Sidney Wolfe, M.D. Michael Carome, M.D. Public Citizen
1600 20th St. NW
Washington, DC 20009
RE: FDA-2014-P-0258
Dear Drs. Wolfe and Carome:
This letter responds to your citizen petition received on February 25,2014 (Petition). You request that the U.S. Food and Drug Administration (FDA or the Agency):
(1) add a "black box" warning about the increased risks of heart attacks and other cardiovascular dangers to the product labels of all testosterone-containing drugs presently on the market in the United States;
(2) ask manufacturers to send "Dear Doctor" letters to warn physicians of these serious adverse effects;
(3) require that the FDA-approved Medication Guide for testosterone products, dispensed to patients when their prescriptions are filled, be updated to include this new warning; and
(4) delay the Agency's decision date on approving a new, long-acting, injectable testosterone product Aveed (testosterone undecanoate, Endo) because its approval, absent the new black box warning, would cause further cardiovascular harm to patients for whom this new formulation is prescribed. 1 2
On March 5, 2014, FDA approved Aveed (testosterone undecanoate) injection for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone, primary hypogonadism (congenital or acquired), or hypogonadotropic hypogonadism (congenital or acquired). The general safety profile of Aveed is comparable to other approved injectable testosterone-containing drugs, with the exception of serious post-injection reactions, and Aveed offered a benefit over currently approved injectable testosterone* containing drugs because it requires considerably fewer injections. For the reasons discussed in this response, the Agency did not believe a delay in Aveed's approval was appropriate based on the evidence submitted in the Petition. You acknowledged the approval in a separate letter to Commissioner Margaret Hamburg dated March 6,2014. In your letter, you requested that FDA "provide, as quickly as possible, all FDA staff documents concerning
the cardiovascular safety of testosterone products, including any documents discussing concerns about these risks in the context of the decision to approve Aveed." Your request for these records, which you subsequently submitted under the Freedom of lnformation Act (FOIA) on March 11, 2014, will be processed as a FOIA request (FOI 2014-1986).
FDA has considered the information submitted in the Petition, comments to the docket, and other relevant data and information.
Based on our review of this information, and for the reasons described below, the Petition is denied.
I. BACKGROUND
A. Testosterone Therapy
Testosterone has been approved or used as a drug in the United States since the 1940s, primarily to stimulate puberty and for the treatment of primary hypogonadism and hypogonadotropic hypogonadism (congenital or acquired) in males.3 Some formulations have also been approved for the treatment of metastatic breast cancer in females.
Some of the clinical manifestations of low testosterone include low libido, increased body fat mass, osteoporosis, muscle wasting, and weakness. Clinical guidelines recommend making the diagnosis of hypogonadism only in men with consistent signs and symptoms, and confirmed low testosterone levels (<300 nanograms (ng)/deciliter (dL)).4 The guidelines also suggest confirmatory testing, additional work-up, and a threshold for starting and monitoring testosterone replacement therapy.
Observational studies have shown that generally low testosterone in men is associated with the worsening of biomarkers of cardiovascular health, such as the progression of atherosclerosis, 5 high cholesterol, and high blood pressure.6 There is a growing body of evidence regarding the association between low baseline testosterone and poor cardiovascular health in men. Some studies have attempted to assess the relationship between low testosterone and adverse clinical outcomes such as myocardial infarction (Mif and cardiovascular mortality,8 but it remains
unclear. Randomized controlled trials have shown that testosterone supplementation generally improves some biomarkers of cardiovascular health.9
B. Regulatory Framework
1. Contraindications, Warnings and Precautions, and Boxed Warnings
FDA regulations state that the Warnings and Precautions section of prescription drug labeling (including the product's package insert) must describe clinically significant adverse reactions, other potential safety hazards, limitations on use imposed by them, and steps that should be taken if such reactions occur (21 CFR 201.57(c)(6)(i)); see also 21 CFR 201.80(e) and (f)).
