor has been fined or penalized, STAT reported — though the Food and Drug Administration had the authority to fine violators more than an aggregate $25 billion since the law went into force in 2008.
  • Neither agency will add such staff, according to Califf, whose agency oversees private sector reporting, and NIH Director Francis Collins, whose agency is responsible for enforcement regarding NIH grant recipients as well as NIH staff scientists.
  • Califf said enforcement instead would be folded into the FDA’s existing bioresearch monitoring program, which collects information related to clinical trials during company inspections.
  • “Typically, when the FDA believes there may be a violation of the law, it sends a warning letter” for voluntary correction, Califf said. He expects this method to handle most problems, and promised that the public will have “a good window of what’s going on” in compliance actions.
  • "This has been a very opaque world up until to now," Food and Drug Commissioner Robert Califf told reporters during an embargoed phone conference Thursday. "These are tremendous changes."
  • For studies that are regulated by the FDA, companies can face fines of $10,000 a day if they don’t comply with the existing rules. Those fines have not been imposed, however, and the FDA will not have additional funding to hire enforcement staff, Califf said. "I really believe that it won’t take much to get people to comply with this once they realize how serious this is."
And I wasn’t in love with this one either:
  • Both agencies will automate compliance checks to ensure trials are properly registered and results reported, and contact institutions as needed to provide all the data required to bring their trials into compliance with the law.
And that was all I could find from the FDA. I would cop to a  charge of over-reading Califf’s comments, in a New York minute, but it’s even worrisome to me that that’s all I can find to read. Best I can tell, the FDA action will be to piggy-back onto some automated NIH/ClinicalTrials.gov automate[d] compliance check[er]. Otherwise, I hear "don’t worry, they will take care of it." And, by the way, it’s the private sector that needs the over·seeing ["according to Califf, whose agency oversees private sector reporting, and NIH Director Francis Collins, whose agency is responsible for enforcement regarding NIH grant recipients"]. So I’m filing the FDA’s response under "wary" cross-referenced with "uh-oh!" This is how reform begins its decline to the state we’re in already.

And in spite of being impressed that the NIH/ClinicalTrials.gov final rule shows signs of some real effort and investigation, I question their solutions. There are two points in the life cycle of a clinical trial where data is entered into ClinicalTrials.gov – Registration and Results:

Here’s a shortened version of what the final rule has to offer:
  • Registration [the final rule]:
    when – "Submission: Within 21 days after enrollment of the first trial participant. Posting: Generally, within 30 days after submission…"
    what – "Descriptive information about the trial: e.g., brief title, study design, primary outcome measure information…"
  • Results [the final rule]:
    when -"Submission: Standard deadline: Within 12 months after the date of final data collection for the prespecified primary outcome measures (primary completion date)…"
    what – "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"
I consider myself a reasonably well-informed consumer, and I’m disappointed for the following reasons:
  • Registration: Preregistration of the Primary and Secondary Outcome Parameters and the Methods by which they will be analyzed is an essential ingredient of a scientifically conducted clinical trial. Changing outcomes after the study is underway has been a major method used to deceitfully jury-rig the results [see ]. Ergo any effective reform must insure that a certified copy of that a priori Protocol and Statistical Analysis Plan is filed before the trial begins. Filing those things with the Results in case there are amendments is also fine, but does nothing to reassure us that these variables haven’t been changed. These documents have just been used in the submission to the Institutional Review Board, so they are at hand. Why not file them with the registration and post them on the public face sheet on ClinicalTrials.gov? To do otherwise is to start off with a huge loophole that has been chronically exploited.
  • Results: While the Sponsors [PHARMA] have succeeded in holding on to their claima of keeping the raw data proprietary [secret], they have no such claim on the results. After all, it’s what they themselves publish in the journal articles they generate. The Results Database on ClinicalTrials.gov should have the results of the predefined Primary and Secondary Outcome Parameters clearly labeled. Any other Outcomes should be labeled ‘exploratory’ or ‘non-Protocol’. In addition, since they have already been calculated for submission, there’s no reason to delay posting them. Posting results at the time of submission to the FDA is essential. Why? So Journal editors, peer reviewers, you and me can see them. And the whole point of this enterprise is to deal with the widespread corruption in the reporting of clinical trials in our literature!
It would be the height of comedy to expect anyone to take the word of the PHARMA Sponsors that late-filed Protocol declarations are accurate or that the belated Results filings were the same as those reported to the FDA. The mis-reporting and non-reporting have been too ubiquitous and too destructive for that. So these filings need to be checked and certified, best done by the FDA who is the responsible and accountable agency in this case. It’s time to evoke evidence-based medicine’s real meaning – evidence in the legal sense. Stay tuned…
Mickey @ 12:33 PM


