Sidney M. Wolfe

Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries.

It was published almost 3 years ago that zidovudine administered orally to HIV-infected pregnant women, intravenously during labor, and later administered to newborn infants reduces the incidence of HIV infection in infants by two-thirds. This regimen, known as the ACTG 076 regimen and capable of saving the life of one of every seven infants born to HIV-infected women, subsequently became the standard of care in the US. However, the high cost of zidovudine and the ACTG 076 regimen impedes their use in developing countries. A regimen as effective but less expensive than ACTG 076 is therefore highly desirable in countries worldwide, but especially in developing countries. The authors oppose the use of placebo-controlled trials as unethical in the search for alternative antiretroviral drug regimens to prevent the perinatal transmission of HIV. 15 trials in developing countries are identified in which some or all of the participants are not being provided with antiretroviral drugs. Those studies violate recent guidelines designed specifically to address ethical issues regarding studies in developing countries. An urgent need exists to develop and adhere to a universally recognized code of ethics for medical research upon human subjects.

Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: A meta-analysis

CONTEXT Hemoglobin-based blood substitutes (HBBSs) are infusible oxygen-carrying liquids that have long shelf lives, have no need for refrigeration or cross-matching, and are ideal for treating hemorrhagic shock in remote settings. Some trials of HBBSs during the last decade have reported increased risks without clinical benefit. OBJECTIVE To assess the safety of HBBSs in surgical, stroke, and trauma patients. DATA SOURCES PubMed, EMBASE, and Cochrane Library searches for articles using hemoglobin and blood substitutes from 1980 through March 25, 2008; reviews of Food and Drug Administration (FDA) advisory committee meeting materials; and Internet searches for company press releases. STUDY SELECTION Randomized controlled trials including patients aged 19 years and older receiving HBBSs therapeutically. The database searches yielded 70 trials of which 13 met these criteria; in addition, data from 2 other trials were reported in 2 press releases, and additional data were included in 1 relevant FDA review. DATA EXTRACTION Data on death and myocardial infarction (MI) as outcome variables. RESULTS Sixteen trials involving 5 different products and 3711 patients in varied patient populations were identified. A test for heterogeneity of the results of these trials was not significant for either mortality or MI (for both, I2 = 0%, P > or = .60), and data were combined using a fixed-effects model. Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication. CONCLUSION Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI.

Left to Their Own Devices: Breakdowns in United States Medical Device Premarket Review

Using examples from recent FDA regulatory proceedings, Jonas Hines and colleagues critique the medical device premarket review and identify eight weaknesses in the process that should be remedied.

Case series of liver failure associated with rosiglitazone and pioglitazone.

The thiazolidinedione drugs rosiglitazone and pioglitazone are not widely known to be hepatotoxic. We evaluated the FDA Adverse Event Reporting System (AERS) to determine the number of reported cases of liver failure associated with rosiglitazone and pioglitazone between 1997 and 2006, and described their clinical characteristics.