FDA's
Guidance for Industry on Warnings and Precautions, Contraindications, and Boxed Warnings Sections of Labeling for Human Prescription Drug and Biological Products- Content and Format (Warnings and Precautions Guidance) describes some factors that FDA may consider in assessing whether there is reasonable evidence of a causal relationship between a drug and an adverse event. These include: "(I) the frequency of reporting; (2) whether the adverse event rate in the drug treatment group exceeds the rate in the placebo and active-control group in controlled trials; (3) evidence of a dose-response relationship; (4) the extent to which the adverse event is consistent with the pharmacology of the drug; (5) the temporal association between drug administration and the event; (6) existence of dechallenge and rechallenge experience; and (7) whether the adverse event is known to be caused by related drugs." 10
Under§ 201.57(c)(l), a boxed warning may be required for certain contraindications or serious warnings, particularly those that may lead to death or serious injury (see also§ 201.80(e)). A boxed warning must contain, in uppercase letters, a heading that includes the word "WARNING" and other words that convey the general focus of information in the box (§ 201.57(c)(l)). A boxed warning briefly explains the risk and refers to more detailed information in the "Contraindications" or "Warnings and Precautions" section(§ 201.57(c)(l)). A summary of a boxed warning (with the heading WARNING and other words that are appropriate to identify the subject of the warning) must be included in the Highlights section in a box and in bold type(§§ 201.56(d)(1) and 201.57(a)(4)).
FDA's Warnings and Precautions Guidance states that a boxed warning ordinarily is used to highlight for prescribers one of the following situations:
o There is an adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using a drug, or
o There is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation), or
o FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if its distribution or use is restricted (e.g., under 21 CFR 314.520 and 601.42 "Approval with restrictions to assure safe use" or under 505-l(f)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) "Risk Evaluation and Mitigation Strategies" Elements to assure safe use). 11
The Warnings and Precautions Guidance also states that there may be other situations in which a boxed warning may be appropriate to highlight information that is especially important to a prescriber. 12
2. Safety Labeling Changes Authority under Section 505(o)(4)
Title IX, Subtitle A, section 90 I of the Food and Drug Administration Amendments Act of 2007 (FDAAA) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to authorize FDA to require holders of approved drug and biological product applications to make safety labeling changes, including changes to Medication Guides, for an approved drug based on new safety information that becomes available after the approval of the drug (section 505(o)(4) of the Act (21 U.S.C. 355(o)(4))). As defined in section 505-1(b)(3), new safety information is information derived from a clinical trial, an adverse event report, a postapproval study (including a study under section 505(o)(3)), or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system under section 505(k) of the Act; or other scientific data deemed appropriate by the Agency about, among other things, a serious or an unexpected serious risk associated with use of the drug that the Agency has become aware of (that may be based on a new analysis of existing information) since the drug was approved.
12 Warnings and Precautions Guidance at I I.
II. DISCUSSION
As the basis for your requests, you cite four studies that you assert "make it clear that testosterone treatment increases the risks of cardiovascular disease, including heart attacks." 13
These four studies are: Basaria eta!.,14 Xu et al./ 5 Vigen et
al.,16 and Finkle et al.17 You also assert that FDA was reckless in making its January 31, 2014, statement that FDA has not concluded that FDA-approved testosterone treatments increase the risk of stroke, heart attack, or death.18
FDA has considered the studies submitted in support of your requests, which were all known to the Agency prior to the submission of your Petition, and concludes that, at this time, there is insufficient evidence of a causal link between testosterone therapy and adverse cardiovascular outcomes to support the regulatory actions requested in your Petition. However, prior to the submission of your Petition, the Agency had already initiated its own evaluation of the cardiovascular risks of testosterone therapy. The Agency's final determination regarding the safety of testosterone therapy, and whether FDA will exercise its authority to require safety labeling changes to the labeling of testosterone-containing drugs , is pending the outcome of that evaluation.
