1 Boring Old Man

Most UK docs support disclosing payments from drug makers: survey

Pharmalot

by Ed Silverman

October 13, 2015

To disclose or not to disclose, that is the question. A new survey of UK health providers finds that an overwhelming majority of those queried – 87 percent – believe that payments from drug makers should be transparent. And 69 percent who currently have a relationship with at least one drug company say they have given – or are likely to give – permission to have payment information disclosed. The survey was conducted by the Association of the British Pharmaceutical Industry, which last year began publishing aggregated payments to doctors and, next year, will publish certain detailed fees. The move to disclose some payments came as part of an updated industry code of conduct, which occurred following concerns about financial ties between providers and companies.

“This project is another step on our journey towards greater transparency, which will allow patients and others to fully understand our relationships,” said Virginia Acha, an ABPI executive director, in a statement. The trade group queried 507 doctors, nurses, hospital specialists, and pharmacists. Nonetheless, there is still some resistance.

Thirty-two percent believe it is unnecessary for drug makers to disclose payments to individual health care providers, and 26 percent feel disclosure will adversely affect medical innovation. Meanwhile, 75 percent said disclosure will not affect their relationships with industry, although 23 percent of general practitioners said they will be less likely to work with drug makers if payment data is published. By contrast, 17 percent of hospital specialists felt similarly. The issue has generated considerable attention, especially in the United States, where a federal database called Open Payments launched last year. The Centers for Medicare & Medicaid Services created the database in response to a US Senate investigation several years ago that raised questions about undue influence drug and device makers may have on medical practice and research.

Although critics of the Open Payments database regularly expressed concern that disclosure would dissuade many physicians from participating in research, there is no indication, to date, to suggest this has happened. The United Kingdom has trailed in mandating disclosure thanks to the ABPI, which has tried to get ahead of the curve and ward off government requirements. But the UK government may require disclosures after an undercover newspaper investigation this summer showed drug makers allegedly paid National Health Service staffers to use specific medicines.

My early years were spent living on the campus of a boys military school where my father taught and coached, a school I later attended for a few years. It was founded and run by a family of [fundamentalist] Presbyterians [of the Scottish John Calvin kind] – an overdose of the Protestant Work Ethic, a strict unforgiving morality, and chapel at least twice a day. By their read, the appearance of sin was almost as bad as the real thing. In mid high school, I fled to a normal 1950s school where I thrived – free at last! But I think some of that Calvinism must’ve gone all epigenetic in those years, because I still can’t think of any reason for physicians to be paid by drug companies unless they work for them. And that feels like it’s in my DNA. Given the choice, I’d rather not have to deal with COIs at all. So although I’m glad that articles now have industry affiliations listed, that there’s a ProPublic Database, and that we passed a Sunshine Act, in my heart of hearts, I’m a Calvinist about doctors with industry ties – the appearance is almost as bad as the real thing. And there’s nothing in all the corruption and scandal [particularly in my specialty of psychiatry] to temper my uncharacteristic moral rigidity on this point. I now read articles in this specific order:

• the title
• the author by-line and the funding sources
  
• the COI declaration and the acknowledgements
  
• and then I read the article
  

In my mind, I call it the global-specter-of-the-mental-illness-epidemic-official-introductory-paragraph. It’s the opener for many articles in our clinical trial literature, Tom Insel’s blogs introducing his most recent NIMH neuroscience initiative, countless psychopharmacology reviews, and sometimes a professional organizations’ articles about insurance parity. When I read them, they remind me of a John Birch Society film I endured in college where a white map of the world was gradually turned bright crimson by the spreading red menace of communism; or the early Steve McQueen film, the Blob, where a town and its inhabitants are eaten by a growing mass of pink jello from outer space; or a Zombie film I recently watched [a little bit of] to see what they were about; or almost any post-apocalyptic sci-fi film. The example above is from a ghost-written review article whose guest authors had undisclosed financial ties to the manufacturer of the reviewed product.

• Burden of Disease – Implications for Future Research [2001]
• THE GLOBAL BURDEN OF DISEASE, 2004 UPDATE [2004]
• The Global Economic Burden of Non-communicable Diseases [2011]

Darkness Invisible: The Hidden Global Costs of Mental Illness

Foreign Affairs

By Thomas R. Insel, Pamela Y. Collins, and Steven E. Hyman

January/February 2015

Four years ago, a team of scholars from the Harvard School of Public Health and the World Economic Forum prepared a report on the current and future global economic burden of disease. Science and medicine have made tremendous progress in combating infectious diseases during the past five decades, and the group noted that noncommunicable diseases, such as heart disease and diabetes, now pose a greater risk than contagious illnesses. In 2010, the report’s authors found, noncommunicable diseases caused 63 percent of all deaths around the world, and 80 percent of those fatalities occurred in countries that the World Bank characterizes as low income or middle income. Noncommunicable diseases are partly rooted in lifestyle and diet, and their emergence as a major risk, especially in the developing world, represents the dark side of the economic advances that have also spurred increased longevity, urbanization, and population growth. The scale of the problem is only going to grow: between 2010 and 2030, the report estimated, chronic noncommunicable diseases will reduce global GDP by $46.7 trillion.

These findings reflected a growing consensus among global health experts and economists. But the report did contain one big surprise: it predicted that the largest source of those tremendous future costs would be mental disorders, which the report forecast would account for more than a third of the global economic burden of noncommunicable diseases by 2030. Taken together, the direct economic effects of mental illness [such as spending on care] and the indirect effects [such as lost productivity] already cost the global economy around $2.5 trillion a year. By 2030, the team projected, that amount will increase to around $6 trillion, in constant dollars — more than heart disease and more than cancer, diabetes, and respiratory diseases combined.

These conclusions were dramatic and disturbing. Yet the report had virtually no impact on debates about public health policy, mostly because it did not manage to dislodge persistent and harmful misperceptions about mental illness. In wealthy countries, most people continue to view mental illness as a problem facing individuals and families, rather than as a policy challenge with significant economic and political implications. Meanwhile, in low-income and middle-income countries and within international organizations, officials tend to view mental illness as a “First World problem”; according to that view, worrying about mental health is a luxury that people living in severe poverty or amid violent conflict cannot afford.

People underestimate the costs and significance of mental illness for many reasons. At the most basic level, policymakers and public health officials tend to view mental illness as fundamentally different from other medical problems. But just like other diseases, mental illnesses are disorders of a bodily organ: the brain. In this respect, they are no different from other noncommunicable diseases.

