1 Boring Old Man

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

by D. Jeffrey Newport, Linda L. Carpenter, William M. McDonald, James B. Potash, Mauricio Tohen, and Charles B. Nemeroff, The APA Council of Research Task Force on Novel Biomarkers and Treatments

American Journal of Psychiatry. 2015 172:950–966.

… Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, D-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.

Conclusions: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

Meta-analyses with industry involvement are massively published and report no caveats for antidepressants

by Shanil Ebrahim, Sheena Bance, Abha Athale, Cindy Malachowski, and, John P.A. Ioannidis

Journal of Clinical Epidemiology. Published on-line September 21, 2015.

Objectives: To identify the impact of industry involvement in the publication and interpretation of meta-analyses of antidepressant tri- als in depression.

Study Design and Setting: Using MEDLINE, we identified all meta-analyses evaluating antidepressants for depression published in January 2007 – March 2014. We extracted data pertaining to author affiliations, conflicts of interest, and whether the conclusion of the ab- stract included negative statements on whether the antidepressant[s] were effective or safe.

Results: We identified 185 eligible meta-analyses. Fifty-four meta-analyses [29%] had authors who were employees of the assessed drug manufacturer, and 147 [79%] had some industry link [sponsorship or authors who were industry employees and/or had conflicts of interest]. Only 58 meta-analyses [31%] had negative statements in the concluding statement of the abstract. Meta-analyses including an author who were employees of the manufacturer of the assessed drug were 22-fold less likely to have negative statements about the drug than other meta-analyses [1/54 [2%] vs. 57/131 [44%]; P < 0.001].

Conclusion: There is a massive production of meta-analyses of antidepressants for depression authored by or linked to the industry, and they almost never report any caveats about antidepressants in their abstracts. Our findings add a note of caution for meta-analyses with ties to the manufacturers of the assessed products.

"In 1984, the late Arnold S. Relman, then the NEJM’s editor in chief, instituted the first conflict of interest policy at any major medical journal. The policy required authors of research papers to disclose all financial ties they had to health industries, and if the ties were deemed significant they were published. In 1990, Relman extended the policy to prohibit authors of editorials and review articles from having any financial interest in a company [or its competitor] that was discussed in the article, since these types of manuscripts do not contain primary data but rely exclusively on the authors’ judgment in citing and interpreting the literature…" [reference]

• Revisiting the Commercial–Academic Interface
• Reconnecting the Dots — Reinterpreting Industry–Physician Relations
• Understanding Bias — The Case for Careful Study
• Beyond Moral Outrage — Weighing the Trade-Offs of COI Regulation

• a contrarian frame of mind…
• wtf?…
• wtf? for real…
• unserious arguments seriously…
• the real editors speak out…

• Say It Ain’t So: Logical Fallacies in Defense of Conflicts of Interest … in the New England Journal of Medicine?
• Justifying conflicts of interest in medical journals: a very bad idea
• Revisiting the commercial-academic interface in medical journals

Martin Shkreli may get competition for his pricey drug, after all

Pharmalot

by Ed Silverman

October 22, 2015

Thanks to a compounding pharmacy, Martin Shkreli’s company may no longer have a lock on the market for its pricey anti-infective drug Daraprim. A little-known company called Imprimis Pharmaceuticals announced plans to make a combination medicine that includes pyrimethamine, the same active ingredient found in Daraprim. And Imprimis intends to charge just $99 for a bottle of 100 capsules, or about $1 each. Daraprim costs $750 per tablet.

Shkreli’s Turing Pharmaceuticals, as you know, caused a recent firestorm by boosting the price of Daraprim from $13.55 less than a month after buying the decades-old, life-saving medicine from another drug maker this summer. The price hike amounted to a whopping 5,433 percent increase.

Turing sparked still more outrage by restricting distribution in order to thwart generic drug makers from obtaining samples needed to develop cheaper versions. This prompted the New York Attorney General to launch an anti-trust probe last week. And US Senator Amy Klobuchar, a Minnesota Democrat and Presidential hopeful Hillary Clinton asked the Federal Trade Commission to do the same.

“We’re going to take care of this patient population and at a fair price and make a great profit,” Imprimis chief executive officer Mark Baum told us. “We think physicians will write prescriptions for the compounded version. And we think insurers will support this”…

In spite of the persistent divisive rhetoric, there seems to be a developing consensus about the treatment of psychotic mental illness [schizophrenia]. The notion that the only treatment is antipsychotic medication "for life" has been laid to rest [largely through the efforts of Robert Whitaker and his colleagues at Mad in America]. Most agree that the medication is indicated for acute psychosis, but controversy persists about maintenance [in general, independent of the advice given, the patients themselves don’t continue to take it long term]. There’s a developing consensus that ongoing care for these patients from a mental health system or provider is essential, over and beyond the issue of medication. The form of that ongoing care is unclear, and the subject of heated debate. Most hope for some way to identify these patients before a psychotic break [but worry that it will lead to overmedication]. There is a concern, mainly in the lay population, that these patients are dangerous. Likewise, there is a concern almost everywhere that chronic psychotic patients are inappropriately housed in jails and prisons. With that as an introduction, yesterday we read this in the New York Times:

New Approach Advised to Treat Schizophrenia

New York Times

by BENEDICT CAREY

OCT. 20, 2015

More than two million people in the United States have a diagnosis of schizophrenia, and the treatment for most of them mainly involves strong doses of antipsychotic drugs that blunt hallucinations and delusions but can come with unbearable side effects, like severe weight gain or debilitating tremors.