In response to your Petition, the Agency evaluated each study you submitted as evidence of a causal relationship between testosterone therapy and adverse cardiovascular outcomes to support the addition of a boxed warning to the labeling, including the Medication Guides, of all FDA* approved testosterone-containing drugs and to support your request that manufacturers send Dear Doctor letters regarding these risks.
The Agency determined that each study had significant limitations. In this section, we will address each study.
Basaria et al.
The Petition first discusses the findings of the July 2010 study by Basaria eta!., which, you contend, showed a higher rate (described in the Petition as a "significant five-fold increase") of adverse cardiovascular events in the testosterone group.19
The Basaria study was a randomized, placebo-controlled trial that evaluated the efficacy of testosterone gel in approximately 200 elderly men at high risk for cardiovascular disease.20 The Data and Safety Monitoring Board for the study recommended study discontinuation due to an overall imbalance of various cardiovascular-related adverse events (e.g., peripheral edema, arrhythmias, chest pain, elevated blood pressure, MI, and stroke) between the testosterone and placebo groups.
FDA has been aware of the Basaria study since its initial publication in 2010.21 After learning of the premature discontinuation of the Basaria study, FDA evaluated the study under a Tracked Safety Issue (TSI) application, an FDA-generated application created for the purpose of tracking and archiving regulatory activities associated with a significant safety issue related to a marketed prescription or over-the-counter drug.22
We reviewed the Basaria study and concluded that it had several significant limitations that precluded a definitive assessment of the role of testosterone therapy in the cardiovascular events noted in the study. The majority of the cardiovascular events reported were not major adverse cardiac events (MACE), MI, stroke, and deaths due to stroke or MI, and represented diverse pathophysiology. When we evaluated only the MACE that occurred in the study population, we found only a very small numerical imbalance between the testosterone and placebo groups. There were four occurrences of MACE in the testosterone group and none in the placebo group. In addition, the testosterone and placebo groups were not balanced for cardiovascular risk factors, which could explain the imbalance in MACE between the two groups. Regardless, the imbalance between the groups prevented a meaningful interpretation of drug causality.
It is also questionable whether the study results are applicable to the population for whom testosterone therapy is indicated. The study enrolled only elderly men with a high risk of cardiovascular disease and low-normal testosterone levels. However, the indicated population for testosterone therapy is men of all ages with confirmed hypogonadism. Patients with hypogonadism are administered testosterone as replacement therapy with the intention of restoring serum testosterone to normal levels. Generally, it is unclear if testosterone therapy in elderly men with low-normal testosterone levels is replacement or supplementation therapy.
In addition, in 2010 we performed a literature search to identify other articles relevant to the cardiovascular risks of testosterone. We identified two meta-analyses of randomized, placebo* controlled clinical trials and one systematic qualitative review 3 and the Division of Epidemiology (now known as the Division of Epidemiology II (DEPI II)) in FDA's Center for Drug Evaluation and Research reviewed the studies. DEPI II also performed a qualitative review of the constituent studies of the meta-analyses. Upon completing both its evaluation of the original studies and their constituent studies, DEPI II concluded that the studies did not supportan association between testosterone therapy and an increased risk of adverse cardiovascular outcomes.
In response to your Petition, we reviewed the Basaria study again, along with the other studies submitted with the Petition. The Basaria study does appear to show an empirical dose-dependent association between testosterone and cardiovascular risk, but it was non-conclusive because of the small sample size and small number of events reported in the study, as well as the limitations with respect to confirming the events. The authors of this study have explicitly indicated that the differences between the groups in cardiovascular adverse events might have been due to chance alone.24
Xu et al.