Posted on Thursday 6 October 2016

Tracking Hurricanes is something of a spectator sport around here, even though we’re mostly bulletproof in North Georgia. But in a lifetime of Hurricane watching, I’ve never seen a prediction like this one – Here we go loop-de-loop…

Mickey @ 10:04 AM

eva cassidy [~1996]…

Posted on Wednesday 5 October 2016

Mickey @ 2:00 PM

what to do? what to do?…

Posted on Tuesday 4 October 2016

I was reading Law Professor Marc Rodwin‘s exploration of the issues involved in taking drug testing out of the hands of PHARMA. That isn’t my topic [at least not quite yet], but I thought he had a very nice summary of the history bringing us into the current era, so I added that piece to this post with his TABLE I [which is what I wanted to talk about]…
by Marc A. Rodwin
Journal of Health Care Law & Policy. 2015 18:45-84.


A. The Origins of Contemporary Pharmaceutical Regulation

Before examining the oversight of clinical trials, let us briefly review the evolution of the pharmaceutical industry over the last century. In the beginning of the twentieth century, the drug market was premised on the doctrine of laissez-faire. Manufacturers did not have to test their drugs or disclose the ingredients, could make any therapeutic claim, and could sell any product directly to consumers.

Reformers and muckrakers—supported by the American Medical Association [“AMA”]—spearheaded the fight for federal drug regulations. In 1906. Congress passed the Pure Food and Drug Act, which required manufacturers to disclose therapeutic ingredients on the drug label, and prohibited the sale of adulterated, misbranded, or deleterious products. The law presumed that, with accurate labeling, individuals could safely choose drugs. Advertising of therapeutic claims remained unregulated until the Shirley amendments in 1912 prohibited false and fraudulent statements regarding the curative or therapeutic effect of drugs."

Industry opposition blocked enactment of the Roosevelt administration’s 1933 bill to regulate drugs until a scandal in 1937. In order to improve the flavor of a sulfa-based drug called sulfanilamide, the Massengill Company added a chemical that was toxic, causing the rapid death of 106 people who had ingested the drug. Congress then passed the Food. Drug, and Cosmetic Act of 1938 [“FDCA”]. which required drug firms to seek FDA permission to market drugs, and which allowed the FDA 60 days to deny authorization if it found that the drug was dangerous or improperly labeled.

Manufacturers then had incentives to conduct research and to evaluate their products. The marketing of Thalidomide led to the birth of children with severe deformations in multiple countries, and created pressure for stronger regulation. The 1962 amendments to the FDCA prohibited marketing of drugs unless the FDA granted approval, and the amendments removed the 60 day deadline for FDA review of new drugs. The amendments required drug sponsors to demonstrate that drugs are effective—not only safe—for a designated use. It also authorizes the FDA to withdraw its approval for drugs already on the market based on new evidence. Manufacturers are required to track drug distribution to facilitate recalls of unsafe products, and to follow FDA standards for good manufacturing practices. The law restricts promotion of drugs to therapeutic uses approved by the FDA. Promotional materials must note risks, as well as benefits, and summarize side effects and contraindications. The FDA specifies what information the label must include, and labels must state the generic name, as well as the brand name.

