Tuesday, April 14, 2015

Yes!

WHO calls for increased transparency in medical research

Note for the media
14 April 2015
 WHO today issued a public statement calling for the disclosure of results from clinical trials for medical products, whatever the result. The move aims to ensure that decisions related to the safety and efficacy of vaccines, drugs and medical devices for use by populations are supported by the best available evidence.
“Our intention is to promote the sharing of scientific knowledge in order to advance public health,” said Dr. Marie-Paule Kieny, WHO Assistant Director General for Health Systems and Innovation. “It underpins the principal goal of medical research: to serve the betterment of humanity.”
“Failure to publicly disclose trial results engenders misinformation, leading to skewed priorities for both R&D and public health interventions,” said Kieny. “It creates indirect costs for public and private entities, including patients themselves, who pay for suboptimal or harmful treatments.”

Unreported trials lead to misinformation

For example, in a study that analysed reporting from large clinical trials (more than 500 participants) registered on clinicaltrials.gov and completed by 2009, 23% had no results reported. These unreported trials included nearly 300 000 participants. Among clinical trials of vaccines against five diseases registered in a variety of databases between 2006-2012, only 29% had been published in a peer-reviewed journal by the WHO recommended deadline of 24 months following study completion.
“We need the collaboration of all these actors to enforce transparency in their jurisdictions in order to increase the benefits and decrease the risks for patients, clinical trial volunteers and the general public,” concluded Dr. Kieny.

International Clinical Trials Registry Platform furthers transparency

WHO’s call for disclosure includes older unreported clinical trials, the results of which may still have an important bearing on scientific research today. WHO also reaffirms the need for all clinical trials to be registered on a WHO primary clinical trial registry so that they can be accessible through the International Clinical Trials Registry platform. This will ensure transparency as to which clinical trials have occurred, and allow verification of compliance with public disclosure requirements.
The recent WHO move expands on a 2005 call for all clinical trials to be registered, and the subsequent establishment of the International Clinical Trials Registry Platform. This registry platform regularly imports trial records from Clinicaltrials.gov, ISRCTN, EU Clinical Trials Register, Australia New Zealand Clinical Trial Registry, Pan African Clinical Trial Registry and Clinical Trial Registries from China, India, Brazil, Republic of Korea, Cuba, Germany, Iran, Japan, Sri Lanka, The Netherlands and Thailand.
For more information please contact:
Tarik Jasarevic
Communications Officer
Mobile: +41 79 367 62 14
E-mail: jasarevict@who.int
Daniela Bagozzi
Senior Information Management Officer
Mobile: +41 79 603 72 81
E-mail: bagozzid@who.int


WHO Statement on Public Disclosure of Clinical Trial Results

Background

Following a ministerial summit on Health Research in 2004, a World Health Assembly Resolution passed in 2005 called for unambiguous identification of all interventional clinical trials. This led to the establishment of the WHO International Clinical Trials Registry Platform, which collates information on trials that have been notified in a network of clinical trial registries (who.int/ictrp/network). WHO’s existing position on registration is available at who.int/ictrp: “The registration of all interventional trials is a scientific, ethical and moral responsibility”. Deposition of information on trials in such registries, prior to their initiation, is a condition for publishing the results of trials in many leading medical journals. However, concerns have been raised that there may be selective publication of trials dependent on their results, with particular concern that trial results which may be viewed as “negative”, are less likely to be submitted, or accepted, for publication in the scientific literature or made public in other ways. Notification of trials to clinical trial registries has become more widespread, and it is possible to evaluate what proportions of recorded trials have not reported results at different times after the planned end dates of the trials. Multiple analyses have confirmed that a substantial number of clinical trials remain unreported several years after study completion, even in the case of large randomized clinical trials.
In the latest version of the Declaration of Helsinki it is stated that “Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.” and that “Researchers have a duty to make publicly available the results of their research .... Negative and inconclusive as well as positive results must be published or otherwise made publicly available”. There is an ethical imperative to report the results of all clinical trials, including those of unreported trials conducted in the past. Furthermore poor allocation of resources for product development and financing of available interventions, and suboptimal regulatory and public health recommendations may occur where decisions are based on only a subset of all completed clinical trials.

Reiteration of WHO position on clinical trial registry sites

Before any clinical trial is initiated (at any Phase) its details are to be registered in a publicly available, free to access, searchable clinical trial registry complying with WHO’s international agreed standards. The clinical trial registry entry should be made before the first subject receives the first medical intervention in the trial.

Updating clinical trial registry entries

All clinical trial registry sites are to be updated as necessary to include final enrolment numbers achieved, and the date of actual study completion (defined as the last data collection timepoint for the last subject for the primary outcome measure). If clinical trials are terminated, their status is to be updated to note the termination, and to report the numbers enrolled up to the point of termination.

Reporting timeframes for clinical trials

Clinical trial results are to be reported according to the timeframes outlined below. Reporting is to occur in BOTH of the following two modalities.

1. The main findings of clinical trials are to be submitted for publication in a peer reviewed journal within 12 months of study completion and are to be published through an open access mechanism unless there is a specific reason why open access cannot be used, or otherwise made available publicly at most within 24 months of study completion.
2. In addition, the key outcomes are to be made publicly available within 12 months of study completion by posting to the results section of the primary clinical trial registry. Where a registry is used without a results database available, the results should be posted on a free-to-access, publicly available, searchable institutional website of the Regulatory Sponsor, Funder or Principal Investigator.

It is noted that several journals allow open access publication of clinical trial findings. Some journals have an explicit policy of supporting publication of negative trials. These 12 month and 24 month timeframes represent the longest possible acceptable timeframe for reporting and shorter timeframes are strongly encouraged. It should be possible in most instances for reporting to occur in shorter timeframes.

Reporting of past clinical trials results

Unreported clinical trials conducted in the past are to be disclosed in a publicly available, free to access, searchable clinical trial registry. In addition it is desirable that unreported clinical trials are published in a peer reviewed journal.

Inclusion of Trial ID in clinical trial publication

The Trial ID or registry identifier code/number is always to be included in all publications of clinical trials, and should be provided as part of the abstract to PubMed and other bibliographic search databases for easy linking of trial reports with clinical trial registry site records. Bibliographic search databases such as PubMed are encouraged to make Trial IDs easily available by inclusion in the abstract of each clinical trial record.

Note on Data Sharing Initiatives


The benefit of sharing research data and the facilitation of research through greater access to primary datasets is a principle which WHO sees as important. This statement is not directed towards sharing of primary data. However WHO is actively engaged with multiple initiatives related to data sharing, and supports sharing of health research datasets whenever appropriate. WHO will continue to engage with partners in support of an enabling environment to allow data sharing to maximise the value of health research data.

Saturday, April 04, 2015

Read it and weep - then get angry!

The Deadly Corruption of Clinical Trials

Illustration: Sam Weber

Update (4/3/2015):  After nearly 11 years of obfuscation and denial surrounding the tragic death of Dan Markingson, the University of Minnesota has suspended enrollment in psychiatric drug trials. This comes in response to a blistering report issued by the Minnesota State Legislative Auditor that cites "serious ethical issues" and vindicates much of the reporting in the story below. Read more from Carl Elliott about the fallout from the report here.

