Opinion
VIEWPOINT
Marc B. Garnick, MD Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Corresponding Author: Marc B. Garnick, MD, Beth Israel Deaconess Medical Center, 375 Longwood Ave, 428 MASCO Bldg, Boston, MA 02215 (mgarnick @bidmc.harvard.edu).
TestosteroneReplacementTherapyFacesFDAScrutiny The use and the potential for cardiovascular risk associated with testosterone replacement therapy (TRT) were examined in September 2014 by a joint US Food and Drug Administration (FDA) advisory committee.1 Prompted by several studies suggesting cardiovascular risk associated with TRT,2,3 the advisory committee discussed whether TRT for age-related hypogonadism (a decline in testosterone levels as a consequence of aging, and for which the majority of testosterone usage is directed to today) is supported by data, evaluated the cardiovascular risks, and determined whether additional studies were warranted to examine the appropriateness of TRT usage in light of these risks. Testosterone replacement products were initially for patients with primary and secondary hypogonadism due to primary testicular or pituitary disorders (classic hypogonadism).HowevertheuseofTRThasincreasedsubstantially,enabledinpartbymorepatient-friendlyformulations of administering testosterone products, such as topical gels. Between 2010 and 2013, the number of patients receiving TRT increased from 1 299 846 to 2 291 266 (with 60%beingprescribedbyprimarycarephysicians).4 These data include only US testosterone sales and do not include other relevant sources of testosterone sales outside the United States. In one sample of health claims data encompassing nearly 250 000 men, the greatest use of testosterone products was among those aged 40 to 64 years, with a substantial proportion of men older than 65 years also being treated. Moreover, 57% of patients taking testosterone replacement products were also taking either oneorseveralconcurrentcardiovascularmedications,such as anticoagulants, antihypertensives, antiplatelet therapies, statins, and nitrates, including men aged 40 to 64 years (60%), 65 to 74 years (71%), and older than 75 years (68%).4 Testicularhypofunction,notelsewhereclassified, led TRT diagnoses (International Classification of Diseases, Ninth Revision [ICD-9] code, 257.20).4 Among a sample of nearly 250 000 men, only 72% had a claim submitted for testosterone level testing prior to receiving a TRT prescription; 21% never had any claim; and only 6% had claims submitted after receiving their initialTRTprescription.4 (NeithertheFDAnoranotherreview of claims data could provide information on what percentage of men who had testosterone levels measured before startingTRTactuallyhadlowtestosteronelevels.4,5)These data are noteworthy, because the indicated use of TRT has generally required a total testosterone value, usually ⱕ300 ng/dL on 2 morning samples. This metric has generally been recommended as an eligibility inclusion criteria for clinical studies aimed at attaining a TRT approval from the FDA.6 Once this eligibility has been met, it is generally followed by a required dose titration phase, a stable dose phase, and a safety extension phase, with required measurements of target testosterone values throughout the study that demonstrate predefined pharmacokinetic
jama.com
parameters.Clinicalpracticeguidelinesfortestosteronereplacement,ontheotherhand(eg,theEndocrineSociety),7 donotplaceanabsolutelowervaluetoinitiateTRT,butsuggest measurement of a morning total testosterone (which should be below a defined lower limit with an accurate and reliable assay), followed by a confirmatory value with the possible addition of free or bioavailable testosterone level inwhomthetotaltestosteroneisnearthelowerlimitofnormal and in men for whom alterations of sex hormone binding globulin are possible—and only in men with consistent symptoms and signs suggestive of androgen deficiency. Historically,thepathwaytoapprovalforaTRTrequired pharmacokineticcriteria—notclinicalefficacycriteria,such as improved libido, sexual performance, bone density, and muscular performance, among others. These products were intended as replacement therapies for men who had no endogenous testosterone, due to either testicular failure or absence of testicular tissue and central dysfunction of the hypothalamic-pituitary axis. The benefits of TRT for these indications were well accepted, and no clinical benefit data were required for regulatory approval. Rather, the FDA required pharmacokinetic parameters to be demonstrated by having product administration attain certain average testosterone levels and not exceed certain levelsduringtreatment.Presetefficacyendpointsincluded a requirement that 75% or more of men achieved a level of 300 ng/dL to 1000 ng/dL after therapy started; and limitations on maximum blood testosterone values were required.Routinesafetyparameterswererequired,butclinicalefficacyendpointswereconsideredexploratoryandnot mandatedformarketingauthorization.Implicitinthisregulatoryapprovalprocesswasphysicianintentiontomeasure both basal and during-therapy testosterone values, making the lack of such measurements so concerning.4 This drug approval process was not indicated for agerelatedhypogonadism,orwhathasbecomeknownas“low T” or age-related decline of testosterone. In part, the loopholethatallowedTRTusageinagingmaleswasperhapsenabled by the inclusion in the indication of “idiopathic” hypogonadism and applying that term to age-related decline intestosterone.Thepaneldidnothearanyconvincingdata from well-controlled clinical trials that TRT provided clinical benefit and was safe to administer in the aging male population. The issue of efficacy evaluation is even more complicated,becausesymptomsoftenattributedtohypogonadism may occur with similar frequencies among men with normal testosterone levels and those with subnormal levels. In 2003, an Institute of Medicine (IOM)8 committee urged that research on TRT be conducted in symptomatic men 65 years or older with low testosterone to determine itsbenefits,ifany.AseriesofstudiesweresuggestedtodeterminetheeffectofTRTon“strength/frailty/disability,cognitivefunction,sexualfunction,orvitality/well-being/quality of life.” These ongoing studies may provide some efficacy results in the future. (Reprinted) JAMA February 10, 2015 Volume 313, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Yale University User on 05/17/2015