Now, results of a landmark government-funded study call that approach into question. The findings, from by far the most rigorous trial to date conducted in the United States, concluded that schizophrenia patients who received smaller doses of antipsychotic medication and a bigger emphasis on one-on-one talk therapy and family support made greater strides in recovery over the first two years of treatment than patients who got the usual drug-focused care.

The report, to be published on Tuesday in The American Journal of Psychiatry and funded by the National Institute of Mental Health, comes as Congress debates mental health reform and as interest in the effectiveness of treatments grows amid a debate over the possible role of mental illness in mass shootings…

Comprehensive Versus Usual Community Care for First-Episode Psychosis:

2-Year Outcomes From the NIMH RAISE Early Treatment Program

by John M. Kane, M.D., Delbert G. Robinson, M.D., Nina R. Schooler, Ph.D., Kim T. Mueser, Ph.D., David L. Penn, Ph.D., Robert A. Rosenheck, M.D., Jean Addington, Ph.D., Mary F. Brunette, M.D., Christoph U. Correll, M.D., Sue E. Estroff, Ph.D., Patricia Marcy, B.S.N., James Robinson, M.Ed., Piper S. Meyer-Kalos, Ph.D., L.P., Jennifer D. Gottlieb, Ph.D., Shirley M. Glynn, Ph.D., David W. Lynde, M.S.W., Ronny Pipes, M.A., L.P.C.-S., Benji T. Kurian, M.D., M.P.H., Alexander L. Miller, M.D., Susan T. Azrin, Ph.D., Amy B. Goldstein, Ph.D., Joanne B. Severe, M.S., Haiqun Lin, M.D., Ph.D., Kyaw J. Sint, M.P.H., Majnu John, Ph.D., and Robert K. Heinssen, Ph.D., A.B.P.P.

American Journal of Psychiatry. Published on-line Oct 20, 2015.

Clinical Trial:  NCT01321177

Publications

Objective: The primary aim of this study was to compare the impact of NAVIGATE, a comprehensive, multidisciplinary, team-based treatment approach for first-episode psychosis designed for implementation in the U.S. health care system, with community care on quality of life.

Method: Thirty-four clinics in 21 states were randomly assigned to NAVIGATE or community care. Diagnosis, duration of untreated psychosis, and clinical outcomes were assessed via live, two-way video by remote, centralized raters masked to study design and treatment. Participants [mean age, 23] with schizophrenia and related disorders and ≤6 months of antipsychotic treatment [N=404] were enrolled and followed for ≥2 years. The primary outcome was the total score of the Heinrichs-Carpenter Quality of Life Scale, a measure that includes sense of purpose, motivation, emotional and social interactions, role functioning, and engagement in regular activities.

Results: The 223 recipients of NAVIGATE remained in treatment longer, experienced greater improvement in quality of life and psychopathology, and experienced greater involvement in work and school compared with 181 participants in community care. The median duration of untreated psychosis was 74 weeks. NAVIGATE participants with duration of untreated psychosis of <74 weeks had greater improvement in quality of life and psychopathology compared with those with longer duration of untreated psychosis and those in community care. Rates of hospitalization were relatively low compared with other first-episode psychosis clinical trials and did not differ between groups.

Conclusions: Comprehensive care for first-episode psychosis can be implemented in U.S. community clinics and improves functional and clinical outcomes. Effects are more pronounced for those with shorter duration of untreated psychosis.

The RAISE early treatment program for first-episode psychosis:

background, rationale, and study design.

by Kane JM, Schooler NR, Marcy P, Correll CU, Brunette MF, Mueser KT, Rosenheck RA, Addington J, Estroff SE, Robinson J, Penn DL, and Robinson DG.

Journal of Clinical Psychiatry. 2015 76[3]:240-246.

[full text online]

OBJECTIVE: The premise of the National Institute of Mental Health Recovery After an Initial Schizophrenia Episode Early Treatment Program [RAISE-ETP] is to combine state-of-the-art pharmacologic and psychosocial treatments delivered by a well-trained, multidisciplinary team in order to significantly improve the functional outcome and quality of life for first-episode psychosis patients. The study is being conducted in non-academic [ie, real-world] treatment settings, using primarily extant reimbursement mechanisms…

• a fabrication?…
• where’s the beef?…
• out of the loop…

• its effectiveness…
• another IRT prequel…
  
• on IRT, some comments…
• the manual…

So why the long introduction? It’s because when I looked at Dr. Kane et al’s paper, I could find little relationship to the AJP paper and Benedict Carey’s New York Times article [or for that matter, any of the other media reports]. Carey had reported lower antipsychotic doses, but the paper says nothing about medications. Cary’s article mentioned one-to-one talk therapy but I found not much about that in this report.  What I did find first off were graphs of the answers to quality assurance questionnaires:

