APA Weighs in on Pharmaceutical Conflicts of Interest: 
Highlights Problems But Light on Solutions to Crisis

Pharms Across the Water

[Pharmola.com March 10, 2008] IRENE (Investigative Reporters Network, Europe) is a newly-formed network of journalists working in Denmark, Germany, the Netherlands and Belgium who are investigating the pharmaceutical industry in Europe.  The stories they are covering should sound familiar to anyone following recent news here in the U.S.: the supression of negative information about medications; the cultivation of connections with researchers; and drug advertising.  An English translation of their first stories appears on IRENE's web site; they include investigations of "secret reports about side-effects of medicines, lobbyism in the European Union, including financing of patient-organizations and academic opinion leaders, as well as safety of highly popular medicines for ADHD."

Complaint alleges kickbacks to MDs

By Liz Kowalczyk

March 6, 2009

Federal prosecutors say that a Massachusetts General Hospital psychiatrist became a "star spokesman" in helping a pharmaceutical company promote its drugs for treating depressed children, even though the medications were not approved for pediatric use by the US Food and Drug Administration.

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In a complaint unsealed last week in US District Court in Boston, prosecutors allege that New York-based 

Forest Laboratories Inc.  illegally marketed the drugs Celexa and Lexapro for use in children by paying kickbacks, including lavish meals and cash payments disguised as grants and consulting fees, to induce doctors to prescribe the drugs. They also say the company misled doctors and the public by failing to disclose the results of a negative study.

In the 34-page complaint, prosecutors said that from 1999 to 2006, Dr. Jeffrey Bostic, director of school psychiatry at the hospital, gave more than 350 Forest-sponsored talks and presentations in 28 states, many of which addressed pediatric use of Celexa and Lexapro.

"Forest also paid Dr. Bostic to meet other physicians in their offices in order to ease their concerns about prescribing" the drugs, the complaint said. Doctors are allowed to prescribe children drugs not approved by the FDA for pediatric use, a practice called "off label" use.

The government said that Bostic became "Forest's star spokesman in the promotion of Celexa and Lexapro for pediatric use" and that the company paid him more than $750,000 between 2000 and 2006 for his presentations. The complaint quotes an unnamed Forest sales representative as saying, "Dr. Bostic is the man when it comes to child psych."

Bostic declined to be interviewed, but the hospital gave the Globe a statement describing him as a "highly regarded practitioner and educator in the field of psychiatry." The hospital said Bostic cooperated with the government, providing investigators with information about his speaking engagements.

"The United States complaint is brought against Forest Laboratories, not Dr. Bostic," the statement said. "The complaint consists of characterizations and allegations by the United States, not established facts. In those speaking engagements, Dr. Bostic talked to fellow physicians about the treatment of patients with various mental health conditions, not about one or two specific drugs."

On his Mass. General website on school psychiatry, Bostic outlines several treatments for depression in children and teenagers, including counseling and cognitive behavior therapy, as well as antidepressants. He mentions Lexapro and Celexa along with several other medications, and says, "There is no best medicine to treat depression."

Dr. Michael Jellinek, president of Newton-Wellesley Hospital and chief of child psychiatry at Mass. General, said he has known Bostic for years. "He has absolute integrity," Jellinek said. "I have seen no bias in terms of any choice of treatment or particular medication."

The allegations against Forest are part of a legal and political backlash against potential conflicts of interest in medicine, particularly in psychiatry. US Senator Charles E. Grassley, Republican of Iowa, has accused another Mass. General child psychiatrist, Dr. Joseph Biederman, of failing to tell Harvard Medical School until last March about most of the more than $1.5 million that the pharmaceutical industry paid him in consulting and speaking fees between 2000 and 2007. Biederman has said in statements and letters to the Globe that he has been conscientious about requirements that he disclose payments to his employers and that drug company money has not biased his research.

Harvard would not comment on whether Bostic disclosed his speaking fees, saying faculty disclosure forms are confidential.

In a statement, Forest said it "is committed to adhering to the highest ethical and legal standards, and off-label promotion and improper payments to medical providers have consistently been against Forest policy."

In the article (below) Harris quotes Lewis Morris, chief counsel to the Inspector General of HHS, as saying:

Crackdown on Doctors Who Take Kickbacks

Twenty-One and Bust

At least 21 pubished medical studies involved the use of falsified data and fraud in what is being called one of the largest cases of academic misconduct to date.

The research was conducted by Massachusetts doctor Scott S. Reuben, MD, according to a March 2009 article in Anesthesiology News. The article also reported that a "cornerstone of Dr. Reuben's approach has been the use of [Celebrex] ... and the neuropathic pain agent [Lyrica], both manufactered by Pfizer.  Dr. Reuben has received research grants from the company and is a member of its speakers’ bureau."  (See list of reserach studies involved at bottom). 

Fraud Case Rocks Anesthesiology Community

Mass. Researcher Implicated in Falsification of Data, Other Misdeeds  

In what experts are calling one of the largest known cases of academic misconduct, a leading anesthesiology researcher has been accused of falsifying data and other fraud in potentially dozens of published studies.

Scott S. Reuben, MD, of Baystate Medical Center in Springfield, Mass., a pioneer in the area of multimodal analgesia, is said to have fabricated his results in at least 21, and perhaps many more, articles dating back to 1996. The confirmed articles were published in Anesthesiology, Anesthesia and Analgesia, the Journal of Clinical Anesthesia and other titles, which have retracted the papers or will soon do so, according to people familiar with the scandal (see list). The journals stressed that Dr. Reuben’s co-authors on those papers have not been accused of wrongdoing.

In addition to allegedly falsifying data, Dr. Reuben seems to have committed publishing forgery. Evan Ekman, MD, an orthopedic surgeon in Columbia, S.C., said his name appeared as a co-author on at least two of the retracted papers, despite his having had no hand in the manuscripts. “My names were forgeries on the documents,” Dr. Ekman told Anesthesiology News. 

Dr. Reuben has been an extremely active and visible figure in multimodal analgesia, particularly as an advocate for its use in minimally invasive orthopedic and spine procedures. His research has provided support for several mainstays of current anesthetic practice, such as the use of nonsteroidal anti-inflammatory drugs and neuropathic agents instead of opioids and preemptive analgesia. Dr. Reuben has also published and presented data suggesting that multimodal analgesia can significantly improve long-term outcomes for patients.

Incomprehensible Course

All of that is now in question, said Steven L. Shafer, MD, editor-in-chief of Anesthesia and Analgesia, which retracted 10 of Dr. Reuben’s articles. “We are left with a large hole in our understanding of this field. There are substantial tendrils from this body of work that reach throughout the discipline of postoperative pain management,” Dr. Shafer said. “Those tendrils mean that almost every aspect will need to be carefully thought through. What do we still believe to be true? Do the conclusions hold up to scrutiny?”

Dr. Shafer said that although he still believes “philosophically” in multimodal analgesia, he can no longer be absolutely certain of its benefits without confirmation from future studies.

Dr. Shafer called the scandal “a tragedy” for the profession, for patients and for Dr. Reuben personally. “I cannot begin to comprehend why a person would take this course,” he said of the research fraud.

Efforts to reach Dr. Reuben were unsuccessful.

Internal Inquiry Revealed Sweeping Misconduct 

The retractions came after an internal investigation by Baystate turned up evidence of widespread fraud in Dr. Reuben’s research. Jane Albert, a spokeswoman for Baystate, said the inquiry was undertaken after an internal reviewer at the medical center had raised questions last year. Ms. Albert said the hospital’s investigation raised “no allegations concerning any patient care. This was focused on academic integrity.”

Dr. Reuben is on medical leave from his position as chief of the acute pain service at Baystate, Ms. Albert said. 

Dr. Reuben, who was educated at Columbia University and received his medical degree from SUNY at Buffalo School of Medicine, is well-known among anesthesiology researchers for his studies of multimodal analgesia, the practice of combining several forms of pain relief to better control postoperative discomfort and promote faster recovery from surgery. 

Rumors of a problem with Dr. Reuben’s research have been circulating among academic anesthesiologists for a year, according to people familiar with the matter.

"Interestingly, when you look at Scott’s output over the last 15 years, he never had a negative study,” said one colleague, who spoke on the condition of anonymity. “In fact, they were all very robust results—where others had failed to show much difference. I just don’t understand why anyone would do this or how anyone could pull this off for so long.”

A recent PubMed search for Dr. Reuben’s name turned up 72 citations, the most recent an article in the December issue of the Journal of Cardiothoracic and Vascular Anesthesia on preventing the development of chronic pain after thoracic surgery.

“Massive” Breach of Trust

Josephine Johnston, an attorney specializing in research integrity at the Hastings Center, in Garrison, N.Y., called the scope of the Reuben fraud “massive.” 

"It’s usually just one article, not a body of work,” Ms. Johnston said.

What’s particularly surprising given the dimensions of the case, Ms. Johnston said, is that Dr. Reuben’s research managed to raise no alarms among peer reviewers. However, she added, “the peer review system can only do so much. Trust is a major component of the academic world. It’s backed up by the implication that your reputation will be destroyed if you violate that trust.” 

A cornerstone of Dr. Reuben’s approach has been the use of the selective cyclooxygenase-2 inhibitor celecoxib (Celebrex) and the neuropathic pain agent pregabalin (Lyrica), both manufactured by Pfizer. Dr. Reuben has received research grants from the company and is a member of its speakers’ bureau. However, a source told Anesthesiology News that Pfizer recently alerted its speakers to remove any reference to Dr. Reuben’s data from their presentations. Pfizer was unable to comment by the time this article went to press. The company has not been accused of wrongdoing in the matter.

Jacques Chelly, MD, PhD, MBA, director of the Division of Regional Anesthesia and Acute Interventional Perioperative Pain at the University of Pittsburgh Medical Center (UPMC), said that the Reuben episode has left multimodal analgesia “in shambles concerning many of the drugs we use”—particularly celecoxib and pregabalin. “The big chunk of what people have based their protocol on is gone.”

In light of the situation and economic concerns, UPMC has stopped giving celecoxib and pregabalin to surgery patients “until we have some very formal evidence that we should do something else,” Dr. Chelly said. “In this day and age, doing multimodal [therapy] is expensive. Any institution is going to look at evidence-based clinical decisions, and unless we have very strong data, it is a problem.”

One of the pillars of support for combining celecoxib and pregabalin was a 2006 study inAnesthesia and Analgesia—for which Dr. Reuben has been a reviewer—by Dr. Reuben and colleagues that found the approach effective in patients undergoing spinal surgery. That paper has been withdrawn. “If we take out [those] data in spinal,” Dr. Chelly said, “you really don’t have any evidence that the combination is working.”

E-Mail: AstraZeneca Knew in 1997
that Seroquel Caused Weight Gain

Senator Asks Pfizer About Harvard Payments

By Duff Wilson
March 3, 2009

Senator Charles E. Grassley on Tuesday asked the drug maker Pfizerto provide details of its payments to at least 149 faculty members at Harvard Medical School. (See Grassley letter to Pfizer.)  

The senator, an Iowa Republican who is investigating the drug industry’s influence on the practice of medicine, also asked for any Pfizer e-mail, faxes, letters or photos regarding Harvard medical students who have protested drug company influence.

