Medical Ethics and Research with the Elderly
Editors Note: Please also see: Conflict of Interest-Prescription Drugs, Medical Equipment and the Medical Profession
(10/28/08)- Pfizer Inc. acquired Warner Lambert in 2000, a company that sold Neurontin, a medication that had been approved by the FDA for the treatment of epileptic fit seizures, and for one kind of pain related to shingles. Pfizer pleaded guilty in 2004, to felony charges that it promoted the drug for uses that were not approved by the FDA.
Pfizer paid $430 million to resolve the charges and reimburse state Medicaid programs for off label uses of Neurontin. As a matter of fact, the writer of this article used Neurontin in connection with trying to alleviate the pain associated with my bout with spinal stenosis. To read more about this matter see our article "Spinal Stenosis- A Personal Story". I found that the drug did not work to alleviate my pain associated with my spinal stenosis.
There is presently a case before the U.S. District Court in Boston, wherein Pfizer is being sued by consumer groups and third-party payers such as insurance companies and trade unions who are seeking $4.9 billion in repayment for fraudulent misrepresentation in promoting the off-label usage of Neurontin.
Papers in the case show that Pfizer sought to conceal harmful studies and clinical trials involving Neurontin.
Michael Rowbothan, the Neurontin team leader wrote in an email in 2000 saying, " I think we can limit the potential downsides of the …. Study by delaying the publication for as long as possible,". The study in question was a study done in Europe late in the 1990s by Warner-Lambert to measure Neurontin's use for diabetic nerve pain that showed that the drug did not prove effective in dealing with the patient's pain.
The study's scientific manager, Beate Roder, wrote in an email to employees after Pfizer had acquired Warner-Lambert that she had been instructed "that we should take care not to publish anything that damages Neurontin's marketing success."
In 2002, Angela Crespo, then Neurontin's senior marketing manager, emailed an outside firm that was contracted to write up the study's results, "We are not interested at all in having this paper published because it is negative!!".
(2/4/08)- In the latest example of a breach of medical ethics, a prominent diabetes expert leaked an article critical of the diabetes drug Avandia to the manufacturer of the drug, GlaxoSmithKline PLC. Dr. Steven M. Haffner of the University of Texas Health Science Center in San Antonio had been given an advance copy of the article that was to appear in The New England Journal of Medicine, since he was a member of the peer review group for the article.
In a statement issued by Senator Charles E. Grassley (R-Io.), who is also the ranking Republican on the Senate Finance Committee he stated: "The most troubling aspect of this situation is that the integrity of another aspect of the scientific process is called into question-scientific peer review". Mr. Grassley also released a copy of a letter he sent to the company asking what action Glaxo took after Dr. Haffner faxed a copy of the article to them.
An article on the matter published online by the journal Nature quoted Dr. Haffner as saying: "Why I sent it is a mystery. I don't really understand it. I wasn't feeling well. It was bad judgment."
A spokeswoman for Glaxo, Nancy Pekark said that Dr. Haffner had faxed the copy of the article to the company on May 3, more than two weeks before the article was published in the journal.
Under The New England Journal's rules, reviewers are prohibited from disclosing an article's content before publication. The University of Texas Health Center issued a statement said that it was aware of the matter and was investigating the event.
Dr. Haffner had previously disclosed that he had conducted research and served as a paid speaker for Glaxo, for which he had been paid about $75,000 since 1999.
Dr. Steven E. Nissen of the Cleveland Clinic had submitted the article in question that Dr. Haffner was peer-reviewing for publication. Dr. Nissen's article was a pooled analysis of Avandia studies that suggested that Avandia increased the risk of heart attack by more than 40%. The article was published in the journal in May 2007. Dr. Haffner had faxed a copy of the article to Glaxo 17 days before it was published.
In his study, Dr. Nissen reviewed 42 previous clinical trials of Avandia, and concluded that patients taking the drug had a 43% higher risk of suffering a heart attack than those taking other oral diabetes medications or placebo pills.
Under pressure from the FDA, Glaxo agreed to add a "black box" warning that Avandia's label describing Dr. Nissen's findings.
(12/17/07)- Jay Yadav, the former head of the Cleveland Clinics vascular intervention unit has sued the hospital over alleged defamation of character and discrimination. He further alleges that the institution is ripe with conflicts-of-interests similar to the kind that were cited as grounds for his dismissal.
Dr. Yadav was fired by the hospital in 2006 for not complying with the institution's conflict-of-interest policies. He filed his lawsuit in state court in Ohio, the state in which the clinic is located.
The clinic denied his allegations and said it planned to file a response as well as a "counter claim for substantial expenses incurred to review his research." The clinic instituted tougher conflict-of-interest policies in 2006, after an article in the Wall Street Journal pointed out the fact that many of the doctors in the clinic had undisclosed interests in companies that made some of the medical equipment used on them. The patients were never informed about this possible conflict.
