1 Boring Old Man

Clinical trial registration, reporting, publication and FDAAA compliance:

a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012

by Jennifer E Miller, David Korn, and Joseph S Ross

BMJ Open 2015;5:e009758.

[full text on-line]

Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: [1] legal requirements and [2] the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge.

Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration [FDA] for drugs approved in 2012, sponsored by large biopharmaceutical companies.

Data sources: Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications.

Main outcome measures: Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts [FDAAA], analysed on the drug level.

Results: The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99,599 research participants. Per drug, a median of 57% [IQR 32–83%] of trials were registered, 20% [IQR 12–28%] reported results in ClinicalTrials.gov, 56% [IQR 41–83%] were published, and 65% [IQR 41–83%] were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% [IQR 8–20%] of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% [IQR 0–100%] were FDAAA-compliant. 68% of research participants [67,629 of 99,599] participated in FDAAA-subject trials, with 51% [33,405 of 67,629] enrolled in non-compliant trials. Transparency varied widely among companies.

Conclusions: Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal [FDAAA] and ethics standards and the quality of medical knowledge.

Transparency by legal standards

There are at least three reasons why compliance with current disclosure laws might be suboptimal. First, legal requirements are perceived to be unclear or ambiguous, as a spectrum of interpretations of FDAAA has emerged…

Second, mergers, acquisitions, collaborations and licensing agreements may complicate compliance. Two companies in our sample acquired or licensed drugs initially developed by smaller companies, and another used a partner company for some trials, raising questions about whose responsibility it was to ensure trials complied with FDAAA.

Finally, compliance may be affected by a perceived lack of enforcement. FDAAA empowers the FDA to impose a $10,000 a day penalty for non-compliance. To date, this penalty has never been imposed.

Motivating transparency

Given the wide variation in compliance with both legal and ethical standards across drugs and companies, we propose continuing our clinical trials transparency monitoring, evaluations and scoring of new drugs approved by the FDA, along with their sponsors. These ongoing rankings— developed initially with support from Harvard University, Duke University, Susan G. Komen Foundation and the Raskob Foundation [for a full list of sponsors, see the Acknowledgements section] — will be conducted annually under the auspicious of Bioethics International, with grant support from the Laura and John Arnold Foundation.

This system will help identify best practices, incent better behaviours and standardise the industry’s practices and thereby contribute importantly to an enrichment of medical knowledge. Moreover, the scorecard and rankings have the potential to benefit consumers of clinical trial information by helping to assure them of the integrity and completeness of their data. Not least, full transparency of clinical trials would also strengthen the protection of human research participants by avoiding their unknowing recruitment into already failed experiments.

I won’t list all the reasons that these ads make me so angry, but I do want to mention one that has been added since I moved to a rural area. I’ve always been someone who prescribes generic drugs if possible – not just because of cost, but because they’ve been around long enough to pass the test of time. There’s nothing in medicine that says newer is better. But working in the charity clinic, the patients see those ads and think that the generics we provide are "less than." In truth, in those instances where a new drug is genuinely better, we go out of our way to procure it through scholarships or our general medical fund. They’ve never not gotten such a drug when I’ve asked for it. But that’s not the point.

But my surprise was that the AMA voted to oppose these ads. That says something positive about our medical community that was unexpected. Who knows? Maybe next on the agenda will be a move to stop ordering un-necessary scans and lab tests? to actively oppose the gajillion fee-churning maneuvers that happen in our emergency rooms and hospitals [including inappropriate screening]. And how about those faux-televisions in the waiting rooms with their infinitely looping infomercials for diabetic supplies and vitamins? Doctor-Power. I like it!

Lieberman, [or maybe it’s Ogas] writes with particular vehemence about the period when most psychiatrists did analytic training. It made me wonder if he was rejected from a training program at one point, or if he was in an analysis that he quit because he found it intolerable. I have absolutely no basis for these thoughts- they’re just conjecture.

Speculating about the self-serving motives of others isn’t all that hard. We almost all do it – particularly when we disagree with what the other person is saying. In the process, we are discounting what’s being said, sometimes for valid reasons, sometimes colored by self-serving motives of our own. Speculating with therapeutic intent is a different enterprise. The speculation itself is only of value if it’s confirmed by some positive change in attitude, understanding, or behavior. Many psychoanalysts of yore died on the vine by treating their speculations as having an intrinsic value outside of that context.