In 1970, the FDA promulgated regulations that set standards for the evidence that manufacturers would have to submit in order to demonstrate that new drugs were safe and effective. Since then, testing of drugs follow set stages. After researchers have identified a potentially therapeutic molecule, they test its effects in laboratories on chemicals, cells, or tissues. The FDA then requires firms to test its drugs for toxicity on animals. Drug candidates that have not been ruled out due to toxicity or lack of efficacy can then be tested on humans in three phases. In Phase I. researchers test the drug on a small number of human subjects only to determine whether it is toxic in humans, and if so, at what doses. Phase II testing consists of a clinical trial in a larger group of patients in order to measure its benefits and risks. Drugs that are not highly toxic are tested in Phase III clinical trials on a large number of human research subjects, and researchers then compare its effect with a control group. Typically, the control group uses a placebo or an alternative therapy. Human subjects are randomly assigned to either the test group or the control group. It is a double blind study, which means that the medication must be coded so that neither the physician who administers the drug, nor the individual taking the drug, knows which individuals receive the test drug and which individuals receive the placebo [or the standard therapy to which it is compared] until the code is broken after collection of data. To counter the risk of fraud or unreliable studies, regulations establish standards for research methods, record keeping, and data reporting. The FDA also inspects toxicological laboratories and facilities that conduct clinical trials in order to monitor compliance.

B. Options for Control of Clinical Trials

There are six options for addressing conflicts of interest in clinical trials, which are displayed in Table 1 below. At one extreme, the drug sponsor has complete control over clinical trials; at the other extreme, the federal government conducts the clinical trials. Between these two poles are four strategies that can be used individually or combined. The FDA relies mainly on the second strategy, which has been supplemented in recent years by the fourth strategy…

As appalled as I’ve been by the corrupt clinical trial reporting that contaminates our medical literature particularly in my specialty of psychiatry, I’ll have to add that when I’ve been able to look at the FDA medical and statistical reviews, I’ve thought that they were pretty thorough and honest appraisals. I hasten to add that they’re voluminous, hard to read, and regularly quite late in coming to Drugs@FDA. The thing I’ve liked best is that they’ve consistently stuck to what I consider the fundamental rule – the results that matter are the outcomes declared before the study started – a priori. And the thing about Rodwin’s article I liked best is that he assumes that the PHARMA COI is just a given – a fact of life that will never go away – in everyday parlance, "Give them an inch, and they’ll take a mile." He begins his paper with:
Drug manufacturers face a fundamental conflict of interest. Pursuit of profit compromises drug manufacturers" impartial assessment of the risks and benefit of their drugs. Their biased evaluation can corrupt public knowledge of drugs, lead to marketing unsafe and/or ineffective drugs, and undermine rational physician prescribing. Over the last century, federal regulation has mitigated, but not eliminated, this problem…
In my mind, it resonates with the point made by Alastair Matheson in his articles [How Industry Uses the ICMJE Guidelines to Manipulate Authorship – And How they Should be Revised, Ghostwriting: the importance of definition and its place in contemporary drug marketing, The Disposable Author: How Pharmaceutical Marketing Is Embraced within Medicine’s Scholarly Literature]. To [perhaps overly] pharaphrase Matheson, of course PHARMA is driven by profit, not medical ethics – the point is to look at the whole system and see what the other players are getting out of abrogating their medical/ethical responsibilities to counteract rampant corporate greed.

Right now, we’re operating in what Rodwin calls "the fourth strategy" – regulation. And it hasn’t gone so very well. At least in psychiatry, we’ve had 25 years of grossly exaggerated indications, efficacy reports, and safety claims. And even now that these medications’ failings are more publicly known, mental health care policy is still being formulated with these meds as the central strategy [eg collaborative care], metastacizing into the domain of primary care – a particularly shaky idea in my [and many other’s] opinion.

What to do? What to do? Should we move towards Rodwin’s "fifth strategy" [Government selects independent entities to conduct clinical trials]? or even his "sixth strategy" [Government agency conducts clinical trials]? Or should we keep slugging away at federal regulation? I’ll try to synopsize the rest of Rowin’s article at some future point, but for the moment, I want to stay with the idea that we’re in a time of regulatory failure rather than a time to take the jump into a government takover over as in the "fifth" or "sixth" strategies…
Mickey @ 2:42 PM

the petition – NETWORKthe movie version…

Posted on Friday 30 September 2016

I’ve heard from several people that they’re not sure exactly what we’re asking Congress to do. Our narrative is long because it coveres many bases. Here’s the short version. We want Congress to mandate that the FDA talk to us directly through clinicaltrials.gov about the clinical trials of FDA regulated drugs. The drug and device manufacturers have created a whole fabulist industry that fills our journals with articles about clinical trials that are often/usually inaccurate and used as marketing tools. Meanwhile the FDA, the only kid on the block that can actually see the data in the raw, watches all of this happening but does nothing. The public interface designed to give us an alternative to these journal articles, the NIH’s clinicaltrials.gov, has withered from disuse atrophy because nobody populates it on time [if at all] or checks up on it.

