Is industry-funded science killing you? The overrated risks and underrated benefits of pharmaceutical research "conflicts of interest".IN 2004 GLAXOSMITHKLINE became the first major drug manufacturer to publicly disclose all the data from clinical studies of its products, including information that is usually treated as a trade secret. It was responding to a lawsuit by Eliot Spitzer Eliot Laurence Spitzer (born June 10 1959 ) is an American lawyer, politician and the current Governor of New York. Spitzer was elected governor in the November 2006 election. , then New York's attorney general and now its governor, who accused Glaxo of hiding data about the safety and efficacy of one of its drugs. Sure enough, the company had concealed data indicating its antidepressant antidepressant, any of a wide range of drugs used to treat psychic depression. They are given to elevate mood, counter suicidal thoughts, and increase the effectiveness of psychotherapy. Paxil increased the risk of adolescent suicide. More-recent research suggests that link might not exist after all, but even if that proves true, it doesn't excuse the initial concealment.
A month later, Merck pulled its new pain reliever, Vioxx, off the market after clinical trial data showed that patients taking it had a 400 percent greater chance of heart attack than those taking the comparison drug, naproxen naproxen and naproxen sodium, potent nonsteroidal anti-inflammatory drugs (NSAID) used to alleviate the minor pain of arthritis, menstruation, headaches, and the like, and to reduce fever. . Merck researchers implausibly argued that the difference was due not to damage caused by Vioxx but to the other drug's cardio-protective properties. No previous research had found that naproxen protects the heart.
For critics of the pharmaceutical industry, the Vioxx and Paxil incidents are evidence that conflicts of interest have thoroughly corrupted American medical research. "The Vioxx withdrawal serves as a reminder of the dangerous potential for conflict of interest that exists when pharmaceutical and other for-profit businesses control the dissemination of findings generated by medical research" warned a November 2004 editorial in the Dayton Daily News The Dayton Daily News (DDN) is a daily newspaper published in Dayton, Ohio. It is owned by Cox Enterprises.
On August 15, 1898, James M. Cox purchased the Dayton Evening News. . In March 2005, the left-leaning Center for Science in the Public Interest (CSPI CSPI Center for Science in the Public Interest
CSPI Corporate Service Price Index
CSPI Cumulative Schedule Performance Index ) pointed out that a Food and Drug Administration (FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. ) panel that reviewed data on the risks posed by COX-2 painkillers like Vioxx included 10 researchers with financial ties to the companies that manufactured those drugs. Had the panelists with conflicts been excluded, a majority of the remaining members would have voted against approving Vioxx for distribution.
The Paxil incident prompted a June 2004 statement from the New York New York, state, United States
New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of Attorney General's Office warning that "the ability of drug companies to pick and choose the research they provide doctors in support of their product is an outrageous conflict of interest and puts us all in harm's way harm's way
A risky position; danger: a place for the children that is out of harm's way; ships that sail into harm's way. ." An August 2005 story about industry-funded medical research in the San Jose Mercury News The San Jose Mercury News is the major daily newspaper in San Jose, California and Silicon Valley. The paper is owned by MediaNews Group. Its headquarters and printing plant are located in North San Jose next to the Nimitz Freeway (Interstate 880). quoted Sheldon Krimsky, a longtime critic of pharmaceutical companies, who asserted that "the entire system of drug testing is filled with conflicts of interest."
There's no question that some companies have behaved badly in some cases. But are these cases typical or rare?
Activists, politicians, and other critics claim conflicts of interest are pervasive in pharmaceutical research. Several years ago CSPI established an Integrity in Science Project to investigate and publicize the destructive influence of industry-sponsored science. Not to be outdone out·do
tr.v. out·did , out·done , out·do·ing, out·does
To do more or better than in performance or action. See Synonyms at excel. , the Union of Concerned Scientists The Union of Concerned Scientists (UCS) is a nonprofit advocacy group based in Cambridge, Massachusetts, United States. The UCS membership includes many private citizens in addition to professional scientists. launched its own Scientific Integrity Program to "push for reforms that will protect our health, safety, and environment."
Politicians are jumping on the bandwagon, proposing more-stringent regulations of private clinical research. Sens. Christopher Dodd This article or section contains information about one or more candidates in an upcoming or ongoing election.
Content may change as the election approaches. (D-Conn.) and Edward Kennedy (D-Mass.) recently introduced the Fair Access to Clinical Trials Act, which would require all clinical trials to be registered in a central government database. Marcia Angell Marcia Angell, M.D. (born 1939) is an American physician, author, and the first woman to serve as editor-in-chief of the New England Journal of Medicine (NEJM). She currently is a Senior Lecturer in the Department of Social Medicine at Harvard Medical School, in Cambridge, , a senior lecturer senior lecturer
n. Chiefly British
A university teacher, especially one ranking next below a reader. in social medicine at Harvard University Harvard University, mainly at Cambridge, Mass., including Harvard College, the oldest American college. Harvard College
Harvard College, originally for men, was founded in 1636 with a grant from the General Court of the Massachusetts Bay Colony. , wants to ban privately funded clinical trials altogether. Instead, she proposes that drug companies be forced to pay into a government fund that would finance a new National Institute of Prescription Drug prescription drug Prescription medication Pharmacology An FDA-approved drug which must, by federal law or regulation, be dispensed only pursuant to a prescription–eg, finished dose form and active ingredients subject to the provisos of the Federal Food, Drug, Trials to conduct all future clinical testing.