It was also pointed out that many of the medical professionals received payments from the drug companies as well as the medical equipment companies for doing consulting work while never revealing this fact to the institute or their patients.
Dr. Yadov had financial stakes in two companies whose experimental products were tested on clinic patients. He was fired shortly before the Cleveland Plain Dealer had an article about his outside activities.
According to the complaint in this pending case the clinic has "widespread and pervasive" conflicts-of-interest, as is exemplified by the chief executive of the clinic Delos "Toby" Cosgrove. The clinic heavily promotes and uses an invention by Dr. Cosgrove's in patients undergoing heart valve surgery. The device is known as the Cosgrove-Edwards ring for which both the clinic and Dr. Delos receive substantial royalties. Edwards Lifesciences Corp markets the product.
Dr. Yadav lawsuit also cited the surgeon Isador Lieberman, a member of the hospital's conflict-of-interest committee, who failed to disclose his significant financial interests in Kyphon Inc. That company manufactures equipment for an orthopedic procedure that Dr. Lieberman advocated and tested at the clinic. Dr. Yadav, was born in India and also alleges discrimination in his lawsuit.
Dr. Yadav says the clinic accused him of not properly disclosing royalty payments for a device he invented to prevent blockages in patients who receive a neck stent. Among the other shareholders in Angioguard Inc., the company that acquired the technology from Dr.Yadav, which in turn was acquired by Johnson & Johnson are several other top officials at the hospital.
Dr. Kenneth Ouriel, a surgeon at the hospital received some small payments for the neck device but he did not reveal them to the clinic, and yet he was not terminated for that failure to report those payments.
Dr.Yadav said that he properly disclosed the deferred payments as early as 2002 in a document filed with a clinic review board. In 2003 he made a similar disclosure to the FDA.
(5/28/01)-No one disagrees that advances in medicine depend on innovative and bold clinical research. Read the first half of Dr. James Le Fanu’s book, "The Rise and fall of Modern Medicine" (Carroll and Graf, 426 pp.), to become familiar with the some of the extraordinary developments in clinical medicine during the period from 1940 through the 1970s. This book reinforces a awareness that much of the advances in the effectiveness and safety of disease treatment, diagnosis and prevention results from intensive research involving human research subjects where results at first were not particularly pleasant for the individuals involved in the research.
While research is done in the interest of the health of the individual and the general public, it may have deadly consequences for the individual involved in the research. In 1966, Dr. Henry Beecher, a renowned anesthesiologist at Harvard Medical School, had a paper published in the New England Journal of Medicine (1966; 274:1354-1360) in which he pointed out 22 examples of research studies that contained ethical lapses in research carried out by physician-scientists in renowned universities and published in the world leading journals. Thirty-five years later, we are still subject to such lapses.
Just prior to 1996 the World Medical Association, aware of some of the ethical dilemmas involved in medical research, issued the Declaration of Helsinki in an effort to eliminate research violations and establish ethical norms. These norms have since been amended and revised over the years. The most recent revision to the Declaration of Helsinki was in the year 2000. The Declaration of Helsinki now reads: "Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research." It goes on to state that at the conclusion of a study, any patient participating in the study should be assured of access to the best proven therapeutic methods identified by the study. In discussing use of placebos in a study it states, " The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude the use of placebo or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists." It is considered ethical to delay or omit the use of an available treatment in order to conduct a placebo-controlled trial, provided that only temporary discomfort and no serious adverse consequences are expected, and that the study participants are fully informed about alternative forms of treatment and their right to opt for them. The well being of the individual must always take precedence over the needs of science or the interests of society.
In industrialized countries research costs continue to rise steeply. Suitable patients are in short supply, and clinical institutions are overloaded with research projects. Sponsors are seeking quicker and bigger returns on investment and are attracted to countries in which costs are less, and untreated patients plentiful. Dr. David Rothman, Professor of Social Medicine at Columbia College of Physicians and Surgeons, writing in the November 30, 2000 issue of The New York Review of Books, states, "Until the 1990s American medical researchers performed most of their experiments on other Americans--frequently choosing subjects who were poor and vulnerable. Now, however, they are increasingly likely to conduct their investigations in third world countries on subjects who are even poorer and (more)vulnerable."
Couple the above essay by Rothman with the fiction book "The Constant Gardener" by James Le Carre and you see interesting parallels. A substantive issue in Carre’s book is the use of poor patients by pharmaceutical companies in third world countries and the justification of drug research by the researchers. Fiction may be stranger than the truth, or is it?
Two tendencies appear to be injuring relationships between medicine and the drug industry. First, companies may frequently manipulate information in a way that goes beyond the bounds of acceptable marketing. Second the relationship between many doctors and pharmaceutical companies has become close to corrupt. A recent study at the University of California-San Francisco found that a third of faculty investigators received payments from companies for delivering lectures and accepting consultancies. Some would question the ethics of such relationships.
