Clinical trials & tribulations

New restrictions on drug companies aim at keeping them honest and ethical in the face of big money.

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October 29, 2006 04:09
Clinical trials & tribulations

transplant doctors 88. (photo credit: )

 
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Pharmaceutical companies are interested primarily in making profits. They would do anything, even hiding, manipulating and falsifying research results, to make their product look good. Look at how many people were hurt by Merck's Vioxx and other drugs whose manufacturers knew in advance there were problems. Doctors who do the research are mainly interested in the prestige from publishing clinical studies in well-known journals. Some will hide the dangers from patients they want to include in clinical trials. Is it any wonder that from time to time, Israelis are treated to medical scandals about abuse of patients who have no one to protect them? or Drug companies spend an average of $500 million and 10 years to develop just one approved, effective drug. There are many experimental ones that don't pan out, and companies deserve credit for the miracle-working drugs that all of us take for granted. These are big international organizations with highly qualified doctors serving as advisers; they don't fool around. And physicians who conduct medical research are motivated first and foremost by concern for their patients. They just want them to live longer and better lives. As with most things in life, the truth lies somewhere in the middle. After listening for some five hours to more than half-a-dozen experts - physicians, attorneys and pharmaceutical executives - at the recent Jerusalem Ethics Center symposium on "Ethical Dilemmas in Clinical Trials," one could easily feel like the rabbi's wife who, hearing two men fervently presenting conflicting arguments before her husband, declared: "They're both right!" The symposium, held at the Konrad Adenauer Conference Center in Jerusalem's Mishkenot Sha'ananaim, was initiated by the Israel Medical Association (IMA) long before the latest arrests of Harzfeld Geriatric Hospital doctors suspected of conducting illegal medical experiments on elderly patients, some of them nonagenarians and demented. Possible charges could include abuse of helpless victims, aggravated assault, causing death through negligence, fraud, forgery and obstruction of justice. Prof. Avinoam Reches, a senior neurologist at Hadassah University Medical Center in Jerusalem's Ein Kerem and chairman of the IMA's ethics bureau, sent a shiver up his listeners' spines by saying: "It is shocking that a woman who survived Nazi Dr. Josef Mengele's experiments died at Harzfeld in an Israeli clinical trial. This pulls the carpet out from under us doctors. There were allegations about falsification of patient signatures at [the Rabin Medical Center's] Beilinson [Campus] and others at [Tel Aviv Sourasky Medical Center's] Ichilov Hospital. I don't know if they are true or not, but these cases deter the public from participating in clinical trials." Nevertheless, some 1,200 studies are performed each year on Israeli patients. Reches, who was vocally critical of drug companies, said he himself has carried out 40 in his career. "The State of Israel will lose if they are halted." Reches charged that pharmaceutical companies that sponsor clinical trials don't change data, but some may intentionally tailor data to make their product look good by comparing it with one known to be less efficient and picking misleading end points for studies. In July 2005, Reches said, international medical journal editors insisted that researchers register their trials in advance on a US government Web site (www.clinicaltrials.gov) with details on who financed them, when it started and ended and other details. This requirement has already improved transparency. IMA LEGAL department head Malka Borow looked back at the execrable behavior of German doctors during the Nazi era who conducted merciless medical experiments on helpless Jews and other victims, often killing them when they were finished. "They argued that they were not crazy; they said they worked according to the rules. Some said the Jews would die anyway, so 'they will want to contribute their bodies for the good of humanity.' " But in 1947, the Nuremburg Code declared that in clinical trials, no patient can be included without consent. In 1964, the World Medical Association - a roof body representing the planet's physicians - adopted the Declaration of Helsinki, which has been revised several times since. Participants in trials were given the right to leave them whenever they wished; negative, as well as positive, results must be reported; and other limitations were put in force, Borow said. Today, the Helsinki declaration is the basis for Israeli regulations dealing with medical experimentation, and for a Health Ministry-sponsored bill due to be presented soon in the Knesset, to regulate it. Ministry legal adviser Mira Huebner noted that in 1980, regulations covering clinical trials took effect; before that, there were no rules at all - although there was medical experimentation. The bill will establish strict rules and punishments. Clinical trials will be permitted only in hospitals or clinics that are under hospital supervision; approval by the hospital's Helsinki Committee must be granted in advance, and no trials will be allowed unless their aim is improved prevention, diagnosis or treatment of disease. If the risk to the patient, his discomfort or pain are greater than the possible benefit to the individual, the experiment will not be allowed. No participant in trials may be dependent for treatment or other benefits on the doctor who does the research, and the researcher must not enlist participants himself, said Huebner. The researcher must not promise the participant that he will be treated earlier or better if he joins the trial, and if he declines to join, the patient may not be punished in any way. Complete separation between the donor of the research money and the researchers must be established, and the money will go to a hospital research fund rather than directly to the researcher. Every sponsored trip abroad must be approved in advance by a ministry committee. "We know there have been three-day trips to other countries at drug company