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For Gene Haislip, a former official of the U.S. Drug Enforcement Agency, the perennial debate over Ritalin, the stimulant commonly prescribed for children with "attention deficit hyperactivity disorder (ADHD)," is an aching reminder of a moral battle he fought – and lost – to big drug companies.
For 17 years, the now retired director of the DEA´s Office of Diversion Control set production quotas for controlled substances like methylphenidate (MPH), the federally restricted stimulant commonly known as Ritalin. During that time, he fought hard to raise public awareness about over-prescribing of stimulants to children, about the drug's high rate of street diversion, and about its long-term health impact on young patients.
"This affects the most sensitive part of our population," says Haislip, now a consultant for drug companies on issues of compliance to federal law. "When I was at the DEA, we created awareness about this issue. But the bottom line is we didn't succeed in changing the situation because this – prescribing methylphenidate, for example – is spiraling.
"A few individuals in government expressing concern can't equal the marketing power of large companies," he adds. "I have doubts that the truth is driving this issue. It seems that market forces and money is behind it."
As public scrutiny of drug companies grows, so do questions about what critics say is a vast over-prescribing of MPH, especially as more adults are taking other MPH-based medicines such as Concerta. According to the DEA, production of the central nervous system stimulant, which is pharmacologically similar to amphetamines, grew from 5,000 kilograms in 1993 to 20,967 kilograms in 2002 – probably the largest ever prescribing explosion for a controlled substance, says Haislip.
Echoing the sentiments of many in and outside the scientific community, Haislip says he suspects the dubious marketing tactics of big drug money have fueled the spiraled use of MPH. Specifically, he suspects the compromise of a small group of prolific ADHD researchers whose work is funded by corporate producers of ADHD drugs. He also suspects that one or more ADHD patient advocacy groups that receive drug company donations have essentially become fronts to push the prescribing of stimulants to children.
And evidence suggests Haislip may be right.
"It Was Like A Whitewash"
Enter Dr. William Pelham, director of the Center for Children and Families at State University of New York at Buffalo (SUNY).
A leading ADHD researcher for 30 years, Pelham is a former member of the scientific advisory board for McNeil Pharmaceuticals, which produces Tylenol and markets Concerta, a popular stimulant medication trademarked by Alza Corp. of Mountain View, Calif. Over his career, Pelham has penned over 250 research papers on ADHD, many with industry grants. In 2002, he was given a lifetime achievement award by the world's largest ADHD patient advocacy group, Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD).
In interviews with AlterNet, Pelham provided glimpses into the dubious methods drug maker McNeil-Alza uses to ensure that studies it funds produce favorable results for its ADHD medications.
Between 1997 and 1999, he was paid by McNeil to conduct one of three studies used to get FDA approval. The company currently uses the three studies to claim that 96 percent of children taking Concerta experience no problems in appetite, growth, or sleep. But Pelham says the studies were flawed. The original intent of the studies was to measure both side effects and main effects of the drug. But two of the three studies, including Pelham's, required that the subjects had to already be taking MPH and responding well to it in order to enter the study. In other words, by stacking the studies with patients already successfully taking stimulants, McNeil ensured the subjects would be unlikely to register side effects, Pelham says.
"It's really misleading and I'm surprised the FDA is letting them use the studies to advertise no side effects," he says. "They had no side effects because they took only people with only a positive history of medication. This is really pushing meds without telling the full picture."
There was also pressure from the company to tweak the findings, he says. Part of Pelham's study involved "providing parent training to parents, having a simple behavioral program in place on Saturday lab days, and establishing simple behavioral programs in the children's regular school classrooms." When his paper was in the galley proof stage at the medical journal Pediatrics, Pelham says he joined a conference call with a number of senior people from the corporation who lobbied him to change what he had written in the paper.
"The people at Alza clearly pushed me to delete a paragraph in the article where I was saying it was important to do combined treatments (medication and behavioral)," he says, adding that they also pushed him to water down or eliminate other sentences and words that did not dovetail into their interests. "It was intimidating to be one researcher and have all these people pushing me to change the text."
McNeil offered no direct response to the allegations.
"We cannot comment on unsubstantiated allegations," says Gary Esterow, a spokesman for McNeil Consumer & Specialty Pharmaceuticals, in a written statement. "The protocols and full study reports for these clinical trials were reviewed by the FDA, and provided the basis for FDA approval. Prior to publication, there was ample opportunity for full discussion of the data among the investigators. Publication of the findings reflect the prevailing opinion of the authors and is further supported by the peer review process of the scientific journals in which these studies appear."