Such steps will go a long way toward reducing the damage mental disorders inflict on societies and economies all over the world. But for such measures to succeed, policymakers and experts must first pull mental illness out of the shadows and into the center of debates about global public health.

In the past, I’ve accused Dr. Insel of misunderstanding the meaning of his title, Director. The usual meaning would be Director as in person who directs the agency that funds research. He seems to me to think it means Director as in person who directs what researchers do. There are lots of checks to keep researchers from following esoteric or trivial projects. Translational research means projects that can be put into clinical use quickly. The NIH/NIMH powers are big on Translational Research and Translational Centers [a particularly paradoxical mandate given Dr. Insel’s recent comment, "Dr. Insel reflects on the recent, great advances in brain science, and his disappointment that these developments have yet to reach a great majority of those who suffer from mental illness" – see a reset button…].

• NIMH Strategic Plan for Research
• Strategic Research Priorities
• The Anatomy of NIMH Funding
• Research Domain Criteria (RDoC) Initiative
• Future Funding Recommendations [Concept Clearances]
• FY 2015 Funding Strategies for Research Grants

• Neuroscience and Basic Behavioral Science
• Translational Research
• Services and Intervention Research
• AIDS Research
• Research Training and Career Development
• Small Business Research Opportunities
• Technology Development and Coordination
• Genomics Research Coordination
• Research on Disparities and Global Mental Health

In its first almost 40 years, NIMH enjoyed the leadership of five directors who were astute politicians and administrators. They saw their job as running interference for the scientists for funding, for Congressional support, and for public image. None of the first five Directors had reputations as scientists. They let the field shape the science through a bottom-up process. Over the last almost 20 years, the two most recent Directors acted very differently, operating with a top-down style of management that frequently was abrasive…

Given the NIMH output during the twenty years under discussion, there’s little evidence that exerting this much control has been very productive – too much form without accompanying substance. And it doesn’t take much reading of the strategic directives above to see that there is a theme to what is considered strategic [we might call it Insel’s theme]. Hopefully, the next Director will have more faith in our research community. Likewise, given the freedom to follow their intuition, they will likely be more committed [and more productive]…

Tom Insel came to the NIMH at the height of the rise of neuroscience. It was a new century. The future DSM-5 team was just setting its sights on finally adding the hard science fixings to the psychiatrized brain. The drugs were steadily pouring from the pharmaceutical pipeline and were hitting the top of the charts in sales. New drug strategies were closing in on the treatment resistant cases. With the human genome cracked and a maturing of neuroimaging, it was just a matter of time before the dream of the new  psychiatry would be a reality. A few years into his reign, Dr. Insel announced this new paradigm, Psychiatry was to become Clinical Neuroscience:

Balancing Immediate Needs with Future Innovation

NIMH Director’s Blog

by Thomas Insel

January 26, 2012

NIMH, like all Institutes at NIH, has an advisory council that meets three times each year. The National Advisory Mental Health Council [NAMHC] is a distinguished group of scientists, advocates, clinicians, and policy experts. Each of our meetings includes a closed session to review individual grants considered for funding and a session open to the public that engages this diverse group in discussions about the larger issues that guide NIMH funding.

At last week’s session, we heard a recurrent tension around one such larger issue. Some members of Council bear witness to the poor quality of care, the unmet medical need, and the diminishing investments by states on behalf of people with mental disorders. They reasonably ask, “How are we ensuring that the science that NIMH has produced is implemented where the need is greatest?” They also question on the pay-off of genetics research. After all, two decades after the gene for Huntington’s disease was identified, we still have no effective treatments, and Huntington’s disease is genetically far simpler than schizophrenia or bipolar disorder. In contrast to so many neurological diseases, we have effective treatments for schizophrenia and bipolar disorder. NIMH should be investing to ensure these are available.

The opposing argument runs something like this. There has been no major innovation in therapeutics for most mental disorders since 1960. Current treatments are not good enough for too many. Rather than investing scarce dollars for incremental improvements or increased dissemination of mediocre interventions, we need invest in the fundamental science of brain and behavior so that we can understand how to develop better treatments.

While I may have oversimplified the two sides of this debate, the divide is substantial. Some advisors want more funds in services research; other advisors want more funds in basic neuroscience. Some are thinking of the immediate needs; others are focused on the paradigm shifts that may be revealed by another decade of research. And with the NIMH budget stretched, tough choices must be made…

Sixty years ago, the nation faced a similar short-term vs. long-term debate about polio. The needs were growing and the causes were unknown. Some wanted funds invested only in better services, including improved iron lungs. Others argued for investing in a vaccine with a long-term goal of eradication. As David Oshinsky explains in his outstanding retelling of this debate, the government went with the services approach, leaving advocates and families to raise funds for vaccine development. Let us hope we don’t short-change our grandchildren, sixty years from today, by failing to invest in the long-term promise of more effective diagnostics and therapeutics for mental disorders.

Dr. Thomas Insel: Our Mental Health System Is ‘Badly Broken’

The American Conversation

The Takaway

October 07, 2015

[audio]

Millions of Americans suffer from mental illness. The vast majority of them have never been violent and never will be. But over the last few years, a good number of the young men involved in mass murders have suffered from mental illness: Christopher Harper-Mercer, the gunman who killed nine people at Umpqua Community College last week, had Autism Spectrum Disorder.

James Holmes, recently sentenced to life in prison for murdering 12 people in Aurora, Colorado, was diagnosed with a disease similar to schizophrenia. Adam Lanza, who shot and killed 26 people at Sandy Hook Elementary School, had severe anxiety, obsessive-compulsive disorder, anorexia and a number of other problems.

As the director of the National Institutes of Mental Health [NIMH], Dr. Thomas Insel has kept track of these headlines. As he steps down from his position after 13 years at the NIMH, Dr. Insel reflects on the recent, great advances in brain science, and his disappointment that these developments have yet to reach a great majority of those who suffer from mental illness.

"The mental health system is badly broken," Dr. Insel tells The Takeaway. "The problem right now is that we have a lot of people with mental illness that are not treated at all, treated very late, or treated very inadequately."

In November, Dr. Insel will step down after 13 years leading NIMH for a job at Google Life Sciences. He tells John Hockenberry about his hopes for his new position, and technology’s potential in treating mental illness…

Dr. Insel went straight from his psychiatry residency [1976-1979] to the NIMH [1979-1994], then to the Yerkes Primate Center [1994-1999], followed by administrating a translational behavioral neuroscience program [1999-2002], then he finally returned to the NIMH as Director [2002-2015]. I happen to know this history [which is devoid of any clinical experience] because I was trying to understand how he had come to have such a simplistic view of mental illness. He apparently believes those population estimates he often quotes are accurate ["… by 20xx, depression will be the number x cause of xxxxx"] [epidemic?]. He seems to have accepted the notion that all mental illnesses are biomedical circuit problems and the solution to the mental health system is badly broken is a new crop of drugs/treatments and some kind of outreach to find the untreated cases. Having failed to achieve the 2015 goal of "Biodiagnostics" and "Treatment of Core Pathology", he just went ahead and declared a new Biodiagnostic System anyway – the RDoC [whatever that is].