We’re proposing that Congress give us an alternative to the jury-rigged articles published by industry in our journals. All the pieces to create that alternative system are already in existence. The NIH’s clinicaltrials.gov is a well designed system for telling us what we need to know. The FDA has access to all of the information about the clinical trials on FDA regulated drugs, submitted in applications for approval. If it’s not all there, they can suspend action until they get it. So we are asking Congress to make the NIH clinicaltrials.gov the official interface between the FDA and the physicians/patients who need to know about these clinical trials.

Clinical Trials reduce down to a simple process:
  • Create a Protocol that  defines the target population, the intervention(s) to be tested, and define the PRIMARY and SECONDARY OUTCOME  PARAMETERS and how they will be analyzed BEFORE the study begins.
  • Then do the study.
  • Perform the a priori defined analyses on the a priori defined PRIMARY and SECONDARY OUTCOME PARAMETERS [a priori means BEFORE anyone gives the first subject the first pill].
  • Display the RESULTS.
That’s what the FDA does and that’s what we all need to see. Our proposal asks Congress to mandate that the FDA actively provide that information to us all along the way through the NIH interface clinicaltrials.gov.

We want the FDA to actively check that the original REGISTRATION on clinicaltrials.gov is filed before the study starts, that the PRIMARY and SECONDARY OUTCOME PARAMETERS and how they will be analyzed are clearly specified, and that the version on clinicaltrials.gov is the same as the version filed with the FDA [NDA and PMA trials]. We want the FDA to post a notice on clinicaltrials.gov that this has been done.

We want the same thing with the RESULTS. We want the FDA to actively check that the results are posted on clinicaltrials.gov for every trial submitted to the FDA at the time of submission. We want the FDA to insure that those results on clinicaltrials.gov are the same as those in the FDA analysis [the a priori defined analysis of the a priori defined the PRIMARY and SECONDARY OUTCOME PARAMETERS]. We want the FDA to post a notice on clinicaltrials.gov that this has been done.

The sponsors of these clinical trials have so far succeeded in their bizarre claim that the clinical trial data is proprietary. But they can’t claim that that’s true of their version of the results. These are FDA regulated drugs and those results are part of the regulatory process. While the FDA has no jurisdiction over journal articles, if the articles misrepresent the FDA certified results or include other parameters or analyses without clearly annotating them as non-protocol results, the FDA should have the injunction to act [false advertising].

There’s more, but that’s enough. You get the drift. If the sponsors of these trials and the journals they publish in can’t give us accurate scientific reports on these crucial clinical trials, we are petitionong Congress to mandate that the FDA provide  it to us – by law. Like many of you, we’re as…

… mad as hell and we’re not going to take it anymore!

Mickey @ 2:20 PM

please sign the petition!…

Posted on Thursday 29 September 2016

[see also  clinical trials – an act of congress!…]