And then there was this showing some modest improvements in the NAVIGATE group [though the metrics seem odd and fairly distant from the data – statistical testing of only the treatment×time interaction???]:

This issue of the Journal includes a report on the primary outcomes from the Recovery After an Initial Schizophrenia Episode [RAISE] Early Treatment Program clinical trial. …RAISE was not a test of a breakthrough intervention or high-tech diagnostic but a trial of adapting and optimizing currently known, evidence-based practices. The RAISE question was simple and urgent: Will a comprehensive, person-centered, team-based approach for first-episode psychosis improve outcomes? For RAISE, the outcomes measured were quality of life, participation in school or work, and symptomatic improvement. The setting was “ real world ”— 34 community mental health centers in 21 states.

This issue of the The study compared the efficacy of an experimental intervention, called NAVIGATE, with standard community care for people with first-episode psychosis. NAVIGATE consisted of four evidence-based interventions: personalized medication management, family psychoeducation, resilience-focused individual therapy, and supported employment and education. The component interventions were offered as a package, with the addition of a team leader who coordinated services and served as a primary point of contact for individuals and their families. The NAVIGATE programs also involved a proactive focus on engagement. In contrast to standard community care, these multiple components were offered within a shared decision-making framework and implemented according to patient preference.

Just as the dramatic improvements for treatment of acute lymphoblastic leukemia reflected incremental gains over time, the results for NAVIGATE take a palpable step toward markedly better outcomes for young people following first-episode psychosis. A measure of quality of life improved modestly more in the NAVIGATE group than in the standard community care group over 24 months [effect size = 0.31], and the NAVIGATE group had lower levels of symptoms as measured by the Positive and Negative Syndrome Scale [effect size = 0.29]. Participants in the NAVIGATE group stayed in treatment longer than the standard community care group [a median of 23 months compared with a median of 17 months]. In contrast to some earlier studies of first- episode psychosis , the intervention did not decrease hospitalization probably because the rates of hospitalization were relatively low in both groups [over the 2 years of treatment, 34% of the NAVIGATE group and 37% of the standard community care group were hospitalized for psychiatric indications].

One of the most remarkable aspects of this study was the substantial moderation of the treatment effect by the duration of untreated psychosis. The median duration of untreated psychosis in the entire sample was 74 weeks — a clear indication of the need to identify young people with mental illness at much earlier stages and to get them into effective treatment more rapidly. Those with a duration of untreated psychosis of less than the median of 74 weeks responded far better to the NAVIGATE intervention than those with a longer duration of untreated psychosis at baseline. Indeed, the overall effects of NAVIGATE were largely driven by the robust response [the effect size was 0.54 for the quality of life measure and was 0.42 for overall symptoms] from those with shorter duration of untreated psychosis. These results demonstrate the importance of early detection, early engagement, and integrated care following the onset of psychosis…

Researchers May Have Finally Found a Better Way to Treat Schizophrenia

VICE NEWS

By Colleen Curry

Oct 21, 2015

A landmark study into the treatment of newly diagnosed schizophrenics has found that talk therapy combined with medication can be more effective in treating symptoms than just strong doses of drugs. The findings, which emphasize the success of therapy and how unusual it is for schizophrenics to be treated with it, could help shift the way health insurers in the United States cover mental health treatment costs.

Researchers spent four years studying more than 200 newly diagnosed schizophrenics. Half of the subjects were treated solely with medication, while the other half received a lower-dose medication combined with individual therapy, coaching sessions in the workplace or school, and family counseling.

The study involved patients at 34 treatment centers in 21 states. The results, released Tuesday in the American Journal of Psychiatry, found that individuals in the early stages of schizophrenia were better off receiving lower-doses of antipsychotics in conjunction with therapy. The National Alliance of Mental Illness (NAMI) praised the study and said it would be used as part of the organization’s push to broaden access to services for the mentally ill…

The study’s release coincided with hearings on Capitol Hill for mental reform amid a bipartisan push to improve mental health treatment, partially due to the increase in mass shootings in which mental illness is thought to have played a role.

Study suggests new way to treat people after first schizophrenia episode

Washington Post

By Lenny Bernstein

October 20, 2015

Quickly identifying people who have suffered a first schizophrenic episode and treating them with coordinated, sustained services sharply boosts their chances of leading productive lives, according to a major study being published Tuesday. And the treatment can be provided in a typical community mental health setting, the researchers concluded…

The study, called Recovery After an Initial Schizophrenia Episode (RAISE), found that people who are provided years of “coordinated specialty care” in community clinics had a greater quality of life, more involvement in work and school, and less ongoing pa­thol­ogy than others who received typical care.

Although this approach is more expensive and labor-intensive, the researchers suggest that it may be cost-effective in the long run. The approach includes psychotherapy, medication, supported employment and education, help for families of the mentally ill person, and case management. Much of the effort can be funded under insurance and government reimbursement policies, the researchers note.