Mr. Grassley, in a letter to Pfizer, wrote that he was “greatly disturbed” to read an article in The New York Times on Tuesday describing a Pfizer representative taking cellphone photographs of the medical students last October at a campus demonstration against industry influence. “I find this troubling as I have documented several instances where pharmaceutical companies have attempted to intimidate academic critics of drugs,” he wrote.

The request for information about Pfizer payments to Harvard Medical faculty members in the last two years expands Mr. Grassley’s investigation of industry payments to three Harvard psychiatrists who had promoted antipsychotic medicines for children. According to records Mr. Grassley obtained from drug companies, the professors were accused of not properly reporting at least $4.2 million in payments from 2000 to 2007. One of them has been suspended from conducting clinical trials. The investigation continues.

A Pfizer spokesman said on Tuesday that the company “will fully cooperate with Senator Grassley’s request for information.” The spokesman, Ray Kerins, said Pfizer regrets if the photograph taken by the sales representative “was offensive to anyone involved,” but believes the company has acted legally and ethically and that collaboration with medical schools is “a valuable source of innovation and scientific advancement.”

David Cameron, spokesman for Harvard Medical School, said in an e-mail message, “We are unable to provide comment on this matter."

Mr. Grassley, the ranking Republican on the Senate Finance Committee, asked Pfizer to provide details of faculty payments since Jan. 1, 2007, and communications regarding the students since Jan. 1, 2008, to be delivered to him by next Wednesday.

At the October demonstration, which involved about 50 Harvard Medical students and was sponsored by the American Medical Student Association, some protesters saw a man photographing them with a cellphone. He later identified himself as a Pfizer representative but did not give his name. David Tian, one of the students, photographed the man and said he worried that the man had been sending photos to Pfizer.

Mr. Kerins said recently that the man had told him the photos were for the man’s personal use. Mr. Kerins said the man, whom he declined to name, had done nothing improper. Harvard policy prohibits drug representatives from interacting with students on the medical campus but does not bar them from the campus or from taking photographs.

The dean of the medical school, Dr. Jeffrey S. Flier, recently appointed a 19-member committee to review the school’s financial conflict of interest policies. Its first meeting, which will not be public, is planned for Thursday.

The American Medical Student Association, in a national survey of medical schools last year, gave the Harvard Medical School an F grade for how well it controlled drug company payments to faculty members. Dr. Flier said Harvard deserved an “incomplete” rather than an F because it had not submitted paperwork to the association. But the students said they had based their grade on Harvard’s published policies.

The Times reported Tuesday that Harvard officials had said about 1,600 of the medical school’s 8,900 professors and lecturers informed the dean that they or a relative had a financial interest in a business related to their teaching, research or clinical care. The faculty disclosures do not specify how much money they receive, nor are they public.

Harvard Medical School in Ethics Quandary
(See related story on Pfizer's surveillance of Harvard student protesters)

The students argue, for example, that Harvard should be embarrassed by the F grade it recently received from the American Medical Student Association, a national group that rates how well medical schools monitor and control drug industry money.

Harvard Medical School’s peers received much higher grades, ranging from the A for the University of Pennsylvania, to B’s received by Stanford, Columbia and New York University, to the C for Yale.

Harvard has fallen behind, some faculty and administrators say, because its teaching hospitals are not owned by the university, complicating reform; because the dean is fairly new and his predecessor was such an industry booster that he served on a pharmaceutical company board; and because a crackdown, simply put, could cost it money or faculty.

Further, the potential embarrassments — a Senate investigation of several medical professors, the F grade, a new state law effective July 1 requiring Massachusetts doctors to disclose corporate gifts over $50 — are only now adding to pressure for change.

The dean, Dr. Jeffrey S. Flier, who says he wants Harvard to catch up with the best practices at other leading medical schools, recently announced a 19-member committee to re-examine his school’s conflict-of-interest policies. The group, which includes three students, is to meet in private on Thursday.

Advising the group will be Dr. David Korn, a former dean of the Stanford Medical School who started work at Harvard about four months ago as vice provost for research. Last year he helped the Association of American Medical Colleges draft a model conflict-of-interest policy for medical schools.

The Harvard students have already secured a requirement that all professors and lecturers disclose their industry ties in class — a blanket policy that has been adopted by no other leading medical school. (One Harvard professor’s disclosure in class listed 47 company affiliations.)

"Harvard needs to live up to its name,” said Kirsten Austad, 24, a first-year Harvard Medical student who is one of the movement’s leaders. “We are really being indoctrinated into a field of medicine that is becoming more and more commercialized.”

David Tian, 24, a first-year Harvard Medical student, said: “Before coming here, I had no idea how much influence companies had on medical education. And it’s something that’s purposely meant to be under the table, providing information under the guise of education when that information is also presented for marketing purposes.”

The students say they worry that pharmaceutical industry scandals in recent years — including some criminal convictions, billions of dollars in fines, proof of bias in research and publishing and false marketing claims — have cast a bad light on the medical profession. And they criticize Harvard as being less vigilant than other leading medical schools in monitoring potential financial conflicts by faculty members.

Dr. Flier says that the Harvard Medical faculty may lead the nation in receiving money from industry, as well as government and charities, and he does not want to tighten the spigot. “One entirely appropriate source, if done properly, is industrial funds,” Dr. Flier said in an interview.

And school officials see corporate support for their faculty as all the more crucial, as the university endowment has lost 22 percent of its value since last July and the recession has caused philanthropic contributors to retrench. The school said it was unable to provide annual measures of the money flow to its faculty, beyond the $8.6 million that pharmaceutical companies contributed last year for basic science research and the $3 million for continuing education classes on campus. Most of the money goes to professors at the Harvard-affiliated teaching hospitals, and the dean’s office does not keep track of the total.

But no one disputes that many individual Harvard Medical faculty members receive tens or even hundreds of thousands of dollars a year through industry consulting and speaking fees. Under the school’s disclosure rules, about 1,600 of 8,900 professors and lecturers have reported to the dean that they or a family member had a financial interest in a business related to their teaching, research or clinical care. The reports show 149 with financial ties to Pfizer and 130 with Merck.

The rules, though, do not require them to report specific amounts received for speaking or consulting, other than broad indications like “more than $30,000.” Some faculty who conduct research have limits of $30,000 in stock and $20,000 a year in fees. But there are no limits on companies’ making outright gifts to faculty — free meals, tickets, trips or the like.

Other blandishments include industry-endowed chairs like the three Harvard created with $8 million from sleep research companies; faculty prizes like the $50,000 award named after Bristol-Myers Squibb, and sponsorships like Pfizer’s $1 million annual subsidy for 20 new M.D.’s in a two-year program to learn clinical investigation and pursue Harvard Master of Medical Science degrees, including classes taught by Pfizer scientists.

Dr. Flier, who became dean 17 months ago, previously received a $500,000 research grant from Bristol-Myers Squibb. He also consulted for three Cambridge biotechnology companies, but says that those relationships have ended and that he has accepted no new industry affiliations.

That is in contrast to his predecessor as dean, Dr. Joseph B. Martin. Harvard’s rules allowed Dr. Martin to sit on the board of the medical products company Baxter International for 5 of the 10 years he led the medical school, supplementing his university salary with up to $197,000 a year from Baxter, according to company filings.

Dr. Martin is still on the medical faculty and is founder and co-chairman of the Harvard NeuroDiscovery Center, which researches degenerative diseases, and actively solicits industry money to do so. Dr. Martin declined any comment.

A smaller rival faction among Harvard’s 750 medical students has circulated a petition signed by about 100 people that calls for “continued interaction between medicine and industry at Harvard Medical School.”

A leader of the group, Vijay Yanamadala, 22, said, “To say that because these industry sources are inherently biased, physicians should never listen to them, is wrong.”

Encouraging them is Dr. Thomas P. Stossel, a Harvard Medical professor who has served on advisory boards for Merck, Biogen Idec and Dyax, and has written widely on academic-industry ties. “I think if you look at it with intellectual honesty, you see industry interaction has produced far more good than harm,” Dr. Stossel said. “Harvard absolutely could get more from industry but I think they’re very skittish. There’s a huge opportunity we ought to mine.”

Brian Fuchs, 26, a second-year student from Queens, credited drug companies with great medical discoveries. “It’s not a problem,” he said, pointing out a classroom window to a 12-story building nearby. “In fact, Merck is right there.”

Merck built a corporate research center in 2004 across the street from Harvard’s own big new medical research and class building. And Merck underwrites plenty of work on the Harvard campus, including the immunology lab run by Dr. Laurie H. Glimcher — a professor who also sits on the board of the drug maker Bristol-Myers Squibb, which paid her nearly $270,000 in 2007.

Dr. Glimcher says industry money is not only appropriate but necessary. “Without the support of the private sector, we would not have been able to develop what I call our ‘bone team’ in our lab,” she said at a recent student and faculty forum to discuss industry relationships. Merck is counting on her team to help come up with a successor to Fosamax, the formerly $3 billion-a-year bone drug that went generic last year. But Dr. Marcia Angell, a faculty member and former editor in chief of The New England Journal of Medicine, is among the professors who argue that industry profit motives do not correspond to the scientific aims of academic medicine and that much of the financing needs to be not only disclosed, but banned. Too many medical schools, she says, have struck a “Faustian bargain” with pharmaceutical companies.

“If a school like Harvard can’t behave itself,” Dr. Angell said, “who can?”

Pfizer Worker Photographed Protesters at Harvard
Duff Wilson
March 2, 2009

 

U.S. Probes Emory Doctor's Glaxo Ties

That promotion involved fishing trips, golf and spa outings as well as tickets for physicians to attend sporting events and the Broadway theater as well as meals at fine restaurants, the complaint said.

Some were also given cash for participating on advisory boards.

"Ostensibly, Forest paid physicians to attend these advisory boards to get their feedback on the marketing of Celexa and Lexapro," the complaint said. "In reality, as repeatedly reported in internal company documents, Forest intended that the advisory boards induce the attendees to prescribe more Celexa and Lexapro."

The Justice Department said those actions violated laws that forbid kickbacks.

"The United States alleges that federal health care programs have paid thousands of false and fraudulent claims for Celexa and Lexapro prescriptions that were not covered for off-label pediatric use and/or were ineligible for payment as a result of illegal kickbacks paid by Forest," the department said in a statement.

And Then There Were Two:  
Big Pharma's Continuing Intrusion into the Newsroom

The recent New York Times report that Fred Goodwin, host of public radio's The Infinite Mind, had received more than $1.2 million in undisclosed speaking fees from the pharmaceutical company GlaxoSmithKline at the same time he was hosting the award-winning radio program sent shock waves through the journalistic, public broadcasting and medical worlds. 

While over the years it has been known that pharmaceutical companies have intruded on medicine and science through undisclosed payments to doctors and researchers that have created conflicts of interest, Fred Goodwin was the first case of a drug company's undisclosed payments to a working journalist, the host of a nationally broadcast public radio program, no less.  For that reason, the disclosure about Fred Goodwin's speaking fees from GlaxoSmithKiline was a watershed event. 

On the heels of the Goodwin matter, comes former New York State Lieutenant Governor Betsy McCaughey, who wrote a February 9, 2009 commentary for Bloomberg News entitled "Ruin Your Health with the Obama Stimulus Plan."  In her essay, McCaughey attacked President Obama's proposed stimulus plan as being "dangerous to your health,"  and she falsely claimed that the stimulus package would allow the government to "monitor treatments to make sure your doctor is doing what the federal government deems appropriate and cost effective ... to reduce costs and 'guide' your doctor's decisions.”  