IT'S NOT EASY TO WORK UP a good feeling about the institution that destroyed your life, which may be why Mary Weiss initially seemed a little reluctant to meet me. "You can understand my hesitation to look other than with suspicion at anyone associated with the University of Minnesota," Mary wrote to me in an email. In 2003, Mary's 26-year-old son, Dan, was enrolled against her wishes in a psychiatric drug study at the University of Minnesotawhere I teach medical ethics. Less than six months later, Dan was dead. I'd learned about his death from a deeply unsettling newspaper series bySt. Paul Pioneer Press reporters Jeremy Olson and Paul Tosto that suggested he was coerced into a pharmaceutical-industry study from which the university stood to profit, but which provided him with inadequate care. Over the next few months, I talked to several university colleagues and administrators, trying to learn what had happened. Many of them dismissed the story as slanted and incomplete. Yet the more I examined the medical and court records, the more I became convinced that the problem was worse than the Pioneer Press had reported. The danger lies not just in the particular circumstances that led to Dan's death, but in a system of clinical research that has been thoroughly co-opted by market forces, so that many studies have become little more than covert instruments for promoting drugs. The study in which Dan died starkly illustrates the hazards of market-driven research and the inadequacy of our current oversight system to detect them.

Mary Weiss is a slight, white-haired woman in her late sixties who smiles ruefully at any question, no matter how painful. She is the sort of Minnesota liberal who volunteers for political campaigns and signs her email with flowers. When we first met at a coffee shop in St. Paul, she was wearing an Obama pin on her sweater. Mary raised Dan alone, working a job at the postal service. Old photographs show Dan growing into his good looks; according to Mary, he was also a gifted student. In high school, Dan got a perfect score on the verbal portion of his SAT. He graduated from the University of Michigan in 2000 with an English degree, and that fall he moved to Los Angeles, hoping to become a screenwriter or an actor. To support himself, he got a job as a celebrity-tour bus driver.

Dan and his mom, Mary WeissDan and his mom, Mary Weiss
Photo: Courtesy Mary Weiss

When Mary went out to Los Angeles for a visit in the summer of 2003, it was clear Dan had changed. He'd adopted a new last name, Markingson. His behavior was bizarre. "He said, 'You haven't told me when the event is going to be,'" Mary said. She had no idea what he was talking about. The next day, he took her to his apartment. He'd encircled his bed with wooden posts, salt, candles, and money, which he said would protect him from evil spirits. He showed her a spot on the carpet that he said the aliens had burned.

I asked Mary how she'd reacted to all of this. "I panicked. I called 911," she replied. But when the police arrived, Dan was able to convince them she had overreacted. "He said, 'Oh, my mother just drove from Minnesota and she's very tired,'" she recalled. Worried that Dan was seriously ill, she tried to convince him to return to St. Paul. He visited her in August, returned briefly to California, and then came back to St. Paul in October.

Dan grew convinced that the Illuminati were orchestrating an event in Minnesota—a "storm" in which he would be called upon to murder his mother.

Dan grew convinced that the Illuminati were orchestrating an event in Duluth, Minnesota—a "storm" in which he would be called upon to murder people, including Mary. Some of his emails from late September 2003 suggest the extent of his delusions:

"I'm aware that people can cast spells that can hurt you at a distance.
I'm aware that some people can read minds.
I'm aware that some people might actually be 'hybrids' and not altogether human."

In another email, Dan wrote:

"I'm especially eager to attend this storm and SLAY those who deserve slaying.
I will choose victims immediately...
I HAVE NO EMOTIONAL ATTACHMENTS. I KILL FOR FUN!!"

On November 12, Dan said he would kill Mary if called upon to do so. She called the police. Dan was taken to Regions Hospital in St. Paul. But the hospital had no psychiatric beds available, so after a few hours Dan was transferred to Fairview University Medical Center, a teaching hospital for the University of Minnesota Academic Health Center. He was treated by Dr. Stephen C. Olson, an associate professor in the university's psychiatry department, who prescribed Dan Risperdal (risperidone), an antipsychotic drug often prescribed for patients with schizophrenia or bipolar disorder. (In Minnesota, doctors are allowed to give antipsychotic drugs to mentally incompetent patients without their consent for up to 14 days, but only to prevent serious, immediate physical harm to the patient or others.) Olson believed Dan was psychotic and dangerous, and lacked the ability to make decisions regarding his treatment; on November 14 he signed a document that recommended Dan be committed involuntarily to a state mental institution, noting that he "lacks the capacity to make decisions regarding such treatment." Three days later, a clinical psychologist also recommended involuntary commitment, reiterating that Dan had threatened to slit his mother's throat.

In Minnesota, patients who have been involuntarily committed are given another option: a "stay of commitment." Patients can avoid being confined to a mental institution as long as they agree to comply with the treatment program laid out by their psychiatrist. On November 20, Olson asked for a stay of commitment. The court granted the stay for six months, stipulating that Dan had to follow the recommendations of his treatment team. Olson, however, did not simply recommend standard medical treatment. Instead, he proposed that Dan take part in an industry-funded study of antipsychotic drugs. The university's study coordinator, Jean Kenney, had Dan sign a consent form when Mary wasn't present, and on November 21, he was enrolled in the study.

On the surface, the study appeared benign. Its purpose was to compare the effectiveness of three "atypical" antipsychotic drugs, each of which had already been approved by the FDA: Seroquel (quetiapine), Zyprexa (olanzapine), and Risperdal (risperidone.) The study was designed and funded by AstraZeneca, the manufacturer of Seroquel, and it called for 400 subjects experiencing their first psychotic episode to take one of the three drugs for a year. AstraZeneca called it the "CAFE" study, which stood for "Comparison of Atypicals in First Episode." The management of the CAFE study had been outsourced to Quintiles, a contract research organization, which was conducting it at 26 different sites, including the University of Minnesota. (For more on CROS, see "Trial by Hire.")

Yet the CAFE study was not without risks. It barred subjects from being taken off their assigned drug; it didn't allow them to be switched to another drug if their assigned drug was not working; and it restricted the number of additional drugs subjects could be given to manage side effects and symptoms such as depression, anxiety, or agitation. Like many clinical trials, the study was also randomized and double-blinded: Subjects were assigned a drug randomly by a computer, and neither the subjects nor the researchers knew which drug it was. These restrictions meant that subjects in the CAFE study had fewer therapeutic options than they would have had outside the study.

In fact, the CAFE study also contained a serious oversight that, if corrected, would have prevented patients like Dan from being enrolled. Like other patients with schizophrenia, patients experiencing their first psychotic episode are at higher risk of killing themselves or other people. For this reason, most studies of antipsychotic drugs specifically bar researchers from recruiting patients at risk of violence or suicide, for fear that they might kill themselves or someone else during the study. Conveniently, however, the CAFE study only prohibited patients at risk of suicide, not homicide. This meant that Dan—who had threatened to slit his mother's throat, but had not threatened to harm himself—was a legitimate target for recruitment.

Dan, age 10Dan, age 10
Photo: Courtesy Mary Weiss

When Mary found out that Dan had been recruited into the CAFE study, she was stunned. "I do not want him in a clinical study," she told Olson. Just a few days earlier, Olson indicated in a petition to the court that Dan was both dangerous and mentally incapable of consenting to antipsychotic medication. How could he now be capable of consenting to a research study with the very same antipsychotics—especially when the alternative was commitment to a state mental institution?