Supporters of such changes argue that conflicts of interest undermine public trust in and support for scientific research, endanger research subjects and patients, and boost medical costs by encouraging physicians and patients to use new treatments that are no better than cheaper alternatives. Yet public trust in biomedical research Biomedical research (or experimental medicine), in general simply known as medical research, is the basic research or applied research conducted to aid the body of knowledge in the field of medicine. remains high, and that trust seems to be justified. Subjects in clinical trials hardly ever suffer serious harm, and instances in which dangerous side effects Side effects
Effects of a proposed project on other parts of the firm. turn up after drugs are approved are relatively rare. Rather than making medicine unnecessarily expensive, pharmaceutical innovation ultimately reduces health care costs, because new drugs usually have advantages that pay off in lower medical bills.
The critics' concerns are not entirely groundless. Driven by self-interest, drug companies and researchers do occasionally hide data or run drug trials that produce data of scant clinical value. But private initiatives by medical journals, universities, and companies are already addressing these challenges, making government action unnecessary.
In 2005 The Journal of the American Medical Association JAMA: The Journal of the American Medical Association is an international peer-reviewed general medical journal, published 48 times per year by the American Medical Association. JAMA is the most widely circulated medical journal in the world. reported that 5.6 percent of health spending in the U.S. goes to biomedical research, more than in any other country. In nominal dollars Nominal dollars
Dollars that are not adjusted for inflation. , funding for biomedical research in this country rose from $37 billion in 1994 to $94 billion in 2003. Even adjusted for inflation, that's an increase of almost 100 percent. The National Institutes of Health provided 28 percent of that funding; industry gave 57 percent; state, local, foundation, and other federal agencies accounted for the remainder.
This cooperation between academia and industry has been essential to speeding new treatments from lab bench to hospital bedside. "By any measure, the interactions between academic research and industrial research and development, as epitomized by biotechnology, have been overwhelmingly positive," wrote Thomas Stossel, a professor of medicine at Harvard and a co-director of the Hematology Division at Boston's Brigham and Women's Hospital Brigham and Women's Hospital (BWH) is a hospital in the Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill. With Massachusetts General Hospital, it is one of the two founding members of Partners HealthCare. , in a 2005 New England Journal of Medicine The New England Journal of Medicine (New Engl J Med or NEJM) is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It is one of the most popular and widely-read peer-reviewed general medical journals in the world. article. "We should celebrate their achievements and protect the process that led to them."
But one man's beneficial cooperation is another's conflict of interest, a phrase that has acquired an inappropriately sinister connotation. As defined by the former Harvard epidemiologist Kenneth Rothman in a widely cited 1993 New England Journal of Medicine article, a conflict of interest is "any situation in which an individual with responsibility to others (which includes professional responsibilities) might be influenced, consciously or unconsciously, by financial and personal factors that involve self-interest."
Such conflicts are not at all unusual. David Korn David Korn is an American computer programmer, who is probably best known for creating the Korn shell (ksh), a command line interface/programming language. The Korn shell is a de facto standard for UNIX-like systems and many other environments. , senior vice president for biomedical bi·o·med·i·cal
1. Of or relating to biomedicine.
2. Of, relating to, or involving biological, medical, and physical sciences. and health sciences research at the Association of American Medical Colleges Association of American Medical Colleges,
n.pr a nonprofit organization founded in 1876 to reform medical education and represent medical schools, major teaching hospitals, scientific and academic faculty, medical students, and residents. , noted in 2000 that "conflicts of interest and commitment are ubiquitous in academic life (and indeed, in all professional life), and conflicting pressures inherent in the academic milieu, e.g., for faculty advancement, obtaining sponsored research funding Research funding is a term generally covering any funding for scientific research, in the areas of both "hard" science and technology and social science. The term often connotes funding obtained through a competitive process, in which potential research projects are evaluated and , winning the acclaim of one's professional peers, competing for prestigious research prizes, and yes, desiring to alleviate human pain and suffering, all may be more powerful in influencing faculty behavior than the prospect of material enrichment" Such conflicts do not in themselves imply wrongdoing wrong·do·er
One who does wrong, especially morally or ethically.
wrongdo , Korn stressed: "Since these conflicts can never be eradicated from professional life, their existence must be accepted and not equated with professional misconduct professional misconduct,
n conduct inappropriate to the practice of health care.
professional misconduct Behavior by a professional that implies an intentional compromise of ethical standards. ."
Corrupt or Well-Informed?