This is not the first time that McCaughey has used a news outlet to undermine proposed innovations to the U.S. medical system.  In 1994, McCaughey lead the attack on the Clinton administration's health care plan, with an article in the New Republic entitled "No Exit," which, as the title suggested, claimed the Clinton health proposal would lock people into government-run health care, with no right to seek doctors or treatments of their choice.  McCaughey's assertions were later shown to be blatantly false, but at the time her article helped derail the Clinton health care plan. 

Not surprisingly, in the wake of McCaughey's attack on the Obama stimulus plan's health provisions, Fox News, the Drudge Report and Rush Limbaugh were quick to pick up on McCaughey's report.  Fox News went so far as to report that "new rules buried deep inside the [stimulus] bill" would allow the government to engage in "healthcare rationing," set "limits on research" and establish "new rules guiding decisions your doctor can make about your healthcare."  Fox News called the supposed healthcare provisions in the stimulus bill "Washington's best kept secret."  

As it turns out, none of what McCaughey reported in her Bloomberg News story, nor what was re-reported by other conservative news outlets, is true, as was detailed by Keith Olbermann on MSNBC's "Countdown": 

McCaughey is an adjunct fellow of the Hudson Institute, a conservative think tank that includes among its other fellows former Supreme Court nominee Robert Bork and convicted former White House aide "Scooter" Libby.  As Olbermann pointed out, it is funded, in part, by pharmaceutical companies and biomedical suppliers.  

McCaughey also serves on the board of Cantel Medical, a medical device company, which according to documents filed with the Securities and Exchange Commission, paid her with 750 shares of stock options worth approximately $11,250 nine days before she wrote her Bloomberg commentary, and $55,000 for the year ending July 31, 2008  after the company realized record revenues in 2008 of $250 million. McCaughey admits she got the payments, but released a statement denying any conflict of interest.  McCaughey was also formerly on the board of Genta, a biotechnological company, whose web site and all information about the company was taken off-line due to an "increase in web traffic" following the report of McCaughey's connection to the company (see below).  

In the wake of the Fred Goodwin disclosure, questions have been raised about how to increase the transparency with regard to possible conflicts of interest among journalists and commentators, particularly with regard to funding from pharmaceutical and medical device companies. Journalism as a field continues to rely on self-disclosure, which clearly is not sufficient to identify cases like Goodwin and McCaughey.  Since Bloomberg News and others who ran the McCaughey story apparently weren't aware of her financial ties to the medical industry, it needs to be asked what sorts of efforts need to be made in the future to help insure transparency.  

(Disclosure: Pharmola.com is published by LCMedia, Inc., formerly Lichtenstein Creative Media, which was the producer of The Infinite Mind.) 

Harvard will stiffen rules for staff at med school

Conflict of interest will be redefined

By Liz Kowalczyk 

Globe Staff / February 3, 2009

Harvard Medical School plans to strengthen its conflict-of-interest rules for doctors and researchers, amid a US Senate investigation into several faculty members and a new state law that will make public some of the paymentsdoctors receive from pharmaceutical and medical-device companies.

Many top medical schools, including Stanford University, the University of Pennsylvania, the University of California at Los Angeles and at San Francisco, and the University of Massachusetts have adopted stricter policies in the past two years. Last year, the American Medical Student Association graded Harvard with an F on its conflict-of-interest policy because it does not address issues like whether companies can provide gifts and meals for faculty.

But Dr. David Korn, Harvard University's vice provost for research and a nationally known leader on conflict-of-interest policies, said Harvard's job is considerably more challenging, because the medical school does not own or control its affiliated teaching hospitals, where clinical faculty members see patients and interact with drug company salespeople. And most clinical faculty are employees of the hospitals, not the medical school.

"I personally would like to see the medical profession above public reproach to the maximum extent possible," said Korn, who was hired several months ago and will oversee a review of all the university's conflict-of-interest policies, including those at the medical school. He said the gifts doctors receive from drug companies "are unnecessary and distracting and in some ways demeaning to the medical profession." But the medical school "has to bring the hospitals along with it," he said.

Harvard's teaching hospitals, including Massachusetts General, Brigham and Women's, and Beth Israel Deaconess Medical Center, each have their own conflict-of-interest rules, which overlap with but are separate from those for Harvard Medical School.

The medical school's policy focuses on limiting research conflicts; for example, it bars faculty or their family members from holding more than $30,000 worth of stock in publicly traded companies, and any equity in privately held companies that sponsor their research, or from receiving more than $20,000 a year in consulting or other fees. The hospital policies generally cover research conflicts but also set rules for whether drug companies can provide meals for doctors during educational talks and give them gifts. Doctors are required to fill out various forms for the hospitals and medical school each year, disclosing many of their relationships with industry.

A 19-member committee will review the entire policy, which could take a year, said the medical school dean, Dr. Jeffrey Flier. He said that the policy is revised regularly - most recently in 2004 - and that the current review was not prompted by the Senate investigation or the new state law. US Senator Charles E. Grassley, a Republican from Iowa, has accused three Mass. General psychiatrists of not fully disclosing payments they received from drug companies for consulting and other activities. The doctors have said they believed they complied with the rules. Harvard Medical School and Mass. General are conducting their own investigations.

"The public and regulatory agencies are saying we have to be much more transparent about any relationships faculty have with industry," said Dr. Richard Schwartzstein, a member of the review committee and a pulmonologist at Beth Israel Deaconess. "The trend is to become more and more stringent, there's no question about that."

Flier said one area the committee probably will focus on is continuing medical education. The medical school sponsors several hundred courses for doctors each year, Harvard officials said, and drug companies pay about 13 percent of the cost. He said the medical school does not allow pharmaceutical companies to influence the content of courses. But some medical schools have adopted additional safeguards against industry influencing education for physicians, such as requiring companies to give money to a central office, which then distributes it to pay for courses. Others are discussing banning industry funding altogether.

"I don't think we need to go there," Flier said, about entirely barring company funding for education. "If you have the appropriate separation between the source of funding and the speakers and the topics, it's not a problem in my point of view."

Harvard also is under pressure from some medical students demanding stricter rules. Last year, a group of students pushed for and won a new policy requiring lecturers, faculty members, and visiting professors to disclose any financial interests they have in a company or treatment they discuss. Students say enforcement of the policy is spotty.

"We do see that interaction between industry and [doctors and hospitals] can be very beneficial in providing new therapies," said one of the students, Kirsten Austad. "But when it's not above board it can create mistrust between patients and doctors."

Drugmaker wants to seal info— for you

By Kris Hundley, Times Staff Writer 

February 14, 2009

AstraZeneca, maker of the blockbuster anti psychotic Seroquel, is battling to keep information about the drug out of the public's view … for the public's own good.

This month in Orlando, lawyers for the drugmaker will argue that unsealing company documents, including unpublished clinical trial data and letters from the FDA, could harm "a vulnerable patient population."

"This (disclosure) could jeopardize public safety by causing confusion and alarm in patients, who may then discontinue their medication without seeking the guidance of a medical professional,'' lawyers for the drugmaker said in a recent filing in federal court.

Seroquel is approved only for schizophrenia and bipolar disorder, but its use for everything from depression to insomnia to ADHD in kids is so widespread that the drug has been prescribed for more than 22 million patients. Its $4.5 billion in sales last year put it among the top-selling drugs in the world.

In light of Seroquel's popularity, the argument that hiding information protects patients has public health advocates throwing up their hands.

"They don't want anybody to know about the side effects of their drug, and they're keeping secret the results of studies from patients, their doctors and the FDA,'' said Dr. David Egilman, clinical associate professor at Brown University's Department of Community Health.

"Saying they're protecting the patient is a self-serving, fraudulent argument."

• • •

Though Egilman is merely an observer of the Seroquel proceedings, he knows the power of sealed documents in drug liability cases. He played a key role when similar lawsuits were lodged against another mega-selling antipsychotic, Eli Lilly's drug Zyprexa. As in the Seroquel cases, thousands upon thousands of patients claimed Zyprexa caused weight gain and diabetes.

Hired as an expert witness for the plaintiffs in Zyprexa cases, Egilman was given access to reams of internal Lilly documents that had been sealed by the court. The documents showed that the drugmaker had ignored evidence of diabetes among patients while pushing Zyprexa's off-label use for anxiety and dementia.

Egilman defied the judge's orders and helped leak thousands of damaging Lilly documents to the New York Times. Egilman ended up paying a $100,000 fine to Lilly for releasing the sealed documents.

The leaked documents, meanwhile, helped the U.S. Department of Justice build a criminal case against Lilly. The company pleaded guilty to marketing Zyprexa illegally and last month paid a record $1.4 billion fine. Though a landmark amount, Lilly's fine amounts to about 3.5 percent of the $39 billion in revenues Zyprexa has posted since the FDA approved it 1996.

• • •

Seroquel's parent, Astra Zeneca, has a similarly valuable franchise to protect. The anti psychotic accounted for 14 percent of AstraZeneca's sales of $31.6 billion last year. Avoiding negative publicity — one of the reasons the company wants to seal documents in the Orlando cases — is critical as it seeks to maximize sales before Seroquel loses patent protection in about three years.

The skirmish over document disclosure in Orlando is part of a hornet's nest of litigation against AstraZeneca, a British company with U.S. headquarters in Wilmington, Del. More than 15,000 patients have filed over 9,000 personal injury lawsuits. About 40 percent of these claims have been consolidated for pretrial motions in U.S. District Court for the Middle District of Florida.

Plaintiffs say the company knew as early as 2000 that Seroquel caused diabetes, weight gain and other health problems, but failed to adequately warn patients and doctors.

Dr. William C. Wirshing, a California psychiatrist, has lectured doctors on AstraZeneca's behalf and has prescribed Seroquel to as many as 5,000 patients. Though he has been a paid consultant for the drugmaker, in a pretrial deposition he left no question about the links he sees between the drug, weight gain and diabetes.

"You literally just got to watch them get bigger … it was riveting to me," said Wirshing who estimated that several hundred of his patients developed diabetes.

AstraZeneca denies the allegations and has spent more than $500 million defending itself against Seroquel claims. Key to the company's strategy has been its insistence that millions of pages of documents produced in discovery should remain under seal, out of the public eye.

To Egilman, such blanket agreements in drug liability cases are outrageous. "Confidentiality agreements that prohibit disclosure of important information that may impact public health to state and federal authorities should be illegal,'' he said. "The court should at least send all discovery in drug cases to the FDA and DOJ (Department of Justice) for review if they intend to seal them."

The upcoming hearing is expected to focus on specific items that the plaintiffs' lawyers say have no legal right to secrecy. Among them: unpublished results of several drug studies, sales reps' notes on Seroquel's marketing strategies and letters from the FDA.

The drugmaker also hopes to keep under seal information about sexual relationships that Dr. Wayne MacFadden, AstraZeneca's former U.S. medical director for Seroquel, had with an independent researcher as well as with a woman who wrote papers supporting the drug's safety and efficacy. Correspondence shows that MacFadden, who was also director of clinical research for neuroscience drugs, "promised sexual favors in exchange for intelligence on AstraZeneca's competitors."

The plaintiffs say the affairs "can create bias which can affect the integrity of the science.''

Lawyers for the drugmaker counter that the affairs are not relevant to the lawsuits. Other disputed documents, they say, contain trade secrets, could taint the jury pool and could "harm public health."