Osteosarcoma risk in rats using PTH 1-34

We read with interest the recent research article ‘Reconstructing the skeleton with intermittent parathyroid hormone’ by Ego Seeman and Pierre Delmas, published in Trends in Endocrinology & Metabolism 1xReconstructing the skeleton with intermittent parathyroid hormone. Seeman, E. and Delmas, P.D. Trends Endocrinol. Metab. 2001; 12: 281–283Abstract | Full Text | Full Text PDF | PubMedSee all References1 and at http://www.HMS_Beagle.com. The article is a good review of the efficacy of the first parathyroid hormone to treat osteoporosis, PTH 1-34, including the limits of that efficacy.We would like to bring attention to the fact that there is a primary safety issue (the induction of osteosarcomas in a rat carcinogenicity study) related to the use of PTH 1-34, which was discussed at some length in the article by Neer et al. 2xEffect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. Neer, R.M. et al. New. Engl. J. Med. 2001; 344: 1434–1441Crossref | PubMed | Scopus (2670)See all References2 (http://www.fda.gov/ohrms/dockets/ac/01/briefing/376162_fda.htm).In trials with rats, osteosarcomas occurred in rats treated from the age of six to seven weeks for two years with PTH 1-34 (representing near lifetime treatment) at frequencies of 0%, 5%, 35% and 52% (control, low, middle and high dose) in males and in 0%, 7%, 20% and 38% of females (http://www.fda.gov/ohrms/dockets/ac/01/briefing/3761b2_05_PharmTox.htm). No ‘no-effect level’ for osteosarcomas was established because tumors were present at even the lowest dose tested. There was also a statistically significant increase in osteoblastomas in both sexes.As a result of these findings, the clinical trials were prematurely stopped in December 1998. Consequently, the median treatment duration was only 19 months for the main trial, rather than the three years that were originally planned (http://www.fda.gov/ohrms/dockets/ac/01/briefing/3761b2_04_Statistics.htm). The human significance of these osteosarcomas has been rationalized away by citing: (1) the lack of osteosarcomas in the clinical trial; (2) the absence of bone tumors in an 18-month monkey study; (3) the lack of genotoxicity; and (4) the lack of tumors in patients with hyperparathyroidism.The absence of bone tumors in the clinical trial patients is not surprising given that osteosarcomas are rare and the time to appearance for chemically induced tumors, in general, ranges from ten to 20 years from the time of exposure. Similarly, the monkey study was much too short (not lifetime) and lacked statistical power, having only four monkeys per group rather than the 60 individuals per group in the rat study.Because the formation of osteosarcomas is mechanism based (PTH stimulates proliferation of osteoblasts, thus increasing the likelihood of mutations), the absence of positive results in genotoxicity tests is not relevant. A probable mechanism for carcinogenicity is drug-induced cell division, increasing the chances for generating genetic errors and then magnifying them.Finally, that osteosarcomas are not seen in patients with hyperparathyroidism is of limited relevance, because those patients are exposed to chronically elevated PTH levels, whereas patients being treated with PTH are on an intermittent dosing schedule, which can induce a differential effect on osteoblastic gene expression (http://www.fda.gov/ohrms/dockets/ac/01/briefing/3761b2_05_PharmTox.htm).In summary, these data present a compelling case for the carcinogenicity of PTH 1-34. Moreover, the rat study might have actually underestimated the incidence of bone tumors. Tumors were detected by a clinical finding of a bone nodule and/or by microscopic evaluation, but only four bones per animal were routinely examined. The limits of clinical detection are illustrated by one bone tumor that was fatal yet was only detected upon microscopic examination. Patients could have microscopic tumors that could not yet be detected clinically.For these reasons, we feel that if PTH 1-34 is approved to treat osteoporosis, (a) its use should be restricted to a second-line drug to minimize population exposure to this carcinogen; (b) there should be a black-box warning on the carcinogenicity findings; (c) patients should be given an FDA-approved Medguide each time a prescription is filled; and (d) the sponsor should be required to establish a registry in order to identify patients with PTH 1-34-associated osteosarcomas.

The vanishing health care safety net: New data on uninsured Americans

New data obtained from the Census Bureau shows that the number of Americans without any health insurance increased by 1.3 million between 1989 and 1990, bringing the total number of uninsured to 34.7 million, more than at any time since the passage of Medicare and Medicaid 25 years ago. This increase coincided with a 10.5 percent increase in health spending, the second largest in the past three decades. The number of people covered by Medicaid grew by 3.1 million, due to a one-time expansion of eligibility mandated by Congress, but this was more than counterbalanced by a population growth of 3 million and a decrease of 1.3 million in people covered by private insurance. Had Medicaid not been expanded, the number of uninsured would have increased by 4.4 million. The increase in the uninsured affected virtually all parts of the nation. Seven states had increases of more than 100,000 persons each. Only Texas experienced a decrease of that magnitude, but still had the second highest rate of uninsurance of any state. Of the 1.3 million additional uninsured in 1990, 77 percent were male, 32 percent had family incomes in excess of

Safety of sildenafil citrate

50,000 per year, and 74 percent had annual family incomes above

The growing epidemic of uninsurance: new data on the health insurance coverage of Americans.