In the course of a Clinical Trial on an FDA regulated drug, the Sponsor submits information to three distinct entities – each with a different purpose:
  1. NIH [clinicaltrials.gov]: …clinicaltrials.gov is intended to be the public interface for the clinical trial, The first submission [registration] describes the trial and lays out how it is to be conducted and should be submitted after the study has been approved by the Institutional Review Board and before the study begins. It is a proxy for the a priori Protocol identifying the Primary and Secondary Outcome Variables and how they will be analyzed – a basic element of the RCT process. At the end of the clinical trial proper with the breaking of the blind, there is a second submission to clinicaltrials.gov [results database] giving the results of the analysis of the Primary and Secondary Outcome Variables. clinicaltrials.gov hasn’t had the desired impact, not because it wasn’t a good idea or well designed. People just ignored it. Trials have not been registered prior to starting the study. The results database has rarely been populated on time, if at all. The only consequence for ignoring it, even when it’s required by law, is being listed in one of many articles documenting that it’s being ignored.
  2. FDA: …The Sponsor’s submissions to the FDA re formal requests for a New Drug Approval, an approval for a new indication, an application for the pediatric extension of Exclusivity. Those submissions include the results of multiple trials [see Evidence of Clinical Effectiveness and Data Requirements For an NDA]. The Sponsor’s FDA Submission is not publicly available and the results of the FDA’s analyses are not published promptly – added much later for selected studies on Drugs@FDA. Those not posted can be requested via an FOIA request. The FDA’s decisions are yes/no and what’s published are the mutually negotiated package inserts whicg are collected yearly in the PDR [Physician’s Desk Reference].
  3. Medical Journal: …articles in peer reviewed academic medical journals have been the traditional source of physicians for medical information for well over a century. Academic Medical Journals are independent and self-regulated. In the case of these clinical trial reports, the only information the editors and peer reviewers have is what’s submiited by the trial sponsor. No one these days think that the data was analyzed or the paper was written by the academic authors on the by-line. The analysis was done by the sponsor and the paper written by a professional medical writer from a prepared summary provided by the sponsor. The listed non-industry authors are involved in that to a greater or lesser extent. Over time, the purpose of the publications has essentially become a powerful advertising tool for marketing the drug – often inflating efficacy and minimizing harms.
So in spite of the fact that there should be four versions of the data results for a clinical trial, from where we sit, there’s only one. The clinicaltrials.gov version is usually empty. The IPD [Individual participant data] and the CRFs [Clinical Report Forms] are locked away in the sponsor’s filing cabinet/computer. The only other access is through the FDA who is sworn to secrecy. And so all we can see is the published article. Not even the ghost-writers, the listed academic authors, the journal editors, or the peer reviewers have access to the actual data and unfiltered results in the study.
Notice the bifurcation in the pathways followed for the FDA Submission and the Article Submission. Add in the fact that both clinicaltrials.gov submissions are either misused or ignored. So while we appreciate the recent initiatives by the NIH and the FDA to do something about all of this, what they propose is not enough! In the current system in the graphic above or the system as proposed by their initiative, the only entity with eyes-on access to the raw data [the FDA] surveys neither the information on clinicaltrials.gov nor that published in journal article for accuracy.

So that’s why we’re urging you to sign our petition for Congressional action mandating that the FDA and NIH take an active role and use these already-in-place tools to put some teeth into ending the scientific disgrace of our clinical trial reporting! That’s what these agencies are for!

[click the ostriches to see and or sign the petition]

Mickey @ 5:00 PM

clinical trials – an act of congress!…

Posted on Thursday 29 September 2016

My posts last week were meant to be a prequel to this one. In clinicaltrials.gov revisited… and drugs@FDA visited…, I tried to present a simple outline of the two agency online windows into the world of clinical trials for anyone who hasn’t already explored them. And in clinical trials visited again… and clinical trials – concordance…, I wanted to frame the giant loophole in our system of evaluating clinical trial data. Those posts were in anticipation of my being part of an initiative that I think might really help us get something done about finally plugging the loophole.

Back in May, in commenting here on why is that?…, Dr. Bernard Carroll had a spark of an idea about something that could lead us out of the morass of confusion and corruption that surrounds the industry-funded clinical trial reports that contaminate our literature and medical practices. In June, he expanded that initial comment into a blog post on Healthcare Renewal [see CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL]. Over the summer, there’s been a lot of back and forth on this proposal and I’m grateful to be a part of the group that’s formed around deciding how to proceed. Also included in the group are John H. Noble Jr., a noted academic and longtime advocate for honesty in science and clinical trials, and Shannon Brownlee, well-known author, activist, and journalist, now with the Lown Institute and its Right Care Movement. Working through the Lown Institute, today we are launching a petition on Change.org designed to get this gaping loophole in government oversight and  the proposed solution into the place where it belongs, the United States Congress. Let me repeat that:


[click the ostriches to see and or sign the petition]