… Then it was my turn, and I was the last questioner, which suited me fine because the room had cleared out a lot by then. I’m a pretty comfortable public speaker, so I was surprised to note how much my voice was shaking, until I realized it was rage, not stage-fright.

I told him I had read his book, that there’s a lot more evidence for PSA than he’s allowing for, and I paraphrased the passage where he states that if Willem Reich’s patient were alive today, she would be diagnosed with an anxiety disorder and treated with an SRI and CBT, which made it sound easy. I pointed out that he was concerned about gaining credibility by fessing up to psychiatry’s history, but the fessing up was selective, and that nowhere does he mention the difficulties with treatment, including things like metabolic effects of antipsychotics, or Paxil Study 329, and how does he mean to engender trust in the public by omitting those kinds of facts?

I know I was far less eloquent in my phrasing, and what I just wrote is not so great to begin with. I think he cut me off towards the end, because I never said anything about the severe limits of what we actually know about mental illness. He rolled his eyes and said, "Medications have side effects. Am I supposed to list every side effect in the book?" I have the impression he was still yelling something, but I could be wrong…

The book Shrinks is billed on Amazon.com as "The fascinating story of psychiatry’s origins, demise, and redemption, by the former President of the American Psychiatric Association." The story-line of psychoanalysis capturing psychiatry, and its liberation with the coming of the DSM-III, medicalization, the newer psychotropic drugs, and the advances in neuro-matters has been with us for three plus decades, delivered by Dr. Lieberman with an unusually heavy dose of contempt. But it’s his response, or perhaps his non-response, to the question at the end of Psych Practice’s comment that deserves attention: "… and that nowhere does he mention the difficulties with treatment, including things like metabolic effects of antipsychotics, or Paxil Study 329, and how does he mean to engender trust in the public by omitting those kinds of facts?"

It’s the redemption part of Dr. Lieberman’s playbill that doesn’t pass muster. And his eye-rolling sarcastic "Medications have side effects. Am I supposed to list every side effect in the book?" doesn’t address the question asked. What about the academic·pharmaceutical complex with its guest authors, ghost authors, conflicts of interest, speaker’s bureaus, commercially oriented CME, and its jury-rigged or invisible clinical trials? How about the minimized adverse effects of the drugs – the metabolic syndrome, akathisia with violence, the withdrawal symptoms, tardive dyskinesia, addiction, etc? And then there’s the part of the question Psych Practice didn’t get to ask, "…he cut me off towards the end, because I never said anything about the severe limits of what we actually know about mental illness." Dr. Lieberman’s and his colleagues’ over-simplification of the complex human experiences we call mental illness imply an unsupportable level of mastery. So this is hardly a period of redemption – by any stretch.

FDA nominee Robert Califf must prove his independence from industry

Pharmalot

By Ed Silverman

November 16, 2015

As a US Senate committee meets on Tuesday to consider Dr. Robert Califf for the top job at the Food and Drug Administration, an open question remains whether he is biased toward industry. Califf is held in high regard by drug makers and academics alike. A cardiologist by training, he spent years as a professor at the Duke University School of Medicine and is one of the most influential biomedical authors in the world. He’s also run numerous clinical trials and served on various FDA advisory committees. But ever since Califf was named a deputy commissioner at the FDA in January and then nominated to be chief regulator in September, his long-standing working relationship with the pharmaceutical industry has prompted debate. Among those opposing his nomination are Democratic presidential aspirant Bernie Sanders and Public Citizen, a consumer advocacy group.

Califf was the founding director of the Duke Clinical Research Institute, which conducts studies for companies. Last year, six drug makers — including Merck and Novartis — partly supported his salary, and several others paid him for consulting work. He has also authored numerous papers with industry researchers. No other commissioner in the recent past has held such close ties to pharmaceutical manufacturers. [The last commissioner, Margaret Hamburg, for example, was a career public health administrator.] All this has led some to challenge whether Califf can be an honest broker. “I do think hard questions should be asked,” said Daniel Carpenter, a Harvard University political scientist, who has studied the FDA but has not taken a position on Califf. “He will have a fair amount of power to push for change”…

What to expect from FDA nominee Robert Califf’s confirmation hearing

Boston Globe

By Sheila Kaplan

November 17, 2015

Supported  by  Johnson  &  Johnson  Pharmaceutical  Research and Development and Bayer HealthCare…

Dr. Califf, receiving consulting fees from Kowa, Nile, Orexigen, Sanofi Aventis, Novartis, and Xoma and grant support from Novartis, Merck, and Amilyn/Lilly and having an equity interest in Nitrox…