To illustrate the dangers allegedly posed by conflicts of interest, industry critics repeatedly point to a handful of atypical cases featuring erroneous results, suppressed data, or harmful side effects. (See "Ties That Blind," page 38.) In addition to such anecdotal evidence anecdotal evidence,
n information obtained from personal accounts, examples, and observations. Usually not considered scientifically valid but may indicate areas for further investigation and research. , they cite studies that show a correlation between industry funding and results that are favorable to the sponsors. As the researchers themselves acknowledge, however, there are benign explanations for such correlations.
In 1998 The New England Journal of Medicine published an article that claimed to show how commercial interests influenced the scientific evaluation of data on the relative safety and effectiveness of calcium-channel blockers, a class of drugs used to control high blood pressure. The study found that "authors who supported the use of calcium-channel antagonists were significantly more likely than neutral or critical authors to have financial relationships with manufacturers of calcium-channel antagonists (96 percent vs. 60 percent and 37 percent, respectively)." The authors concluded that this "strong association" meant the "medical profession needs to develop a more effective policy on conflict of interest."
But the study did not actually demonstrate that researchers had been inappropriately influenced by their ties to industry. The authors acknowledged as much, saying, "We believe that the authors we surveyed expressed their own opinions and were not influenced by financial relationships with pharmaceutical manufacturers." If financial relationships had no clearly discernible influence on the clinicians, what were the study's authors concerned about? Appearances. "We wonder how the public would interpret the debate over calcium-channel antagonists" the authors mused, "if it knew that most of the authors participating in the debate had undisclosed financial ties with pharmaceutical manufacturers."
Reviewing the data from that study, Thomas Stossel, the Harvard hematologist he·ma·tol·o·gist
A physician specializing in hematology.
A medical specialist who treats diseases and disorders of the blood and blood-forming organs. , noted that consultants working for companies that were not producing calcium-channel blockers were as likely to favor the drugs as those that consulted for companies that did produce them. Do scientists who do consulting work for one company have an interest in promoting its competitors' products? Stossel suggests a more logical explanation is that the researchers who consult with drug companies are better informed.
That argument seems credible, especially since, according to according to
1. As stated or indicated by; on the authority of: according to historians.
2. In keeping with: according to instructions.
3. a 2002 meta-analysis of blood pressure treatments in the Journal of the American College of Cardiology The American College of Cardiology (ACC) is a nonprofit medical association established in 1949 to educate, research and influence health care public policy. The president for the 2006–2007 year is Steven E. Nissen.  The organization has 39 chapters in the U.S. , calcium-channel blockers have turned out to be at least as safe and effective as alternative drugs. Calcium-channel blockers are still widely used to control blood pressure. A 2005 study published in The Lancet found that a combination of calcium-channel blockers and angiotensin-converting enzyme angiotensin-converting enzyme /an·gio·ten·sin-con·vert·ing en·zyme/ (-ten´sin kon-vert´ing en´zim) see peptidyl-dipeptidase A.
n. (ACE) inhibitors was safer than a more conventional treatment combining diuretics Diuretics Definition
Diuretics are medicines that help reduce the amount of water in the body.
Diuretics are used to treat the buildup of excess fluid in the body that occurs with some medical conditions such as congestive heart with beta blockers Beta Blockers Definition
Beta blockers are medicines that affect the body's response to certain nerve impulses. This, in turn, decreases the force and rate of the heart's contractions, which lowers blood pressure and reduces the heart's demand for . People with high blood pressure who take calcium-channel blockers are significantly less likely to develop diabetes than those treated with cheaper diuretics.
At the time of the 1998 New England Journal of Medicine article, activists claimed drug companies were duping Duping refers to the practice of exploiting a bug in a video game to illegitimately create duplicates of unique items or currency in a persistent online game, such as an MMOG. physicians and patients into using more expensive treatments that were no more effective than earlier, cheaper medicines. Nine years later, further research shows the situation is more complicated: There is no one-size-fits-all treatment for hypertension. Based on what we know now, the more benign interpretation--that companies consulted with the most knowledgeable experts rather than that researchers favored companies that paid them--is more plausible.
Suspiciously Effective Medicine
A number of other studies have concluded that research results are biased by industry funding. Thirty-seven of those investigations were summed up in a review article by three Yale Medical School researchers that was published in The Journal of the American Medical Association (JAMA JAMA
Journal of the American Medical Association ) in 2003. This meta-analysis found that "industry-sponsored studies were significantly more likely to reach conclusions that were favorable to the sponsor than were non-industry studies." But it also noted that "there are several possible reasons for this finding. It is possible that, given limited resources, industry only funds potentially winning therapies."
That explanation was bolstered by a 2006 study, also published in JAMA, that analyzed the outcomes of 202 randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. trials evaluating cardiovascular drugs reported between 2000 and 2005. Forty percent of the randomized drug trials funded by nonprofit organizations favored newer agents, compared to 54 percent of the jointly sponsored trials and 65 percent of the industry-funded trials.