Pelham says McNeil didn't stop there. The company commissioned a follow-up study on the conversion study mentioned above. This time McNeil did the data analysis and coordinated the paper writing. "I insisted on seeing the analyses and having major inputs into the manuscript and it was like pulling teeth to get wording and analyses changed," he says. "It was like a whitewash, a praise to Concerta."
Pelham says the company submitted the paper twice to the Journal of the American Academy of Child and Adolescent Psychiatry. Drafts were sent to Pelham several times but he says he never returned anything with his signature. In the end, however, he says the paper was accepted without his knowledge and published with his name on it.
Sins of Omission
Besides pressuring researchers they fund, companies also seem to pepper their direct-to-consumer marketing materials with only the science that favors their products.
Makers of stimulant medications fight hard to downplay several longstanding theories.
One theory is that consistent use of stimulants suppresses a child's growth. Concerns increased in April when the journal Pediatrics published a federally-funded study, the largest yet investigating the long-term health impact stimulants have on children. That study, funded by the National Institutes of Mental Health and known as the MTA Follow Up Study, found that consistent use of the stimulants stunts growth in children at a rate of about one inch every two years. The study also questioned a theory, apparently one still promoted by drug companies, that children make up lost growth over time.
Yet some seven months after the study was published, neither Novartis, the maker of Ritalin, nor McNeil mention the study in their web-based marketing materials.
An information document for prescribing physicians found on the Concerta web site tells doctors that Concerta causes "no clinically significant impact on growth with long-term use."
Likewise, the Ritalin website says stimulants may cause "initial, mild slowing of growth," but tells consumers the effect is temporary, that children will make up the lost growth and eventually reach their normal height.
"We used large, well-designed studies to provide factual easy-to-understand information to readers," says Denise Brashear, a spokeswoman for Novartis. "There are hundreds of studies conducted regarding methylphenidate treatment making it difficult to include every study on each topic."
In their written statement to AlterNet addressing questions for this article, McNeil officials did not respond to a question regarding the MTA Follow Up Study.
Potentially most damaging to stimulant sales is that medications like Ritalin may not work over the long run and that behavioral modifications may serve just as well.
According to Pelham, who is on the steering committee for the MTA studies, much of his research, as well as data gleaned from the MTA studies, shows the efficacy of medication declines over time.
"No drug company in its literature mentions the fact that 40 years of research says there is no long-term benefit of medications," he says. "That is something parents need to know."
The pharmaceutical industry has long donated money to patient advocacy groups that critics say become conduits for spreading industry-friendly information.
In the world of ADHD advocacy, CHADD, based in Landover, MD, is an 800-pound gorilla, claiming 20,000 members and 200 affiliates, even offering members a CHADD Visa Card. Though the organization, which also engages in lobbying, claims to provide "science-based, evidence-based information about ADHD" to parents and the public, critics say CHADD basically promotes stimulant medications manufactured by its corporate donors. Pharmaceutical companies – including Novartis and McNeil – donated a total of $674,000 in fiscal year 2002-2003, making up 17 percent of the group's budget, according to CHADD financial documents posted on its website.
Pelham, who is currently listed by CHADD as a member of its professional advisory board, came face to face with what he says are the group's glaring conflicts of interest.
In 2002, after he received the CHADD Hall of Fame Award, he was subsequently interviewed for Attention!, the organization's magazine. In the interview, Pelham said, among other things, that stimulant drugs have serious limitations when employed alone and at high doses. He also pointed out that psychosocial treatments should be the treatment of first choice in ADHD, with adjunctive medication when necessary.
But eight months later, after CHADD's board of directors tried to quash the article, CHADD published Pelham's interview – but with large swaths cut out, particularly his comments about the limitations of the stimulants.
"In recent years, I have come to believe that the individuals who advocate most strongly in favor of medication – both those from the professional community, including the National Institutes of Mental Health, and those from advocacy groups, including CHADD – have major and undisclosed conflicts of interest with the pharmaceutical companies that deal with ADHD products," Pelham wrote in a foreword to the unedited version of the article he provided AlterNet. "I believe that parents of ADHD children and the public at large should be made aware of this situation. That is one of the points that I was attempting to make in my interview. As I think is clear from examining the edited sections, the CHADD CEO and board of directors did not share my concerns."
Chadd officials say their board is not involved in any aspects of the magazine and that some of Pelham's claims "were not scientifically supported."
"CHADD did not withhold information because of pressure from pharmaceutical companies," says Phyllis Anne Teeter Ellison, who chairs the editorial advisory board for the magazine. "After extensive review and consultation with the scientific community, CHADD took a responsible position by not publishing some of Dr. Pelham's unsubstantiated claims that were not supported by available data and were not supported by his colleagues on the MTA group."