The Petition then discusses a meta-analysis by Xu eta!. of 27 randomized, placebo-controlled trials. The Petition notes that the "13 drug industry-funded trials collectively failed to show any increase in cardiovascular events in the testosterone subjects, but the 14 non-industry-funded trials collectively showed a significant 2.06-fold increased risk with testosterone. There was a significant difference between the cardiovascular risk results from the industry-funded studies and the clearly positive results
from those studies not industry-funded."25 The authors ofthe Xu study conclude that testosterone increased the risk of cardiovascular-related events.
The meta-analysis by Xu et al. assessed the risks of cardiovascular events in 2,994 men who received testosterone therapy or placebo for at least 12 weeks during 1986-2012. The authors used fixed effect models to compare the risks between testosterone and placebo based on trial* level data from peer-reviewed published papers. The authors conducted two post-hoc sensitivity analyses, including a subgroup analysis that defined subgroups by funding sources. This subgroup analysis used meta-analysis regression models.
The analysis included 1,733 testosterone therapy patients and 1,261 placebo patients. A total of 180 cardiovascular-related events (CREs) were identified among these patients. The risk of CRE was marginally higher among testosterone patients compared with placebo patients (Odds Ratio (OR), 1.54; 95% confidence interval (CI), 1.1-2.2). However, for trials not funded by the pharmaceutical industry, the risk of CRE was more than double among testosterone patients compared with placebo patients (OR, 2.1; CI, 1.3-3.2), while a non-significant protective effect of testosterone for CRE was observed among industry-funded trials (OR, 0.9; CI, 0.5-1.6).
We evaluated the Xu study as evidence for increased cardiovascular risk associated with the use of testosterone therapy. We identified a number of limitations of the study that call into question its utility as evidence to establish a causal relationship between testosterone therapy and increased cardiovascular risk. One major concern is the heterogeneity of the trials and their suitability for integration. The component trials included in this meta-analysis were heterogeneous in almost all aspects of study design-age of participants, inclusion and exclusion criteria, study duration, drug formulation, and dose. The trials included in the analysis differed
24 See Basaria, p. 118. "The cardiovascular adverse events reported in the TOM trial were diverse and may have variable clinical importance. The lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance
alone."
25 Petition at 3.
in terms of duration of exposure (13 weeks-3 years), year of study (1986-2012), location (10 countries), route of administration of testosterone therapy, formulation of testosterone therapy, and dose of testosterone therapy. The trials also varied widely with regard to their inclusion criteria for hypogonadism, baseline testosterone levels, and the baseline health status of participants, with some trials specifically including certain comorbidities (e.g. rheumatoid arthritis, end-stage renal disease, metabolic syndrome) and some including only healthy individuals. Moreover, the trials differed markedly in the baseline cardiovascular risk of participants.
Another concern was the broad outcome definition used in the Xu meta-analysis. Xu et a!. defined the primary safety outcome as "composite cardiovascular-related events" because they anticipated too few events for a robust assessment by cardiovascular event type. Just as in clinical trials, however, a composite outcome in a meta-analysis must be interpretable and appropriate. The composite outcome measure used here included more than 20 categories of cardiac and vascular events, ranging from bleeding esophageal varices, pericarditis, peripheral edema, aortic aneurysm, hypotension, and syncope to events such as death from MI, giving each equal weight. While combining these clinically heterogeneous events with widely varying severity and biological mechanisms may provide the necessary power to detect a difference between treatment arms, the aggregated outcome is difficult to interpret and may mask or distort the signal for the most clinically important cardiovascular outcomes. The authors did perform a
secondary analysis that was restricted to serious events and found similar results. However, even this subset was clinically heterogeneous, including such events as "death from bleeding esophageal varices," "constrictive pericarditis," and "early elective coronary angioplasty," while excluding "cardiac disorders not involving death." The limited interpretability of such broad composite outcomes is one reason that FDA typically uses MACE to assess cardiovascular risks.