I would prefer that Dr. Califf were as clean as a whistle and had no financial connections with any pharmaceutical company. And I would be much happier if he didn’t bother messing with drugs of convenience. Even reading his paper, I wouldn’t take or recommend Xarelto®. My focus would be on being either being the patient or the doctor in the situation when there was a bad car wreck, and I’d say to hell with convenience if I could save a life with a Vitamin shot instead of watching someone bleed to death, I don’t mind insisting on the countless routine blood tests it took to keep that possibility open. But that’s my clinical decision, that would be made in concert with my patient when we’re both playing with a fully informed deck of cards – including this study. I said that to my friend [which was the whole point of my even looking at the paper], and he chose Xarelto® anyway. That’s what his doctor recommended, and that’s what he did [by getting a needed scholarship from J&J]. Their choice. But my friend was fully informed, so I did my job. And in so far as I could tell, so did Dr. Califf [I hope. See this article by the POGO Editor in Chief: Drug Problems: Nominee to Head FDA Led Clinical Trial FDA Faulted].

Looking at other things I’ve written about Dr. Califf, the one real negative was guilt by association [predictable repetitions…]. It was an editorial in the New England Journal of Medicine, Revisiting the Commercial–Academic Interface, by Dr. Jeffrey Drazen supporting Dr. Califf for FDA head  [see also a contrarian frame of mind…, wtf?…, wtf? for real…, a narrative…, not so proud…]. In the first place, since when is the editorship of the NEJM a position from which to weigh in on such matters? And Dr. Drazen’s recent showing with his editorial and series on industry-tainted authors writing review articles was an outrageous rationalization, worthy of considering a change in his employment. He’s the paradigm of an industry-friendly guy who assured us fifteen years ago that his PHARMA-connections were behind him and it was… well, it just wasn’t true [sleeper cell comes to mind]. I have no idea how he and Dr. Califf are connected, but I don’t have a bit of question about Dr. Drazen’s Conflicts of Interest. So I see that endorsement from Dr. Drazen as a major black-mark on Dr. Califf’s resume.

But when it’s all said and done, I don’t really think that the FDA is a major problem except in two areas. I don’t like the fact that the boss over-rode the opinion of the evaluator on drugs like Zoloft or Latuda, but those aren’t my main beefs. They are that the FDA continues to honor industry’s claim that Clinical Trial data and the submitted Clinical Study Reports or Individualized Participant Data are proprietary – keeping secrets for industry – and have made none of the moves towards data transparency like those occurring in the European Medicines Agency. My second complaint is that the trials known as Phase IV [post-marketing] Trials which should be rigorous and ongoing are essentially worthless. They’re done by PHARMA, and rarely mentioned. In reading about a drug, even late in its patent-life, we still mostly hear about those PHASE III Clinical Trials done to get the various approvals. We need to know how the drugs perform [or don’t perform] once they’re out there, and we don’t know – at least in any formal way. The whole Contract Research Organization industry was built to get drugs approved. Once approved, they’re in the hands of the marketeers and then later the Civil and Federal Courts. The latter may be getting better at punishment, but that’s hardly the point.

What matters is what happens once the drug is in general use. I can "vet" products I order on-line from Amazon.com not long after they appear [Amazon.com is the major store for those of us who line in the woods], but even as a doctor, I can’t do that with drugs until they’re almost out of patent except by word of mouth or trial and error. Dr. Healy’s giving it a really serious try with RxISK, but he’s going to need a lot of help. The FDA has a reporting system but it’s woefully lackluster.

The FDA isn’t mandated to do anything but certify safety and minimal efficacy. The agency has no control over drug pricing, and really isn’t set up to survey advertising in a comprehensive way.  It just picks up on big lies, not spin. So the questions that matter in today’s hearings are about Data Transparency and post-marketing Trials. I doubt they’ll be asked, but I sure hope they are. And when it comes down to it, the real question is whether Dr. Califf is a person of integrity who will make the right hard decisions when the issues that really matter come across his desk [two of my favorite unlikely heros, James Comey and Earl Warren, come to mind]? Or will he follow Dr. Drazen’s sleeper cell mentality? Will the Office make the man? I don’t know how one knows something like that in advance…

Califf: I’ll never lower FDA’s approval standards

Boston Globe

Sheila Kaplan

November 17, 2015

Senators Hint at Confirmation of Califf as Next FDA Commissioner

Regulatory Affairs

By Zachary Brennan

17 November 2015

FDA nominee faces questions about drug industry ties

Washington Post

By Brady Dennis

November 17, 2015

• The European Medicines Agency [EMA] has embraced the concept of Data Transparency [a no-brainer] and is working out its policy.
• The EMA is centralized, seems more transparent, more distant from the "powerful set of forces" and is more accessible than our FDA.
• The same drugs are independently evaluated by the EMA and FDA, so transparency in one becomes transparency for both.
• And then, there’s the European Ombudsman.