Tom Insel was a surprise pick as Director of the NIMH in 2002. He came in like a lion championing the cause of Clinical Neuroscience. My guess is that he, the powers that be in the APA, and the DSM-5 Task Force  thought that their bet that scientific advances in genetics and the identification of biomarkers was a slam dunk – and would come in time to complete the biomedical paradigm shift begun in the 1980s. They were dead wrong about that, but unable to alter their trajectory. Dr. Insel has been silent about the set-backs: record fines against the makers of the psychiatric-drugs, the scandals involving psychiatrists in high places, the embarrassment of the DSM-5 and its COI problems, the disappointment in the progress in psychiatric research, ghostwriting and guest authorship, and a growing sentiment that instead of new drug development we should be focusing on the over-use and misuse of the drugs we already have. The refrain, "Dr. Insel reflects on the recent, great advances in brain science…" has been oft-repeated, but I can’t come up with anything that might justify that assertion. Let’s hope that his replacement will be someone who is able to find a reset button that might get us on a new path [and acknowledge the sins of the fathers].

Senator asks FTC to investigate Shkreli for antitrust violations

Pharmalot

by Ed Silverman

October 8, 2015

A US Senator has asked the Federal Trade Commission to investigate whether drug makers are hiking prices and then restricting distribution to prevent generic drug makers from making lower-cost versions of their medicines. In a letter to the agency, Minnesota Senator Amy Klobuchar cited Martin Shkreli and his Turing Pharmaceuticals, which created a nationwide sensation after recently buying a life-saving medicine and then raising the price from $13.50 a pill to $750. This 5,000 percent price hike triggered a new round of scrutiny of prescription drug costs that is now spilling over into the presidential election campaign.

In her letter, Klobuchar noted that Turing uses a controlled distribution system to prevent generic drug makers from purchasing its pill. Without sufficient supplies, a generic drug maker is unlikely to have enough medicine to run clinical tests needed for FDA approval. And a generic medicine must be bioequivalent with a brand-name drug, meaning it must produce the same sort of effect in a patient.

As we explained earlier this week, Turing maintains a select list of qualified buyers, including a specialty pharmacy to fill individual prescriptions, as well as certain hospitals and clinics. But all shipments come from a division of a major wholesaler that must clear any other purchase requests with Turing. And a Turing executive acknowledged that he would reject any orders from a generic drug maker. Klobuchar complains that this system, which is sometimes employed by other pharmaceutical companies, deserves investigation because it may preclude competition and, ultimately, force consumers to pay higher prices for medicines.

“As a public policy matter, this practice is disturbing, but as you know, the antitrust laws do not apply to unilateral price increases, no matter how unfair,” Klobuchar wrote in her letter to FTC chairwoman Edith Ramirez. “If a company were to employ this strategy to deny competitors supply for use in a generic application, it would be doing more than simply raising prices,” she continued. “It could be excluding competition from the market to the detriment of consumers and violating the Federal Trade Commission Act.”

• Academic·Industrial·Complex I…
• Academic·Industrial·Complex II…
• Academic·Industrial·Complex III…

They hit a glitch when a subject, Dan Markingson, killed himself while in a study in 2004. He had been recruited in an absurd way. He was declared incompetent, committed to treatment, but was offered a much less restrictive placement if he volunteered for a Clinical Trial. The paradox is obvious – declared incompetent? but volunteered? By my read of his records, Dan remained in a psychotic state throughout his stay in a halfway house until his suicide six months into the study. Ultimately, the legislature passed "Dan’s Law" in 2009 which prohibited the recruitment of committed patients for drug trials.

U owes mistreated psychiatric subjects an apology

Star-Tribune

By Carl Elliott

October 7, 2015

Thanks to a former Fairview Hospital patient with the courage to speak out about his mistreatment, the University of Minnesota is finally ending a controversial research practice. As of last month, the university will no longer test experimental drugs on mentally ill patients who have been involuntarily confined to a locked psychiatric unit under a 72-hour hold [“U halts recruiting of confined patients,” Sept. 26].

In July 2007, Robert Huber came to Fairview for help. He was hearing voices and feeling panicked. His treating psychiatrist, Dr. Stephen Olson, used a 72-hour emergency hold to confine Huber to a locked psychiatric unit. Then Olson asked Huber to sign up for a research study testing an experimental drug.

A pharmaceutical company was testing an unapproved antipsychotic drug called bifeprunox. Huber had never been prescribed any antipsychotic drug before, much less an experimental one, but he agreed to take part because he thought it was the only way to escape confinement. “I was so afraid they were going to lock me up,” Huber told the Star Tribune.

The study went very badly. The drug caused severe side-effects. Huber considered suicide. Only a few weeks after he was enrolled, the FDA rejected the drug for marketing approval, citing the death of a research subject in Europe. Yet nobody at the university told Huber — or for that matter, any of the other subjects enrolled in the U study — that the FDA had rejected the drug.

When Huber’s story was made public by KMSP-TV news in 2014, the university tried to smear him. A press statement prepared with the assistance of Brian Lucas, the senior communications director for the U’s Academic Health Center, read in part: “His medical record shows extreme anxiety and paranoia, a history of head injuries and lengthy battle with alcoholism. It is highly inappropriate for him to be put in the media spotlight as a spokesperson for clinical trial safety.”

In early 2013, Huber and I filed separate complaints to the university. It took over 14 months for the university to respond. The university hired an external consulting firm at a cost of $22,000, but neither the university nor the consulting firm ever bothered to interview Huber about what had happened to him. Finally, on May 6 of last year, the university sent Huber a letter informing him of its conclusion. The letter conceded minor problems but said, “You were not pressured or coerced to participate in this study.”

Huber deserves an apology from the university. He also deserves our gratitude, for having the courage to step forward and tell his story. There may well have been many other patients like him over the years. If the university is genuinely committed to research reform, it will find out how many other involuntarily committed patients have been recruited into research studies, and will apologize to them as well.