The authors of the analysis suggested an explanation for these differences: "When the first trial report of a truly novel therapy is null or negative, it becomes less likely that any funding source will support subsequent studies. On the other hand, when the first trial of a truly novel therapy is positive, the likelihood of further trials is increased. These subsequent trials understandably and perhaps appropriately are more likely to be funded by for-profit organizations."
In other words Adv. 1. in other words - otherwise stated; "in other words, we are broke"
put differently , government and foundations are more likely to fund earlier stages of drug development, where the risk of failure is higher. Companies jump in to sponsor drug research at later stages of development, when success is more likely. Thus it is not surprising that industry-funded research is more likely to reach positive conclusions. If a drug company's trials regularly turned up negative findings, that would signal serious flaws in its drug discovery process.
Another concern related to conflicts of interest is that publication bias dangerously skews the medical literature by favoring studies that reflect well on new therapies. "Studies with positive findings are more likely to be published than studies with negative or null results," said American Medical Association American Medical Association (AMA), professional physicians' organization (founded 1847). Its goals are to protect the interests of American physicians, advance public health, and support the growth of medical science. trustee Joseph M. Heyman at the organization's 2004 meeting. "We are concerned that this pattern of publication distorts the medical literature, affecting the validity and findings of systematic reviews, the decisions of funding agencies, and, ultimately, the best practice of medicine." Any tendency to put negative results into a file drawer and forget them can bias reviews of treatments reported in the medical literature, making them look more effective than they really are.
Because of the fear that industry funding and commercial motives skew (1) The misalignment of a document or punch card in the feed tray or hopper that prohibits it from being scanned or read properly.
(2) In facsimile, the difference in rectangularity between the received and transmitted page. research results, most prominent life science journals now require financial disclosures from researchers whose work they publish. JAMA's disclosure policy is one of the more demanding, requiring authors to "provide detailed information about all relevant financial interests and relationships or financial conflicts within the past 5 years and for the foreseeable future (e.g., employment/affiliation, grants or funding, consuhancies, honoraria, stock ownership or options, expert testimony Testimony about a scientific, technical, or professional issue given by a person qualified to testify because of familiarity with the subject or special training in the field. , royalties, or patents filed, received, or pending), particularly those present at the time the research was conducted and through publication, as well as other financial interests (such as patent applications in preparation) that represent potential future financial gain." These disclosures, which must be included with each manuscript before it's submitted to peer reviewers, are typically published on the last page of the article.
The Public's Trust
Advocates of such precautions argue that they will help restore public trust in biomedical research. But public trust is already at a very high level. A 2006 Harris poll found that physicians and scientists are among the professional groups most trusted by Americans. Indeed, medicine is the single most trusted profession, with 85 percent of Americans saying doctors can be trusted to be truthful. Trust in scientists is only slightly lower, at 77 percent.
More tellingly, a 2006 survey of cancer patients participating in five research trials found that the vast majority (more than 90 percent) were unconcerned about any financial ties their doctors might have with drug companies. According to the poll results, published in The New England Journal of Medicine last November, large majorities of the patients said they would have enrolled in the trial even if the drug company had paid the researcher for speaking or consulting, if the researcher had received royalty payments, or if he owned stock in the drug company. More than 80 percent of the patients believed it was ethical for researchers to receive speaking or consulting fees from the company. Most patients said they opposed bans on relationships between researchers and drug companies, and some said they would be more likely to participate in a trial if a drug company were involved. Even among the respondents with at least some post-graduate training, less than a third said they wanted to know about potential financial conflicts.
That trust appears to be justified. It's hard to get firm numbers, but the Boston-based medical information and publishing firm CenterWatch, which tracks clinical trials, estimates that more than 40,000 are in progress, involving more than 20 million subjects. There are very few documented examples in which research subjects were seriously harmed. Looking at studies that led to the approval of one-third of all new drugs between 1987 and 2001, CenterWatch found that one in 30 subjects experienced a serious side effect. The 200l report also noted that "each year, an average of 3.6 deaths attributed to study drug effects are reported to the FDA for approved drugs." The FDA does not collect systematic data for injuries and deaths in studies of drugs that don't get approved. And "unlike industry-sponsored clinical trials that are regulated by the FDA," CenterWatch noted, "government-funded studies conducted by individual investigators at academic medical centers frequently have risks that go unreported" to the federal Office for Human Research Protection.
CenterWatch President Ken Getz summed up the evidence in a 2002 interview with the San Francisco Chronicle The San Francisco Chronicle was founded in 1865 as The Daily Dramatic Chronicle by teenage brothers Charles de Young and Michael H. de Young. The paper grew along with San Francisco to become the largest circulation newspaper on the West Coast of the : "It is not a patient-beware situation. The vast, vast majority of clinical trial participants have very positive experiences."
