A February 22, 2006 internal FDA memorandum, obtained by staffers of the Senate Finance Committee, proves that safety officials within the agency recommended that GlaxoSmithKline add a black box warning about congestive heart failure to the label of the diabetes drug Avandia well over a year ago.
The memo also shows that FDA reviewer Dr David Ross recommended a highlighted boxed warning for CHF, a life-threatening condition that occurs when fluid builds up in the lungs causing a severe shortness of breath that requires immediate medical attention.
The memo also recommended that macular edema, a condition that causes swelling of the retina and can lead to blindness, be listed as a serious adverse event on the label. Although the recommendations were approved by Dr Rosemary Johann-Liang, the Deputy Director of the FDA's Division of Drug Risk Evaluation, they were never added to Avandia's label.
Instead of forcing Glaxo to post warnings to protect Americans, top FDA officials basically demoted Dr Johann-Lang for approving the warnings to begin with.
Congestive heart failure "is a very, very clear adverse reaction syndrome" with Avandia, Dr Johann-Lang told reporter, Rita Rubin, according to an article in USA Today on June 11, 2007. She also noted a concern that some patients might blame symptoms, such as shortness of breath, on the underlying diabetes and mistakenly take more of the drug.
Dr Johann-Lang has now left her position at the FDA for personal reasons, but said in her interview with USA Today, that she might have tried to figure out a way to stay "if the agency had a vision of promoting and protecting public health."
However, her departure does not mean that the misconduct by senior FDA officials will be overlooked. On June 4, 2007, Senator Charles Grassley (R-Iowa) and the Senate Finance Committee sent a letter to the FDA Commissioner Andrew von Eschenbach demanding answers to questions by June 20, 2007, about the retaliation waged against the safety evaluators who tried to warn the public about the risks of Anvandia a year ago.
Although Glaxo downplayed the risks, according to a June 1, 2007 report by Andrea Gerlin for Bloomberg News, the FDA knew about risks associated with Avandia as far back as April 1999, when GlaxoSmithKline executives told the FDA that the drug caused "minimal" cardiovascular side effects and "mild to moderate" fluid buildup,
The agency approved Avandia on May 25, 1999, even though some FDA advisory panel members had recommended that more research should be conducted to detect potential complications.
On February 8, 2001, the FDA Web site shows the agency approved revisions to the Prescribing Information for Avandia to include a new warning regarding cardiac failure and cardiac effects.
But 3 months later, Glaxo sales representatives were "denying the existence of serious new risks associated with Avandia" in presentations at Glaxo's promotional exhibit booth during the Annual American Association of Clinical Endocrinologists Meeting in San Antonio, Texas on May 2-6, 2001, according to a July 26, 2001 FDA letter to Glaxo.
The letter also pointed out that Glaxo had already been warned about this conduct several times. "Your promotional activities that minimize serious new risks are particularly troublesome," it said, "because we have previously objected, in two untitled letters, to your dissemination of promotional materials for Avandia that failed to present any risk information about Avandia or minimized the hepatic risk associated with Avandia."
The untitled letters were sent to Glaxo on June 29, 1999 and October 20, 2000. "Despite your assurance that such violative promotion of Avandia had ceased," the July 2001 letter states, "your violative promotion of Avandia has continued."
In a December 3, 2006 interview, diabetes researcher Rury Holman of Oxford University in the UK, an investigator in the Glaxo study known as ADOPT, told Bloomberg News that the results of that study, which were released in November 2006, were cause for concern.
"These people are early diagnosis, they haven't got complications," he said. "The fact that we're seeing these cardiovascular effects in them we can't deny that."
The concern, he noted, was that a signal emerged in "relatively healthy patients." In addition, according to the FDA web site, significantly more female patients who received Avandia in the ADOPT study, "experienced fractures of the upper arm, hand, or foot, than did female patients who received either metformin or glyburide."
type 1 diabetes is could be decreased if the public knew the
There is a known but not publicized connection between advancing paternal and maternal age and the risk of an offspring having type 1 diabetes. Have the government agencies the academics and the pharmaceutical companies avoided publicizing the robust connection?
Eur J Pediatr. 1999 May;158(5):362-6. Links
Risk factors for type I diabetes mellitus in children in Austria.Rami B, Schneider U, Imhof A, Waldhör T, Schober E.
University Children's Hospital Vienna, Austria.