In both of these Minnesota cases, recruitment and retention by any means necessary trumped clinical care, scientific observation, and the intent of the involuntary hospitalization procedures of the legal system. I question whether Charles Schulz stepping down is even close to enough. He apparently provided administrative support and brought in the studies, but left the actual conduct of the Clinical Trials in the hands of others [like Stephen Olson]. With the same people in charge, what’s to guarantee that the same forces won’t be at work in the future?

My complaint about the FDA is that they protect the drug companies claim of Clinical Trial data being private property, and they are slow as molasses with FOIA requests on newer drugs. We should at least be able to get the NDA medical reports when the drugs are approved, and we can’t. The lag time is forever because they vet them – and I vehemently object to that. The other thing is that they respond to the pressure to get new drugs on the market. It reminds me of the "body counts" from the Viet Nam days as if that number mattered. The safety and efficacy of a drug has nothing to do with the other drugs being evaluated. A drug is either approvable or not, and that rate of approval is a measure of nothing worth knowing. I don’t particularly like approving drugs for "diagnoses" because our DSM-III, IV, & 5 diagnoses suck, but I can’t think of an better alternative. The thing I don’t like Califf’s resume is that he directed a Translational Program. I’m not keen on the "translational" concept. What’s the hurry? But other than that, my criteria for FDA Director are simple – honesty and common sense.

FDA official took name off papers

Nominee to lead agency wrote series examining clinical trials

Boston Globe

By Sheila Kaplan

October 07, 2015

This story was produced by STAT, a national publication from Boston Globe Media Partners that will launch online this fall with coverage of health, medicine, and life sciences. Learn more and sign up for STAT’s morning newsletter at statnews.com.

President Obama’s nominee to lead the Food and Drug Administration recently coauthored a series of scientific papers raising concerns about the agency’s oversight of clinical trials but asked that his name be removed before publication, according to other authors. Dr. Robert Califf, the Duke cardiologist first named a deputy commissioner in January and then nominated for the top post last month, was the driving force behind the series, which was published in the October issue of the journal Clinical Trials.

The heart of the series is an examination of what are known as pragmatic clinical trials — an increasingly popular type of study that seeks to compare two or more treatments in a real-world setting instead of in a traditional clinical environment. Portions of the papers are critical of the agency and recommend policy changes that would be highly divisive. Califf, who completed most of the series before he joined the FDA, remained as an editor of the publication but asked that his name be removed from the three articles he had co-written, according to other authors and the publisher of the series. He also remained a coauthor on the brief introduction to the series.

It’s unclear what prompted Califf to remove his name — a decision that could raise ethical concerns. It is highly unusual for authors of scientific papers to have their names removed before publication. A spokeswoman for Califf said he declined to comment. A coauthor on one paper, speaking on condition of anonymity because of the sensitivity of the matter, said Califf had been told to mask his authorship by the FDA. A spokeswoman for the agency suggested it was his decision. “Dr. Califf requested that his name be removed as a coauthor from these three articles out of an abundance of caution to avoid any perception that he would be commenting as an FDA official through these articles,” the spokeswoman said in a statement to STAT…

Exploring the ethical and regulatory issues in pragmatic clinical trials

by Robert M Califf and Jeremy Sugarman

Clinical Trials. 2015 12[5]:436-441.

[full text online]

The need for high-quality evidence to support decision making about health and health care by patients, physicians, care providers, and policy-makers is well documented. However, serious shortcomings in evidence persist. Pragmatic clinical trials that use novel techniques including emerging information and communication technologies to explore important research questions rapidly and at a fraction of the cost incurred by more “traditional” research methods promise to help close this gap. Nevertheless, while pragmatic clinical trials can bridge clinical practice and research, they may also raise difficult ethical and regulatory challenges. In this article, the authors briefly survey the current state of evidence that is available to inform clinical care and other health-related decisions and discuss the potential for pragmatic clinical trials to improve this state of affairs. They then propose a new working definition for pragmatic research that centers upon fitness for informing decisions about health and health care. Finally, they introduce a project, jointly undertaken by the National Institutes of Health Health Care Systems Research Collaboratory and the National Patient-Centered Clinical Research Network [PCORnet], which addresses 11 key aspects of current systems for regulatory and ethical oversight of clinical research that pose challenges to conducting pragmatic clinical trials. In the series of articles commissioned on this topic published in this issue of Clinical Trials, each of these aspects is addressed in a dedicated article, with a special focus on the interplay between ethical and regulatory considerations and pragmatic clinical research aimed at informing “real-world” choices about health and health care.

The Food and Drug Administration and pragmatic clinical trials of marketed medical products

by Monique L Anderson, Joseph Griffin, Sara F Goldkind, Emily P Zeitler, Liz Wing, Sana M Al-Khatib, Rachel E Sherman,
«and formerly Robert M Califf»

Clinical Trials. 2015 12[5]:511–519.

[full text online]

Pragmatic clinical trials can help answer questions of comparative effectiveness for interventions routinely used in medical practice. Pragmatic clinical trials may examine outcomes of one or more marketed medical products, and they are heterogeneous in design and risk. The Food and Drug Administration is charged with protecting the rights, safety, and welfare of individuals enrolled in clinical investigations, as well as assuring the integrity of the data upon which approval of medical products is made. The Food and Drug Administration has broad jurisdiction over drugs and medical devices [whether or not they are approved for marketing], and as such, clinical investigations of these products are subject to applicable Food and Drug Administration regulations. While many pragmatic clinical trials will meet the criteria for an exemption from the requirements for an investigational new drug application or investigational device exemption, in general, all clinical investigations of medical products that fall under Food and Drug Administration jurisdiction must adhere to regulations for informed consent and review by an institutional review board. We are concerned that current Food and Drug Administration requirements for obtaining individual informed consent may deter or delay the conduct of pragmatic clinical trials intended to develop reliable evidence of comparative safety and effectiveness of approved medical products that are regulated by the Food and Drug Administration. Under current regulations, there are no described mechanisms to alter or waive informed consent to make it less burdensome or more practicable for low-risk pragmatic clinical trials. We recommend that the Food and Drug Administration establish a risk-based approach to obtaining informed consent in pragmatic clinical trials that would facilitate the conduct of pragmatic clinical trials without compromising the protection of enrolled individuals or the integrity of the resulting data.

Gatekeepers for pragmatic clinical trials

by Danielle M Whicher, Jennifer E Miller, Kelly M Dunham, Steven Joffe,
«and formerly Robert M Califf»

Clinical Trials. 2015 12[5]:442-448.