But some drug makers no doubt find the magazine interesting: Peg Nichols, CHADD's director of communications and executive editor of Attention!, confirmed that Shire Pharmaceuticals, makers of the stimulant medication Adderall, buys 65,000 of the 100,000 copies each print run. Shire sales representatives, in turn, place them in doctors' offices.
Pelhams suspects his comments in the article, while edited heavily, were still "conservative" enough to cause problems with his pharmaceutical industry contacts. For several years, Pelham has hosted a conference on treatment for childhood mental health disorders for which drug companies, including McNeil and Shire, have provided educational grants. Since the article ran, he says his former contacts have not underwritten the conference.
Other types of organizations are also targets for pharmaceutical industry contributions. Concerta.net, for example, references guidelines issued by the American Academy of Pediatrics and the American Academy of Child & Adolescent Psychiatry that recommend stimulant medications like Concerta as the first choice of treatment for children with ADHD.
Those prominent trade groups also have links to Big Pharma. McNeil, according to a document from The American Academy of Pediatrics, has given at least $25,000 in donations to the academy. It could not be confirmed if AACAP receives direct donations but links do exist. Dr. Graham J. Emslie, a professor at the University of Texas Southwestern Medical Center and a consultant for McNeil, serves on the corporate contributions and research committee for the AACAP, according to the Center for Science in the Public Interest (CSPI).
Criticism of industry-funded research is growing. But drug companies dismiss claims of conflicts of interest, saying industry needs experts and has long turned to them for clinical trials. Moreover, says Brashear of Novartis, "when the results of the trial are published or presented, there is transparency about the physician's involvement."
But conflicts can clearly arise, especially with something so controversial and hard-to-define as ADHD.
Dr. Russ Barkely, considered by some to be the world's leading ADHD expert, says he has taken money from drug companies and that problems can occur when financial connections run too deep. "Whenever there is a financial arrangement between people or organizations, there always exists the potential for a conflict of interest and to influence the outcome of that arrangement," he says. "That is just human nature. It does not mean that one always does exist or that the products of such arrangements are always biased adversely in some way."
Barkely recognizes potential conflict of interest can arise when findings from the study don't merge perfectly with the commercial interest of the drug company. But many researchers, he says, insist on "unrestricted" grants that give researchers a green light to conduct the study and promote the results in ways that don't just advance the company's financial interest.
"Nevertheless, if the researcher wants subsequent grants from a drug company, there may be an indirect conflict of interest for researchers here," says Barkely. "But so long as consumers want drug companies to produce state-of-the-art, safe, and well-tested drugs for disorders, you cannot then restrict drug companies from having access to the world's leading researchers to help them in providing such products."
For Barkely, the real test is a matter of degree, that is the percentage of a researcher's income that's directly derived from grants or consulting arrangements, not simply whether or not such an arrangement exists.
"I consult for four or five drug companies a year, yet I derive less than 10 percent of my income from such consultations and speaking engagements for them," he says. "It is the degree of support that can raise the specter of a conflict of interest and not just the existence of a relationship. And we especially want to know if the researcher has stock options, royalties, or other financial arrangements with the company such that results which are favorable to the drug in a research project result in a proportionate and direct financial advancement of the researcher."
Most scientific journals, Barkely points out, require researchers to say in their articles what, if any, financial arrangements they have with a commercial interest that supported the research or may be mentioned in the article.
"The results from drug company-funded research are not essentially different from federal studies," says Eugene Arnold, an ADHD expert and Ohio State University researcher who has taken money from drug companies. "Much of the new research funding surge has been for development of better products, such as longer-lasting delivery formulations. In order to obtain FDA approval, the companies have to sponsor research to demonstrate efficacy and safety. Naturally, they turn to experts in the disorder and its treatment to help do that research."
Arnold says that all researchers heavily involved in new product research take money from drug companies. But he points out that research supporting efficacy of MPH, amphetamine, and other FDA-approved drugs for ADHD was originally done in the 1930s, '40s, and '50s without drug company support and even now some studies are done solely with federal funding.
Sam Goldstein, a clinical neurologist and member of the faculty at the University of Utah who has in the past served as a general consultant for drug companies and authored educational materials for them, says the profit motive can hurt research in other ways. "The nature of our capitalist system is such that if there is a profit to be made it is much more likely a treatment will be investigated," he says. "There are many good psychosocial treatments that with sufficient research would probably benefit children with ADHD. No one is going to fund them because there is no profit to be made. I don't think this is a bad thing. It is just the way the system works."
Goldstein notes that the system of industry funding has produced medications that have dramatically in a positive way altered the lives of millions of people.
"For me the issue is not so much ethics but the fact that only those treatments that stand to lead to profit are funded for research," he says.
Kelly Hearn is a correspondent for The Christian Science Monitor and a former science and technology writer for UPI.