What about the patients who use drugs after they're approved? "Between i997 and 2004," the pharmaceutical industry critic Sheldon Krimsky noted in a 2005 oped piece in the Newark Star-Ledger, "12 major prescription drugs, with a market value of billions of dollars, were recalled by the FDA." Krimsky claims such dangerous drugs have been allowed to reach the market because "conflicts of interest have become endemic in the system of drug evaluation," a trend that "has been exacerbated by the rise of for-profit clinical trials, fast-tracking drug approvals, government-industry partnerships, direct consumer advertising and industry-funded salaries for FDA regulators" since the mid-1990S.
There's little evidence that the FDA is more likely to approve harmful drugs than it was in the past. A 2005 report by the Tufts University Tufts University, main campus at Medford, Mass.; coeducational; chartered 1852 by Universalists as a college for men. It became a university in 1955. Jackson College, formerly a coordinate undergraduate college for women, merged with the College of Liberal Arts in Center for the Study of Drug Development found that faster approval times do not correlate with more frequent drug withdrawals. The share of drugs withdrawn for safety reasons was 3.2 percent in the 1980s, 3.5 percent in the '90s, and 1.6 percent from 2000 to 2004. The approval times for drugs that are withdrawn are not appreciably shorter than the average approval time for all drugs.
Meanwhile, the FDA removes dangerous drugs from the market much sooner than it used to. The average time between FDA approval and subsequent safety withdrawal dropped from 3.7 years in the 1980s to 1.4 years in the '90s and is now seven-tenths of a year. The bad news is that an overcautious o·ver·cau·tious
Excessively cautious; unduly careful.
over·cau FDA can kill people too. A 2005 study by economists at the University of Chicago calculated that the speed-up in FDA drug approvals that occurred after 1992 may have been responsible for saving the equivalent of 180,000 to 310,000 life-years (the sum of the years of life that would have been lost had the new drugs not been available). Over the same period, about 56,000 life-years at worst were lost to drugs that were eventually withdrawn for safety reasons. Unfortunately, it's much easier to identify people who are harmed by drugs than those who are saved by drugs. In the face of this information asymmetry Information asymmetry
Condition that information is known to some, but not all, participants. , regulators tend to focus on reducing lives lost to unsafe drugs rather than preventing deaths by speeding effective new therapies to patients.
Saving Money by Spending More
What about the charge that biased reporting of scientific results boosts overall medical costs by encouraging physicians and patients to select new, expensive treatments that are no better than older, cheaper medicines? "The cost of pharmaceutical drugs--and health care in general--in America continues to skyrocket," Jennifer Washburn of the New America Foundation The New America Foundation is a non-profit public policy institute and think tank located in Washington, D.C. that promotes innovative political solutions transcending conventional party lines -- what they call radical centrist politics. wrote in the June 2005 In These Times. "Expensive new drugs are aggressively marketed on TV and in doctors' offices the moment they hit the market. Yet physicians warn that many of these hyped prescriptions are simply 'me-too drugs' that vary only slightly from medications already on the market, despite being far more expensive."
Health care as a share of U.S. gross domestic product has tripled from 5 percent in 1960 to 16 percent today. Some analyses project the number will reach 25 percent by 2030. But this inflation is not due to spending on drugs. In a 2002 study for the National Bureau of Economic Research The National Bureau of Economic Research (NBER) is a "private, nonprofit, nonpartisan research organization" dedicated to studying the science and empirics of economics, especially the American economy. , the Columbia University Columbia University, mainly in New York City; founded 1754 as King's College by grant of King George II; first college in New York City, fifth oldest in the United States; one of the eight Ivy League institutions. economist Frank Lichtenberg estimated that, on average, "reducing the mean age of drugs used to treat a condition from 15 years to 5.5 years ... increases prescription drug spending by $18 [averaged over the total population] but reduces other medical spending by $129, yielding a $111 net reduction in total health spending. Most of the savings are due to reductions in hospital expenditure ($80) and in physician office-visit expenditures ($24)." In other words, using newer drugs reduces other medical expenditures by more than seven times the extra amount spent on drugs.
Today 30 percent of the $2.2 trillion Americans spend on health care each year goes to hospitals. Physicians get 20 percent, and 10 percent pays for dental and other professional services (job) professional services - A department of a supplier providing consultancy and programming manpower for the supplier's products. . All of these are labor-intensive treatments. By comparison, prescription drugs account for about 10 percent of health care spending. "Within a generation or two" Peter Huber of the Manhattan Institute The Manhattan Institute for Policy Research is a self-described "free market think tank" established in New York City in 1978, with its headquarters on Vanderbilt Avenue in Midtown Manhattan. noted in the July 2006 Commentary, "they will undoubtedly account for most of it--which will be another good thing. Pharma's biochemical cures always end up far cheaper than the people-centered services they replace."