25,000. Fewer than 9 percent had incomes below the poverty line. The numbers of uninsured children and senior citizens fell slightly (but not significantly), while the number of uninsured working-age adults rose by 1.4 million. The number of uninsured workers in each of four of 20 major industry groups increased by more than 100,000 in 1990. None of the industry groups showed a significant decline in the number of uninsured. Among professionals, there were substantial numbers of uninsured doctors, engineers, teachers, college professors, clergy, and others, but all legislators and judges were insured. The data presented here largely predate the recession and understate current problems. In 1991 the number of uninsured will likely reach nearly 40 million. Also, these estimates are based on the number of people uninsured at a single time during 1990; a far higher number were temporarily uninsured at some point during the year. Moreover the Census Bureau survey ignores the problem of the underinsurance of at least 50 million insured Americans. Patchwork public programs are grossly inadequate to plug the holes. A national health program covering all Americans could assure access to care and contain costs.

Florbetapir-PET Imaging and Postmortem β-Amyloid Pathology

Sir—In your editorial on sildenafil citrate (Viagra), you state that “Public information to consumers and health professionals covers safety adequately, if not to the total satisfaction of consumer groups such as the US Public Citizen”. Although this editorial involved an internet search, we point out information that is not in the FDA-approved label for the drug but in our petition for stronger warnings filed with the FDA on Aug 20, 1998, and available on our web site (www.citizen.org/hrg), as follows. “[We] demand that the FDA immediately convene a meeting on Viagra of its cardiovascular advisory committee—a committee which was completely bypassed during the dangerously-rushed six months between the submission of the new drug application for Viagra to the FDA and its approval . . . An ongoing joint task force of the American College of Cardiology and the American Heart Association (ACC/AHA) . . . has just issued an interim report which expresses concerns about the risks of the drug to new categories of patients with cardiovascular disease. . . . the ACC/AHA said that: The cardiovascular effects of Viagra may be potentially hazardous for patients with certain medical profiles, and clinicians need to exercise caution when advising the following patients who are considering taking Viagra: Patients with active coronary ischemia [decreased blood flow to the heart] who are not on nitrates; Patients with congestive heart failure and borderline low blood pressure and borderline low volume status; Patients on a complicated multidrug, anti-hypertensive program; and Patients on drugs (erythromycin cimetidine) or who have conditions (eg, liver or renal disease) that can prolong the half-life of Viagra.” Summarising these concerns, none of which (other than the above drug interactions) are reflected in the current labelling for Viagra, Dr Adolph M Hutter Jr, co-chair of the expert committee that developed the statement, said: “It can be dangerous for some patients to take Viagra, even if they are not on nitrates. Their medical condition or their medications can alter the effect that Viagra might have on their bodies, which might lead to an excessive drop in blood pressure”. In addition to the ACC/AHA suggestions for new warnings with which we agree, there is no information in the current label that addresses the findings of severe periarteritis that occurred in both rats and dogs, even though the (FDA) pharmacology reviewer stated that this was the most important toxicological finding and seems closely related to the inhibition of the phosphodiesterase type 5 enzyme which is located in vascular smooth muscle. The “special attention and warnings” referred to in your editorial for patients with a history of heart disease are not included in the official labelling for the drug but should be included, otherwise public information does not cover safety adequately.

Health care paper chase, 1993: The cost to the nation, the states, and the district of Columbia

Despite a massive expansion of Medicaid and an upswing in the economy, the total number of Americans uninsured in 1993 was 39.7 million, more than at any time since the passage of Medicaid and Medicare in the 1960s. Since 1989, the ranks of the uninsured have swelled by 6.3 million. Millions more would be uninsured if Medicaid enrollment had not risen dramatically, by 10.5 million people since 1989. Loss of health coverage is a growing problem for middle-income families, women, and children, as it has long been for low-income families. Even in Hawaii, whose employer mandate program is often cited as a model of universal coverage, there was a large increase in uninsurance. Nationwide, the sharp upswing in the number of Americans who are uninsured has coincided with government and corporate policies to encourage medical competition and push people into managed care plans. Republican proposals to limit AFDC benefits threaten to further increase uninsurance, particularly among women and children. Only a Canadian-style single-payer reform can assure universal coverage and simultaneously contain costs.