Happy birthday Ombudsman

British Medical Journal

by Tom Jefferson

13 Nov, 2015

The institution of the European Ombudsman celebrated its first 20 years of activity with a party for staff and all those who have and still are contributing to its work. The shindig was held in the European Parliament. In the words of the current Ombudsman, Emily O’Reilly, the Ombudsman’s function “was born out of the debate on the emerging European citizenship in the early 1990s, and its purpose precisely is to enable those European citizens to hold the ever more powerful EU institutions to account, as the direct effect of what they do impacts more and more on the daily lives of the people. It acts in a complementary way to the courts and to the parliament, as a check on EU institutional power.”

In the current climate, O’Reilly’s words may seem like a wish rather than reality. Except that the office’s record in the matter of access to secret clinical data is exemplary. It is to the Ombudsman that the Nordic Cochrane Centre referred in its attempt to access clinical study reports from the European Regulator, the European Medicines Agency [EMA], and it was the Ombudsman who sided with Peter Gotzche and colleagues. This led to the recognition that data relating to clinical trials cannot be considered confidential, as it is a public good.

I have chronicled the evolution of the EMA’s policy and its forthcoming release of large quantities of reports. Reports have also been released since the Ombudsman’s ruling in 2010. The visibility of such documents has finally lead to the realisation that clinical trials published in journals may not be trusted because they do not provide sufficient information and detail to understand the strengths and weaknesses of a trial…

Serotonin Transporter Occupancy of Five Selective Serotonin Reuptake Inhibitors at Different Doses:

An [¹¹ C] DASB Positron Emission Tomography Study

by Jeffrey H. Meyer, Alan A. Wilson, Sandra Sagrati, Doug Hussey, Anna Carella, William Z. Potter, Nathalie Ginovart, Edgar P. Spencer, Andy Cheok, and Sylvain Houle

American Journal of Psychiatry 2004 161:826–835.

[full text on-line]

Objective: Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin [5-HT] transporter [5-HTT]. The authors used [11 C] DASB positron emission tomography to measure occupancies of three other selective serotonin reuptake inhibitors [SSRIs] at minimum therapeutic doses. The relationship between dose and occupancy was also investigated.

Method: Striatal 5-HTT binding potential was measured in 77 subjects before and after 4 weeks of medication administration. Binding potential is proportional to the density of receptors not blocked by medication. Subjects received citalopram, fluoxetine, sertraline, paroxetine, or extended-release venlafaxine. Healthy subjects received subtherapeutic doses; subjects with mood and anxiety disorders received therapeutic doses. Percent reduction in 5-HTT binding potential for each medication and dose was calculated. To obtain test-retest data, binding potential was measured before and after 4 weeks in six additional healthy subjects.

Results: Substantial occupancy occurred at subtherapeutic doses for all SSRIs. Compared to test-retest data, each drug at the minimum therapeutic dose had a significant effect on striatal 5-HTT binding potential. Mean occupancy at this dose was 76%–85%. At higher plasma SSRI concentrations, 5-HTT occupancy tended to in- crease above 80%. For each drug, as the dose [or plasma level] increased, occupancy increased nonlinearly, with a plateau for higher doses.

Conclusions: At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.

hat tip to alto et al… 

Later: At the end of a three year Air Force assignment to the USAFE hospital in Lakenheath England, it was about time to come home to our real lives. For our last trip to the Continent, we decided on camping through France. I had several weeks of leave and though we’d been to France often, we hadn’t ‘toured.’ So we loaded our diminutive Morris Minor with camping gear and took the Ferry to Calais. It couldn’t have been a more perfect trip. Somewhere in the middle we awoke in our tent and simultaneously noticed that our teeth were slightly purple [so we changed to white wine]. The trip back to Paris from the South was our only autoroute leg [superhighway], and our top-speed-low-sixty-miles-per-hour Morrris was definitely out classed, but we made it to the outskirts of Paris at midnight. The next morning, we decided that a ride down the Champs-Élysées would be  a nice way to end our European adventures before getting on the Ferry, and soon onto the plane home.