What about the use of older individuals with dementia in medical research? What ethical questions are raised about this group of individuals? What does the demented individual understand about the research projects in which they take part? Again according to an essay ("The Shame of Medical Research") by Dr. Rothman in The New York Review of Books (Nov. 30, 2000) "[I] n the United States, where consent has been better investigated, anywhere from 25 to 50 percent of patients and subjects do not understand what it is that they have agreed to. Among two hundred patients treated at the University of Pennsylvania Cancer Center, 40% did not know the purpose or the nature of the procedure and 45% could not give one major risk or cite a possible complication resulting from it." A demented individual cannot understand any of the possible implications of the research study, let alone the aim of the study or the nature of the adverse effects if some invasive procedure is involved.
In the USA, federal agencies sponsor and regulate research, but usually delegate responsibility beyond that assumed under the "Common Rule" to Institutional Review Boards (IRB) at academic medical centers. The IRBs monitor all research. No research can proceed without its approval. Most of the members of these Boards are researcher, whose objectivity may be clouded by collegiality. We have been told that assorted egos, ambitions, rivalries and moments of genius make these meetings "interesting", "productive" and "contentious", not necessarily in that order.
Today institutions seem to be linking up with private drug and other profit making organizations in order to reap the financial benefits of their research. Many of these agreements give the drug companies "editorial rights", enabling them to "control" the flow of information about the drug, for which they have a strong financial incentive and enthusiasm to get into clinical use. The sponsors of these agreements, the drug companies, are seeking quicker and bigger returns on investments. This could make for some "unintentional" overlooking of certain adverse effects of the drug. Who could ever forget that during the years between 1956 and 1962 the drug thalidomide caused as many as twelve thousand birth defects. According to Richard Horton’s review of the book "Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine" by Trent Stephens and Rock Brynner (Perseus Press) "Medical journals in the late1950s did much to create widespread clinical enthusiasm for thalidomide. The Lancet ran an advertisement claiming that thalidomide had ‘no known toxicity’ and was ‘free from untoward effects.’ …the drug was ‘outstandingly safe.’" When reports of nerve and muscle disorders were reported the drug company labeled the reactions ‘rare.’"
A positive thing to come out of this dreadful situation was the Kefauver-Harris amendments to the Food, Drug and Cosmetic act of 1938, which set up guidelines for drug approval that included attempts to withstand commercial pressures placed on the FDA.
Research into the causes and drug treatment of dementia continues to grow as witnessed by the vast numbers of research articles and the large list of drugs in the different clinical phases of testing. Health proxies and powers of attorney are ways of planning for the time one is unable to make decisions effecting treatment. These forms of advanced consent enable the individual to issue instructions authorizing future research participation. However, individuals need to understand that research studies may expose them to relatively substantial psychological burdens or physical risks, or both, without reasonable prospect of direct health benefit. The desire to do something about the medical condition of the patient may drive the authorized person to make decisions that can unduly expose the person to harm, simply because the choice of doing nothing about the current medical condition is too threatening or the corollary belief that it is important to take action because it may help.
Can the individual who signs a health proxy or power of attorney understand what would be involved in the research study, when such study will occur at some future date with no advanced knowledge of the tasks and procedures involved in the study? How is research participation understood once decisional capacity is lost? We do know that people have difficulty foreseeing how they will respond to future illness situations. (See: Hibbard JH., Slovic P., Jewett JJ. Informing Consumer Decisions in Health Care: Implications from Decision Research. Millbank Quarterly. 1997; 75: 395-406.) Extrapolating from this study suggests that any research involving advanced consent, where the individual is not aware of the nature of the research, should not involve an intervention presenting more than "a minor increase over minimal risk." In NYS, this is defined as "more than a remote possibility of substantial or prolonged pain, discomfort or distress; or clinically significant deterioration of a medical or mental condition." It would call for scrupulous attention to protocol regimen, especially the potential adverse effects and spelling out the safeguards that promote the welfare of the incapable participant during the research process. It also must provide access to the best-proven therapeutic methods identified by the study. This should be especially true in case of the elderly, now that researchers are trying to involve them more in their protocols.
Research is a necessary step in improving the health of society. Patients involved in this research need to be protected. It is the ethical responsibility of the researcher to make sure patients understand the nature of the research (risk-benefits), get the benefit of the most sophisticated treatment available and is not exposed to "a minor increase over minimal risk."
FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "How to Select a Nursing Home"
Allan Rubin and Harold Rubin, MS, ABD, CRC, Guest Lecturer
Updated October 28, 2008
http://www.therubins.com
To e-mail: hrubin12@nyc.rr or rubin@brainlink.com