Safety outcome ascertainment and incomplete reporting is another major concern with the Xu meta-analysis. Reporting of adverse events in published trials has been shown to vary widely, and a substantial proportion of published trials exclude adverse event information entirely.Z6 The reported incidence of CREs in the Xu meta-analysis component studies ranged from <1% to 45%, likely reflecting both heterogeneity in study design factors and variable adverse event ascertainment and reporting. Although Xu et a!. do not specify the exact number of trials excluded for incomplete adverse event reporting, they note that 138 out of 169 potentially relevant studies (82%) were excluded for "no cardiovascular-related events reported by study arm." Seven additional studies were either excluded altogether or only a subset of the study's
cardiovascular outcomes were included because of incomplete or conflicting information, despite attempts to contact the study authors. For example, Kaufman eta!., one of the larger studies included in the meta-analysis, reported in the text a total of 19 CREs, 17 in the treatment arm, and two in the placebo arm. 27 However, Xu eta!. included only 11 "vascular disorders" reported in the paper's adverse event table. Inclusion of CREs in the seven excluded (or partially excluded) studies could potentially add almost 40 additional CREs to the analysis, which could substantially affect the summary estimate.
Almost none of the component articles pre-specified cardiovascular safety outcomes, and only two of the included trials attempted to verify events via hospital records. Among the included studies, a substantial portion reported only study withdrawals and it is unclear whether other cardiovascular events-including the types of events reported in other studies and the meta* analysis-may have occurred in these studies. There were additional inconsistencies in component article authors' approaches to recording the number of CREs. For some trials, they reported the number of CREs that occurred and for other trials they reported the number of patients who experienced a CRE. Fifteen of the included trials reported the number of patients who experienced aCRE; seven trials reported the total number of CREs experienced; and five trials reported both the number of CREs and the number of patients who experienced a CRE. In trials that reported the number of CREs, they were not tied to individual patients, so it is possible that one patient experienced multiple CREs. And, even though some of the reported CREs were not tied to an individual patient, the authors used the total number of patients as the denominator in their analysis. Combined with the overly broad definition of CRE and concerns regarding incomplete ascertainment and reporting of safety events, this lack of precision in counting CREs further calls the results into question.
Xu eta!. excluded trials under 12 weeks' duration "to assess long-term rather than acute effects of testosterone therapy," but the authors do not specify how many trials were excluded for this reason or how many CREs occurred in these trials.28 It is questionable whether excluding trials of shorter duration was appropriate in this meta-analysis, where excluding a subset of adverse events occurring early in treatment could affect results in an unpredictable manner. Cardiovascular effects of testosterone may vary across treatment time. Shorter trials may be less vulnerable to certain biases, such as discontinuation and loss to follow up, that could arise in longer studies. It is possible that systematically excluding adverse events that occur early in treatment could create bias.
There were also a number of methodological issues pertaining to the design and conduct of the individual component studies:
• While all included studies were randomized, placebo-controlled trials, a substantial portion were pilot studies or trials with very small sample sizes, and a number of trials had study arm imbalances in baseline cardiovascular risk factors and pre-existing cardiovascular disease. Because many of the studies provided minimal information on baseline cardiovascular risk factors, particularly tobacco use, it was impossible to determine whether there was an imbalance in these risk factors, particularly in the smaller trials.
• The majority of the studies did not specify whether the assessor of cardiovascular* related events was blinded to study drug. Moreover, testosterone therapy can produce noticeable changes in appearance, potentially unmasking both
participants and clinicians to study drug and creating bias with respect to patient reporting or clinician assessment of adverse events. The lack of pre-specified, blinded, and systematic collection of CREs may have increased the risk of ascertainment bias.
• Studies varied widely in their discontinuation rates. Many discontinuations were, because of elevated prostate specific antigens and hematocrits, events more likely to occur in the treatment arm. Such a differential study discontinuation rate would be expected to bias the results toward the authors' conclusions, although it is difficult to predict with certainty the overall effect of study dropouts.