After Dan was enrolled, he stayed at Fairview for about two more weeks. By that point, Olson thought Dan's symptoms were under control, but Mary was still very worried by his erratic behavior. She recalls meeting with the doctor: "Olson came in and sat down and opened his file and said, 'Oh, Dan is doing so well.' And I said, 'No, Dr. Olson, Dan is not doing well.' I think he was taken aback." Even so, on December 8, 2003, Dan was transferred to Theo House, a halfway house in St. Paul. He was required to sign an agreement confirming that he understood he could be involuntarily committed if he didn't continue taking his medication and keeping his CAFE study appointments.

At the halfway house, Dan often stayed in his room for days. On March 26, 2004 nearly four months after his discharge from Fairview, his thoughts were still "delusional and grandiose," according to a social worker's note. An occupational-therapy report from April 30 detailed Dan's condition: "Personal appearance disheveled. Isolated and withdrawn. Poor insight and self-awareness." Entries in a personal journal that Dan kept during this period don't show any obvious changes, suggesting that he was improving little, if at all. Mary felt he was becoming angrier. "He was so tense, with this ready-to-explode quality."

When the blind on the study was broken, researchers found that Dan was being treated with Seroquel, the drug manufactured by the study sponsor, AstraZeneca.

Olson saw things differently. "I disagree that he had significant deterioration," he testified in a 2007 deposition. However, it's unclear whether Olson actually saw Dan enough to make an informed judgment about his condition. Records suggest most of Dan's care was managed by social workers. In his deposition, Olson said he saw Dan approximately six times from the date he was admitted in November until he committed suicide in May. Whatever the doctor thought, his actions don't suggest that he felt Dan was improving. In late April 2004, as Dan's stay of commitment was about to expire, Olson recommended extending it for another six months—the duration of the CAFE study. He noted that Dan still had "little insight into his mental disorder" and might "place himself at risk of harm if he were to terminate his treatment."

Mary tried to get Dan out of the study or have his treatment changed. She called Olson and tried to see him. She wrote long, detailed letters expressing concerns about everything from Dan's diet and sleep habits to his medications. In total, she sent five letters to Olson and Dr. Charles Schulz—the chairman of the university's psychiatry department and a co-investigator on the CAFE study—communicating her alarm about Dan's condition, especially his inner rage. She received only one reply, dated April 28, from Schulz, who wrote that "it was not clear to me how you thought the treatment team should deal with this issue." Around that time, Mary left a voice message with Jean Kenney, the study coordinator, asking, "Do we have to wait until he kills himself or someone else before anyone does anything?"

Before dawn on the morning of May 8, a police officer and a Catholic priest knocked on Mary's door. Mike Howard, a family friend who lives at her house, answered. Later, in a deposition, Howard described what happened next: "Mary jumped out of her bed and went into the kitchen and stood there, and the priest extended his hand out and said, 'Mary, I'm here to tell you that Dan passed away.' And Mary just literally fell down to her knees and started to shriek and cry, and just started begging, 'Please, no, no, don't let this happen.'"

Dan had stabbed himself to death in the bathtub with a box cutter, ripping open his abdomen and nearly decapitating himself. His body was discovered in the early hours of the morning by a halfway-house worker, along with a note on the nightstand that said, "I left this experience smiling!" Later, when the blind on the study was broken, researchers found that Dan was being treated with Seroquel, the drug manufactured by the study sponsor, AstraZeneca.

For most of the past half-century, physicians have considered antipsychotic drugs to be among the most unpleasant chemicals in the medicine closet. Thorazine (chlorpromazine), the first antipsychotic, was developed in 1950, and while it could relieve some of the worst symptoms of schizophrenia, that relief came at a serious cost. Not only do antipsychotics often make patients feel sedated and sluggish (they used to be called "major tranquilizers"), they can also cause irreversible "extrapyramidal" symptoms, such as the shuffling gait, rigid muscles, and involuntary lip-smacking sometimes seen in patients who have been taking the drugs for years. The antipsychotics can also cause akathisia, a type of driven, agitated restlessness that ranges from unpleasant to excruciating. Until recently, psychiatrists reserved the drugs for patients with very severe mental illnesses.

By 2008, antipsychotics were the most lucrative class of drugs in America. Seroquel alone had nearly $4 billion in sales.

Over the past decade or so, however, antipsychotics have undergone an extraordinary rehabilitation. By 2008, they were the most lucrative class of drugs in America. Seroquel alone had nearly $4 billion in sales, making it the country's fifth most profitable drug. The transformation began in the mid-'90s, when pharmaceutical companies began pitching atypical antipsychotics such as Risperdal, Zyprexa, and Seroquel as more effective than older antipsychotics, but relatively free of their ugly side effects. The drugs were also very expensive—one study pegged the cost at 70 to 100 times that of an older drug—but if they didn't produce extrapyramidal symptoms, their enormous expense seemed justifiable. By the mid-2000s, atypicals were being prescribed not just for schizophrenia but also for anxiety, agitation, insomnia, attention deficit hyperactivity disorder, and depression. The most remarkable upswing came for patients diagnosed with bipolar disorder, which used to be seen as a rare illness. Once bipolar disorder could be treated with atypicals, rates of diagnoses rose dramatically, especially in children. According to a recent Columbia University study, the number of children and adolescents treated for bipolar disorder rose 40-fold between 1994 and 2003. Another study found that nearly one in five children who visited a psychiatrist came away with a prescription for an antipsychotic drug, despite early reports of alarming side effects.

Recent years have seen a backlash. The most damaging blow to the atypicals was an authoritative 2005 study funded by the National Institute of Mental Health—the so-called CATIE study—which found that the atypical antipsychotics worked no better than a much older antipsychotic called Trilafon (perphenazine), which was developed in the 1950s. The CATIE study also found that, contrary to the way the drugs had been marketed, side-effect profiles of the atypicals were generally no better than the older drug. Other research showed that atypicals were associated with significant weight gain, increased risk of diabetes, and greater possibility of death in patients with dementia. After another large analysis in The Lancet found that most atypicals actually performed worse than older drugs, two senior British psychiatrists penned a damning editorial that ran in the same issue. Dr. Peter Tyrer, the editor of theBritish Journal of Psychiatry, and Dr. Tim Kendall of the Royal College of Psychiatrists wrote: "The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed."

The cleverest manipulation has been with the clinical trials themselves. For years, critics have charged that pharmaceutical companies massage trials to make their own drugs look better than they really are. One common tactic is to suppress unfavorable data. A notorious example came in the 1990s, when a Wyeth safety officer overwrote the company's computer files, erasing evidence indicating that its diet drug, fen-phen, caused valvular heart disease. A less risky strategy is simply not to publish potentially damaging trials. In 2004, theCanadian Medical Association Journal described a leaked document indicating that GlaxoSmithKline had deliberately hidden two studies from regulators showing that its antidepressant, Paxil (paroxetine), could increase the risk of suicide in children. The company has paid nearly a billion dollars in legal settlements over Paxil, including $390 million for suicides and attempted suicides related to the drug. Evidence of manipulation has also emerged in many of the high-profile pharmaceutical scandals of the past decade, from Merck's pain drug Vioxx to the recent Senate investigation into GlaxoSmithKline's diabetes drug Avandia.

"Thus far, we have buried trials 15, 31, 56. The larger issue is how do we face the outside world when they begin to criticize us for suppressing data."