The study confirms previous research results that the most critical element of treatment may be starting it as quickly as possible after a first psychotic episode. It found “a substantial difference” in effect for patients who began treatment less than 74 weeks after their first symptoms — the median length of time that people in the study went untreated after the onset of psychosis.

“Doing the right thing — and doing the right thing at the right time — that’s the key finding,” said Robert Heinssen, director of the division of services and intervention research at the National Institute of Mental Health, which funded the $25 million, six-year study. “That is guiding our efforts going forward. That has become the north star of where we’re going”…

Cost remains a challenge, because some of the services offered by the comprehensive care model are not reimbursed under traditional fee-for-service arrangements, Kane and his colleagues said. Last week, though, three federal agencies issued guidance to help states design benefit packages for treatment of first-episode psychosis using Medicaid and mental health block-grant funds.

In sum: Patients with schizophrenia do better if they get comprehensive services, and they do better if they are treated early in the course of their illness. And now we officially know what we all knew.

But after reading and reading, I’m afraid my reaction is a bit more critical than that. I suspect that the published paper casts the study is the best possible light [or better], and that the untouched data is less glowing. The NIMH track record with naturalistic studies isn’t so hot [as in STAR*D]. And from what I’ve highlighted above, it’s obvious that this paper in linked to a campaign for more mental health funding [which is more than fine by me]. So to the dilemma. I support the conclusions and their implications, but am suspicious that a closer look at RAISE would raise lots of questions. Like I said at the outset…

Confusion Over Antipsychotic Dosing Data in RAISE Study

Mad in America

by by Justin Karter

October 21, 2015

New hope for treating psychosis

NIMH: Director’s Blog

by By Thomas Insel

October 20, 2015

Study May RAISE Standard for Treating First Psychotic Episode

NIH: Director’s Blog

by Dr. Francis Collins

October 20, 2015

I wish that what I write about could always be interesting, but I just can’t bring it off. Writing is my way of gathering my thoughts, and sometimes that’s pretty boring, even to me. My daughter who named this blog has apologized for her sarcasm, but to be honest, I’m very appreciative. The injunction to be interesting is just too daunting. So here’s some more details about that last post – what that EMA email clarified about what regulatory documents they are actually going to make available. It’s a two phase process, and we’re in phase 1. All we have right now from the clinical drug trials are the registration documents from a registry like clinicaltrials.gov and a published paper [if one is even published]. The inadequacy of that level of access is legend.

What the European Medicines Agency is planning to make available:
I’ve used some version of this diagram to relate the documents to the actual process of the trial itself.

The PROTOCOL and the SAP [STATISTICAL ANALYSIS PLAN] are the two major documents that are a priori [written before the trial begins] and shouldn’t be changed without good reason along the way [and if they are, it needs to be by formal amendment filed with the Institutional Review Board]. The confusion in all the deliberations is about what is in the CSR [Complete Study Report]. There is a long narrative, much more detailed than any published paper could ever be. And then there are Appendices. In the EMA system, the PROTOCOL is an appendix. The STATISTICAL ANALYSIS PLAN is an appendix. The SAMPLE CASE REPORT FORMS are an appendix. The compiled raw data [INDIVIDUAL PARTICIPANT DATA] is spread among several appendices. And finally, the actual CASE REPORT FORMS [CRF] filled out by the subjects or study personnel might be an appendix. So when people say CSR, it matters what appendices are actually included. Here’s what that email [some clarity?…] and the referenced documents said:

After a drug has completed the regulatory process, the documents in the phase 1 box above will be made available. The availability or conditions for availability of the various appendices with the raw data will be decided at a later date [phase 2].

Why I have perseverated [been hung up on] this point:
With Study 329, the CSR narrative was available and with that, one could tell something[s] was/were fishy. The PROTOCOL/STATISTICAL ANALYSIS PLAN  became available along the way. In terms of efficacy, we needed the IPD to do the definitive analysis that we published in September [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence]. With only the article to go on, one could only speculate and suspect. It was over three years after the article was published that the CSR became available, and eleven years before the IPD was public. If the information in the phase 1 box above is available on every drug in a timely fashion, anyone can look to see if the reported article follows the protocol directed outcome variables using the pre·specified analytic techniques. That is a massive improvement over what we have now.

And if the phase 2 documents can be accessed when there is a just cause, the whole seedy racket of jury-rigging clinical trials that we’ve lived with for several decades will be quickly exposable. The issue of adverse effects is a special case in that the CRFs themselves may be required to determine harms.

Back in August, I sent this email out to a number of people

I got a number of responses, mostly from people like me who are interested in Data Transparency as a reform movement. But today, I got a response from the European Medicines Agency, people who are actually in the driver’s seat. I’m posting it in its entirety as a reference. My comments to follow after some digestion. I certainly appreciate the detailed response from whomever wrote this:

APA Urges Creation of Payment Codes Specific to Collaborative Care Model

PsychiatricNews

by Mark Moran

September 24, 2015

Separate codes should be created for the care-management and psychiatric-consultation components of the collaborative care model. Appropriate payment codes need to be developed to reflect the work of physicians — including psychiatrists — participating in collaborative care models treating patients with mental illness in primary care settings, said APA CEO and Medical Director Saul Levin, M.D., M.P.A., in a letter last month to the federal Centers for Medicare and Medicaid Services.