The aim of this study was to investigate environmental risk factors in the development of type 1 diabetes mellitus in a population-based case-control study. Parents of all patients with manifestation of type 1 diabetes between 1989 and 1994 in Vienna were asked to complete a questionnaire (n = 114). Control children (n = 495), matched for age and sex, were randomly recruited from all schools in Vienna. Fathers of diabetic children were significantly older at the time their children were born than fathers of control children (P = 0.015). Children with diabetes were more likely to be second- or third-born children (P<0.05) and fewer went to kindergarten than the control group children (P = 0.007). No significant difference in duration of gestation, percentage of delivery by caesarean section, birth weight or length was found. Neonatal jaundice was more often observed in the patient group (P = 0.038). Breast feeding was reported by 82.7% of mothers of diabetic children and by 81% of mothers of control children, and the duration of breast feeding was longer in patients than in controls (n.s.). CONCLUSION: In our study, the development of type 1 diabetes mellitus was associated with higher paternal age and neonatal jaundice. No correlation could be found with dietary intake of cow's milk products in early infancy, vaccination and other environmental factors.
PMID: 10333115 [PubMed - indexed for MEDLINE]
Diabet Med. 2005 Feb;22(2):200-6. Links
Parental age at delivery, birth order, birth weight and gestational age are associated with the risk of childhood Type 1 diabetes: a UK regional retrospective cohort study.Cardwell CR, Carson DJ, Patterson CC.
Department of Epidemiology & Public Health, The Queen's University of Belfast, Belfast, UK. c.cardwell@qub.ac.uk
AIMS: To investigate perinatal risk factors for childhood Type 1 diabetes in a UK population cohort. METHODS: Perinatal data have been routinely recorded in Northern Ireland for all births in the period 1971-86 (n = 447 663). Diabetes status at the age of 15 years was ascertained in this cohort by identifying 991 children from 1079 registered with Type 1 diabetes diagnosed from 1971 to 2001 and date of birth in the period 1971-86. RESULTS: Increased Type 1 diabetes risk was associated with higher maternal age, paternal age, birth weight and birth weight for gestational and lower gestational age. After adjustment for maternal age, the association between Type 1 diabetes and paternal age remained significant [relative risk (RR) = 1.52 (1.10, 2.09) comparing father's age 35 years or more to less than 25 years] but not vice versa [RR = 1.11 (0.80, 1.54) comparing mother's age 35 years or more to less than 25 years]. Increased birth order was associated with a significant decrease in the risk of Type 1 diabetes [adjusted RR = 0.75 (0.62, 0.90) comparing birth order three or more with firstborn], but this only became apparent when adjustment was made for maternal age. Furthermore this association with birth order was significant only for diabetes diagnosed under the age of 5 years. CONCLUSIONS: Our analysis demonstrates, for the first time in a UK regional cohort setting, that maternal age and paternal age at delivery, birth order, birth weight and gestational age are significantly associated with Type 1 diabetes risk.
PMID: 15660739 [PubMed - indexed for MEDLINE]
: BMJ. 2000 Aug 12;321(7258):420-4. Links
Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study. Bart's-Oxford Family Study Group.Bingley PJ, Douek IF, Rogers CA, Gale EA.
Diabetes and Metabolism, Division of Medicine, University of Bristol, Southmead Hospital, Bristol BS10 5NB.
OBJECTIVES: To examine the influence of parental age at delivery and birth order on subsequent risk of childhood diabetes. DESIGN: Prospective population based family study. SETTING: Area formerly administered by the Oxford Regional Health Authority. Participants: 1375 families in which one child or more had diabetes. Of 3221 offspring, 1431 had diabetes (median age at diagnosis 10.5 years, range 0.4-28.5) and 1790 remained non-diabetic at a median age of 16. 1 years. MAIN OUTCOME MEASURES: Disease free survival and hazard ratios for the development of type 1 diabetes in all offspring, assessed by Cox proportional hazard regression. Results: Maternal age at delivery was strongly related to risk of type 1 diabetes in the offspring; risk increased by 25% (95% confidence interval 17% to 34%) for each five year band of maternal age, so that maternal age at delivery of 45 years or more was associated with a relative risk of 3.11 (2.07 to 4.66) compared with a maternal age of less than 20 years. Paternal age was also associated with a 9% (3% to 16%) increase for each five year increase in paternal age. The relative risk of diabetes, adjusted for parental age at delivery and sex of offspring, decreased with increasing birth order; the overall effect was a 15% risk reduction (10% to 21%) per child born. CONCLUSIONS: A strong association was found between increasing maternal age at delivery and risk of diabetes in the child. Risk was highest in firstborn children and decreased progressively with higher birth order. The fetal environment seems to have a strong influence on risk of type 1 diabetes in the child. The increase in maternal age at delivery in the United Kingdom over the past two decades could partly account for the increase in incidence of childhood diabetes over this period.