Something similar has happened with the atypicals. A 2006 study in The American Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals, found that 90 percent of them came out positively for whichever company had designed and financed the trial. This startling result was not a matter of selective publication. The companies had simply designed the studies in a way that virtually ensured their own drugs would come out ahead—for instance, by dosing the competing drugs too low to be effective, or so high that they would produce damaging side effects. Much of this manipulation came from biased statistical analyses and rigged trial designs of such complexity that outside reviewers were unable to spot them. As Dr. Richard Smith, the former editor of the British Medical Journal, has pointed out, "The companies seem to get the results they want not by fiddling the results, which would be far too crude and possibly detectable by peer review, but rather by asking the 'right' questions."

Initially, the controversy over atypical antipsychotics was focused largely on Eli Lilly (PDF), the manufacturer of Zyprexa. In early 2009, it settled litigation for a record-breaking $1.4 billion for illegal marketing and allegedly hiding the risks of the drug. More recently, however, the scandal has spread to Seroquel. In April 2010, AstraZeneca agreed to pay $520 million to settle two federal investigations and two whistleblower lawsuits alleging that it had marketed Seroquel illegally and concealed its health risks. The company faces more than 25,000 civil suits.

Documents unsealed in related civil suits suggest an alarming pattern of deception. Sales reps were instructed to tell doctors that Seroquel doesn't cause diabetes, even though the company knew about the link to diabetes as early as 1997. Internal correspondence reveals company officials discussing how to hide or spin potentially damaging studies. "Thus far, we have buried trials 15, 31, 56," wrote a publications manager in 1999. "The larger issue is how do we face the outside world when they begin to criticize us for suppressing data."

One of those potentially damaging studies led back to the University of Minnesota. In the late 1990s, a clinical trial known as Study 15 unexpectedly failed to show that Seroquel was any better than Haldol, a generic antipsychotic that's been on the market since the 1960s. In fact, on the main measures, Seroquel performed worse than Haldol. The study also showed that Seroquel increased the risk of weight gain and diabetes. Internal correspondence repeatedly refers to Study 15 as a "failed study," and company officials discuss possible ways to spin or bury it. "I am not 100% comfortable with this data being made publicly available at the present time," wrote Richard Lawrence, a senior AstraZeneca official, in 1997. "However I understand that we have little choice...Lisa [Arvanitis, a company physician] has done a great 'smoke-and-mirrors' job." Lawrence referred approvingly to a strategy that he said would "put a positive spin (in terms of safety) on this cursed study." Later, apparently hoping to find a way to present Seroquel in a better light, the "commercial support team" performed an analysis of a number of other studies, but even that did not show Seroquel to be better than Haldol. Yet when a summary of the AstraZeneca data was presented at the American Psychiatric Association annual conference in 2000, the author claimed Seroquel was "significantly superior" to Haldol. That author was Dr. Charles Schulz, the University of Minnesota psychiatry department chair—and a well-compensatedconsultant for AstraZeneca. In a press release claiming Seroquel's superiority over Haldol, Schulz praised it enthusiastically as a "first-choice antipsychotic."

Although the documents unsealed in the Seroquel litigation do not specifically mention the CAFE study in which Dan was enrolled, they do suggest that AstraZeneca planned to establish Seroquel as the "atypical of choice in first-episode schizophrenia," according to a 2000 "Seroquel Strategy Summary." A later document titled "Seroquel PR Plan 2001" discusses the agenda for an advisory panel meeting in Hawaii. Among the potential topics were the marketing of Seroquel to first-episode patients, adolescents, and the elderly. The document refers to these populations as "vulnerable patient groups."

"R&D is no longer responsible for Seroquel research—it is now the responsibility of Sales and Marketing." 

Even more alarming are internal documents suggesting that AstraZeneca was designing clinical trials as a covert method of marketing Seroquel. In 1997, whenDr. Andrew Goudie, a psychopharmacologist at the University of Liverpool, asked AstraZeneca to fund a research study he was planning, a company official replied that "R&D is no longer responsible for Seroquel research—it is now the responsibility of Sales and Marketing." The official also noted that funding decisions would depend on whether the study was likely to show a "competitive advantage for Seroquel."

Another set of documents from 2003 describes a glucose metabolism study apparently designed to fend off the charge that Seroquel causes patients to gain weight and become diabetic. One slide describes two purposes for the study: a "regulatory" purpose and a "commercial" purpose. The regulatory purpose was to "produce data that will help us defend the Seroquel label." The commercial purpose was to "produce data that will enable us to generate commercially attractive and competitive messages in relation to diabetes and weight." The document suggests several possible names for the study, including "Flexible Dose Approach Trial for Atypical Responses to Metabolism," which could be usefully shortened to the acronym FATFARM. (When I contacted AstraZeneca, a spokesperson would say only that Seroquel has been found "safe and effective" by the FDA and that it stands behind the CAFE study and the rest of its clinical research.)

Many clinical studies place human subjects at risk—at a minimum, the risk of mild discomfort, and at worst, the risk of serious pain and death. Bioethicists and regulators spend a lot of time and energy debating the degree of risk that ought to be permitted in a study, how those risks should be presented to subjects, and the way those risks should be balanced against the potential benefits a subject might receive. What is simply assumed, without much consideration at all, is that the research is being conducted to produce scientific knowledge. This assumption is codified in a number of foundational ethics documents, such as the Nuremberg Code, which was instituted following Nazi experiments on concentration camp victims. The Nuremberg Code stipulates that an "experiment should be such as to yield fruitful results for the good of society," and "the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment."

But what if a research study is not really aimed at producing genuine scientific knowledge at all? The documents emerging in litigation suggest that pharmaceutical companies are designing, analyzing, and publishing trials primarily as a way of positioning their drugs in the marketplace. This raises a question unconsidered in any current code of research ethics. How much risk to human subjects is justified in a study whose principal aim is to "generate commercially attractive messages"?

In January 2005, the FDA began investigating the circumstances of Dan's suicide. In a report issued that July, before the larger pattern of Seroquel research had begun to emerge, Sharon L. Matson, the FDA investigator, exonerated the university. She wrote, "I did not find any evidence of misconduct, significant violation of the protocol, or regulations governing clinical investigators or IRBs"— the university institutional review board charged with reviewing studies to ensure that they measure up to recognized ethical standards. Matson specifically dismissed the suggestion that Dan was mentally incompetent to consent to the study, writing that "there was nothing different about this subject than others enrolled to indicate that he couldn't provide voluntary, informed consent." (The FDA refused my request to speak with Matson and would not answer questions about the case, citing privacy concerns.) Mary Weiss eventually sued the University of Minnesota, AstraZeneca, Olson, and Schulz, but her case did not even get to trial. District Court Judge John L. Holahan dismissed the suit in 2008 with a partial summary judgment. He ruled that in approving the CAFE study, the university IRB was performing the type of "discretionary function" that is protected from liability under the state's Tort Claims Act. The malpractice suit against Schulz was also dismissed, and the suit against Olson was eventually settled—for $75,000, which Mary says wasn't enough to cover the fees of the expert witnesses her attorneys hired. (Both Schulz and Olson declined to speak about the specifics of the clinical trial or the resulting suit. University spokesman Nick Hanson would say only, "To date, there has been no finding of wrongdoing from any of the investigations or reviews done by the university on this issue.")

The judge also dismissed the case against AstraZeneca. He blasted Mary's lawyers, saying that they had failed to establish that AstraZeneca had a duty to put the interests of research subjects over the interests of the company and the researchers. But he also lamented the lack of case law about clinical trials, saying on this particular point, "Try as it may, this Court's independent research has unearthed not a single case or statute to evidence or support such an alleged duty."