[full text online]

To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure [e.g. clinics, facilities, staff], eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the US clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This article provides a framework to help guide gatekeepers’ decision-making related to the use of resources for pragmatic clinical trials. Relevant ethical considerations for gatekeepers include [1] concern for the interests of individuals, groups, and communities affected by the gatekeepers’ decisions, including protection from harm and maximization of benefits; [2] advancement of organizational mission and values; and [3] stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers’ actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding the use of limited and valuable resources.

Considerations in the evaluation and determination of minimal risk in pragmatic clinical trials

by John D Lantos, David Wendler, Edward Septimus, Sarita Wahba, Rosemary Madigan, Geraldine Bliss,
«and formerly Robert M Califf»

Clinical Trials. 2015 12[5]:485-493.

[full text online]

Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule [45 CFR 46, Subpart A] and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes “minimal risk,” there are important practical implications: the institutional review board may then allow a waiver or alteration of the informed consent process; the study may be carried out in certain vulnerable populations; or the study may be reviewed by institutional review boards using an expedited process. However, it is unclear how institutional review boards should assess the risk levels of pragmatic clinical trials. Such trials typically compare existing, widely used medical therapies or interventions in the setting of routine clinical practice. Some of the therapies may be considered risky of themselves but the study comparing them may or may not add to that pre-existing level of risk. In this article, we examine the common interpretations of research regulations regarding minimal-risk classifications and suggest that they are marked by a high degree of variability and confusion, which in turn may ultimately harm patients by delaying or hindering potentially beneficial research. We advocate for a clear differentiation between the risks associated with a given therapy and the incremental risk incurred during research evaluating those therapies as a basic principle for evaluating the risk of a pragmatic clinical trial. We then examine two pragmatic clinical trials and consider how various factors including clinical equipoise, practice variation, research methods such as cluster randomization, and patients’ perspectives may contribute to current and evolving concepts of minimal-risk determinations, and how this understanding in turn affects the design and conduct of pragmatic clinical trials.

Ketamine is an anesthetic, sold on the streets as the club drug Special K, and is much mentioned as an antidepressant for Treatment Resistant Depression. It began to be discussed around the time the CNS drug pipeline from PHARMA ran dry – a flurry among those who had shepherded the psychopharmacology waves of the twenty-five years following the introduction of Prozac®. Ketamine is given intravenously and its beneficial effect is short-lived [a week +]. I assumed it was a Hail Mary Pass – a long shot by people who had made a career out of discussing new biomedical psychiatric treatments just around the corner who suddenly didn’t have anything new to talk about. The notion of an I.V. anesthetic/street-drug with a short duration of action being a viable therapy just didn’t fit my idea of psychiatric practice. I’ve avoided discussing Ketamine here because my cynicism is based more on the climate and my opinion of the people who have jumped on the band-wagon than anything particularly scientific or medical. There’s more than enough bias going around. So why add to the din? But now there are two recent meta-analysis/review articles about Ketamine and other glutamate receptor modulators that made me change my mind. First, the Cochrane Systematic Review:

Ketamine and other glutamate receptor modulators for depression in adults:

PLAIN LANGUAGE SUMMARY

The Cochrane Library 2015, Issue 9.

[abstract]

What does the evidence from the review tell us?
Among the 11 drugs included in this review, only ketamine was more effective than placebo at reducing symptoms of depression. These effects lasted no more than one week after treatment and clearly disappeared after two weeks. Ketamine did, however, cause more confusion and emotional blunting than placebo. These findings were based on low quality evidence.

^{My summary of the review: Ketamine has an ‘antidepressant’ effect for a week or so. There’s no way to blind the studies because of the up front club drug effect, so there’s no solid way to differentiate Ketamine’s feel-good versus its specific antidepressant properties.}

The Cochrane Systematic Reviews are as close as we can come with the current level of data transparency to having reports on various medical treatments that are comprehensive and free of outside influence. While nothing’s perfect, the rigor and techniques used to produce these reports is certainly impressive. They are published in brief or in the encyclopedic variety. I included the PLAIN LANGUAGE SUMMARY and linked the abstract. The fullest report is a 326 page document. In this case, the reviewers rated the quality of the data as pretty low.

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.

^{My summary of the review: Ketamine has an ‘antidepressant’ effect for a week or so. The authors are sure taken with rapastinel [GLYX-13] in spite of the fact there’s only really one study – a phase 2 trial with only company authors.}

I was recently describing NIMH chief Tom Insel as a breakthrough·freak… – always focusing on some future leap forward in biomedical psychiatric treatment. He is certainly not alone in that category. Before his fall from grace, the senior author in this review lead the pack of the breakthrough·freaks – Dr. Charles Nemeroff [once nick-named "bling-bling" because of his penchant for new novel treatment possibities]. His downfall came with review articles of treatments where he was exposed as having undeclared financial interests – see hubris… and sally’s world…]. I once even compiled his review article publication rate.

Given Dr. Nemeroff’s history of allowing commercial interests to slip into review articles, one would be remiss in not looking carefully at an article like this review of Ketamine. And it’s another breakthrough kind of treatment like his recent interests in personalized medicine [genetic and other testing to pick medications, also outrunning its science – Genetic tests for psychiatric drugs spur hope, doubts]. In fact, everyone on the author byline of this AJP article is in the breakthrough freak category [Transcranial Neuromodulation, Vagal Nerve Stimulation, Deep Brain Stimulation, etc] and there are plenty of industry connections in the declaration section of this article, some raising eyebrows.

For the moment, I just want to mention that the Cochrane Meta-analysis, while confirming the short-term effect of Ketamine, found little promise from other glutamate receptor modulators. There’s no commercial breakthrough with Ketamine itself as it’s off patent and readily available. But finding other glutamate receptor modulators that could be developed commercially is another matter altogether. The AJP article mentions them repeatedly and paves the way for their future development – one in particular.