AstraZeneca's lawyers say the information to be discussed at the hearing scheduled Feb. 26 is so sensitive that the court should be closed to the public. "The potential harm of dissemination of documents at this stage in the litigation far outweighs the public's right of access, particularly when trials in these cases are on the near horizon,'' company lawyers said in a filing Feb. 6. "The whole picture will be presented to the public at once."

The judge has not ruled on the request.

There's a good chance that many of these cases will never come to trial, and the underlying documents will never become public. In a victory for Astra Zeneca, the judge dismissed the first two cases in late January, saying plaintiffs had not sufficiently established that their health problems were caused by Seroquel. Up to nine trials are slated for 2009.

In the Zyprexa litigation, Lilly paid $1.2 billion to settle injury claims involving 31,000 patients. Damaging company documents were never released by the court, though they were available on the Internet after Egilman leaked them and excerpts appeared in the New York Times.

Egilman is well aware of the big money in liability lawsuits, having made $2.3 million as an expert witness in Vioxx cases. He contends that patients' lawyers are motivated by maximizing their share of any settlement, which can be 30 percent or more. He says attorneys should be required to get their client's approval before agreeing to seal documents.

"The client may be more interested in making sure that health information gets to their doctor than money," he said. "They have a real interest and it's called their health."

Gary Farmer, a Fort Lauderdale lawyer who represents more than 100 Seroquel patients, said Egilman has a point.

"If we can get the documents to win the case and get compensation, you have to ask yourself, 'Is it necessary to make that information public?' " he said.

Whether the mountains of Seroquel material now sealed in Orlando's federal court ever see the light of day may depend on the progress of related cases. Four states — Pennsylvania, Montana, Arkansas and South Carolina — are suing Astra Zeneca for off-label marketing of Seroquel.

The company said it is aware that the U.S. Attorney's Office in Philadelphia is investigating Seroquel's marketing practices, most likely based on whistle blower complaints.

Regulators also seem to be taking note. In December, the FDA sent AstraZeneca a warning letter after learning a sales rep had pitched Seroquel to a doctor as a treatment for depression. Though doctors can prescribe a drug for any use, it is illegal for pharmaceutical companies to promote such uses.

The FDA also reportedly sent AstraZeneca two letters in late December, telling the company to strengthen Seroquel's warnings about diabetes. The drugmaker declined to comment, saying its communications with the FDA are confidential. The letters remain sealed in Orlando's federal court.

The patients at Danvers, their symptoms softened by the new medications, began to venture forth, almost miraculously, into the world beyond the hospital. Pirrotta took a group that included schizophrenics to a children's camp in New Hampshire, off-season, where they spent a week cleaning and grooming the grounds. "For most of them, it was the first time they'd been out of an institution in their adult lives," he recalls. But the state's budget crunchers had wanted to close places like Danvers for years — pills, after all, were far cheaper than hospitals — and the new drugs made the move clinically defensible. To the staff at Danvers, it seemed as if the state had abandoned its responsibilities to the mentally ill. "It felt like we'd been sold a bill of goods," Pirrotta says. "It felt like a betrayal."

By 1992, when Danvers closed, something even more vivid and hopeful was looming: A whole new class of drugs, called atypical antipsychotics, were being tested in clinical trials. The atypicals held the promise of a more perfect tranquilizer, one that would calm the storms of schizophrenia while eliminating the side effects that made the older drugs so despised. Psychiatrists reserved their greatest excitement for a molecule being developed by Eli Lilly, a pharmaceutical company based in Indianapolis. The new chemical mirrored the powers of clozapine but without its fatal flaw. It was called olanzapine, and the scientists working on it believed it might be the One.

Dr. William Wirshing, a UCLA psychiatrist who had a grant from Lilly to conduct clinical trials on olanzapine, was one of those enthused by the early results. He believed the hype was warranted, and Lilly was flying him around the country to brief other psychiatrists on his work and to seed excitement for the coming medication. Then one morning in 1995, as Wirshing was driving to LAX to catch a pre-dawn flight, a story came on the radio about olanzapine. Wirshing listened in astonishment as a top Lilly executive announced the company's plans for the new drug, which it was preparing to market under the name Zyprexa.

"He says it's got the potential to be a billion-dollar-a-year drug," Wirshing recalls. "I almost pulled off the road and crashed into the side rail." At the time, the entire market for atypical antipsychotics was only $170 million. "How the hell do you make $1 billion?" Wirshing thought. "I mean, who are we gonna give it to? It's not like we're making any more schizophrenic brains."

There is a well-known feature of medical science called the placebo effect, which suggests that, in a clinical trial, patients who are told they are being medicated but are in fact given only a sugar pill will see their symptoms improve, merely out of the misplaced conviction that they are being healed. During the late 1990s, and then with increasing speed during the current decade, Wirshing and other psychiatrists watched as the market for atypical antipsychotics swelled well beyond its marked territory, far exceeding the country's supply of schizophrenic brains — past $2 billion a year, $5 billion, $10 billion, all the way to $16 billion. What had begun as niche drugs are now the third-largest class of medication in the world, their sales greater than those of the antidepressants. The mechanisms used to leverage this growth were in some ways the most modern and perfect the pharmaceutical industry had developed, but they were also, according to state and federal prosecutors, illegal. Lilly has already agreed to pay $2.6 billion to settle charges that it built the market for Zyprexa first by concealing its side effects, and then by marketing it "off-label," for diseases for which it had not been approved.

"It was a very clever sort of con," says Dr. Peter Tyrer, a leading psychiatric researcher at Imperial College in London who wrote in the latest issue of the respected medical journal The Lancet about a new study that debunks the effectiveness of the atypicals. "Almost the whole scientific community was conned into thinking — as a consequence of good marketing — that this was a different and better set of drugs. The evidence, as it's all added up, has shown this to be untrue."

Eli Lilly insists that it has not marketed Zyprexa off-label and that it has accurately represented the drug's side effects. But some medical researchers who have studied the atypical antipsychotics say that, in the final tally, the drugs, which have already been linked to some deaths, may eventually be responsible for tens of thousands of cases of diabetes and other potentially fatal diseases. And despite their early promise for treating schizophrenia, the drugs have not even performed any better than the crude and imprecise earlier medications that preceded them. "We have been paying $16 billion a year instead of $2 billion a year for drugs that seem to be no better and might be worse," says Douglas Leslie, a researcher at the Medical University of South Carolina who contributed to an extensive federal study of the drugs. The story of how Zyprexa and other atypicals became a multibillion-dollar market suggests that the medical community — doctors, researchers, the institutions that back them — may be themselves prone to a placebo effect: the willed conviction that a new drug, presented as a breakthrough, must in fact be one, that a product sold as healing must in fact do good.

FOREVER UNQUIETED
Few diseases are as haunting — and as poorly understood — as schizophrenia. Even in the psychiatric wards of major hospitals, where every patient is severely mentally ill, the schizophrenics stand out. In the depressives, the manic-depressives, the alcoholics and the addicts, you can still detect echoes of healthier people now and then; at their worst they pass in and out of episodes of insanity. But in schizophrenics, the old, familiar personality is often obliterated. The exact nature of the disease has not yet been precisely mapped, and so schizophrenia is defined by its manifestations, by the dramatic onset of psychosis, of delusions and hallucinations. Those who suffer from it can seem forever unquieted, as if by an alarm bell constantly ringing.

Some schizophrenics have hallucinations that are purely auditory — a demon they are convinced loiters just behind their eyeballs; others are beset by colors and figures — religious images, or distorted body parts that disrupt their visual field. The clash of this detached and fervently received world with the actual one has unusual effects — a compulsion to lay down in traffic, a need to wear heavy jackets under the delusion that it is not really summer. Psychiatrists identify schizophrenics by clusters of symptoms, the most common being paranoid and chaotic delusions, illogical thinking and behavior, and a severe and persistent lethargy. The onset of the disease comes so suddenly and so late in life — in the teens to late 20s — that the families of schizophrenics end up watching the people they knew being rapidly submerged, like an island busily eroding. "The most disturbing part for the families is dealing with the sense of loss — the knowledge that we can't get back the way you were before," says Dr. Geoffrey Neimark, a psychiatrist who met me at Pennsylvania Hospital in Philadelphia to explain life in the mental ward.

Every medical treatment has a glimpse of mystery in it, the ghost lingering in the algorithm, but psychiatry is even closer to alchemy than most. The diseases are too complex to be fully understood, and when the drugs work it can seem as if the patient has been visited by something magical and benign. In the 1950s, French scientists looking for an alternative anesthesia discovered that a chemical compound eventually marketed as Thorazine seemed to calm schizophrenics. The drug, and those that followed (what are now referred to as the "typical antipsychotics"), were crude instruments, often derived by accident and luck rather than through the process of discovering the disease's source in the brain and then refining a drug to repair it. Besides slowing down the brains of patients, the drugs had awful effects that doctors came to call "extrapyramidal" — muscular tremors, facial twitching. Patients on Thorazine were often stunned into immobility; in extreme cases, they wound up staring at the ceiling, their eyeballs locked in place. Others drifted aimlessly, a compulsion so common that it became known as the "Thorazine Shuffle."

Psychiatrists had expected that the science of schizophrenia would improve, but the more they looked for the disease's source, the murkier it seemed to get. Then, in the early 1990s, Dr. Ezra Susser, an epidemiologist and psychiatrist at Columbia University, was scouring the historical record when he happened upon something amazing: the prevalence of schizophrenia in the children of the Dutch war famine. In the fall of 1944, as the German armies were holding tensely on to Holland, the Nazis found themselves fighting an uprising by the Dutch resistance. In retaliation, they imposed an embargo. It was a harsh winter, and the country's canals froze over; food could not reach the cities, and Holland suffered a sudden famine. People ate tulip bulbs to survive. The next spring, when the Allies conquered the country, the famine lifted as suddenly as it had begun. Researchers later tracked the babies born to mothers pregnant during the famine, hoping it would help them understand the effects of malnutrition in the womb. As Susser paged through the records, he noticed that the children had developed schizophrenia at a far higher rate than those born in Holland only a few months later. It was a hint that schizophrenia isn't determined solely by our genes.

Schizophrenia, epidemiologists noticed, was popping up in all kinds of strange places: It was associated with children born to older fathers, with those who had suffered brain injuries in the womb, with the families of Caribbean immigrants in England. But despite their best efforts, scientists had been unable to understand what united all these disparate groups, what constituted the disease's unique, underlying cause. "The complexity of schizophrenia is very great," says Dr. Pablo Gejman, director of the Center for Psychiatric Genetics at Northwestern University. "We're probably talking about hundreds of individual factors — many genetic, some the result of environmental exposures. We actually have a profound ignorance on the specific molecular mechanisms of schizophrenia."

THE MOLECULE
Before a pharmaceutical company has completed the long and labored effort of turning a biological insight into a marketable drug, the scientists who are pushing and pulling at its chemical dimensions refer to the thing, with a reverent purity, as "the Molecule." In the early 1990s, as scientists at Eli Lilly were developing the new molecule known as olanzapine, the company faced a strategic problem: Prozac, by far its best seller, would go off patent soon, and the billions it generated would largely dry up. In early reports, olanzapine looked like a promising and potentially lucrative replacement, and by 1992 company executives were searching for experts in schizophrenia willing to conduct the first clinical trials of the drug. They explained their belief in the drug, that it had replicated the successes of clozapine and excised the chemical agents that caused extrapyramidal effects. Some doctors began to wonder if they might be staring at the next Prozac, the coming revolution in mental illness. It was, Wirshing says, "exciting as hell." He signed on.