The judge further ruled that Mary's lawyers hadn't shown a causal link between Seroquel and Dan's suicide: An initial drug screening during autopsy had not found any Seroquel in his bloodstream, which suggested that Dan may not have been taking his medication. After the judgment, however, Mary discovered that Seroquel would not be detected in an ordinary drug screening; a special test is required. In the spring of 2008, she called the coroner's office in hopes of getting a special screening for Seroquel. To her surprise, she found that her lawyers and the defendants had already obtained one. The report was dated several days after the summary judgment was issued. It showed 73 nanograms per milliliter of Seroquel in his blood, suggesting that Dan was almost certainly taking the drug, although he may have missed the last scheduled dose before he died.

Although Mary's lawsuit was unsuccessful, it revealed some disturbing financial arrangements at the university. As a patient on public assistance, Dan's treatment would have normally generated little income for the university. Under its arrangement with AstraZeneca, however, the psychiatry department earned $15,648 for each subject who completed the CAFE study. In total, the study generated $327,000 for the department. In fact, during the months before Dan was enrolled, the department was apparently feeling pressure from Quintiles, the CRO that managed the study, to step up recruitment. According to emails written by Jean Kenney, the university's study coordinator, the site had been placed on probation for its recruitment problems, and they were still "struggling to get patients." In November 2002, Olson had managed to recruit only one subject in six months. That began to change in April 2003, when the psychiatry department established a specialized inpatient unit at Fairview hospital called Station 12, in which every patient could be evaluated for research. By December, Olson had recruited 12 more subjects, including Dan, and Olson had been featured in a CAFE study webcast for "turning an underperforming site into a well-performing site."(Quintiles refused to give comment on the case.)

Olson had another financial reason to maintain good relations with AstraZeneca. According to a disclosure statement for a 2006 conference, he was a member of the AstraZeneca "speaker's bureau," giving paid talks for the company. He had similar arrangements with Eli Lilly and Janssen, the makers of the other atypicals being tested in the CAFE study, as well as Bristol-Myers Squibb and Pfizer. In addition, Olson was working as a paid consultant for Lilly, Janssen, Bristol-Myers Squibb, and Pfizer. Although Olson is not required to disclose how much industry money he received, a public database maintained by the Minnesota pharmacy board indicates that Olson received a total of $240,045 from the pharmaceutical industry between 2002 and 2008, with $149,344 coming from AstraZeneca. Dr. Charles Schulz, his co-investigator and department chair, received an even greater sum: more than $571,000 from the industry, with $112,020 coming from AstraZeneca. The database does not reliably distinguish between payment by drug companies for consulting and speaking, which usually goes directly into a physician's pocket, and research grants, which go to the university and are used to help underwrite the salaries of the grant recipients. (Many academic physicians are required by their universities to generate a substantial portion of their salaries by obtaining research grants.)

In the US, the primary bodies charged with protecting research subjects are known as institutional review boards. (Read how IRBs are becoming privatized, next page.) According to the University of Minnesota, the purpose of its IRB is to "protect the rights and welfare of human research subjects." However, when the university's IRB officials were deposed under oath, they refused to admit that protecting subjects was their responsibility. "So it's not the institutional review board's purpose to protect clinical trial subjects, is that what you're saying?" asked Gale Pearson, one of the attorneys representing Mary Weiss. "That's true," replied Moira Keane, the director of the IRB. Astonished, Pearson kept returning to the question, to make sure that she understood it correctly. Keane refused to budge. Instead, she claimed that the role of the IRB was to make sure that Olson and the trial sponsor had a plan to protect subjects. (If this were true, it would render IRBs worthless: The sponsor and investigator are the ones that the IRB is supposed to protect subjects from.)

The University of Minnesota doesn't exactly have a stellar record of investigating internal misconduct. In 1994, the director of child and adolescent psychiatry, Dr. Barry Garfinkel, was sentenced to federal prison for five felonies related to research fraud involving the Ciba-Geigy drug Anafranil (clomipramine). The research assistant who blew the whistle in 1989 lost her job, and under the terms of a secret agreement struck with Garfinkel, the university kept the fraud secret for four years, until he was finally indicted. In 1995, the university was sanctioned by the National Institutes of Health after revelations that the head of transplant surgery, Dr. John Najarian, had generated millions of dollars for the university by illegally manufacturing and selling an immunosuppressant drug without FDA approval; an investigation by the Minneapolis Star Tribune revealed that the university had known of the illegal activity for years. Still more scandals have recently emerged, including a Senate investigation of the chairman of spinal surgery, Dr. David Polly, for failing to disclose $1.2 million he had been paid to consult for the device manufacturer Medtronic, and a series of investigative reports in the New York Times about the industry ties of Minnesota physicians, including some connected to the university. When the scandals began to escalate several years ago, Dr. Deborah Powell, then the dean of the university's medical school, appointed a task force to devise a new conflict-of-interest policy. The policy was discarded after theStar Tribune revealed that the co-chair of the task force, Dr. Leo Furcht, had funneled $500,000 of university grant money into his own private company, which he later sold for $9.5 million. Furcht remains chairman of the laboratory medicine and pathology department at the university.

In 2007, the American Journal of Psychiatry published the results of the CAFE study. Among the 18 "serious adverse events" recorded for the 400 subjects in the study were an alleged homicide and five suicide attempts, including two successful suicides, both by patients taking Seroquel. (One of these patients, of course, was Dan Markingson.) According to the study authors—three AstraZeneca employees and seven academic physicians, many of whom also consulted for the company—the suicides occurred "despite the close attention provided in clinical research aftercare programs." The authors claimed that the CAFE study showed Seroquel to be of "comparable effectiveness" to Zyprexa and Risperdal for first-episode patients.

According to some experts, the study could hardly have shown otherwise, because it was designed to produce a good result for Seroquel. When I showed the published study to Dr. Peter Tyrer, the editor of the British Journal of Psychiatry, he said, "I would have major problems accepting a manuscript of that nature." According to Tyrer, the main problem is the small sample size. Of the 400 subjects enrolled, all but 119 stopped taking the drug before the yearlong study was finished. With so few subjects, the CAFE study was statistically underpowered and thus unlikely to detect any difference in effectiveness between the three drugs. The failure to detect a difference allowed AstraZeneca to claim that Seroquel was as good as the other drugs (or in the language of the study, "non-inferiority"). Tyrer told me, "In scientific terms this study is of very little value."

That's not the only problem. The CAFE study was supposedly designed to test the effectiveness of the three antipsychotics, but the way it did this was by measuring the rate of "all-cause treatment discontinuation," or the percentage of subjects who stopped taking their drug. That is, the CAFE study counted an antipsychotic as "effective" if a subject kept taking it until the end of the study. On the face of it, this type of measurement seems highly misleading; simply because a patient continues to take an antipsychotic does not mean that it is working. Many psychiatrists defend treatment discontinuation as a "pragmatic" way of measuring a drug's overall acceptability, but even by "pragmatic" standards the CAFE study presents a problem. More than 70 percent of subjects in the CAFE study stopped taking their assigned drug, and the most common reason was simply coded as "patient decision." According to Dr. John Davis, the Gillman Professor of psychiatry at the University of Illinois-Chicago, the authors of the CAFE study obscured their results by failing to say whypatients decided to stop taking the drug—whether patients felt the side effects of the drug were too severe, for example, or if they felt the drug was not working. "It is the hiding of the critical outcomes that gives me pause," he says. "It does not make scientific sense to do a study and not measure one of the most important outcomes."