Dr.Newport has received research support from Eli Lilly, GlaxoSmithKline, Janssen, NARSAD, NIH, and Wyeth; he has served on speakers’ bureaus for AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and he has served on the advisory board for GlaxoSmithKline. Dr. Carpenter has served as a consultant for AbbVie, Magstim, Naurex, Taisho [Helicon], and Takeda/Lundbeck; and she has received research support from Cervel Neurotech, NeoSync, Neuronetics, and NIH. Dr. McDonald has received research support from Cervel Neurotherapeutics, the Health Resources and Services Administration, NIMH, the National Institute of Neurological Disease and Stroke, Neuronetics, Soterix, and the Stanley Foundation; he has served as a consultant for the Center for Devices and Radiological Health, the Food and Drug Administration, and the Neurological Devices Panel of the Medical Devices Advisory Committee; he is a member of the APA Council on Research and Quality representing ECT and Neuromodulation Therapies; he holds a contractwith Oxford University Press to co-edit a book on the Clinical Guide to TranscranialMagnetic Stimulation in the Treatment of Depression; he serves on the editorial boards of the American Journal of Geriatric Psychiatry and the Journal of ECT; and he is Section Editor for Current Psychiatry Reports. Dr. Tohen has been employed with Eli Lilly; he has received honoraria from or consulted for Abbott, Alkermes, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Elan, Eli Lilly, Forest, Geodon Richter Plc., Janssen/Johnson and Johnson, Lundbeck, Merck, Pamlab, Otsuka, Roche, Sepracor Wyeth, Sunovion, Teva, and Wiley Publishing; and his spouse has been employed with Eli Lilly. Dr. Nemeroff has received research/grant support from NIH; he has served as a consultant for Allergan, Clintara LLC, Eli Lilly, Gerson Lehrman Group Healthcare and Biomedical Council, Lundbeck, Mitsubishi Tanabe Pharma Development America, Prismic Pharmaceuticals, Roche, Shire, SK Pharma, Taisho Pharmaceutical, Takeda, Total Pain Solutions, and Xhale; he is a shareholder with Abbvie, Celgene, OPKO Health, Seattle Genetics, Titan Pharmaceuticals, and Xhale; he has served on scientific advisory boards for American Foundation for Suicide Prevention, Anxiety Disorders Association of America, Brain and Behavior Research Foundation [formerly NARSAD], Clintara LLC, RiverMend Health LLC, Skyland Trail, and Xhale; he holds patents forMethod and devices for transdermal delivery of lithium [U.S. 6,375,990B1] and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay [U.S. 7,148,027B2]; he serves on the Board of Directors of American Foundation for Suicide Prevention, Anxiety Disorders Association of America, and Gratitude America; and he has received income sources or equity of $10,000 or more from American Psychiatric Association Publishing, Clintara, CME Outfitters, Takeda, and Xhale. Dr. Potash reports no financial relationships with commercial interests.

Rapastinel [GLYX-13] Study Like D-cycloserine, rapastinel is a partial agonist at NMDA receptor glycine binding sites. Whether rapastinel, like D-cycloserine, possesses pharmacodynamic specificity that varies by the NMDA receptor subunit on which the glycine binding site resides is unknown. The literature search identified one randomized clinical trial of rapastinel, evaluating the antidepressant efficacy of a single intravenous infusion at four doses [1, 5, 10, and 30 mg/kg] with treatment effects assessed at 2, 4, 8, and 12 hours and 1, 3, 7, and 14 days postinfusion.
Efficacy. No statistically significant differences were observed in rates of treatment response or symptom remission associated with placebo [64% and 42%, respectively] versus rapastinel at any dose [up to 70% and 53%, respectively]. However, statistically significant differences in the reduction of the 17-item HAM-D scores were observed for the 5-mg/kg dose at all intervals except day 14 [peak 17-item HAM-D reduction 3.1 points greater than placebo] and the 10-mg/kg dose at day 1 and day 3 [peak 17-item HAM-D reduction 4.3 points greater than placebo]. Neither the low [1 mg/kg] nor high [30 mg/kg] rapastinel doses were associated with significant greater 17-item HAM-D score reduction than placebo, leading the authors to posit an inverted U-shape dose response curve.

Psychotomimetic and dissociative side effects.The BPRS positive symptom subscale was administered in this trial with no differences observed between the placebo group and any of the four rapastinel treatment groups. The Clinician-Administered Dissociative States Scale was not administered in this study.

DUBLIN and EVANSTON, Ill., July 26, 2015 /PRNewswire/ — Allergan plc [NYSE: AGN], a leading global pharmaceutical company, and Naurex Inc., a clinical-stage biopharmaceutical company developing transformative therapies for challenging disorders of the central nervous system, today announced that they have entered into a definitive agreement under which Allergan will acquire Naurex in an all-cash transaction. Under the terms of the agreement, Allergan will acquire Naurex for a $560 million upfront payment net of cash acquired, $460 million of which is payable upon the closing of the acquisition and $100 million of which is payable by January of 2016 [or upon the closing if the closing has not occurred by such time], as well as potential R&D success-based and sales-threshold milestone payments. The Company remains committed to de-leveraging to below 3.5x debt-to-EBITDA by the end of the first quarter of 2016…

After a $560M Allergan buyout, Naurex vets regroup for CNS R&D

FierceBiotech

By Damian Garde

September 16, 2015

The brains behind Naurex, a drug developer acquired by Allergan ($AGN) for $560 million up front, have put the band back together, starting a new biotech with their old company’s technology and setting their sights on central nervous system disorders.

The new operation, Aptinyx, is spinning out of Naurex with much of its management team in tow, reuniting founders with the discovery platform behind the depression drug that first caught Allergan’s eye. Aptinyx is getting started with some early-stage oral treatments that modulate the brain’s NMDA receptors, a pathway the company believes has wide potential beyond GLYX-13, Allergan’s new late-stage antidepressant.

Under the terms of its spinout, Aptinyx is collaborating with Allergan on the discovery and preclinical development of some NMDA modulators for undisclosed psychiatric and neurologic disorders, and the Big Pharma has the right to in-license those as they progress. But the new company retains full rights to everything outside that umbrella, and Aptinyx is working through early-stage studies in traumatic brain injury, neuropathic pain, post-traumatic stress disorder and epilepsy.

The arrangement, Aptinyx CEO Norbert Riedel said, makes use of each party’s strengths. Allergan, a multinational giant, is well suited to take GLYX-13 through Phase III development, regulatory review and commercialization. But the company, under CEO Brent Saunders, has made no secret of its aversion to early drug development, preferring to leave that work to biotech and academia in favor of stepping in after the proof-of-concept stage. And Aptinyx is happy to fill that role in NMDA modulation, Riedel said.

As for the company’s proprietary assets, Aptinyx is in the preclinical stage with a handful of assets and expects to identify its first disease targets in the coming months. If everything goes according to plan, the company should be ready to start its first clinical trial in summer 2016, Riedel said.

Aptinyx rallied some of Naurex’s investors to raise seed money for its preclinical projects, but the biotech plans to put together a Series A financing round in the coming months to fund its clinical aspirations, he said.

Riedel, who served as CEO of Naurex, said his old company negotiated what would become Aptinyx into the Allergan buyout deal "to maintain the truly enormous value that remained in the early stage pipeline and our proprietary platform."