The most vivid models we have of corporate deception come from the tobacco industry, where scientists working in company labs, behind sealed walls, conducted misleading experiments out of public view and then told the wider world they had found things they hadn't. But the pharmaceutical industry is immune to this kind of conspiracy. The size of clinical trials and the federal regulations that govern them mean that a company can never develop and study a molecule in-house; it relies on a platoon of contracted researchers, specialists at academic institutions, who test the molecules and then publish their findings in academic journals. The system is not perfect; studies have found that drug trials sponsored by the industry (which, since rule changes made in the Reagan administration, has meant virtually every large drug trial) are at least four times more likely to suggest that a drug is a success than trials that are independently funded. But when the system fails, the cause is often not outright deceit, but rather a web of overbright enthusiasm, the urge that researchers have to convince themselves that a drug is a little better than it actually is, that it can save lives. Pharmaceutical companies depend, in other words, on the sincere cooperation of people like Bill Wirshing.

Like other psychiatrists who treated schizophrenia, Wirshing had long been convinced that the harsh side effects of the older drugs were so painful that patients simply stopped taking them, and he was excited by the promise of an alternative. Using experimental doses of Zyprexa provided by the company, he gave the drug to his least responsive patients, those who had stopped taking their other meds and seemed permanently adrift, "lost in the ether of space somewhere." As he watched the first patients on the drug, Wirshing was intrigued. It seemed to work better than the older medications. Patients got dizzy when they stood up; their hearts raced; they would get constipated. But in most patients, the most vivid side effects of the typical antipsychotics — the tics, the perpetual restlessness — seemed to vanish.

"Was there a magic efficacy?" Wirshing says. "The answer is no. But the thing that was really dramatic was it was devoid of the neurologic toxicity." Wirshing saw very quickly, however, that Lilly had a problem: Many of his patients taking Zyprexa were gaining a startling amount of weight. The pattern was as sudden as it was consistent. For the first few days they were on the drug, you weren't aware of any palpable difference. But by the end of the week, you could see the weight gain, almost in real time. Bellies and thighs started spreading, faces started puffing out. By the end of a year, the results were stunning. Some of his patients had gained more than 125 pounds.

Clinical trials are not cheap to conduct or lightly undertaken. According to Wirshing, Lilly spent $200 million to test Zyprexa at 175 sites around the world. "They thought they had a drug that was superior," he says. "You don't spend that much money just for the hell of it. They really believed this." But when he brought his concerns about Zyprexa to executives at the company, Wirshing says, they tried to dismiss the evidence. First they told him that it was just the skinny schizophrenics who were getting fat. Wirshing re-examined his data; it wasn't true. Then they told him that it was the schizophrenia itself that was causing the weight gain, rather than the drug. Wirshing was apoplectic: "If schizophrenia causes that much weight gain, how come I've been working with schizophrenics for 20 years and didn't know that?"

At one meeting of researchers who were studying the drug, Wirshing recalls, a scientist from Lilly presented the results of a trial he had conducted at Indiana University, in which a group of healthy male students were given 10 milligrams of Zyprexa a day to test the side effects. Within two weeks, the students gained five pounds more than those in a control group, who didn't take the drug. Wirshing worked out the implications: Taking 10 milligrams of Zyprexa, the study suggested, was the equivalent of eating 1,500 additional calories every day. Some of the students gained as many as 15 pounds in two weeks. "It is just un-stinkin'-believable," Wirshing says. "It is the best drug for gaining weight I've ever seen. If you and I could just put a negative in front of those weight-gain numbers, we'd make billions."

In 1995, as the company was preparing to submit Zyprexa for approval to the Food and Drug Administration, Lilly convened a panel of experts to review the results of its largest study. The specialists concluded that Zyprexa produced an average weight gain of 24 pounds in a single year. One in six patients, clinical trials later revealed, gained more than 66 pounds. Such a staggering side effect, doctors knew, could elevate a patient's blood-sugar levels — an indication that the drug could cause diabetes. The government, if aware of these risks, might have slapped a strong warning label on Zyprexa, suppressing sales. But the data Lilly submitted in its application to the FDA that same year led the agency to draw a far less alarming picture of the drug. Relying on a database of 51 separate and conflicting studies provided by the company, the FDA concluded that patients taking Zyprexa for one year would have an average weight gain of only 11 pounds. "It's akin to the guys from the cigarette companies going, 'Well, it doesn't cause cancer,'Ê" Wirshing says. "It's just plain not true."

Fifteen years after the Reagan administration made it a policy to gut the FDA, however, the agency lacked the staffing and clout to safeguard the public. As the process stood, the government essentially entrusted drug research to the pharmaceutical industry and, given certain protocols on the collection of data, trusted that the results were accurate. Simply put, the FDA was no longer in a position to independently evaluate the effectiveness — and risks — of a drug like Zyprexa.

"What's that parable about the king who goes down to the ocean and asks the waves to stop coming in?" says Paul Leber, who directed the agency's division of neuropharmacological drug products at the time Lilly sought approval for Zyprexa. "That's what we're dealing with here. Congress creates laws that nominally protect the interests of the society and then gives insufficient funds and support to the regulatory agencies to do anything about it. This is what happens."

On September 30th, 1996, the FDA approved Zyprexa for the treatment of schizophrenia. Lilly was so confident of the go-ahead that it had already hired a sales force and stockpiled the drug in warehouses. The very next day, the company filled the first prescription for Zyprexa, making it the fastest drug to market in history. The label did little to warn doctors and consumers of the risk for severe weight gain or hyperglycemia, even though Lilly's own studies, internal documents would later show, raised concerns about these side effects. The FDA would eventually send a warning letter to Lilly, criticizing it for marketing Zyprexa as superior to other antipsychotics and as virtually free of side effects — claims the agency called "misleading" and "lacking in balance." But it would be nine years before a comprehensive government study would reverse many of the claims that surrounded Zyprexa and other atypical antipsychotics, and raise disturbing questions about their risks. And nine years, in the pharmaceutical industry, is a lifetime.

THE SALES PITCH
Every business has its own animating vanity, its conviction of its own social good, but in pharmaceuticals, where a good product saves lives by the thousands, the vanity is closer to the surface than in most. In 1998, a young man named Shahram Ahari, a few months out of Rutgers University, took a job as a drug detailer — a salesman who visits doctors — with Lilly's neuroscience division and was sent to headquarters in Indianapolis for "sales school." The new reps were told, from the beginning, that they were part of an elite. The neuroscience division not only required the most technical sophistication, but it had responsibility for the company's two best sellers, Prozac and Zyprexa. The sales reps had been hired, in part, because of their natural charisma — doctors would like them. Most of the reps, Ahari noticed, were really attractive — the company had recruited cheerleaders and athletes, and there were a couple of girls who plausibly claimed to have been models. But when the new hires were given technical training, it slowly dawned on Ahari that none of the other sales reps seemed to have any college-level science. "I was the only one in the room who could explain a very simple process, like how two neurons communicate," Ahari says. "That was startling."

Though Ahari had not known it when he applied, the company was on a kind of precipice. Its blockbuster drug, Prozac, the pill that provided nearly a third of Lilly's total revenues, was going to lose its patent protection in 2001, a date so significant that executives at Lilly referred to it, in memorandums and annual reports, as "Year X." As Lilly tried to figure out what to do, a consensus began to form around a new strategy. "The company is betting the farm on Zyprexa," one executive wrote in an internal memo in 2001. "The ability of Eli Lilly to remain independent and emerge as the fastest-growing pharma company of the decade depends solely on our ability to achieve world-class commercialization of Zyprexa."

The problem, from a marketing standpoint, was that there simply weren't enough schizophrenics in the world to save Lilly's bottom line. Among the company's most natural markets for Zyprexa, in the early days, were county jails and state prisons, where many schizophrenics and other mental patients — mostly locked up for public-nuisance crimes such as trespassing or creating a disturbance — had wound up after the closing of psychiatric hospitals like Danvers. "Before deinstitutionalization, to study people with severe mental illnesses, you went to hospitals," says Linda Teplin, director of the Psycho-Legal Studies Program at Northwestern Medical School. "After deinstitutionalization, you went to jails." Those in the profession now refer to Riker's Island and the L.A. County Jail as the two largest mental hospitals in the country. Feeling the great weight of inmate numbers, some jail doctors began to prescribe antipsychotics not only to treat schizophrenia but to tranquilize misbehaving prisoners. "It appeared that people were being medicated simply to keep them pacified," says Eric Balaban, senior staff counsel for the ACLU's National Prison Project.

In his new job, persuading psychiatrists to prescribe the drug, Ahari and those like him were pivotal: If Lilly hoped, one day, to break out of the circumscribed market of schizophrenia, it needed psychiatric experts to tell primary-care doctors that Zyprexa was a good drug and a safe drug. Ahari was given a $60,000 expense account and an assignment to cover Brooklyn and Long Island.

Pharmaceutical sales reps think of themselves as the intellectuals of the sales world, but they spend their days in a gauzy suburban existence, driving from hospitals to private offices in big American sedans, their detailing kits and golf clubs in the trunk. They chat up receptionists to get in to see doctors, chat up residents to find out who is on a hospital's formulary committee. What was striking to Ahari, at least at the beginning, was how easy it was. Lilly had spent hundreds of millions of dollars developing Zyprexa, as well as millions more on market research, yet its campaign was built largely around the fact that the drug was newer than rival medications. "The Novel Psychotropic," they called it. Ahari had talking points and brochures that referred to the initial studies and had been trained to stress the lower rates of extrapyramidal symptoms that Zyprexa caused. But frequently the conversations didn't even get that far. "Most doctors were inclined to think that the atypicals were better," Ahari says. "That's one of the things that made selling Zyprexa so much easier. A lot of them just wanted to play with the shiny new toy."

Though Zyprexa cost far more than the older drugs, which were mostly generic, neither insurance companies nor doctors seemed primarily concerned about cost, and Zyprexa was, from the beginning, a vast success. "The existing treatments were so bad that people were willing to pay a lot for the prospect of something better," says Meredith Rosenthal, an associate professor of health economics and policy at the Harvard School of Public Health who has studied the atypicals extensively.

One afternoon during Ahari's first week on the job, a psychiatrist pulled him into a small room. The doctor had put some of his patients on Zyprexa, he said, and he had noticed that they were gaining a troubling amount of weight. What could the sales rep tell him about that? Ahari was "stunned." He'd spent six weeks at sales school, and though he'd been coached extensively on the beneficial features of the drugs, the company had downplayed the risk of weight gain. Ahari passed the doctor on to Lilly's science desk and then put in a query himself. Eventually, the company's reply came back. If he heard similar complaints from doctors, he was supposed to tell them to have patients drink a glass of water before taking the pill, and a glass of water afterward. Ahari started to have doubts. "This was," he says, "a ridiculous way to cope with weight gains of 20 or 30 pounds in a month."