Totally by chance, without our even really noticing, we were the last car allowed onto the boulevard that day. It was inauguration day for Giscard d’Estaing who had defeated François Mitterrand. Neither of us spoke anything more than "menu" French, so after two weeks of wandering, we were news-dumb and had no clue we were crashing a presidential parade. The streets were lined with spectators who were as amused as we were with our toy British car as a one-car parade. They waved their flags, laughed, and clapped as did we – basking in our short-lived fame. It was, indeed, one fine Swan Song.

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

by Ewgeni Jakubovski, M.A., Anjali L. Varigonda, M.D., Nicholas Freemantle, Ph.D., Matthew J. Taylor, Ph.D., Michael H. Bloch, M.D., M.S.

American Journal of Psychiatry. Published online: November 10, 2015.

Objective: Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors [SSRIs] in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.

Method: The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.

Results: Forty studies involving 10,039 participants were included. Longitudinal modeling [dose-by-time interaction=0.0007, 95% CI=0.0001–0.0013] and endpoint analysis [meta-regression: β=0.00053, 95% CI=0.00018–0.00088, z=2.98] demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects [meta-regression: β=0.00207, 95% CI=0.00071–0.00342, z=2.98] and decreased likelihood of all-cause dropout [meta-regression: β=–0.00093, 95% CI=–0.00165 to −0.00021, z=−2.54].

Conclusions: Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents [50 mg of fluoxetine] The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

This study uses some fancy statistical manipulation to conclude that higher doses of antidepressants might be a little more likely to be effective in treating depression. The psychiatric literature is filled with articles about schemes to get more mileage out of the antidepressant treatment. There was the pharmaceutical pipeline that regularly released a new molecule every couple of years. There were several different classes of drugs [TCAs, MAOIs, SSRIs, SNRIs, Buproprion]. We studied sequencing [STAR*D, TMAP], combining [CO-MED], and augmenting [thyroxin, Atypical Antipsychotics]. Here we have the suggestion to try a higher dose. The group a UT Southwestern [Rush, Trivedi] insisted that if we pushed the doses and treated to remission, we would up our odds back when they designed STAR*D, and Dr. Rush is still talking about it [Isn’t It About Time to Employ Measurement-Based Care in Practice? AJP October 2015]. So far, the notion that genetic testing would refine our prescribing remains just that – a notion. Along the way, we’ve had Vagus Nerve, Transcranial Magnetic, and Deep Brain Stimulators. One would think that with such a heavily studied toolkit literally dominating twenty-five years of our journal literature, offering so many combinations and permutations, we would’ve arrived in the promised land. The inconvenient truth is that we haven’t – we haven’t even come close.

Skeptics like me would say it’s because most depression arises in response to psychological, biographical, and social forces that don’t fit the current DSM model of Major Depressive Disorder – that instead of Treatment-Resistant-Depression, we’d be best advised to turn our attention back to Non-Biomedical-Responsive-Depression with a bigger toolkit than simply Cognitive Behavior Therapy – a direction strongly opposed by the Managed Care/Collaborative Care/Integrative Care models. But even Biomedical Devotees like Dr. Insel aren’t satisfied with the current state of play and he has prattled on endlessly about his disappointment with our lack of progress.

Another facet of this inconvenient truth is that the therapeutic zeal accompanying the attempts to expand the effectiveness of the medications has fueled an epidemic of iatragenic illness [illnesses caused by treatment] – overmedication, adverse effects, dysinhibition, violence, withdrawal syndromes, etc. Which brings me back to my starting place. After I saw that abstract suggesting higher antidepressant doses before I headed off to the clinic, I recall thinking about how much time I spend dealing with patients who have iatragenic illnesses from their medications or who show up seeking a change in their medications. I mentioned a mega-overmedicated case recently [blitzed…, some truths are self-evident…] and this man I saw later in the day [it just is what it is…], but that’s just the tip of an iceberg of how many such cases I see. We’re beginning to see Obamacare and Medicaid patients now in the clinic, and I think the local doctors and contract mental health center are beginning to send those cases my way [for me to try to get straightened out]. That obviously can’t go on forever, even at the moment it’s barely manageable. But the point is, the inconvenient truth for me is that I appear to be developing a sub-specialty I would never have imagined – medication untangler.

"Let’s take another look at your story. Maybe there’s something going on in you or your life that needs much more attention, something contributing to your depression that medication can’t possibly change."