Regarding the discrepancy in testosterone-associated risk found between industry-funded and non-industry-funded trials, this was not a pre-specified analysis and may have been the result of chance. 29 This finding could also result from a combination of factors, including differences in adverse event reporting, trial duration, baseline cardiac risk of study participants, discontinuation rates, and drug formulation and dose. A number of differences are apparent between industry* funded and non-industry-funded studies, as grouped by Xu et
al; however, how the authors defined the funding source was not clear. Five of the fourteen trials not funded by industry reported using medication given by pharmaceutical companies and eight of the non-industry funded trials either did not provide clear information on funding source or described industry consultancies or other industry ties.
Mean study duration was longer for non-industry funded studies (as defined by Xu eta!.). Non* industry funded studies also included participants who were, on average, older and appeared to have a higher prevalence of pre-existing cardiovascular disease and baseline cardiovascular risk factors (based on information provided in the published component studies, which was often incomplete). While these differences should affect the incidence of CREs in both the treatment and placebo arms, it is
also possible that they may be due to the differences in age or baseline cardiovascular risk. There was, however,
also some suggestion of differential reporting of adverse events. Of the 13 industry-funded studies, five appeared to report only events that resulted in study withdrawal, while only one of the non-industry funded studies reported only those events that resulted in study withdrawal.
Vigen et at.
The Petition then cites a November 2013 study by Vigen et al. discussing the authors' conclusion that '"among a cohort of men in the VA [Veterans Affairs] health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes."'30 Of note, after the original publication of the study, the investigators received a number of critical comments, which resulted in the issuance of corrections to the initial study. In our evaluation, we reviewed the original paper, the subsequent comments from several research groups, the authors' response, and the authors' correction. The results presented here are obtained from the corrected study
report.31
Part 2 in the following post.
References
3 The first testosterone product, Oreton Methyl (methyltestosterone), was approved as safe by the Agency on
January 6, 1940. The effectiveness of Oreton Methyl for the treatment of eunuchism,
eunuchoidism, and male climacteric was confirmed in the
Federal Register on August I, 1970 (35 FR 12356).
4 Bhasin S, Cunningham GR, Hayes FJ eta!. Testosterone therapy in men with androgen deficiency syndromes: an
Endocrine Society clinical practice guideline.
J C/in Endocrino/ Metab 20 I 0;95:2536-2559; Dandona P, Rosenberg
MT. A practical guide to male hypogonadism in the primary care setting.
!nt J C/in Pract 2010;64:682-696.
5 Hak AE, Witteman JC, de Jong FH, Geerlings Ml, Hofman A, PolsHA. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study.
J Clin Endocrinol Metab 2002;87:3632-
3639; Marin P, Holmang S, Gustafsson C eta!. Androgen treatment of abdominally obese men.
Obes Res
1993; I :245-251; Kalinchenko SY, Tishova YA, Mskbalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Clin Endocrino/ (Oxf} 2010;73:602-
612.
6 Jones TH, Arver S, Behre HM eta!. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study).
Diabetes Care 2011;34:828-837; Haring R, Baumeister SE, Volzke H et al. Prospective inverse associations of sex hormone concentrations in men with biomarkers of inflammation and oxidative stress.
J Andro/20!2;33:944-950.
7 Cauley JA, Gutai JP, Kuller LH, Dai WS. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men.
Am J Cardio/!987;60:77!-777; Basaria S, Coviello AD, Travison TG eta!. Adverse events
associated with testosterone administration.
N Eng/ J Med2010;363:!09-i22; Ho CC, Tong SF, Low WY eta!. A randomized, double-blind, placebo-controlled trial on the effect oflong-acting testosterone treatment as assessed by the Aging Male Symptoms scale.
BJU Int 2012;110:260-265.
8 Khaw KT, Dowsett M, Folkerd E eta!. Endogenous testosterone and mortality due to all causes, cardiovascular
disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) ProspectivePopulation Study.