expense with only about two hours devoted to lectures. I can't say we prevent all violations," said Huebner. "Our bill will soon be presented to ministerial committee on legislation. I hope it will be approved soon. But we need a budget for more supervisors, and the subject must be internalized by doctors and medical students." PROF. AMOS SHAPIRA, who is in charge of biomedical ethics at Tel Aviv University and a member of Supreme Helsinki Committee, recalled that despite the Helsinki declaration, it was ignored by some researchers: Children were intentionally infected with hepatitis virus in one study; in the notorious Tuskeegee experiment by the US government that went on for four decades, 399 black men in Alabama were exposed to syphilis and not treated (even when penicillin became available) so that doctors could observe the natural development of the disease. Mexican women who thought they were being give contraceptives received a placebo and got pregnant. In a Jewish hospital for chronic diseases in Brooklyn, New York more than 40 years ago, demented Jews received cancer cell injections under their skin; it was not fatal but did cause harm to their skin. "Weak, powerless populations - blacks, children, prisoners and the mentally disabled," Shapira said, "are especially vulnerable." He added that Helsinki is not the most advanced document relating to clinical trials; the Council of Europe prepared a better one in 1997, but it is little known. If a new biological agent is being tested, said Prof. Jacques Michel - chairman of the Hadassah Medical Organization's in-house Helskinki Committee - it must not be tried on many patients simultaneously, but only one at a time. "This was done in the UK, and six people ended up in intensive care in one day." In the US, he continued, women were given thalidomide; they didn't know drug wasn't registered. In 2001, a healthy volunteer who worked at Johns Hopkins University died after being included in an asthma trial of a drug whose use was prohibited. At a famous US institute, black children were used as "guinea pigs" to test the effects of exposure to lead paint dust. In India, barren young women thought they were getting expensive fertility treatment, but they were lied to; the drug was meant for cancer. The Pfizer pharmaceutical company, said Michel, tested new antibiotics on 2,000 children without getting informed consent; 11 of them suffered brain damage, hearing loss or death. AMONG VIOLATIONS in a variety of international medical studies over the years have been failure to submit requests to ethics committee; deviation from approval that was given; failure to report serious adverse events or conflicts of interest or to receive informed consent; sometimes, said Michel, patients gave consent based on purposefully false information. Michel said he has encountered researchers who "are arrogant and violate rules because they think nothing will happen. There are those crazed by research, who constantly run after publication opportunities and compromise their principles." Dr. Aharon Schwartz, deputy vice president of Teva Pharmaceuticals and for years a supervisor of the development and marketing of the blockbuster Israeli multiple sclerosis drug Copaxone, said psychiatrist Sigmund Freud never conducted randomized controlled clinical trials or followed evidence-based medicine. "These things are relatively new. Clinical trials for drug companies are in key parts of the economy, and what we do today is harder than it was 20 years ago." He admitted that many patient groups lobbying for drugs to be supplied by health funds are supported financially by drug companies. "You can't avoid it - but it must be organized and transparent. The solution to potential problems is full disclosure and transparency through mandatory registries of clinical trials." Merck Sharp & Dohme-Israel medical director Dr. Yael Weiss, whose mother company produced Vioxx and withdrew it voluntarily from the market, noted that information about side effects are printed on the leaflets inside drug packages, but "most people don't read them." MSD has lost a fortune by withdrawing Vioxx, she said, and is constantly getting bad publicity from ongoing lawsuits and media reports. She added that researchers must get pharmaceutical company funding because companies spend $300 million annually on Israeli studies, while the entire state budget for health research is a pathetic $14 million. It is possible for doctors to do clinical research sponsored by drug companies, or serve as paid advisers and remain ethical, declared Prof. Itamar Raz, head of Hadassah University Medical Center's diabetes center and head of the National Diabetes Council. "I'm known to be a good guy," said Raz - who has a sterling reputation as a humane clinician and painstaking and objective researcher - modestly. "I have been involved in 100 clinical studies in 15 years and been a paid consultant to companies. The money doesn't necessarily mean the doctor is corrupt. In the field of diabetes, we have greatly advanced the level of treatment thanks to pharma companies. Researchers get money for their department, never for themselves, plus exposure in medical journals and invitations to conferences. They benefit from research, but they must also have a conscience. The patient's wellbeing must remain in the center." Raz discussed the ethical considerations in giving a placebo to patients participating in clinical trials. "Placebos often make patients feel better and certainly don't hurt. But there are shortcomings. Placebos can mean patients get injections or take a lot of pills a day, with the discomfort and inconvenience these entail, but they are not really effective. We know that not all patients get optimal treatment in placebo-controlled studies. However, if we see that a patient deteriorating on placebo, we can give an additional drug to improve his situation." The dilemma is most difficult if there is an effective drug but the patient gets only a placebo. The best situation is if all patients in the trial get maximal treatment plus a placebo versus the drug being tested, Raz suggested. "I wouldn't give a patient what I wouldn't give my own brother. Clinical research has advanced medicine. There can always be corruption by a small minority, so you have to supervise more vigilantly."

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