So back to my touch of paralysis. Review articles are meant to keep doctors up to date on medical information. Reading this one, you would leave it with the idea that there’s some new treatment up ahead coming for people who are depressed but don’t respond to the current drugs. That’s tainted information, in a major review article, in the major psychiatric journal, certified by a group affiliated with the American Psychiatric Association. Everything in the chain is "legal," and I look like some kind of lunatic muckraker for even bringing it up. Yet in a rational world, there should never be a review article with that kind of COI statement. The major psychiatric journal should never publish a review article by someone with Dr. Nemeroff’s record of using review articles for commercial promotion. And whereas this journal comes to the mailbox of a large number of practicing psychiatrists, one has to work at having access to the more rigorous and reliable Cochrane Systematic Reviews. Every person on this author by-line is an  Academic Psychiatrist on a major medical school faculty. Although no crime has been committed, and under the current state of play, nothing in this chain of events breaks any specific rule, nonetheless, the unacknowledged fingers of commercial enterprise are all over this review/meta-analysis in the American Journal of Psychiatry – the overall purpose of an academic journal has been subverted in plain view. It may seem a small thing, just a bright note about a coming possibility of a new avenue of treatment. But by now, we ought to know better. We ought to know that it’s just this kind of "bright note" that has edged mediocre and sometimes dangerous drugs into blockbusters leading to overdiagnosis and overmedication. Conflicts of Interest, whether declared or not, are by definition a central enemy in the free flow of honest medical information. In many areas of medicine, that information conduit has been captured and turned into an advertising platform. And Psychiatry has, unfortunately, lead the field… And as for my touch of paralysis, when I read the review in the AJP and chased down the COI and GLYX-13 connections to big doings on the industry side of drug development, the voices inside and outside of my head said that what I found was only circumstantial evidence – wouldn’t hold up in court. I wanted to write about it, but knew through anyone else’s eyes, it could be discounted as idle speculation by someone who has become paranoid by seeing too much corruption, and now is seeing it in everything. But on the other side, too many of us, myself included, sat quietly through decades of this kind of subtle industry influence and look where it got us. We settled for the standards used in the criminal justice system. The real standard in medicine and science in general is that there should not be the appearance of bias, not that there needed to be enough evidence to take to a court of law. And we all should know that declaring conflicts of interest is not the same as not having conflicts of interest. So in the end, I decided that in this case, silence isn’t golden. I’d rather be wrong and say I’m sorry later than be right and have kept my mouth shut like so many to the detriment of our specialty and our patients. I guess I’m saying that this really still is the elephant in the room that needs to be talked about…

Want to understand drug pricing? Tell pharma to open its books

Pharmalot

by Ed Silverman

September 30, 2015

Like it or not, Martin Shkreli is the new face of pharma. And for an industry already struggling with an image problem over the rising costs of prescription drugs, companies are going to have a hard time distancing themselves from one of the most controversial men in America. The reason is a lack of transparency. Drug makers do not really want to explain how medicines are priced and, as a result, they have adopted an air of secrecy in which one cowboy can create havoc for an entire industry.

“The [Shkreli] episode is really an extreme manifestation of an attitude that has taken over the industry,” said Bernard Munos, a former corporate strategy adviser at Eli Lilly who is now a senior fellow at FasterCures, a medical research think tank. Most drug companies “are not raising prices by 5,000 percent, but large prices will leave patients with the same impression.” To recap, the 32-year-old former hedge fund manager caused a firestorm last week when his company, Turing Pharmaceuticals, jacked up the price of a decades-old, life-saving medicine from $13.50 per pill to $750. At the same time, Shkreli made it impossible for competitors to produce low-cost generic versions of the drug…

Then there are the high prices set for new medications — such as the hepatitis C treatments from Gilead Sciences, which cost $1,000 or more per pill. The company argues that the drugs can save money down the line if patients avoid costlier care years later. There is sound logic to this argument, but in the short run health care budgets are strained. The issue is compounded still further by the tug of war between drug makers and insurers, with each blaming the other for the pricing controversy. Drug makers say they offer rebates and discounts to insurers that then shift more out-of-pocket costs onto patients, while insurers argue the prices are set too high in the first place.

In the end, the pricing problem is like peeling the proverbial onion. If the pharmaceutical industry wants to win consumer confidence, it will have to come clean about the mechanics behind its pricing. Otherwise, drug makers should brace themselves for increased scrutiny and calls for greater oversight. Shkreli may seem an aberration to some, but he is, in reality, the latest example of an ongoing and widespread grappling with the cost of medicines. Like safety warnings in a pharmaceutical ad, the industry may hope we look the other way, but Shkreli is a side effect that is simply too hard to ignore.

Why do drug companies charge so much?

Because they can…

Washington Post

By Marcia Angell

September 25, 2015

…The public should demand something in return for all that governmental support. Other advanced countries regulate drug prices in one way or another: Some cap profits, some cap the rate of price increases, some have formularies that limit drugs in each class to those that are most cost-effective, and some regulate in more than one way. But they all have some form of regulation, and the result is much lower prices for the same drugs. In the United States, by contrast, Congress has blocked Medicare from negotiating the price of drugs or creating a formulary for patients. It’s time that we, too, move to stop price-gouging by the pharmaceutical industry — even when no one notices.

What we think of as the good side of our Capitalism is when prices are controlled by the classic supply/demand equation. To make big money, you have to step outside of that equation. One way to do that is to have a monopoly eliminating the competition required to keep the supply and demand dynamics in the forefront. Shiller pointed to another big money ploy [that’s in the same ballpark as a ponzi scheme] – to create a runaway market that relies on unlimited growth that can’t possibly keep going forever and is bound to crash. The money is made on the way up and the secret is to get out before the fall [we don’t like to think about it very much, but our whole economy is a bubble right now]:

That’s just too big for the likes of this old man. But I can manage thinking about something else we all sort of know – the US healthcare industry is in a similar financial quagmire of its own right now [and has been for a while]:

Whether you call it a bubble, a monopoly, a captive audience, or just a mess doesn’t much matter. The point is that the problem isn’t Martin Shkreli. He’s just another greedy baby who jumped into the feeding frenzy. There are plenty more where he came from. He doesn’t have the style points of an Alex Gorsky [to obey the scout law…], but it’s part of the same problem. As a matter of fact, that Paxil Study 329 I can’t stop talking about is too. Sick people really are a captive audience. The pharmaceutical industry really does have a sanctioned monopoly under our current system of approving drugs. The current steep climb in medical costs in every sector really is a financial bubble of sorts. And our government’s attempts at getting into the driver’s seat really has been successfully thwarted so far by the powerful business interests of the greedy babies.