The 18-page letter was in response to CMS’s Proposed Rule for Medicare Program; Revisions to Payment Policies Under the Physician Fee Schedule and Other Revisions to Part B for CY 2016. The letter addresses a range of issues raised in the proposed rule — including improving payment accuracy for primary care and care management services, chronic care management and transitional care management services, the Physician Quality Reporting System, electronic health records, and the Medicare Access and CHIP Reauthorization Act. But the bulk of APA’s comments in Levin’s letter focused on payment and coding issues around reimbursement for the collaborative care model [CoCM]. The model, developed by leaders in integrated care at the University of Washington, involves a primary care physician, a care manager, and a psychiatric consultant.

“The lack of reimbursement for key components of this model has been the principal barrier to its widespread implementation,” Levin stated. “Although there may be other treatment models that engage primary care clinicians and behavioral health specialists, the specific Collaborative Care Model [referenced in the proposed rule] is the only model that has compelling scientific data supporting its effectiveness. Over 80 randomized, controlled trials have shown the CoCM to be more effective than care as usual. … In addition to the robust research evidence for the value of collaborative care, there is also substantial practice experience with this model of care from the Medicaid-funded Mental Health Integration Program in Washington State, the commercially funded DIAMOND program in Minnesota, and similar programs in several other states.”

The letter continued, “[T]he development of codes and requirements to be used for collaborative care for behavioral health conditions must be specific to the CoCM to enable its clinical approach and processes. To create codes that would facilitate any or all of the clinical roles or transactions embedded in the model [such as co-location of a care manager and screening mechanisms] without being tied to the other elements of the model [such as measurement-based care maintained in a registry with psychiatrist oversight] will not realize the substantiated results of the model’s utilization: that is, better quality patient care and outcomes and cost efficiencies”…

^{[click image for description]}

It remains hard for me imagine that anyone takes Collaborative Care as it is being presented seriously or would willingly participate. It begins [top version] with a Primary Care Provider who sees the patient and "Makes initial diagnosis and prescribes medication." So right out of the gate, the model is based on the premise that a symptomatic diagnosis of mental illness should lead to a medication prescription. The patient then gives symptom updates  to the Primary Care Provider and the Case Manager. At some point, the Case Manager discusses the patient’s progress with the Psychiatrist, and the Psychiatrist makes treatment [medications] recommendations. In the second version, there are provisions for the Psychiatrist or other Behavioral Health Clinicians to have infrequent interactions with the patient.

We’re further down that yellow brick road than we used to be.  We know that none of the current psychiatric drugs are benign and that their efficacy is nowhere near what has been widely advertised. We also know that these medications are grossly over-prescribed and many, if not all, can have a withdrawal syndrome that can be problematic. The majority of people who come to a clinic complaining of psychiatric symptoms have some problem in their life, and could benefit from a talk with someone who understands people [I work in such a clinic, and I’m impressed that one can get a lot done even with short and infrequent visits].

• keep the Primary Care Provider from using the medications as badly as they are currently being used
• certify that the patient is receiving psychiatric care

The CNN Democratic debate transcript, annotated

Washington Post

October 13, 2015

COOPER: And welcome back to the final round of the CNN Democratic presidential debate. This is a question to each of you. Each of you, by the way, are going to have closing statements to make. Each of you will have 90 seconds. But a final question to each of you. If you can, just try to – 15 seconds if you can. Governor Chafee, Franklin Delano Roosevelt once said, "I ask you to judge me by the enemies I have made." You’ve all made a few people upset over your political careers. Which enemy are you most proud of?

COOPER: Secretary Clinton?
CLINTON: Well, in addition to the NRA, the health insurance companies, the drug companies, the Iranians. Probably the Republicans.

COOPER: Senator Sanders?
SANDERS: As someone who has taken on probably every special interest that there is in Washington, I would lump Wall Street and the pharmaceutical industry at the top of my list of people who do not like me…

Bernie Sanders rejects donation from drug company CEO

Boston Globe – STAT

By David Nather

October 15, 2015

The man who has become the public face of rising drug prices says he has donated to presidential candidate Bernie Sanders — who has been bashing Big Pharma on the campaign trail — to try to get a meeting so the two can talk it out. Sanders isn’t interested. His campaign said Thursday that he’s giving the money to a Washington health clinic instead — and the drug executive isn’t getting the meeting.

Martin Shkreli, chief executive officer of Turing Pharmaceuticals, became one of the Democrats’ favorite villains after raising the price of the only treatment of a rare parasitic infection by 4,000 percent. He’s an unlikely supporter of the Vermont senator, a self-described socialist who has proposed letting people import cheaper prescription drugs from Canada and requiring Medicare to negotiate lower drug prices. In an interview with Stat on Thursday, however, Shkreli confirmed that he’d donated $2,700 to the Sanders campaign — the maximum individual contribution — on Sept. 28. At the time, the campaign sent the Turing CEO a form e-mail full of populist fervor: “Our political system is corrupt. Big Money controls much of what happens. Together, you and I are changing that. Thank you again for your support. Best, Bernie.”