Yet another problem with the CAFE study is its failure to compare Seroquel to any older antipsychotics. "It's quite a marketing exercise to put all patients in the CAFE study on atypical antipsychotics," says Dr. Glen Spielmans, an associate professor of psychology at Minnesota's Metropolitan State University. "It removes the older drugs from the discussion." One reason AstraZeneca may have done this, he suggests, is that Study 15 had already shown Seroquel to be inferior to the older antipsychotic, Haldol.

The bluntest assessment of the study came from Dr. David Healy, a senior psychiatrist at Cardiff University in Wales. Healy is a former consultant to AstraZeneca, among other pharmaceutical companies, and a prominent critic of the industry. "This is a non-study of the worst kind," he said. "It is designed not to pick up a difference between the three drugs. It looks like an entirely marketing-driven exercise."

If these experts are right, then the study in which Dan Markingson committed suicide was not simply a matter of inadequate informed consent, or financial conflicts of interest, or even failure to monitor a subject's care. The ethical breach was built into the study from the start. It is one thing to ask people to take risks for science, or the common good, or to help other people. It is another thing entirely to ask them to risk their lives for the marketing goals of AstraZeneca.

Mary Weiss is a quiet woman, but her experience has left her angry and bitter. It's not hard to see why. In the years since she lost her son, she has written letters and filed complaints to one oversight body after the other, and so far she's gotten little but form letters, rejections, and dismissals. "Well, I don't think the loss can ever be replaced," her friend Mike Howard said in his deposition. "There is probably not a day in Mary's life that she hasn't thought about her son, and there is probably not a week goes by that she doesn't shed tears." Mary told me that until she and I had coffee last year in St. Paul, no one at the university had ever apologized or expressed regret for her son's death. In fact, after Dan died, Mary received a plant with a card from the CAFE study team. In words that echoed the bizarre, grisly message in Dan's suicide note, the card read, "We will miss his smile."

Of all the ways in which Mary Weiss has been damaged by the University of Minnesota, there is one episode that still brings a sting of shame to my face. When the lawsuit over Dan's death was dismissed, the university filed a legal action against Mary, demanding that she pay the university $57,000 to cover its legal expenses. Gale Pearson, one of Mary's attorneys, says that while such suits are technically permissible, she had never seen one filed in her previous 14 years of legal practice. The university agreed to drop the lawsuit against Mary only when she agreed not to appeal the judge's decision. "Maybe they want to chill anyone who might think of challenging the university, even if her child had died," Pearson said. "It gave me a sick feeling."

http://www.motherjones.com/environment/2010/09/dan-markingson-drug-trial-astrazeneca

Friday, March 06, 2015

Tattoo


Wine anyone?


Friday, February 20, 2015

Tales from the PMCPA contd. - The case of the beer drinking, lederhosen wearing, presenter

​A pulmonologist working in Germany, complained about a scientific symposium organised by Boehringer Ingelheim at the European Respiratory Society (ERS) Congress held in Munich.

The symposium was part of the industry sponsored sessions.  It was advertised in the official meeting programme as ‘Slowing disease progression in IPF [idiopathic pulmonary fibrosis]: New evidence From Phase III clinical trials’.

The complainant stated that his main complaint was that on the main stage, the speakers were allowed to drink beer – with one even dressed in lederhosen.  For a serious, fatal condition, this was not appropriate.  As two of the speakers were from the UK he assumed the UK rules should apply to them.

The detailed response from Boehringer Ingelheim is given below.

The Panel noted that the Code applied to the promotion to UK health professionals and administrative staff at international meetings held outside the UK.  Further, that the Code also applied to some non-promotional activities including the use of consultants in Clause 20.  The Panel noted that two of the four speakers at the symposium were UK health professionals and that Boehringer Ingelheim had sponsored UK health professionals to attend the ERS Congress.  The Panel therefore considered that at the very least certain aspects of the arrangements had to comply with the Code.  It was an established principle under the Code that the UK company was responsible for acts and omissions of its overseas affiliates that came within the scope of the Code.

The Panel considered that the involvement of the UK speakers meant that Boehringer Ingelheim was responsible under the Code for the arrangements for the UK speakers including their travel and subsistence and the impression created by these.

The Panel noted that one of the speakers appeared to be drinking beer on stage during the satellite symposium.  The Panel considered that the overall impression given was unacceptable.  The subsistence in this regard was inappropriate.  The Panel considered that high standards had not been maintained.  A breach was ruled.

Friday, January 30, 2015

Mother brought to tears hearing Johnson & Johnson's Risperdal tactics


David Sell
Posted: Friday, January 30, 2015, 8:05 AM

Benita Pledger dabbed at her tears as she sat in a wooden chair outside a court room in Philadelphia's City Hall early Thursday evening.

"I'm just having a hard time right now," she said, "hearing what the pharmaceutical company was doing."

Pledger had just finished a full day of listening to her attorney, Thomas Kline, and former U.S. Food and Drug Administration commissioner Dr. David Kessler discuss documents that showed Johnson & Johnson's Janssen Pharmaceutical subsidiary tried to manipulated data in versions of reports to hide evidence that the company's antipsychotic drug Risperdal had caused boys like her son to grow breasts.

"The most important thing for me, as someone who worked for the FDA, as a physician and as somebody who served on the boards of pharmaceutical companies, is you tell the truth and you tell the whole truth," Kessler said on the stand. "You tell the whole story. You make sure the data supports the message. What they want to convey doesn’t match what the data shows and to me, that doesn’t tell the whole story. Make sure the FDA knows and make sure the doctors know. Tell them the good and the bad."

Pledger and her husband sued J&J in Philadelphia's Court of Common Pleas, alleging that Risperdal caused their son to grow breasts, a condition called gynecomastia. Judge Ramy Djerassi is presiding over the trial, which might run four weeks.

Kline and Kessler focused Thursday on a 2001 study conducted by Janssen that showed some children (under 12) and adolescents (12 and older), who were already taking Risperdal, had higher-than-normal incidence of gynecomastia. Company emails and drafts of manuscripts being prepared for publication, which were shown in court Thursday, indicate an effort to re-analyze data so as to downplay the prevalence of gynecomastia.

"Janssen appropriately analyzed and reported data from clinical trials," Janssen spokeswoman Robyn Reed Frenze said in a statement. "Risperdal continues to help countless children and adults around the world who suffer from the debilitating effects of schizophrenia, bipolar mania and irritability associated with autistic order in children.

Risperdal was originally approved in 1993 only to treat psychotic disorders in adults. "On March 3, 2002, the approved use was narrowed to treatment of schizophrenia only," phrasing used by the Justice Department in 2013 in its statement after J&J agreed to pay $2.2 billion for settle one criminal charge and other allegations that it illegally promoted Risperdal for unapproved uses.

Doctors are allowed to prescribe medicine as they see fit, including "off-label," meaning for conditions not approved by the FDA and on the official label. Drug companies are not supposed to promote drugs for illnesses or for a group of patients for whom the drug is not approved and not on the label. But the squishiness of definitions of mental illness opens the door even wider for drug companies do such promotion.

Pledger's son is severely autistic. He is 20 now. He was eight when she filled the first prescription in August 2002 at Walmart near the family's home in Alabama. Benita Pledger was reluctant to try medicine when the subject was first raised by her son's pediatric neurologist, but her son's behavior problems, the melt-downs at home and school, prompted her to eventually try Risperdal. He used it until April 2007.