Circulation 2007;116:2694-2701; Menke A, Guallar E, Rohrmann Set a!. Sex steroid hormone concentrations and risk of death in US men.
Am J Epidemiol2010;17l :583-592.
9 Merza Z, Blumsohn A, Mah PM eta!. Double-blind placebo-controlled study of testosterone patch therapy on bone
turnover in men with borderline hypogonadism.
Int J Androl2006;29:38l-39l; Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.
Int J lmpot Res 2008;20:378-387; Aversa A, Bruzziches R, Francomano D eta!. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
J Sex Med2010;7:3495-3503; Marin P, Hohnang S, Gustafsson C eta!. Androgen treatment of abdominally obese men.
Obes Res 1993;1:245-251; Svartberg J, Aasebo U, Hjahnarsen A, Sundsfjord J, Jorde R. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial.
Respir Med2004;98:906-913; Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY. Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Eur J Endocrinol2012;167:531-541; Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonada1 men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Clin Endocrinol (Oxf) 2010;73:602-612.
10 See
Guidance for Industry on Warnings and Precautions, Contraindications, and Boxed Warnings Sections of
Labeling for Human Prescription Drug and Biological Products- Content and Format (October 2011), at 3, available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances!UCM075096.pdf.14 Basaria S, Coviello A, Travison T, Storer T, Farwell W, et al. Adverse events associated with testosterone administration.
The New England Journal of Medicine 2010; 363; 109-122.
15 Xu L, Freeman G, Cowling B, and Schooling CM. Testosterone therapy and cardiovascular events among men: a ststematic review and meta-analysis of placebo-controlled trials.
BMC Medicine 2013; II: 108.
1 Vigen R, O'Donnell 0, Baron A, Grunwald G, Maddox T, et al. Association of testosterone therapy with
mortality, myocardial infarction, and stroke in men with low testosterone levels.
Journal of American Medical
Association 2013; 310:1829-1836.
17 Finkle WD, Greenland S, llidgeway GK, et al. Increased risks of non-fatal myocardial infarction following testosterone therapy prescription in men.
PLoS ONE 2014; 9(1); e85805. Doi:IO.l37lljournal.pone.0085805.
18 Petition at 2. .
19 Petition at 3.20 S Basaria, et al., Adverse events associated with testosterone administration. N Eng!J Med 2010; 363:109.
21 On p. 2 of the Petition you question why FDA had not reassessed the cardiovascular safety of testosterone in light of several studies published in advance of FDA's January 2014 drug safety communication. To be clear, in response to the Basaria study, FDA undertook a clinical and statistical assessment of the cardiovascular risks of testosterone therapy in 20 l 0. The 2014 Drug Safety Communication announced a continuation of that assessment.
22 See FDA Manual of Policies and Procedures 4121.2,
"Tracking of Significant Safety issues in Marketed Drugs-- Use of the DARRTS Tracked Safety Issues."
23 CalofOM, Singh AB, Lee ML, Kenny AM, Urban RJ, et al. Adverse Events Associated With Testosterone
Replacement in Middle-Aged and Older Men: A Meta-Analysis of Randomized, Placebo-Controlled Trials. J Gerontal A
Bioi Med Sci 2005;60(11):1451-1457; Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, Sideras K, et al. Testosterone and Cardiovascular Risk in Men: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials.
Mayo Clin Proc 2007;82(1):29-39; and Gruenewald DA, Matsumoto AM. Testosterone Supplementation Therapy for Older Men: Potential Benefits and Risks.
JAm Geriatr Soc
2003;51(1):101-115.26 Ioarmidis JP. Adverse events in randomized trials: neglected, restricted, distorted, and silenced.
Arch Intern Med 2009;169(19):1737-1739.
27 Kaufman J. M. Miller M.G. Garwin J. L. Fitzpatrick S. McWhirter C. Brennan J. J. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men.
J Sex Med 2011, 8:2079-208928 See Xu, p. 2.