The more Ahari started to poke around, the more skeptical he became. Lilly had instructed its sales reps, if asked about weight gain, to explain that Zyprexa was not statistically worse than other antipsychotics. But this contradicted the company's own data. At this point the drug had 5 million users; a senior Lilly scientist did a quick calculation and estimated that Zyprexa had caused as many as 100,000 of those users to gain 90 pounds. The health risks of that kind of weight gain were profound. "One hundred thousand people putting on 90 pounds of weight," the scientist concluded glumly, "is a lot."

Internally, Lilly's own experts were criticizing the company for covering up the link between Zyprexa and diabetes. "I do believe they made a very strong point that unless we come clean on this, it could get much more serious than we might anticipate," one Lilly executive warned in an internal e-mail in October 2000. But in hospitals and doctor's offices, the company's sales force continued to push Zyprexa as a wonder drug. In a common industry practice, Lilly persuaded leading psychiatric experts to endorse the drug and then paid them to tout it to doctors, who had little expertise when it came to antipsychotics. Ahari was struck by how perfectly the strategy worked: Most doctors, pressed for time, did not "approach the education they were getting from the industry with any skepticism at all."

Nor did the experts, who were all paid to hock the drug, strike Ahari as unbiased. The first time he met a national psychiatric expert, flown in to recommend Zyprexa to local doctors, the expert pulled Ahari aside and started quizzing him about sales in his territory; he was trying to figure out, he said, when he might optimally exercise his stock options. One rep arranged to fix a doctor's swimming pool; another paid a nightclub hostess to spend time with a doctor. Some of the more attractive reps boasted about ways to "exploit sexual tension." Ahari had been taught strategies to manipulate physicians during conversations — such as providing subliminal reminders of the favors he had done for them — and he found himself using the techniques on his girlfriend.

Ahari was becoming convinced that what he had been trained to do was to make a pitch that seemed scholarly and then to let that impression stand in for a flawed product. Because federal law allowed pharmaceutical companies to purchase a doctor's prescribing records, they could measure exactly how much all of this attention was buying. "There were a few doctors where it didn't make any difference, but far more frequently you could see a direct correlation," Ahari recalls. What was particularly striking, in the case of Zyprexa, was that even as more and more studies criticized the drug's side effects, it continued to win market share. The FDA didn't require that sales reps tell a doctor about every single study that had been done on a particular drug, only that what they did say was accurate.

"It's like a magician," says Dr. Robert Rosenheck, a professor of psychiatry at Yale University. "The magician just says, 'Look at my right hand. There's a marvelous rabbit in my right hand.' And you don't pay any attention to what's going on in their left hand. When you have such a devastating illness, and so much yearning for hope, it's easy for marketing to convert that hope into conviction."

THE ALGORITHM
The pharmaceutical industry and the federal government have always had an unusually intimate relationship — the government is both the industry's watchdog and its biggest customer. The FDA regulates the development of a drug and, at least in theory, the marketing that follows its release. Because Medicaid and Medicare buy such a large portion of drugs — particularly in the case of the antipsychotics, since virtually no schizophrenics can afford private insurance — the companies lobby those agencies, and their state subsidiaries, to try to win preferences for their own medications. To make clear which drugs the government will pay for, some states issue complex medication algorithms — detailed "decision trees" that spell out precisely what a psychiatrist seeking government reimbursement should prescribe when confronted with certain symptoms. (Lilly, for its part, has lobbied extensively to keep state legislatures from favoring generics over Zyprexa.) But in 2002, an investigator in the Pennsylvania inspector general's office, a guy named Allen Jones, became convinced that another line had been crossed, and that the government itself had been enrolled in marketing the drugs.,/p>

Following up on a complaint, Jones discovered that the state's chief pharmacist, Steven Fiorello, was receiving checks from drug companies — $2,000 for a speaking fee, $1,765.75 to fly in a psychiatrist for a meeting. Jones wondered if the money was buying anything else. Digging deeper, he learned that Fiorello was heading a panel that wanted to require psychiatrists in state hospitals, prisons and other institutions to prescribe newer, brand-name medications rather than older, cheaper generics. Under the new formula, the state would pay millions more to the pharmaceutical companies for antipsychotics like Zyprexa. Fiorello had touted the newer, more expensive drugs as better than the older ones. But as Jones examined the medical literature and called up experts, he noticed that the studies that Fiorello relied on were industry-sponsored; third-party studies seemed far less convinced of the merits of the atypicals. "Independent science, minus the drug-industry money, had come to a different conclusion," Jones says. "It was a big red flag."The practice of industry-paid doctors and research is so commonplace that for most medical professionals, it barely registers — it's just part of the background noise. Virtually every clinician in the country who conducts original drug research gets money from the pharmaceutical industry, because that's who pays for research. The industry currently spends 50 percent more than the government on basic medical research, a gap that has consistently widened for the past 15 years. But to Jones there was something different happening here: Fiorello was a state employee, not a university researcher. And this looked to Jones a lot like a bribe.

Jones continued to probe. Fiorello's algorithm for Pennsylvania was modeled on a program called TMAP that had been developed by Dr. Steven Shon, medical director of the Texas Department of Mental Health. In all, Jones discovered, Shon and a team of researchers he worked with at the University of Texas had taken more than $2Êmillion in grant money — from atypical manufacturers and their nonprofits — to develop TMAP.

When Shon's group finalized its work in 1997, the manufacturers got far more than they had paid for. The new algorithm made the more-expensive atypicals the preferred drug for doctors treating prisoners, students and poor patients covered by Medicaid. It set rules so stringent that if a doctor prescribed an older, cheaper drug instead of a newer one, they had to explain their decision in writing, making them vulnerable to malpractice lawsuits if the patient developed any problems. Influenced by the new algorithm, the state also reportedly treated the atypicals as the preferred drugs for certain mental illnesses in children, even though the FDA had not approved that use.,/p.

Studies would later show that under the new guidelines, prescriptions of atypical antipsychotics in Texas increased sixfold by 2004. The government of Texas, in effect, had instituted a taxpayer-subsidized marketing scheme for the drug industry, one that gave preferential treatment to the newest and least-tested medications.

The atypical makers paid Shon to fly around the country, taking more than 80 trips to talk up the merits of his new algorithm. In interviews from the period, Shon's sense of social purpose is palpable and zealous, as if he believed he were building a machine to save neglected schizophrenics. There were trips not just to Pennsylvania but to Italy and Japan. Eventually, 17 other states adopted versions of the TMAP program. It was, Jones believed, a classic bait-and-switch. "The scientific evidence didn't back the industry up," he says. "So they paid these experts like Shon and then let their opinions stand in for evidence. What's amazing is how well it worked."

As Jones made progress on the case, his supervisor at the inspector general's office tried to warn him off. "Stop trying to be a salmon," his boss said. "Stop swimming against the stream." When Jones persisted, he was fired. "I could begin to see what was going on," he says now. Jones filed a suit in federal court alleging a cover-up, and his efforts eventually convinced the state of Texas to reject its own algorithm and sue the drug manufacturers for millions in damages. Fiorello was convicted of violating felony conflict-of-interest laws. Shon, who was forced to resign, ended up moving to Las Vegas. But he refuses to admit that he did anything wrong. The studies on the atypicals, he insists, indicated that they really were better drugs. "When you really look at the investigators involved and the procedures they followed," he told reporters, "they were all within what has been defined as appropriate in every medical field."

In this, Shon is, more or less, right. The doctors who studied the atypicals were simply conducting business as usual. Jones, an outsider gazing in, thought he saw a basic quid pro quo, a corrupt transaction between two parties that stood to benefit. But it is possible that he missed a more complex and fundamental truth: that the system of developing and marketing drugs is so broken that it can coax corruption out of well-meaning doctors who think they are doing good. Every incremental permission that the atypical makers allowed themselves, and the regulators allowed them — structuring their studies in the most advantageous ways, omitting studies unhelpful to their cause, publicizing only the most supportive data — helped shift the medical perception of the atypicals. The companies didn't need to pay off doctors. They just needed to put the grant money out there and wait for the true believers, the Steven Shons, to walk through the door.

GOING OFF-LABEL
In the fall of 2000, marketing executives at Eli Lilly summoned the company's sales representatives to a meeting in Orlando, at which they planned to introduce a new strategy, one born not of nervousness but of success. Zyprexa had recently won FDA approval for treatment of bipolar disorder as well as schizophrenia, but these were limited markets. "To get beyond a certain point," says Sandra Chow, a drug-industry analyst with the research firm Decision Resources, "companies that manufactured the atypicals needed to expand into the primary-care market." The big money, in other words, lay in the offices of suburban doctors and family physicians.

At the Orlando conference, Lilly edged close to self-parody, a real-life version of The Office. Someone at the company rewrote the lyrics of "Viva Las Vegas," urging sales reps to target the primary-care market: "Thousands of patients waitin' out there/The way they're livin' just ain't fair/But now you bet they can get/Some help from primary care/Viva Zyprexa! Viva Zyprexa!"

But there was a problem: It was illegal for the company to suggest any "off-label" uses for Zyprexa to doctors, because no treatments other than schizophrenia and bipolar disorder had been approved by the FDA. And almost all schizophrenic and bipolar patients were being treated by psychiatrists, not by primary-care doctors. But that didn't deter Eli Lilly. The company's executives, internal documents would later show, had been planning a strategy shift for about a year, e-mailing suggestions about opportunities in the primary-care market. Some doctors, one executive wrote, might be willing to prescribe Zyprexa for depression, if they could be convinced that what they thought was depression was in fact one half of the mood swings of bipolar disorder. Another executive suggested marketing Zyprexa to treat the elderly. "Dementia should be first message," he wrote, noting that primary-care physicians "might prescribe outside of label."

In Orlando, the executives detailed their plan. As part of their marketing initiative, they had compiled "profiles" for three types of patients they wanted their drug reps to suggest Zyprexa would help. One was "Donna," a single mom in her 30s who came to the doctor's office in "drab clothing," complaining that she felt anxious, irritable and in need of little sleep. The second was "Mark," a middle-aged man who experienced mood swings. The third was "Martha," a widow who had grown agitated and restless since her grown children had left home.

In its marketing strategy, Lilly argued that such common, widespread symptoms actually indicated diseases for which Zyprexa was approved — bipolar disorder in the first two cases, schizophrenia in the last — though to most psychiatrists, the symptoms didn't come close to describing those disorders. The goal for sales reps, according to the Lilly's strategy document, was to "expand the market of Zyprexa by redefining how primary-care physicians help reduce mood, thought and behavioral disturbances." Other company documents, which later came to light during court proceedings, encouraged sales reps to use the term "mental disorders," which was "intentionally broad and vague, providing latitude to frame the discussion around symptoms and behaviors rather than specific indications." Other court documents accuse Lilly of pushing Zyprexa for anorexia, autism and sleep disorders, a charge the company denies.

Some consultants for Lilly grew alarmed. "They were clearly pushing off-label use," says Dr. Lon S. Schneider, a psychiatrist at the University of Southern California who has served as a consultant for Lilly. The company, he says, pushed studies that supported its case while ignoring those that were negative. Schneider discovered ads in journals for geriatricians and nursing-home administrators that seemed to advocate off-label use of the drug to relieve the symptoms of dementia — even though he knew that Lilly's own studies of elderly patients with dementia had found the drug worked no better than a placebo. (In 2005, the FDA required Zyprexa's packaging to include a "black box" warning — the agency's most severe — emphasizing that the drug increases the risk of death for patients with dementia.)