On Thursday, however, campaign spokesman Michael Briggs said Sanders won’t keep the money. Instead, the campaign will make a $2,700 donation to the Whitman-Walker health clinic in Washington. “We are not keeping the money from this poster boy for drug company greed,” Briggs said.

Shkreli made the contribution, he said, partly because he supports some of Sanders’ proposals — just not the ones about drug prices. But mainly, he said, he donated to get the senator’s attention in the hopes that he could get a private meeting to explain why drug companies set prices the way they do.

Shkreli is “furious” that Sanders is using him as a punching bag without giving him a chance to give his side. “I think it’s cheap to use one person’s action as a platform without kind of talking to that person,” Shkreli said in the interview. “He’ll take my money, but he won’t engage with me for five minutes to understand this issue better”…

Clinton takes in big money from drug industry

Boston Globe

By David Nather

October 16, 2015

Hillary Clinton has said she is proud to have drug companies as her enemies – but she is also taking their money. Lots of it. The Clinton campaign received far more money from the drug and medical device industries than any other presidential candidate in either party during the first six months of the campaign, according to figures compiled by the Center for Responsive Politics. She accepted $164,315 during that period.

The figures don’t include the third-quarter contributions, which were filed with the Federal Election Commission on Thursday. They represent mostly individual donors affiliated with the pharmaceutical industry, as well as some political action committee money. The donors also include two senior executives of a company that recently imposed a massive price increase on one of its drugs…

And when we compare ourselves using the metric of the rest of the world, we stand out from the crowd:

Citing FDA Nominee’s Ties to Rx Industry, Sanders to Oppose New Commissioner

October 9, 2015

With prescription drug prices skyrocketing, Sen. Bernie Sanders (I-Vt.) said today he will vote against confirming Dr. Robert Califf as the new commissioner of the Food and Drug Administration because of his ties to the industry. “At a time when millions of Americans cannot afford to purchase the prescription drugs they need, we need a new leader at the FDA who is prepared to stand up to the pharmaceutical companies and work to substantially lower drug prices. Unfortunately, I have come to the conclusion that Dr. Califf is not that person,” Sanders said after speaking with the nominee. Califf’s confirmation will come before the Senate health committee, which Sanders sits on.

Americans pay, by far, the highest prices in the world for prescription drugs. Last year, one in five Americans were unable to afford the drugs their doctors prescribed. Prices for some prescription drugs soared 1,000 percent or more in recent years. Since 2002, total spending on medicine in the United States went up by more than 90 percent. Sanders cited Califf’s extensive ties to the pharmaceutical industry he would oversee.

The New York Times recently reported that Califf ran a multimillion-dollar clinical research center at Duke University that received more than 60 percent of its funding from the pharmaceutical and medical device industry. He has written scientific papers with pharmaceutical company researchers. His financial disclosure form last year listed seven drug companies and a device maker that paid him for consulting and six others –including Merck, Novartis and Eli Lilly – which supported his university salary.

“Instead of listening to the demands of the pharmaceutical industry and their 1,400 lobbyists, it is about time that the FDA and Congress started listening to the overwhelming majority of the American people who believe that medicine is too expensive,” the senator said. “It is time for the United States to join the rest of the industrialized world by implementing prescription drug policies that work for everybody, not just the CEOs of the pharmaceutical industry."

Two American Pharmaceutical Companies [Abbvie and Intermune] sued and the data flow stopped. Things were at a standstill, but then the suits were magically withdrawn and the aforementioned academic halls again filled with hope and joy. But when the details were revealed, the data release plan had been remarkably constricted. There was again an uproar. The EMA was accused of making compromises that destroyed their planned program. The European Ombudsman got involved. And the EMA came back this way some, but postponed definitive action. Meanwhile, the European Union had a new President who planned to put the EMA under Commerce rather than Health. Sabers were once more rattled, and he recanted, scrapping his planned change.

Then [truth is stranger than almost anything], the Director of the EMA, Guido Rasi, the man who had gotten all of this started, was thrown out of office because of some technicality in his original appointment. The ship was again at sea without a captain. Then Dr. Rasi was renominated to the post in January and the final decision is due any day now.

European Medicines Agency’s Management Board nominates Guido Rasi as Executive Director

Executive Director to be appointed following hearing at European Parliament

01/10/2015

The European Medicines Agency’s [EMA’s] Management Board has nominated Professor Guido Rasi as the Executive Director of the Agency. At an extraordinary session on 1 October, the Board selected Professor Rasi from a shortlist of candidates provided by the European Commission. Professor Rasi has been invited to give a statement to the European Parliament’s Committee on the Environment, Public Health and Food Safety [ENVI] on 13 October 2015. The appointment of the new Executive Director will only be made after this session. An information sheet explaining the process for the appointment of the EMA Executive Director is available. A photo and biography of Professor Rasi are also available.