Risperdal was not FDA approved for use in children for any illness until 2006, so officially Janssen could not promote the use of the drug in children. But Jan Mathisen, the pediatric neurologist for Pledger's son, testified Monday that a Janssen sales rep came to his office 20 times between 2002 and 2004. He said he knew he was the most frequent prescriber of the drug in the state. But he also wanted samples for his patients, especially those with challenging financial circumstances. In her 2012 deposition, Benita Pledger said her husband was a self-employed mechanic and the family had no health insurance. She heard about gynecomastia on TV. When the J&J attorney asked in deposition if she had explored Risperdal on the Internet before suing, Benita Pledger said the family had no Internet access.

One of the challenges with many drug candidates for children is that parents are reluctant to have a drug tested on their children. It is perhaps telling that in 2001, when Janssen was pushing for approval to expand the approved uses on its existing official label and sell Risperdal for use in autistic children, it had plenty of children to use in clinical trials to answer FDA questions.

Prolactin is a hormone produced by the pituitary gland and is normally present in low amounts in men and non-pregnant women. Prolactin's primary role is to promote lactation.

Kline and Kessler focused on a Janssen study that showed higher prolactin levels and incidence of gynecomastia, especially in boys but also in a few girls taking Risperdal. They went through emails, company plans, changes to plans and multiple versions of a manuscript the company hoped would be published in a peer review journal to help its case with the FDA.

Kessler testified that based on the documents, Janssen appeared to have changed how it grouped patients in the one study and then merged the data with other studies to report a less significant potential risk.

"You certainly don’t want to change your plan after you know your results,” Kessler said.

J&J's attorney, Diane Sullivan, who declined comment after court Thursday, fought all week to keep the emails, documents and draft manuscripts from being submitted as evidence, shown to the jury and used as a basis for questioning of Kessler. Trying again Thursday, she said drug companies can't unilaterally change the label on a drug, that the label and any warnings must be decided in conjunction with the FDA.

Technically that is correct, Kessler said, but not in reality.

"A manufacturer can always warn about a safety issue and should warn about a safety issue," Kessler said. "There is nothing in the federal register that prevents a manufacturer from warning about a safety problem and there are many different ways. If somebody is sending a sales rep into a doctor's office, into a pediatric neurologist's office and doing it multiple times, you have an obligation to provide adequate direction. If you have information on a safety issue, you have to communicate that. Tell the good. Tell the bad."

Kessler is scheduled to resume testifying Friday.

http://www.philly.com/philly/business/Mother-brought-to-tears-hearing-Johnson--Johnsons-Risperdal-tactics---.html

Thursday, January 29, 2015

NNT - The Website

http://www.thennt.com

Thursday, January 22, 2015

Maurice Saatchi's Medical Innovation Bill is more likely to make its proposer money than it is to help anyone who's sick.

Maurice Saatchi, his Medical Innovation Bill, and the booming ‘orphan drugs’ market

Wikimedia

Maurice Saatchi has had a great deal of media attention lately. This has focused for the most part on his Medical Innovation Bill (also known as the Saatchi Bill), which he has campaigned for in the wake of his wife's death from cancer back in 2011, and which will have its 3rd Reading in the House of Lords on Friday (23rd January). But Lord Saatchi is also, of course, a very astute and successful businessman.

2013 was a good year for M&C Saatchi Plc, of which Maurice Saatchi is a director and shareholder. CEO David Kershaw attributed the company’s 5.2% rise in revenues in part to “getting back into pharma" with clients such as Reckitt Benckiser and Bristol-Myers Squibb’. Swiss pharmaceuticals giant Novartis is also a Saatchi client, and boasts "one of the industry's largest and most robust oncology pipelines". Medical Marketing & Media predicts that Bristol Myers Squibb will be the world’s biggest orphan drug company by 2020.

The term ‘orphan drug’ refers to a drug developed for the treatment of a rare medical condition. Once the poor relation of the pharmaceutical industry, orphan drugs are now big business. Sales are expected to grow 11% per year and the market is predicted to reach US $176 billion by 2020. The anticipated return on investment is almost twice that of non-orphan drugs.

An article in industry newsletter Fierce Pharma reports that "As many drug makers have figured out, a small patient group can prove extraordinarily lucrative." In 2014, the average orphan drug cost per patient per year was $137,782 compared to an average of $20,875 for a non-orphan drug. 

In the same week that Saatchi’s Medical Innovation Bill reached Committee Stage in the House of Lordsa conference on orphan drugs was held at London's Regent’s Park Holiday Inn, with one of the main attractions an "interactive roundtable discussion" with Dominic Nutt, director of the Saatchi Bill’s PR campaign.

The conference brought together "leading experts and companies such as Novabiotics, Pfizer, AstraZeneca, GMP Orphan SAS, Genethon and M&C Saatchi and many more to discuss the latest developments in the market.” It was billed as "suitable for attendees wanting to enhance development pathways with the growth of the commercial pipeline for orphan drugs and rare diseases, to access tools for consideration to gain early market access and enhance patient recruitment…”

Money Week considers the very prospect of Saatchi’s Medical Innovation Bill a boon to the biotech industry. Of course, the NHS provides a large ‘market’ with a vast number of patients for ‘recruitment’, but what is it about the bill that is so exciting to pharmaceutical companies and the biotech industry in general?

Demonstrating to a reasonable level of certainty that a drug is safe and effective takes time and money. And there is financial risk for investors: the drug may turn out to be not much use or actively dangerous.

The Saatchi Bill is designed to prevent doctors being sued for negligence if they give an experimental treatment (though not for purposes of research: this is expressly forbidden). They gain this protection even if no other doctor would support that treatment, so long as they have ‘obtain[ed] the views of one other doctor’ – who doesn’t have to agree. (What’s more, that one other doctor can be a business partner in a private practice, or a doctor who supplements his income with paid consultancy work for pharmaceutical companies.)

Let’s look at ‘negligence’ in the context of current medical law. Nigel Poole QC, a clinical negligence lawyer with Kings Chambers explains: "A doctor is negligent if he acts in a way which no responsible body of medical opinion would support or which has no rational basis. … A patient can only sue a doctor in negligence if they suffered avoidable harm as a result of his or her treatment. The patient’s family can sue if the negligent treatment caused the patient’s death. … Responsible doctors who are not negligent [as defined above] or who do not harm or kill their patients do not need protecting. … The [Medical Innovation] Bill protects doctors who act in a way which no responsible body of medical opinion would support and as a result harm or kill the patient they have treated." Sir Robert Francis QC, who chaired the Mid-Staffs inquiries, concurs in his damning response to the bill: “It explicitly frees the doctor to offer treatment which has no support from responsible medical opinion.”

So with the Saatchi Bill, the need to demonstrate safety and effectiveness is greatly reduced. Doctors can try experimental treatments that have no evidence to support them, the pharmaceutical companies can supply the drugs, and the risk is borne entirely by the patient. “Alarmingly non-specific in its wording, the Bill opens up several potential means of causing harm to patients without recourse to protective legislation," according to an editorial in The Lancet Oncology.

The Medical Innovation Bill’s stated aim is "to encourage responsible innovation in medical treatment." Does it address a lack of funding for research? A lack of resources within the NHS for new treatments? The bureaucracy surrounding regulation of new treatments, or the professional regulation of doctors? No. None of these. Not in any way, shape, or form. Maurice Saatchi has decided that a fear of litigation is the problem.