Rhonda Stovall, a sales rep assigned to sell Zyprexa, had helped Lilly find alternative markets for drugs before, selling a repackaged version of Prozac as a treatment for PMS. At one point, as the company tried to break into the market for general depression, it came out with a formula for what it called "treatment-resistant depression," suggesting that doctors mix Prozac and Zyprexa. Such formulations involved a sort of pharmaceutical sleight of hand: "You focus on the symptoms, that's what we were taught," Stovall says. "You don't focus on the disease." The reps told primary-care doctors that what they thought of as depression might in fact be bipolar disorder — which, conveniently, could be treated with Zyprexa. Internal call sheets from the company's sales reps in Alaska show them visiting doctors, leaving peanut-butter cups and the Donna profile. "You may have some patients who are bipolar, and you've never really thought of the problem like that," Stovall recalls telling physicians. "Let me tell you about Zyprexa, how it can help with these mood swings."

Within three months, the Viva Zyprexa campaign generated 49,000 new prescriptions for Lilly, bringing in hundreds of millions of dollars in revenue. Today, a quarter of Zyprexa's sales are in off-label markets.

But peddling the drug to anxious mothers and mildly depressed middle-aged men meant that Lilly was inflicting the side effects of Zyprexa on tens of thousands of unwitting patients. Dr. John Gueriguian, a retired FDA investigator who has served as an expert witness in lawsuits against Lilly, believes the company was aware of the connection between the drug and diabetes by 1998 but concealed that evidence. Lilly put "profit over concern of the consumer," he said in court testimony. But the new markets only served to amplify the drug's side effects. If schizophrenics gained more weight than they were supposed to, Stovall points out, no one really complained — schizophrenics, after all, have bigger problems to worry about. "But if you've got your soccer mom who comes in, and the doctor gives her Zyprexa, and suddenly she goes from 110 pounds to 200 pounds — well, it could be a problem."

The weight gain was visible and striking. "You'd see it from one visit to the next," says Dr. John Abramson, a clinical instructor at Harvard Medical School who has studied the atypicals. "They'd come back, and they'd look like a different person. It looked like someone stuck an inflation needle in them and pumped them full of air." There were other effects, too. Patients got dizzy; they got tired; some saw their blood-sugar and cholesterol levels spike. (Lilly added strong warnings about these last two side effects in 2007, after publicity over Zyprexa's risks had mounted.) Even more worrying, as researchers examined the many studies that had been conducted on the utility of the atypicals in treating the elderly, they found that tiny, persistent differences in the rates of death between the population given the new drugs and those given a placebo began to accumulate. "There would be one death in the patients on the drug, none on placebo in one trial. Three on the drug, none on placebo in another trial," says Schneider, who conducted some of the analyses. "When we summed this up, we found there was a small but clear risk for death."

Such side effects might have been more easily tolerated if the drug actually eased conditions like depression or dementia. But there was little evidence that Zyprexa did any good for off-label uses. In schizophrenics, the drug at least served a much-needed purpose, and psychiatrists, properly informed, could weigh the benefits against the side effects. But with the new conditions for which the drug was being prescribed — depression, dementia, anxiety — no one knew exactly what the benefits were, because Zyprexa's effectiveness for them had not been studied. All that was left was the side effects. "Doctors had no way of knowing if the drug worked for those indications," Abramson says.

And yet the use of the atypicals continued to spread. To some psychiatrists, their success seemed the emblem of a disturbing new era. "Turn on the television and look at the commercials," says Neimark, the Pennsylvania Hospital psychiatrist. "We sell the magic pill. On one page it's like everything's stormy and downcast, and on the next page the guy's at the bowling alley, and he's the life of the party." The advertising, he says, has consequences. "Everyone comes to doctors expecting cures — but in some ways, they're fantasies."

THE RUNNER
By the early 2000s, the categories of off-label users were beginning to add up: soccer moms, the elderly and now, researchers were increasingly finding, children. This was unusual. Because kids responded badly to the earlier versions of the drugs — they exhibited, as adults had, the characteristic facial distortions, the lethargy and nonfunctionality — the consensus of most psychiatrists was to find other ways to treat children. "During medical school, I remember very vividly one kid we had in the psychiatric unit who we just couldn't get under control," says Dr. Mark Olfson, a professor of clinical psychiatry at Columbia University. "He was attacking other patients on the floor. Because we were at our wits' end, I asked the nurse on duty, 'What about an antipsychotic? And she said, 'Mark we don't use these drugs for behavioral control in kids.' That was exactly the attitude."

But that attitude began to change in the 1990s. The new atypicals carried with them the promise that antipsychotics would be softer and less severe, and the use of the drugs escalated dramatically. Since 1993, the number of kids on the atypicals has soared fivefold. The leap took place in categories where antipsychotics had not previously been prescribed: Children were now being given the drugs for anxiety, ADHD and a newly popular diagnosis, pediatric bipolar disorder. "If I get really mad and throw a piano bench at you, we used to call that aggressive behavior," says Dr. Gabrielle Carlson, director of child and adolescent psychiatry at the Stony Brook University School of Medicine. "Now we call that a mood swing. It's a way of labeling kids that is quite insidious."

The manufacturers of the drugs were not immune to the possibilities offered by the emerging market. In 2003, a Lilly executive named John Lechleiter, who would later become the company's CEO, sent an e-mail to some of his colleagues. "We must seize the opportunity to expand our work with Zyprexa in this same child-adolescent population," he wrote. The drugs grew so prevalent that by 2006, a study found, nearly one in five children who visited a psychiatrist left the office with a prescription for an antipsychotic. "People began to think it was almost completely unethical not to give kids the atypicals," says Dr. Linmarie Sikich, an associate professor of psychiatry at the University of North Carolina. "But we didn't have any long-term studies" of the drugs' effects.

The lack of science, however, didn't deter doctors from prescribing them to children. The attraction was the same as in adults: the calming influence the chemicals could have on kids who otherwise seemed uncontrollable, mad with rages and distraction. "Can I tell you what's going to happen to someone who was put on an atypical 20 years ago, between the ages of 10 and 11?" asks Carlson, the pediatric psychiatrist. "No. That's where it's hard to look someone in the eye and say, 'No sweat.' At the same time, if you have a son who is unmanageable at home and who's being offered residential treatment, and you have the choice of that or giving him this medication, what do you pick?"

As the use of the atypicals overran the evidence, however, disturbing reports began to emerge. Between 2000 and 2004, the deaths of 45 children were linked to the atypicals. Some were strikingly young. An eight-year-old boy died of cardiac arrest. A four-year-old boy died of complications from diabetes. Perhaps most vivid of all was the case of a 15-year-old boy in South Florida referred to by social workers as a "runner," a kid who kept fleeing his exasperated foster parents to return to his birth mother. Admitted to a psychiatric hospital by a judge, the boy was tethered to a chair and pumped full of atypical antipsychotics, presumably to calm him. When his lawyer came to visit him, she found the boy not only sedated, but suffering from another acknowledged side effect of the atypicals: His breasts had become engorged and started to leak milk. The boy was lactating.

The risks of prescribing the atypicals to children became clear last fall, when Sikich, the UNC professor, delivered the results of a study she conducted on behalf of the National Institutes of Health. Not only were the atypicals no more effective than the older, cheaper, antipsychotics, but they caused side effects that prompted more than half of the kids to drop out of the study within a year. (Earlier, industry-funded studies had claimed far lower drop-out rates.) Kids gained as much as 35 pounds in as little as eight weeks, saw their cholesterol and insulin levels rise, and experienced painful rigidity in their muscles — a side effect that the newer antipsychotics were supposed to have eradicated. In fact, Sikich concluded, the atypicals had more-severe side effects than the older antipsychotics that pediatricians had resisted using in children. "All the drugs," she says, "are dirty drugs. They act in different places in the brain, and they all have different effects — some that we want and some that we don't."

LAX OVERSIGHT
By 2001, as the atypicals threatened to break $4 billion in annual domestic sales, officials at the National Institutes of Health decided to undertake the largest-ever investigation of schizophrenia. Studies had continued to appear evaluating the merits of the different types of antipsychotics, but the data was all over the place. Some concluded that the new drugs were a godsend; others said they did little. Most exasperating of all, it was almost impossible for a doctor, investigating in his spare time, to weigh the potential conflicts of interest within any individual study — virtually everyone in research psychiatry was affiliated with one drug company or another, and their findings, oftentimes, seemed to mirror their affiliations. The NIH decided to commission a comprehensive set of studies of its own, free from pharmaceutical influence, to evaluate the merits of the new drugs. Though it had for two decades entrusted drug development to industry, the government was effectively acknowledging that the data this system had produced had become so perplexing to physicians that it needed to settle things itself.

As data from the studies emerged, Robert Rosenheck — the Yale psychiatrist, who helped analyze the findings for the NIH — began to see significant divergences between the government studies and those produced by the pharmaceutical companies. Again and again, the government found, the new drugs were no more effective in treating schizophrenia than the old drugs, which were far cheaper. In addition, the atypicals appeared to dramatically increase the risk for diabetes and other often fatal illnesses. The great advertisement for the new drugs — that because they didn't cause the Parkinson's-like symptoms of the older drugs, patients would stay on them for longer — turned out to be substantially exaggerated as well.

"What you have is both industry and opinion leaders claiming this is a breakthrough drug," Rosenheck says. "And then three large government-funded studies come out, and none of them finds evidence of a breakthrough."

Puzzled by the discrepancies, Rosenheck began to work back through the original studies. What he found was not one smoking gun but a number of small manipulations. Researchers in the original Lilly study, he concluded, had not only skewed the results by concealing data that contradicted their preferred outcomes, they had also failed to administer drugs commonly used to offset the side effects of the older antipsychotics — a decision that made the older drugs perform worse in the clinical study than they did in the real world.

By the time the studies were completed, however, the damage was already done: More than 20Êmillion people worldwide have now taken Zyprexa. As the problems leaked out, lawyers for consumers and states began to look carefully at the industry's atypical studies and the methods the drug companies used to promote their products. In October, Lilly agreed to pay $62 million to 32 states to settle claims that it improperly marketed Zyprexa for off-label uses. "The company's deceptive marketing practices were illegal and highly dangerous," according to Lisa Madigan, the attorney general of Illinois. Although Lilly admitted no wrongdoing, the settlement was the largest ever paid by a drug company in a state consumer-protection case. On January 15th, Lilly agreed to pay an additional $1.4 billion to settle federal charges of illegal marketing — a record settlement in a corporate whistle-blower case.

But the penalties pale in comparison to the money that Zyprexa makes for the company. In 2007, the latest year for which figures are available, the drug generated $4.78 billion in sales, accounting for 25 percent of Lilly's total revenues. As Rosenheck reviewed the marketing history of the atypicals, he concluded that misleading data told only part of the story. "How did this happen?" he wondered. "How did this product that's not very advantageous wind up being marketed as a great advance?" Part of the underlying cause, he concluded, lay in the privatization that began with the Reagan revolution. "Ultimately, the conservative turn — with its faith in deregulation and the virtual infallibility of markets — are at the root of what allowed this to happen," he says.