Considerable progress has been made in the development and evaluation of treatments, both pharmacologic and psychological, for a variety of different psychiatric disorders. This research has emphasized the use of the randomized clinical trial [RCT], which is widely regarded as the gold standard of evaluation of efficacy and effectiveness in medicine. The characteristics of a well-performed RCT are well established. They include the following features:

1. A well-defined and justified population, with a representative sample of sufficient size, to yield power to detect clinically significant differences between treatments and to provide accurate estimates of the effect sizes in that population on which to base considerations of clinical or policy significance.
2. One or more control or comparison groups, with protocols for treatment in each group specified well enough to permit replication in the clinic or another research project.
3. Randomization to treatment and control or comparison groups to avoid confusing selection effects with treatment effects.
4. A few a priori, well-chosen, and justified outcome measures, selected in advance of the trial, obtained either blinded to treatment group or otherwise with measurement bias controlled to avoid confusing the opinions or expectations of patients or researchers with treatment effects.
5. Analysis performed by intention to treat [ie, all randomized subjects are included in the analysis of outcome]. Only those subgroups specified and justified in the a priori hypotheses [eg, baseline severity] or in the design [eg, sites in a multisite study] are addressed in the primary analysis.
6. A valid test for statistical significance and estimates of effect sizes informative enough to guide consideration of clinical and policy significance.

The knowledge derived from such RCTs is of direct relevance to health care system reform and the growing demands for accountability…

In psychiatry, we’re primarily focused on the problems from two classes of drugs – the "SSRI Antidepressants" and the "Atypical Antipsychotics" – both variations on older themes. We thought of their predecessors as dangerous and self limiting, used in dire situations. Their toxicity was on the front page – too many everyday adverse effects to expect people to take them long term even when recommended. One way to frame the modern problems doesn’t have to do with the Clinical Trials that got them on the market but rather with the dramatically broadened indications. With the "SSRI Antidepressants," the DSM-III had handed indications to the pharmaceutical companies on a silver platter. Some was the focus of the neoKraepelinians on the biological aspects of mental illness. But the main gift was the creation of the diagnosis – Major Depressive Disorder [MDD] – that could be expanded to fit the majority of patients showing up for treatment. The combination of the SSRI’s greater tolerability and the catch·all MDD diagnosis was a recipe for success. These are not potent drugs nor is MDD a solid diagnosis, so the challenge was getting through the Clinical Trials for approval.

With the "Atypical Antipsychotics" there were different bridges to cross. At least in terms of felt adverse effects, the incidence of neurological side effects was more in the background than with the older drugs. The dangers were metabolic and insidious – often taking longer to develop than the duration of the usual Phase 3 Clinical Trials. Antipsychotics are potent drugs and Risperdal was no exception. So unlike the Antidepressants, getting a treatment effect in an RCT wasn’t really a problem. But in the words of J&J Sales Manager, Tone Jones, "You can’t make a blockbuster [> $1 B/YR] out of a 1% disease [incidence  of Schizophrenia]." They weren’t handed much of a market, unlike the Antidepressant makers. They had to create their own. They aimed for a particular set of situations where the drugs were sought by someone other than the patients themselves: mentally impaired children; autistic children; the kids with "Super angry/grouchy/cranky irritability" that Joseph Biederman called Bipolar Kids; elderly people in long term care; psychotic and others in government facilities including prisons – something like captive audiences.

Boy Scout Promise:
^{On my honor, I will do my best. To do my duty to God and my country and to obey the Scout Law; To help other people at all times; To keep myself physically strong, mentally awake and morally straight.}

Cadet Honor Code:
^{A cadet will not lie, cheat, steal, or tolerate those who do.}

Ranger Creed:
^{Recognizing that I volunteered as a Ranger, fully knowing the hazards of my chosen profession, I will always endeavor to uphold the prestige, honor, and high esprit de corps of the Rangers.
Acknowledging the fact that a Ranger is a more elite soldier who arrives at the cutting edge of battle by land, sea, or air, I accept the fact that as a Ranger my country expects me to move further, faster and fight harder than any other soldier.
Never shall I fail my comrades. I will always keep myself mentally alert, physically strong and morally straight and I will shoulder more than my share of the task whatever it may be, one-hundred-percent and then some.
Gallantly will I show the world that I am a specially selected and well-trained soldier. My courtesy to superior officers, neatness of dress and care of equipment shall set the example for others to follow.
Energetically will I meet the enemies of my country. I shall defeat them on the field of battle for I am better trained and will fight with all my might. Surrender is not a Ranger word. I will never leave a fallen comrade to fall into the hands of the enemy and under no circumstances will I ever embarrass my country.
Readily will I display the intestinal fortitude required to fight on to the Ranger objective and complete the mission though I be the lone survivor.Rangers Lead The Way!!!}

The Johnson and Johnson Credo:
^{We believe our first responsibility is to the doctors, nurses and patients, to mothers and fathers and all others who use our products and services. In meeting their needs everything we do must be of high quality. We must constantly strive to reduce our costs in order to maintain reasonable prices. Customers’ orders must be serviced promptly and accurately. Our suppliers and distributors must have an opportunityto make a fair profit.
We are responsible to our employees, the men and women who work with us throughout the world. Everyone must be considered as an individual. We must respect their dignity and recognize their merit. They must have a sense of security in their jobs. Compensation must be fair and adequate, and working conditions clean, orderly and safe. We must be mindful of ways to help our employees fulfill their family responsibilities. Employees must feel free to make suggestions and complaints. There must be equal opportunity for employment, development and advancement for those qualified. We must provide competent management, and their actions must be just and ethical.
We are responsible to the communities in which we live and work and to the world community as well. we must be good citizens — support good works and charities and bear our fair share of taxes. We must encourage civic improvements and better health and education. We must maintain in good order the property we are privileged to use, protecting the environment and natural resources.
Our final responsibility is to our stockholders. Business must make a sound profit. We must experiment with new ideas. Research must be carried on, innovative programs developed and mistakes paid for. New equipment must be purchased, new facilities provided and new products launched. Reserves must be created to provide for adverse times. When we operate according to these principles, the stockholders should realize a fair return.}

And so armed with a thorough understanding of the Clinical Trial process, a medical writing firm less than a mile away [Excerta Medica] turning out journal articles faster than they could locate KOL authors to sign up, a keen sense for backroom wheelings and dealings, and winning interpersonal ways, Gorsky set out to create the markets needed to become a blockbuster and then some. The story is masterfully told in the Huffington Post fifteen part series by Steven Brill. It’s all on-line just waiting for you to read it. And you won’t have a bit of trouble understanding why he called it America’s Most Admired Lawbreaker…