The Medical Defence Union and the Medical Protection Society have stated clearly that they do not believe doctors are prevented from innovating by a fear of litigation. The British Medical Association and the Royal Medical Colleges don’t think so either. They do not support the bill; neither does the NHS Litigation Authority or the Medical Research Council. No one has been able to find a single case where a doctor has been sued for innovating. Even Harry Woolf, a supporter of the Bill and a former Lord Chief Justice, cannot cite a single such case.

And yet, as its sole contribution to medical innovation, the Saatchi Bill blandly states: "It is not negligent for a doctor to depart from the existing range of accepted medical treatments for a condition if the decision to do so is taken responsibly." In current law, negligence means falling below a minimum standard of competence. It has nothing to do with a decision to depart from accepted practice, however that might be defined – there is no central register of accepted treatments, as Nigel Poole QC has pointed out. But under the Saatchi Bill, provided the doctor follows a few ill-defined procedures prior to giving the treatment, s/he cannot later be sued no matter how devastating the harm suffered by the patient as a consequence of that treatment.

Most patients condemned to death by a dreadful disease – and those who make decisions on their behalf – are willing to try anything, anything at all to prolong their lives. Under existing law doctors already can and do provide innovative treatments, including orphan drugs both trialled and un-trialled, when it is reasonable to think the treatment is in the best interests of the patient; existing law protects both doctors and their patients. The Ebola patients recently and currently being treated on the NHS are a good example of this.

The Lancet Oncology editorial cited above states "doctors are already able to innovate outside the context of trials." Particularly in oncology and paediatrics, drugs are often used ‘off-label’ (i.e. for a patient group or condition for which the drug has not been trialled). And in fact, proper monitoring, reporting, and appraisal of off-label use can provide valuable insights for future use. He states further that ‘there are many ways in which doctors can access drugs that are in early-stage clinical trials but not yet widely available.” (ibid)

All the Saatchi Bill does is to remove existing protection from patients when the doctor gives a treatment no colleague would support. According to Dr Marika Davies, a medico-legal adviser at the Medical Protection Society said, it “will put patients who are desperate to try anything at risk of harm from unsuccessful, ineffective and possibly harmful treatments.” The Editorial in the Lancet Oncology cited above offers an example, “the provision of [unlicensed drugs] on a desperate whim, in an unmonitored environment, could lead to patient harm. … Even if the drug had advanced to later testing, but is not yet licensed, pharmaceutical companies would be required to disclose data about toxicities to national licensing agencies only. This information may not stop pharmaceutical companies from promoting their treatment to medical professionals. Doctors could end up prescribing drugs that hurt their patients, only to find later that the toxicities were known, but undisclosed. Clearly this would cause preventable harm to patients; it could also cause ‘immeasurable psychological pain for doctors who believed they were providing the best care for their patients’ ibid Pharmaceutical companies have been known to fall short of ethical practice in promoting their drugs to doctors. Novartis, for example, was involved in two scandals in Japan alone last year, one of them for failing to disclose known side effects of leukemia drugs.

Innovation is a word with very positive connotations, but “the history of medicine is littered with good intentions and innovations that seemed like a good idea but turned out to have disastrous side effects” - as Conservative MP Dr Sarah Wollaston, a former GP, pointed out in an Adjournment Debate on the bill in the House of Commons last month. She also pointed out that the extraordinary developments in medicine over the last 40 years have been thanks to clinical trials establishing efficacy and risks.

The Medical Research Council, the Academy of Medical Sciences, the Association of Medical Research Charities, the Motor Neurone Disease Association, Parkinsons UK, the British Heart Foundation, Leukemia and Lymphoma Research and the Wellcome Trust, among others, have pointed out that the Bill may inhibit genuine medical innovation as it could discourage patients and their clinicians from participating in clinical trials by encouraging the provision of novel treatments on an ad hoc basis, thereby producing unlinked anecdotal evidence that is virtually useless. Dr Sarah Wollaston describes as a "fundamental flaw" the fact that the Bill "specifically precludes the treatments being linked in any way, so we will learn nothing from these treatments. Lord Saatchi’s premise is that his Bill will advance medical knowledge, but there is no evidence that it will advance medical knowledge an inch because we will not be able to answer that fundamental question about whether there are unintended harms from the treatments or any long-term benefits." She goes on to say, ‘If the Bill is passed and undermines enrolment in clinical trials, we will be doing a grave disservice to medical innovation, and it will be to our great shame to have done so.’ (ibid)

If the Medical Innovation Bill is enshrined in law, the incentive for pharmaceutical companies to develop their products beyond the experimental stage all but vanishes. With the Saatchi Bill, they can make a return on investment without the need to progress to clinical trials or market authorisation. And without clinical trials, the opportunity to advance the development of effective treatments is lost.

Current law is flexible and innovative practice by individual doctors is expressly permitted where reasonable. Current law does not undermine clinical trials, within which doctors work collectively to produce innovations of great value to patients. Current law protects both patients and doctors and promotes responsible, ethical medical practice.

A vast number of medical professionals and eminent lawyers, along with respected charities and patient advocacy groups oppose Lord Saatchi’s Medical Innovation Bill on the grounds that it is both dangerous and unnecessary. A handful of quotes below indicates the strength of the opposition the Bill’s supporters ignore:

 “If there is misunderstanding [regarding the protection offered by current law] then it should be corrected by guidance, not by legislation which exposes vulnerable patients to unjustified risk and deprives them of remedies when mistreated by those who have no acceptable justification for what they have done.” 

Sir Robert Francis QC

 ‘We are dismayed that the bill is being promoted as offering hope to patients and their families when it will not make any meaningful difference to progress in treating cancer. … We are concerned that rather than promoting responsible scientific innovation in the treatment of cancer, the Medical Innovation Bill will actually encourage irresponsible experimentation producing nothing more than anecdotal ‘evidence’, at the potential expense of causing serious harm and suffering to patients, their families and carers.’ 

Letter from 100 oncologists to The Times 13th November 2014

 ‘[The Medical Innovation Bill] is fundamentally flawed in its premise, it is unnecessary, it removes essential protections for patients, and it increases the risks of their exposure to maverick doctors. I believe it will undermine not only patients’ safety but medical innovation…’

Dr Sarah Wollaston MP ibid 

“I conclude with the words of Michael Baum, one of the leading innovative surgeons in cancer in this country, whose contribution to breast cancer is second to none. He has said to me that in his view, “Their Lordships are walking over a precipice if they pass this Bill”. We have to listen to that very carefully.”

Lord Robert Winston

The Lancet Oncology’s opinion is this Bill should never be enshrined in law.” 

If neither patients nor doctors nor medical science nor British law are well served by this bill, what purpose does it serve? Who benefits from it? M&C Saatchi Plc had another very good year in 2014 and the noble Lord and his team are "looking forward to the Third Reading of the Medical Innovation Bill this Friday in the House of Lords."

I have looked through Hansard and other relevant documents to see if Maurice Saatchi has declared a financial interest in his Medical Innovation Bill. I’ve found no evidence that he has done so.

The British public are entitled to full, clear, and accurate information about this bill, not the smoke and mirrors of a PR campaign.

https://www.opendemocracy.net/ourkingdom/anne-williams/maurice-saatchi-his-medical-innovation-bill-and-booming-‘orphan-drugs’-mark?