The full text of our petition is long and detailed. This snippet has its essence:
"A Specific Proposal
We now petition Congress to require the FDA and NIH to coordinate their monitoring and sharing of key information through ClinicalTrials.gov. Working together, the two agencies could enable stakeholders to verify whether purported scientific claims are faithful to the a priori protocols and plans of analysis originally registered with the FDA. Publication of analyses for which such fidelity cannot be verified shall be prohibited unless the deviations are positively identified (as in openly declared unplanned, secondary analyses). This prohibition shall include scientific claims for on-label or off-label uses made in medical journals, archival conference abstracts, continuing education materials, brochures distributed by sales representatives, direct-to-consumer advertising, and press releases issued by companies or their academic partners. It shall extend to FDA Phase 2, Phase 3, and Phase 4 clinical trials. By acting on this petition, Congress will create a mechanism for stakeholders independently to verify whether inferences about clinical use suggested by the unregulated corporate statistical analyses can be trusted."
But please read over the whole document. It has a lot of sweat equity in the details.

Even though petitioning Congress may seem like a long shot, this is the right time to take it. There is a general outrage at the behavior of the pharmaceutical industry over disreputable practices including clinical trials. The FDA, NIH, and clinicaltrials.gov just last week released their own planned reforms [see a blast off…]. And while they didn’t plug the giant loophole, their reforms will help [and they telegraph a willingness to go after a solution]. But as I said in clinical trials visited again…:

No reform of the clinical trials system will work if any part of it relies on either ethical or voluntary compliance. The stakes are just too high. Clear legalistic rules with surveillance and predefined consequences are essential requirements.

If our experience with previous reform efforts [particularly clinicaltrials.gov] has taught us anything, it’s that we need a mandate from Congress, the law of the land, behind any moves forward. An Act of Congress. And this petition is a first step in that direction.

So please read our petition over and sign it if you agree. If you’ve got a blog or are on a listserve or email chain, pass it on. We’re going to need a lot of signatures to push for a Congressional Hearing…
Mickey @ 12:00 PM

study 329 – something new…

Posted on Wednesday 28 September 2016

Well our second Paxil Study 329 paper was published at the end of last week. I waited to mention it here until David Healy had a post about it – out today [see Study 329 Continuation Phase]. We originally submitted it to the Journal of the American Academy of Child and Adolescent Psychiatry who turned it down [their peer review comments are on our website Restoring Study 329 – interesting in their own right]. I think what I’ll do is show a couple of graphs from that data, then reverse my usual m.o. by talking about it first and ending with the abstract:

Paxil Study 329 had a Continuation Phase where they followed the responders only, blinded on the same meds for six months. In the a priori Protocol, it was a Secondary Outcome Variable hoping to measure the relapse rate. They didn’t mention it in Keller et al. I think they must’ve looked at that upper graph of the drop-out rate and shied away from the Continuation Phase altogether. The lower graph has the Raw HAM-D scores and, as expected, they showed no differences. But we never said that this was a badly designed study. To the contrary, it’s better than most and this six month follow-up data is about the only longer term SSRI dataset around, certainly in kids – so we decided to take a look.

In our original RIAT paper [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence], we wanted to analyze the data as it should have been analyzed in the first place – according to the a priori Protocol [see faith-based medicine…]. We were able to do that with the efficacy data. We couldn’t exactly do that with the safety analysis. For one thing, the Protocol didn’t specify a system. And for the other, the system used by Keller et al obscured suicidality. So we used a more modern, more appropriate system. But even with that change, we remained in the Hypothesis Testing mode. However, with this Continuation Phase, from my point of view we were doing something else – called Material-Exploration by Adrianne de Groot in his 1956 classic [The Meaning of “Significance” for Different Types of Research] [see also the hope diamond…]:
Hypothesis Testing Research vs Material-Exploration

Scientific research and reasoning continually pass through the phases of the well-known empirical-scientific cycle of thought: observation – induction – deduction – testing [observe – guess – predict – check]. The use of statistical tests is of course first and foremost suited for “testing”, i.e., the fourth phase. In this phase one assesses whether certain consequences [predictions], derived from one or more precisely postulated hypotheses, come to pass. It is essential that these hypotheses have been precisely formulated and that the details of the testing procedure [which should be as objective as possible] have been registered in advance. This style of research, characteristic for the [third and] fourth phase of the cycle, we call hypothesis testing research.