Marcia Angell rails against the pharmaceutical industry's "obscene profits." But Princeton health economist Uwe Reinhardt told USA Today USA Today
National U.S. daily general-interest newspaper, the first of its kind. Launched in 1982 by Allen Neuharth, head of the Gannett newspaper chain, it reached a circulation of one million within a year and surpassed two million in the 1990s. in October 2006 that he had "once calculated that if you rebated all the drug company profits to patients, health spending would only go down by 1.2%." Seizing drug company profits would do nothing to address the current health care spending "crisis," but it would shut off the flow of funds Flow of funds
In the context of municipal bonds, refers to the statement displaying the priorities by which municipal revenue will be applied to the debt.
In the context of mutual funds, refers to the movement of money into or out of a mutual funds or between or among to many biomedical researchers and drastically slow the discovery and development of new and more effective drugs.
As for "me-too" drugs, the implication is that companies are trying to take market share from each other without providing any "real" benefits to patients. Of course, "trying to take market share away" is better known as "competition," which ultimately results in lower prices.
Everybody's a Critic
Although critics of the drug industry exaggerate the problems created by conflicts of interest, in rare instances drug companies have withheld or misreported data, and some researchers have put their financial gain above the safety of their patients. It therefore makes sense to keep an eye on to watch.
See also: Eye potential conflicts.
One safeguard--disclosure in journals--is here to stay. Even Stossel, a strong proponent of industry-financed research, favors disclosure. "To be sure," he wrote in a February 2005 Forbes column, "it is reasonable to require disclosure of corporate sponsorship by investigators and institutional monitoring of collaborations. But academic administrators and government officials respond to rare incidents of misconduct and to the barrage of criticism that follows by rushing to pile on restrictions."
Peer review has been the traditional means of assuring a study's validity. By requiring disclosure, journal editors are in effect admitting peer review's failure. Since their reviewers are not competent to evaluate findings based solely on the data, warning labels need to be slapped onto industry-funded studies. And peer review overlooks honest errors as well as deliberate fraud. "Peer review doesn't necessarily say that a paper is right," said Martin Blume, editor-in-chief of the American Physical Society's nine journals, in a January 2006 interview with science. "It says it's worth publishing."
Fortunately, a new age of more-robust peer review is dawning. With the advent of online journals like those published by the Public Library of Science (PLoS), peer review is changing from a one-time appraisal of a self-contained research article to a continuous online process. Since 2003 PLoS has launched eight open-access, peer-reviewed biomedical journals. In 2006 it started a new comprehensive online journal, PLoS One PLoS ONE is an open access, online scientific journal from the Public Library of Science. It covers primary research from any discipline within science and medicine. Submissions go through pre-publication peer review but are not excluded on the basis of lack of perceived importance , which will feature reports of primary research from all disciplines in the biological and physical sciences. The editorial board will make prompt decisions on whether papers merit publication and may refer them to outside reviewers.
With PLoS, unlike print journals, publication is not the end of the peer review process. Once an article has been published in PLoS One, community-based post-publication peer review begins, in full view of anyone who visits the site. Post-publication reviewers can post corrections, additions, or links to other relevant articles. They can engage in online debates concerning the content, conclusions, and consequences of a specific paper. Users can assign ratings to papers. (Anonymous annotations are not allowed.)
According to the PLoS good practice guidelines practice guidelines Medical practice A set of recommendations for Pt management that identifies a specific or range of range of management strategies. See Peer review organization, Practice standards. Cf 'Cookbook' medicine. , post publication reviewers should confine their criticisms to the content of papers and avoid speculation about the motivations or prejudices of authors. That may be considered good practice now, but in the future post-publication reviewers may begin to note any associations they believe relevant to the findings reported in the paper. In other words, if a researcher doesn't disclose potential conflicts, someone will do it for him.
All the Data That Are Fit to Post
Private initiatives are also achieving the goal that Sens. Dodd and Kennedy want to legislate: registration of all clinical trials. In 2004 the International Committee of Medical Journal Editors (ICMJE ICMJE International Committee of Medical Journal Editors ) adopted a policy that requires, as a condition of consideration for publication in their journals, registration of clinical trials in a public registry. Trials beginning after July 1, 2005, must be registered at or before the onset of patient enrollment. The ICMJE established criteria that each trial must meet to insure transparency and required that the registry be accessible to the public free of charge. At the time, the only website that qualified was ClinicalTrials.gov,run by the United States National Library of Medicine Noun 1. United States National Library of Medicine - the world's largest medical library
National Library of Medicine, U.S. National Library of Medicine .
The ICMJE policy has had an effect. After the policy was announced, the number of clinical trial registrations increased by 73 percent--from 13,153 to 22,714. As of April 2007, the registry contained over 40,000 trials, with more than 200 new trial registrations occurring weekly. Now four other clinical trials registries meet the ICMJE criteria, and many more journals have adopted the ICMJE clinical trials registration policy.
Also in 2004, the Pharmaceutical Research and Manufacturers Association announced that it was launching an online registry of clinical trial results. The association's members, which include the world's leading drug companies, will provide the results of all clinical trials completed after October 1, 2002, at clinicalstudyresults.org.