Following his nomination, Professor Rasi said, “I am honoured to have been nominated as EMA’s Executive Director and am grateful for the opportunity to continue our efforts to make the Agency fit for the challenges ahead. I am enormously proud of the Agency and its network. Looking to the future, we must continue to meet patients’ legitimate expectations for access to new and safe therapeutic options. This requires that the medicines authorisation process not only supports the early stages of research and development, but also strives to make the best possible use of real world data throughout a medicine’s lifecycle.”

Following Professor Rasi’s nomination, the Chair of the Management Board, Professor Sir Kent Woods said, “The Management Board is pleased to announce the nomination of Guido Rasi as Executive Director of EMA. The decision of the Management Board is the result of a robust recruitment process over the last months. We look forward to Professor Rasi resuming his leadership of the Agency.” Deputy Executive Director Andreas Pott will continue to lead EMA operations and to legally represent the Agency until the new Executive Director has officially taken up his duties.

Guido Rasi set for return as EMA executive director

PMLive

by Dominic Tyer

7th October 2015

Nearly a year after his leadership of the European Medicines Agency [EMA] was prematurely annulled by a European Court, Guido Rasi is set to return to his role as its executive director. The European Union Civil Service Tribunal’s ruling came after a case was made against the EMA’s 2011 selection of Rasi and left deputy executive director Andreas Pott in charge.

Now the EMA’s management board has nominated Rasi for his old job, selecting him from a shortlist of candidates provided to it by the European Commission. Before his appointment can be confirmed Rasi must face a hearing at the European Parliament, as well as its Committee on the Environment, Public Health and Food Safety on October 13, on his proposed appointment. Rasi said: “I am honoured to have been nominated as EMA’s executive director and am grateful for the opportunity to continue our efforts to make the Agency fit for the challenges ahead…

Health Canada hands over documents but muzzles doctor

Toronto doctor muzzled, not allowed to talk about morning sickness drug info

Toronto Star

By David Bruser and Jesse McLean

Oct 14 2015

Dr. Navindra Persaud aims to publish a medical journal article based on his findings on the drug Diclectin. However, under the terms of the confidentiality agreement with Health Canada, Persaud said he can share his findings but not the data underlying them. Four years after he first asked Health Canada for all the information it had on a popular morning sickness drug, Toronto doctor Nav Persaud finally has the documents. But he cannot tell his patients or any other Canadians what’s in them.

Under the terms of a confidentiality agreement he had to make with the federal regulator in order to receive the 35,000 pages, he can’t even tell his wife. “I think it’s important information that could change clinical practice, that could change the informed decisions that pregnant women make about whether they want this medication,” said Persaud, who teaches at the University of Toronto and researches drug safety at St. Michael’s Hospital.

“But because I have signed this confidentiality agreement, I can’t talk to you about it.” Persaud has previously raised concerns about Diclectin’s efficacy. This article is about transparency, not drug safety. The maker of Diclectin, a commonly prescribed morning sickness drug, says its product has been proven safe and effective.

The Star first reported on Persaud’s protracted battle with government secrecy in April. A pregnant patient of Persaud’s had questions about Diclectin. So in 2011, Persaud went to Health Canada for all the records it had that could help him give an informed response. He got a three-and-a-half-year runaround before getting a 359-page document, 60 per cent of it completely censored. Other pages had blacked-out sections under titles such as “Adverse Events.” Canada’s drug regulator had deemed those details “confidential business information” under access to information legislation, and was required to consult the drug’s manufacturer, Quebec-based Duchesnay, on what should be kept from the doctor.

So Persaud made his request again, this time under the new legislation, Vanessa’s Law. This 2014 law empowers the health minister to disclose this kind of information to a doctor, in some cases without consulting a drug company. In September, he finally received 35,000 pages, none of them blacked out, the disclosure made by Health Canada for the “exclusive use” of Persaud’s research about the drug. The release includes a nearly 9,200-page report from a recent clinical trial sponsored by Duchesnay to assess, among other things, the drug’s efficacy — a measure of how well it treats a condition.

“I don’t view it as business information because it’s related to the clinical effects of a medication, and I think the women who would have participated in this trial thought they were contributing to science, not to the business interests of one company,” Persaud said. “That’s exactly the sort of information that should be publicly available.” Persaud co-authored an article published Monday in the Canadian Medical Association Journal that calls for North American regulators to make all clinical trial data publicly available.

Persaud aims to publish a medical journal article based on his findings. However, under the terms of the “absurd” confidentiality agreement, Persaud said, he can share his findings but not the data underlying them. Health Canada noted in a Sept. 16 letter to Persaud, “You should be aware that Health Canada will closely monitor compliance with this Agreement and has recourse to legal action in the event of a breach.” Though he feels muzzled, Persaud commended the regulator for releasing the documents. “In the past, information that was confidential business information would not be disclosed at all,” he said. “Health Canada has made [this recent] decision independently and did not consult with the pharmaceutical company Duchesnay, and I think that’s the way that regulators should operate.”