This should be distinguished from a different type of research, which is common especially in [Dutch] psychology and which sometimes also uses statistical tests, namely material-exploration. Although assumptions and hypotheses, or at least expectations about the associations that may be present in the data, play a role here as well, the material has not been obtained specifically and has not been processed specifically as concerns the testing of one or more hypotheses that have been precisely postulated in advance. Instead, the attitude of the researcher is: “This is interesting material; let us see what we can find.” With this attitude one tries to trace associations [e.g., validities]; possible differences between subgroups, and the like. The general intention, i.e. the research topic, was probably determined beforehand, but applicable processing steps are in many respects subject to ad hoc decisions. Perhaps qualitative data are judged, categorized, coded, and perhaps scaled; differences between classes are decided upon “as suitable as possible”; perhaps different scoring methods are tried along-side each other; and also the selection of the associations that are researched and tested for significance happens partly ad-hoc, depending on whether “something appears to be there”, connected to the interpretation or extension of data that have already been processed.

When we pit the two types so sharply against each other it is not difficult to see that the second type has a character completely different from the first: it does not so much serve the testing of hypotheses as it serves hypothesis-generation, perhaps theory-generation — or perhaps only the interpretation of the available material itself…
If you only take one thing away from this entire 1boringoldman blog, let this be it. What’s been wrong with the clinical trial literature is that the papers are written as if they are some kind of anything-goes, free-wheeling, Material Explorations with changing outcomes, creative statistics, and speculations-presented-as-facts. That’s dead wrong. They are Hypothesis Testing enterprises that require every bit of the rigor and attention to protocol described by de Groot. Product Testing exercises, not Exploratory Research! Hypothesis Testing not Material-Exploration! …End of Sermon…

Now back to our Paxil  Study 329 Continuation Phase paper. I’m not even going to try to summarize it because fellow author David Healy has done such a good job in Study 329 Continuation Phase. He and Jo Le Noury have a collective knack for looking at adverse event data. We did find some things after all, in spite of the drop-out rate – primarily by looking closely at the timing and various states of medication use. So look over the paper and be sure to read David’s posts, the one today and the one coming next week, for the details of what we found. Some pretty interesting Material Explorations in my book. Here’s another graphic and the abstract:

by Le Noury, Joanna; Nardo, John M; Healy, David; Jureidini, Jon; Raven, Melissa; Tufanaru, Catalin; and Abi-Jaoude, Elia.
International Journal of Risk & Safety in Medicine. 2016 28[3]:143-161.

OBJECTIVE: This is an analysis of the unpublished continuation phase of Study 329, the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The objectives of the continuation phase were to assess safety and relapse rates in the longer term. The objective of this publication, under the Restoring Invisible and Abandoned Trials [RIAT] initiative, was to see whether access to and analysis of the previously unpublished dataset from the continuation phase of this randomized controlled trial would have clinically relevant implications for evidence-based medicine.
METHODS: The study was an eight-week double-blind randomized placebo-controlled trial with a six month continuation phase. The setting was 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. 275 adolescents with major depression were originally enrolled in Study 329, with 190 completing the eight-week acute phase. Of these, 119 patients [43%] entered the six-month continuation phase [paroxetine n=49; imipramine n=39; placebo n=31], in which participants were continued on their current treatment, blinded. As per the protocol, we have looked at rates of relapse [based on Hamilton Depression Scale scores] across both acute and continuation phases, and generated a safety profile for paroxetine and imipramine compared with placebo for up to six months. ANOVA testing [generalized linear model] using a model including effects of site, treatment and site x treatment interaction was applied. Otherwise we used only descriptive statistics.
RESULTS: Of patients entering the continuation phase, 15 of 49 for paroxetine [31%], 12 of 39 for imipramine [31%] and 12 of 31 for placebo [39%] completed as responders. Across the study, 25 patients on paroxetine relapsed [41% of those showing an initial response], 15 on imipramine [26%], and 10 on placebo [21%]. In the continuation and taper phases combined there were 211 adverse events in the paroxetine group, 147 on imipramine and 100 on placebo. The taper phase had a higher proportion of severe adverse events per week of exposure than the acute phase, with the continuation phase having the fewest events.
CONCLUSIONS: The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.
Mickey @ 11:22 PM