And since May 2006, researchers no longer can complain that journal editors will not publish negative or inconclusive results. PLoS's journal PLoS Clinical Trials PLoS Clinical Trials is a scientific journal covering randomized trials from all medical and public health disciplines. External links
• explicitly addresses the problem of publication bias: It will publish the results of randomized trials from all medical and public health disciplines. Publication does not depend on the trial's outcome, size, or implied importance. Even negative results provide useful information about the effectiveness of treatments, alerting other researchers not to waste their time and resources on therapeutic dead ends. Indeed, researchers arguably have a moral obligation to publish their results, whether positive or negative, since subjects undertake risks to generate the data.
Collaboration between academia and industry should be encouraged, not attacked. In most areas of research, including computer science, geology, and chemistry, such ties are correctly seen as a source of innovation that has dramatically improved the quality of our lives during the last half-century. Given the potential life-or-death consequences for patients, collaboration between the pharmaceutical industry and medical researchers needs to be monitored, and adjustments should be made whenever abuses come to light. But through such private efforts as financial disclosure requirements, registration of clinical trials, and peer-reviewed publication of all clinical trial results, the scientific research enterprise has shown itself capable of protecting the validity of research results without new government regulations.
"In a transparent atmosphere, misconduct can be detected, challenged, and if necessary, purged and punished," Stossel noted in his 2005 New England Journal of Medicine article. "The intense energy currently dedicated to demonizing academic-industrial research relationships should be redirected toward developing better ways to identify and facilitate the type of partnerships that have brought more good, by far, than harm." He added, "The public wants trustworthy science, and it can get that without new ethical rules. Even more it wants results--real lives saved--and it can't get those if commercial sponsorship of research is made difficult, or impossible."
RELATED ARTICLE: Ties That Blind
The canonical conflict-of-interest cases
Ronald Bailey (born November 23, 1953) is the science editor for Reason magazine.
Considering that thousands of clinical trials are undertaken every year, it's reassuring that the pharmaceutical industry's critics can turn up only a few instances of bad behavior caused by financial conflicts of interest during the last two decades. They repeatedly cite the same handful of cases.
The Tseng Case: In 1985 a young researcher at Harvard Medical School Harvard Medical School (HMS) is one of the graduate schools of Harvard University. It is a prestigious American medical school located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts. , Scheffer Tseng, published several scientific articles reporting that topical vitamin A vitamin A
also called retinol
Fat-soluble alcohol, most abundant in fatty fish and especially in fish-liver oils. It is not found in plants, but many vegetables and fruits contain beta-carotene (see ointment ointment /oint·ment/ (oint´ment) a semisolid preparation for external application to the skin or mucous membranes, usually containing a medicinal substance.
n. could relieve a chronic dry eye condition called keratoconjunctivitis sicca keratoconjunctivitis sic·ca
See dry eye.
keratoconjunctivitis sicca (ker´ . Tseng rushed to found a company, Spectra Pharmaceutical Services, to produce and distribute the treatment; he and his relatives made more than $1 million by selling stock in the business. Later research showed the ointment was no better than a placebo.
Harvard reacted by instituting some of the country's strictest rules governing university researchers' financial ties to private business. The good news is that Tseng's ineffective ointment caused no harm, so patient health was not compromised.
Until 2002 Tseng was a professor at the University of Miami This article is about the university in Coral Gables, Florida. For the university in Oxford, Ohio, see Miami University.
The University of Miami (also known as Miami of Florida, UM, or just The U School of Medicine's Bascom Palmer Eye Institute. He now sits on the boards of directors of three biomedical companies and still receives research grants from the National Institutes of Health.
The Dong Case: In 1987 Betty Dong, a researcher at the University of California The University of California has a combined student body of more than 191,000 students, over 1,340,000 living alumni, and a combined systemwide and campus endowment of just over $7.3 billion (8th largest in the United States). at San Francisco San Francisco (săn frănsĭs`kō), city (1990 pop. 723,959), coextensive with San Francisco co., W Calif., on the tip of a peninsula between the Pacific Ocean and San Francisco Bay, which are connected by the strait known as the Golden , contracted for $250,000 with the U.K.-based Boots Pharmaceutical to compare its thyroid drug, Synthroid, with the cheapercompounds produced by competitors. Synthroid replaces the hormone thyroxine in patients whose thyroids no longer produce enough. Dong found that Synthroid was no more or less effective than the cheaper compounds.
Dong wanted to publish her results in The Journal of the American Medical Association (JAMA), and Boots responded by threatening to sue her. The university initially backed Dong but later withdrew its legal aid after its lawyers found out that, in direct violation of university policy, Dong had signed a research contract stating that "the study results were not to be published or otherwise released without the written consent" of Boots. Turned out the company was afraid that publication of Dong's results might derail de·rail
intr. & tr.v. de·railed, de·rail·ing, de·rails
1. To run or cause to run off the rails.
2. the sale of Boots for $1.4 billion to Knoll Pharmaceuticals.