The BMJ requires data sharing on request for all trials

by Elizabeth Loder and Trish  Groves

British Medical Journal. 2015 350:h2373

Heeding calls from the Institute of Medicine, WHO, and the Nordic Trial Alliance, we are extending our policy. The movement to make data from clinical trials widely accessible has achieved enormous success, and it is now time for medical journals to play their part. From 1 July The BMJ will extend its requirements for data sharing to apply to all submitted clinical trials, not just those that test drugs or devices. The data transparency revolution is gathering pace.2 Last month, the World Health Organization [WHO] and the Nordic Trial Alliance released important declarations about clinical trial transparency.

These announcements come on the heels of the US Institute of Medicine’s [IOM] report on sharing clinical trial data, which called for a transformation of existing scientific culture to one where “data sharing is the expected norm.” The efforts of industry, too, must be acknowledged, some of which caught many people by surprise. In particular, Medtronic’s cooperation with the Yale University Open Data project and GlaxoSmithKline’s leadership on data disclosure efforts stand out…

• agreeing with the BMJ’s move for Data Transparency
• an author on a paper advocating Data Transparency
• having spent countless hours working on a remote desktop that was really hard to work with [we called it the periscope]
• And my coauthors and the journal editors were wondering why I hadn’t posted the data!

I couldn’t post the data because in order to see it, we signed an agreement with GSK that forbade us from taking the data out of the remote desktop or releasing it directly. In our case, there was a fortuitous anomoly, a loophole or workaround. The efficacy data had been posted already by GSK [belatedly] [under court order] in 2012. It’s in graphics-based .pdfs and would have to be transcribed into some kind of tabular form to be analyzed [either by hand or with some super-duper OCR magic that I couldn’t bring off]. I’ve done some of it by hand and can attest to the fact that it’s a Herculean task. In fact, we were doing our paper from that data originally, but changed tactics when we realized that we needed the raw CRFs to analyze the harms. So we applied to GSK for access. I could at least post the links to the public version fulfilling BMJs requirements, though working with the data in this form is a real bear:

I don’t want to seem ungrateful. After all, we did get access in the end and that rarely happens. But the amount of effort it took to reanalyze the data in the format supplied was impressive and, in my opinion, unnecessary. There was nothing in that data that would breach Subject Confidentiality or in any way fit the criteria for Commercially Confidential Information [CCI]. It’s just numbers. So neither argument really offers a reason for secrecy.

I can’t mount a formal argument that the difficulty using the system or the restrictions on publishing the data were deliberate attempts to interfere with our doing the analysis, though it certainly felt that way at times. Since the Subject Confidentiality and Commercially Confidential Information assertions seem spurious, I suspect that the motive was to maintain control. And as I’ve said repetitively, there’s no reason to hide the data except to have the option to distort the analysis without letting others do any checking. There are simply too many examples where corrupted analysis has been documented to justify continuing to see this Clinical Trial data as proprietary.

So I have nothing but sympathy for Dr. Navindra Persaud.  He’s playing against a stacked deck that makes reanalysis a heroic act rather than what it should be – a necessary piece of oversight. In his case, it directly goes against the intent of Canada’s Vanessa’s Law [see doing the right thing…], and I hope he takes it to their Parliament for clarification.

I was looking at my old patent-life graph I used in a reset button…, and was updating it while I watched the debates on television. It didn’t take very long, and I found myself doodling a frequency distribution on the back of a nearby envelope. It looked kind of interesting, so I made an accurate version [it looked like the-rise-and-fall-of something]. While I realize that there have been a few new drugs in each class that aren’t represented here, these are the major players. There were several things I thought about looking at the frequency distribution of my major-psych-drugs-in-patent-timeline.

There’s the obvious thing [forgetting about the late-comers and me-toos for the moment]. We’re beyond the "pipeline" days when the detail-reps and KOLs were paid to go from place to place pushing these drugs. There’s also some relief from the horrible Direct-To-Consumer ads, so I’ve essentially stopped talking back to the television set. I would hope that this is a time when we can properly evaluate each of these classes and its members without the roar from advertising, ideologues, and tainted KOLs. And since the majority of the prescriptions are being written by primary care physicians, it behooves us to clarify the efficacy, toxicity, and rational indications for every one of  these drugs. Some think they’re inert. Some think they’re poison. Some think they are the great leap forward. Those are scientific, not ideological, issues, and the real answer is more elusive than it ought to be at this point.

But even without the pressure from PHARMA and an empty pipeline, these drugs are selling like hot-cakes, and the consensus is that they are still way over-prescribed [at least my consensus]. With the increasingly large databases from healthcare plans and the government, we ought to be able to figure out why. And we need to know how many stay on the drugs just to avoid withdrawal symptoms, and figure out how to help them safely get off. Many of the problem come with long term use, and a lot of patients and doctors continue them as "preventive insurance" or something like that in inproven situations. Also, it appears that the generic drug makers are jumping on the high price band-wagon along with the patent-holders, so somebody needs to curb that trend. And I suspect that PHARMA isn’t the only industry pushing these medications. Managed Care and other third party payers like the drugs because in spite of their high cost, they are still cheaper than other interventions and they get a checkmark in the treatment box [an analogy to deinstitutionalization comes to mind].