In January 2002, as the Bush administration's second-tier appointees were beginning to settle into their jobs, a former pharmaceutical lawyer named Daniel Troy, who had just been appointed the chief counsel at the FDA, was given striking new powers. The agency's medical evaluators would no longer have the authority to send a warning letter directly to a drug manufacturer engaged in questionable marketing practices — marketing like the kind that Lilly had used to sell Zyprexa. Now, FDA evaluators would have to get approval from the Office of the Chief Counsel — from Troy himself, effectively — before sending out such a letter. The shift had a remarkable chilling effect on government oversight of the drug industry: The length of time it took the FDA to issue a warning letter about deceptive advertising quintupled.

For a decade, the FDA had been instituting small but significant accommodations that increased the intimacy of its relationship with the drug industry. First, in 1992, it began requiring drug companies to pay application fees when submitting new drugs for review — a move that made the agency dependent on industry for more of its budget. Throughout the 1990s, with a Republican Congress demanding a new friendliness to industry, the posture of the agency continued to shift; by the time Bush took office in 2001, the FDA's approval rate for all new drugs had jumped from 60 percent to 80 percent. The agency was so industry-friendly that even the vast and powerful pharmaceutical lobby wasn't pushing particularly hard to further weaken lax regulations. "After 2000, the companies saw that the agency was going to be very lax," says a retired senior FDA official who asked not to be identified.

Bureaucracies, like fraternities, are idiosyncratic places, formed of personality, habit and tradition. In the FDA, Bush's political appointees were coaxing the agency's bureaucrats and scientists to go easy on the drug manufacturers. "What's different now is a lot of these higher-up career officers are much more industry-friendly than was the case two decades ago," says Dan Carpenter, Freed Professor of Government at Harvard and a leading scholar of the agency. By 2000, when the Los Angeles Times documented how the FDA had approved seven deadly drugs, it turned out that the agency had repeatedly ignored strenuous objections from its own experts.

Under Bush, experts say, the FDA has effectively become enrolled in the erosion of its own power. Instead of supporting consumers harmed by dangerous drugs, Troy's office began filing briefs on behalf of drug companies facing lawsuits from the families of people harmed by medications. In some cases, congressional investigators found, Troy operated in concert with the pharmaceutical companies. The number of warning letters issued by the FDA, a key indicator of how vigilant the agency is at tracking violations by drug manufacturers, has now fallen to half what it had been at the end of the Clinton administration. The industry is also well connected with Republican power: Former president George H.W. Bush has served on the board of directors of Eli Lilly, and Mitch Daniels, his son's former budget director, served as the company's vice president.

"With the FDA where it is, the pharmaceutical companies control far too much of the process, from the trials to the marketing," says Abramson, the Harvard instructor. A decade ago, it was a few figures on the fringe of the medical profession who sensed the trouble in this, and they had the feel of people who had been gazing into the vortex too long. Now it is professors at Yale and Harvard, and, in the case of the atypicals, by implication, the government itself.

BEYOND DRUGS
During the late 1960s, the World Health Organization assigned a psychiatrist named Norman Sartorius to study schizophrenics in different parts of the world. Years later, Dr. Sartorius and his fellow researchers followed up on his patients in the initial study, to track their recovery. The researchers expected to find that patients in the West, who have far better access to modern medications than those in the Third World, live longer and participate more fully in society. But the study found precisely the opposite: Schizophrenics in the developing world, with minimal access to medication, do better than those in the West. "It was a very surprising finding," Sartorius says. It was also controversial. But as follow-up studies confirmed Sartorius' initial findings, epidemiologists began to wonder if the evidence suggested something profound and definitive about the shortcomings of antipsychotic drugs. If Egyptians and Bangladeshis did better without the drugs than Americans did with them, the thinking went, how good could the drugs be?

One of the scientists who found himself fascinated by the discrepancy was William Eaton, a leading schizophrenia researcher who chairs the department of mental health at Johns Hopkins University. As he explored the ways in which schizophrenics live in the developing world, he began to think that the drugs were still crude enough that social factors might have a bigger effect on treating the disease. In the cluttered bazaar in Aswan, Egypt, Eaton met a schizophrenic man — his tongue flicking, his face bent by the tremors of Haldol — who was employed in his father's tiny shop; later he visited the man's home, where his wife had just given birth to the couple's first child. "The point is that this guy's family structure was such that he could get married because he was being protected by his father," Eaton says. "That's bound to be better than someone in the West who has to drop out of college and ends up on the street homeless."

Eaton began to see similar patterns elsewhere. In the surreal destitution of India, he visited the house of a schizophrenic — a dozen relatives crammed into three rooms, a portrait of John F. Kennedy tacked to the wall — where the family rotated round-the-clock care of the sick man. In such settings, Eaton believed, lay a basic illumination about the mystery of schizophrenia: Drugs might do some good, but they still weren't as effective as a supportive, caring environment. "The medications are helpful, but they don't work for everybody, and they have lots of side effects," Eaton says. We tend to think of drugs as solving discrete problems — penicillin to eliminate bacteria, insulin to modify diabetes — but the antipsychotics are shooting at an invisible target. With schizophrenia, says Eaton, "we don't know what the hell is going on."

Visiting the most celebrated mental-health centers in the United States, it is hard to conclude that, even after the innovation of the atypicals, the drugs make a decisive difference in care. In November, I spent a day with Dr. Ralph Aquila, a schizophrenia specialist at Columbia University, who works with a legendary center in New York called Fountain House. The "clubhouse model" developed there — which stresses job placement for even the most severely mentally ill, and a transition to functionality — has been widely praised and adopted; there are now 400 such centers in the United States, as well as dozens overseas. "Schizophrenia used to be synonymous with a death sentence," Aquila tells me. "I can get them paying taxes."

There are cases, Aquila says, where drugs play an important role. Unlike many other psychiatrists, he still prescribes Zyprexa — believing that social workers in the closely monitored environment of Fountain House can track unwanted side effects and make any necessary adjustments. But as he spends an afternoon treating patients, it becomes clear that the challenge for those treating schizophrenics goes far beyond tinkering with dosages and medications. One long-term patient, who had been focused earlier in the day, is suddenly skittish and distracted; Aquila suspects a crack relapse. A woman on Zyprexa has gained 80 pounds and had to have her stomach stapled; Aquila checks her weight, asks about her new apartment. A young man has a new job with a messenger service; Aquila, pleased, asks him how frequently he is making it to work.

This is incremental and shaky-footed work: Aquila expects his patients to have false starts and relapses, shifting, suddenly, from a medicated, functional state to more-florid and dysfunctional psychosis. Some elements of the medical establishment — at Harvard, even at Columbia — still view such efforts as social work rather than medicine. But to Aquila, the up-close contact with patients is what is essential. Many schizophrenics see a doctor only once a month, for a 15-minute consult, and Aquila believes that those psychiatrists have no chance to follow up on the things that matter most. "You don't know what the person's really about — you miss out on something that you could latch on to, to really develop a relationship," he says. "The meds are just a small part of the equation."

Aquila has learned a truth like those that Eaton discovered more distantly: a feel for the enormity of the problem, and a sense that the solution lies in hard and incremental work, with frequent backsliding. He has learned, in other words, that there is only so much the drugs can do. He has come to believe that there is no magic here.

[From Issue 1071 — February 5, 2009]

Behind "Bitter Pill": Q&A With Ben Wallace-Wells

Pfizer Takes $2.3 Billion Charge Linked to Bextra Probe

Who broke the Fred Goodwin/ The Infinite Mind story? 

Writer David Dobbs posted a story on his "Neuron Culture" blog about Philip Dawdy, who runs the pharmaceutical watchdog site, FuriousSeasons.com.

Dobbs' thesis is that Dawdy is a "one man army" when it comes to covering the pharmaceutical industry, but the New York Times steals his reporting and doesn't give him credit.  A story Dobbs cites as an example is the $1.2 million in undisclosed speaking fees that went to The Infinite Mind's former host, Fred Goodwin. However, Dobbs undermines his point about the quality of reporting in the blogosphere by not getting his own facts straight as he tries to argue that bloggers in their pajamas can out-report major news organizations.  See Dobbs' story: ("Zyprexa, Infinite Mind and mainstream vs. pajama press") and Pharmola's response to it, below. Given the ongoing debate about blog journalism vs. mainstream media, this was an interesting object lesson.

1) Dawdy did not, as the posting maintains, "lead the way" with his reporting about The Infinite Mind and "inspire" Jeanne Lenzer and Sharon Brownlee to write their May 2008 Slate.com story about The Infinite Mind's "Prozac Nation: Revisited" episode. I am not sure from where that information came, but Jeanne Lenzer called me in late March 2008, immediately after the show aired, and weeks before Dawdy posted his first piece on The Infinite Mind on April 14, 2008, to discuss the program and issues she had about it that had been kicked around at a health journalism conference she attended. Jeanne and I also discussed her helping to produce a one-hour The Infinite Mind special on the subject of anti-depressants and suicide. When we turned down the idea of her doing the radio show, she and her co-author, Sharon Brownlee, wrote the Slate.com story. Therefore, to say that Lenzer's Slate.com story was "inspired" by Dawdy's reporting is not true.

2) Despite the implication that The Infinite Mind ceased production due to the November 2008 New York Times article, in fact the Times' story had nothing to do with the award-winning public radio series ending its 10-year run. The program, which was independently produced and distributed, had already announced to public radio stations before the New York Times story appeared that it would be ceasing production at the end of 2008 due to funding concerns.

3) The posting says that Dawdy "broke the [New York Times] story" about The Infinite Mind's former host, Fred Goodwin, but this couldn't be further from the truth.

Dawdy's focus with regard to The Infinite Mind was on issues related to anti-depressants and their links to suicide, and whether the program had erred by not disclosing the publicly-known pharmaceutical ties of three guests on a program that examined anti-depressants and suicide.

By contrast, the focus of the November 2008 New York Times article was the undisclosed acceptance by former host Dr. Fred Goodwin of $1.2 million in speaking fees from GlaxoSmithKline. To say that Dawdy broke that story is simply wrong.

In fact, the story of Goodwin's speaking fees was not broken by the New York Times nor Philip Dawdy. It first appeared on Ed Silverman's "Pharmalot.com" web site on November 20, 2008, prior to the Times posting it on their web site, and a full two days before the Times story went to print.

(See Silverman's story at http://www.pharmalot.com/2008/11/talk-is-not-cheap-npr-host-has-ties-to-pharma/ )

Silverman had the whole story first, including the spreadsheet from Senator Grassley's office that detailed the $1.2 million in payments to Goodwin. Silverman got the story from the same place the New York Times did: Senator Grassley, who had read all of the details of his office's investigation of Goodwin into the Senate record the day before, on November 19, including payments, speaking venues and radio programs that related to talks he had been paid to give. If anyone deserves the credit for the Goodwin story, it's Grassley's staff.

Finally, with regard to Dawdy's relentless attacks on The Infinite Mind for questioning what hard scientific evidence exists linking anti-depressants to suicide, I offer the following: in May 2008, the Slate.com article, critical of The Infinite Mind, was reviewed by STATS, a nonprofit, nonpartisan research organization affiliated with the George Mason University that works to improve the quality of scientific and statistical information in public discourse. STATS concluded that "The Infinite Mind needs to deal with the fact that it underplayed the risk [of antidepressants and suicide]; but Slate and Brownlee and Lenzer need to consider something less palatable: whether their approach to reporting this issue is putting, on balance, more lives at stake." The same, arguably, can be said about Dawdy and his writing on this story.

- Bill Lichtenstein

Medtronic Pays Surgeon ‘$20,000 or More’ -- Much, Much More
(Hint: Try $19 million).