After The Wall Street Journal reported the story, Boots relented, and JAMA published Dong's study a year later. The company was soon hit with several class action lawsuits class action lawsuit
A lawsuit in which one party or a limited number of parties sue on behalf of a larger group to which the parties belong. For example, investors may bring a class action lawsuit against a brokerage firm that has actively promoted a tax alleging that it had overcharged patients and insurance companies. Boots eventually settled a patient class action suit for up to $135 million and another suit by 37 state attorneys general for $42 million. As other drug makers eventually would learn, trying to suppress research findings might temporarily protect a company's bottom line, but it costs the firm much more in terms of profits and reputation in the long run.
The Olivieri Case: Treating the inherited blood disorder Noun 1. blood disorder - a disease or disorder of the blood
cytopenia - a deficiency of some cellular element of the blood
acidemia - a blood disorder characterized by an increased concentration of hydrogen ions in the blood (which falls thalassemia Thalassemia Definition
Thalassemia describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin, the oxygen-carrying protein inside the red blood cells. requires repeated transfusions, which lead to a damaging buildup of iron in heart and liver tissue. In the early 1990s, Canadian thalassemia researcher Nancy Olivieri contracted with the pharmaceutical company Apotex to investigate the effectiveness of its chelating compound deferiprone in removing iron from the body. Olivieri came to believe that deferiprone caused substantial liver damage to some of her research subjects, and she asked the company for support for further research along those lines. The company then showed her results to other researchers who disagreed with her interpretation, and the company decided not to continue to support her research. At that point, Olivieri told Apotex she was going to publish her negative results. The company responded by threatening to sue her.
The threat turned Olivieri into an academic hero. By 1998 her cause was taken up by the editors of JAMA and The New England Journal of Medicine, who publicized the dispute as an egregious example of greedy commercial interests trying to gag a courageous researcher.
So was this a case of a feisty, honest, academic David fighting a greedy, dishonest, commercial Goliath? Not exactly. The legal threats were stupid, but the science has sided with Apotex. More than 50 peer-reviewed studies have now shown that most patients respond well to deferiprone and that it protects them from heart disease caused by iron buildup. The drug is now approved for use in more than 40 countries. The pharmaceutical company was scientifically right, and the scrappy researcher was wrong, but that hardly matters in the ongoing battles over conflicts of interest.
The Gelsinger Case: One of the often-expressed concerns about conflicts of interest is that greedy researchers will harm subjects and patients as they rush treatments to market. One case stands out in this respect. An 18-year-old named Jesse Gelsinger Jesse Gelsinger (June 18 1981 - September 17 1999) was the first person publicly identified as having died in a clinical trial for gene therapy. He was 18 years old. Gelsinger suffered from ornithine transcarbamylase deficiency, an X-linked genetic disease of the liver, whose suffered from a genetic disorder, partial ornithine transcarbamylase Ornithine transcarbamylase (OTC) (also called ornithine carbamoyltransferase) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). (OTC OTC
See over-the-counter market (OTC). ) deficiency, that put him in constant danger of building up toxic amounts of ammonia in his blood. In 1999 he volunteered for a gene therapy study at the University of Pennsylvania (body, education) University of Pennsylvania - The home of ENIAC and Machiavelli.
Address: Philadelphia, PA, USA. in which he was injected with cold viruses modified to carp/the normal version of the OTC gene.
Shortly after the injections, Gelsinger suffered from a severe immune reaction immune reaction
The reaction resulting from the recognition and binding of an antigen by its specific antibody or by a previously sensitized lymphocyte. Also called immunoreaction. and died of multiple organ failure. There were a number of irregularities in the trial. Most damningly, the principal investigator Noun 1. principal investigator - the scientist in charge of an experiment or research project
scientist - a person with advanced knowledge of one or more sciences , James Wilson, did not disclose that he had a strong personal financial interest in the research. If the treatment had been successful, Wilson would have received stock in Genovo, the company which had the exclusive right to commercialize his discoveries, worth $13.5 million. In 2005 the University of Pennsylvania made a $517,000 settlement with Gelsinger's family.
Science Correspondent Ronald Bailey (rbailey@reason. com) is the author of Liberation Biology: The Scientific and Moral Case for the Biotech Revolution (Prometheus Books). This article derives in part from research commissioned for a white paperon scientific conflicts of interest by the nonprofit consumer education consortium the American Council on Science and Health The American Council on Science and Health (ACSH) is a scientific organization founded in 1978 by Dr. Elizabeth Whelan. It produces reports on issues related to food, nutrition, chemicals, pharmaceuticals, lifestyle, the environment and health. . ACSH ACSH American Council on Science and Health, Inc.
ACSH Avionic and Control System Hardware receives no-strings-attached funding from individuals, foundations, associations, and corporations. Bailey would also like to note that he owns various fairly speculative biomedical stocks that he really hopes will benefit a lot from industry-academic collaborations. The number of shares he holds in any one company amounts to a few hundred at most.