563
Opinion Viewpoint
For cardiovascular safety, the panel considered several extensive analyses—both observational and meta-analysis. The specific language of the panel summary stated9: . . . there was agreement amongst committee members that a weak signal of cardiovascular risk had emerged from results of recent large epidemiologic studies. Given this signal coupled with biologic plausibility for cardiovascular-related adverse events with testosterone use, committee members believed that the need for additional studies was critical and that some commented that clinical trials for safety would be necessary. . . . The committee commented, however, that safety in higher cardiovascular risk populations, such as older men, those with diabetes, and obese men, had not been adequately studied. Some committee members suggested heightened caution for patients at higher risk for cardiovascular disease. Overall the committee agreed that the potential signal for cardiovascular risk should be added to the labeling. Most committee members recommended cautionary wording that would reflect the known information regarding potential risk, while a few others suggested a boxed warning. The public commentary portion of the advisory meeting was both encouraging and concerning. Benefits to patients with testicular failure syndromes clearly articulated the quality-of-life improvements associated with TRT. On the other hand, 2 men in their 40s reported that shortly after receiving TRT for low T, one developed paralysis from a spinal vessel thrombosis and another had an unexpected myocardial infarction with the implication that exogenous testosterone had contributed in some way to these events. The creation and evolution of the low T disease state and the implication that improved energy, and even improved sexual performance resulting from TRT are instructive. Low T advertising or informational programs (that do not mention a specific product, but rather characterize the condition) that have commonly been seen on television and advertisement campaigns are considered Disease Awareness Campaigns, informational programs that are intended to discuss a particular disease or health state, and cannot mention any specific drug or any suggestion of drug benefit. These ARTICLE INFORMATION Published Online: December 11, 2014. doi:10.1001/jama.2014.17334. Conflict of Interest Disclosures: Dr Garnick has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. He reports being a member of the Joint Advisory Committee that evaluated testosterone replacement therapy. REFERENCES 1. US Food and Drug Administration. 2014 Meeting materials of the Bone, Reproductive, and Urologic Drugs Advisory Committee. http://www.fda.gov/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /ucm404895.htm. Accessed November 20, 2014. 2. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.
564
programs and advertisements are not under the jurisdiction of FDA regulations, but rather the Federal Trade Commission. In contrast, specific product claims and promotional materials are under FDA regulation. Claims of efficacy ascribed to a particular product but not supported by labeling and data are regulated under the Federal Food, Drug, and Cosmetic Act and the FDA can issue warnings to the offending manufacturer. In practice, manufacturers of TRT products may have exploited this separation of regulatory authority by introducing the low T disease concept followed by carefully scripted portrayals of actual products that address symptoms of low T. The advisory panel also deliberated on the appropriateness of the current indication and labeling of TRT products. There was overwhelming support that the use of TRT should exclude men with agerelated testosterone decline. The panel voted 20 to 1 in favor of revising the current indication by limiting TRT to those with classic hypogonadism, and including in the label the potential for cardiovascular risk, the need for testosterone monitoring, and a statement that both the safety and efficacy of TRT in age-related hypogonadism had not been established. A 20 to 1 vote in favor of the need for additional studies to assess cardiovascular risk was also recorded. Less clear was the assignment of responsibility (both operational and financial) for the conduct of such studies. Subsequent to the advisory panel, the American Urological Association published a position paper10 emphasizing support for the panel’s findings, emphasizing the cardiovascular and other safety considerations of TRT, the need for testosterone monitoring both at baseline and during therapy, and the need for additional educational awareness—for both clinicians and patients. The emergence of TRT as a multibillion-dollar industry without appropriate supporting data or oversight of its proper usage emphasizes the need for stricter controls as well as reassessment of approval pathways when the usage is not consistent with approved labeling. However, this advisory committee meeting represented a remarkable convergence of many disciplines—academics, industry, regulatory scientists,expertpanel,andthepublic—thatcollaborativelyandeffectively charted a blueprint for better controls, further study, and educational outreach to both physicians and patients for this important class of drugs. The safety of the public was well served by this process.
3. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of nonfatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1);e85805. 4. Mohamoud MA, Chai G, Staffa J. Drug use review. http://www.fda.gov /downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /UCM412536.pdf. Accessed December 8, 2014. 5. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465-1466. 6. Hirsch MS, Nguyen CP, Joffe HV. Testosterone replacement therapy. http://www.fda.gov /downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /UCM412536.pdf. Accessed December 8, 2014. 7. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen
deficiency syndromes. J Clin Endocrinol Metab. 2010;95(6):2536-2559. 8. Blazer DG, Barrett-Connor E, Brody BA, et al. Testosterone and aging:clinical research directions. http://www.iom.edu/~/media/Files/Report %20Files/2003/Testosterone-and-Aging-Clinical -Research-Directions/testosteroneonepagerFINAL .pdf. Accessed December 9, 2014. 9. Bhatt K, Johnson J. Summary minutes of the joint meeting of the Bone, Reproductive, and Urologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee. http://www.fda.gov /downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /UCM418144.pdf. Accessed December 8, 2014. 10. American Urological Association. AUA position statement on testosterone therapy. http://www .auanet.org/about/testosterone-therapy.cfm. Accessed December 2, 2014.
JAMA February 10, 2015 Volume 313, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Yale University User on 05/17/2015
jama.com
VIEWPOINT
Marc B. Garnick, MD Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Corresponding Author: Marc B. Garnick, MD, Beth Israel Deaconess Medical Center, 375 Longwood Ave, 428 MASCO Bldg, Boston, MA 02215 (mgarnick @bidmc.harvard.edu).
TestosteroneReplacementTherapyFacesFDAScrutiny The use and the potential for cardiovascular risk associated with testosterone replacement therapy (TRT) were examined in September 2014 by a joint US Food and Drug Administration (FDA) advisory committee.1 Prompted by several studies suggesting cardiovascular risk associated with TRT,2,3 the advisory committee discussed whether TRT for age-related hypogonadism (a decline in testosterone levels as a consequence of aging, and for which the majority of testosterone usage is directed to today) is supported by data, evaluated the cardiovascular risks, and determined whether additional studies were warranted to examine the appropriateness of TRT usage in light of these risks. Testosterone replacement products were initially for patients with primary and secondary hypogonadism due to primary testicular or pituitary disorders (classic hypogonadism).HowevertheuseofTRThasincreasedsubstantially,enabledinpartbymorepatient-friendlyformulations of administering testosterone products, such as topical gels. Between 2010 and 2013, the number of patients receiving TRT increased from 1 299 846 to 2 291 266 (with 60%beingprescribedbyprimarycarephysicians).4 These data include only US testosterone sales and do not include other relevant sources of testosterone sales outside the United States. In one sample of health claims data encompassing nearly 250 000 men, the greatest use of testosterone products was among those aged 40 to 64 years, with a substantial proportion of men older than 65 years also being treated. Moreover, 57% of patients taking testosterone replacement products were also taking either oneorseveralconcurrentcardiovascularmedications,such as anticoagulants, antihypertensives, antiplatelet therapies, statins, and nitrates, including men aged 40 to 64 years (60%), 65 to 74 years (71%), and older than 75 years (68%).4 Testicularhypofunction,notelsewhereclassified, led TRT diagnoses (International Classification of Diseases, Ninth Revision [ICD-9] code, 257.20).4 Among a sample of nearly 250 000 men, only 72% had a claim submitted for testosterone level testing prior to receiving a TRT prescription; 21% never had any claim; and only 6% had claims submitted after receiving their initialTRTprescription.4 (NeithertheFDAnoranotherreview of claims data could provide information on what percentage of men who had testosterone levels measured before startingTRTactuallyhadlowtestosteronelevels.4,5)These data are noteworthy, because the indicated use of TRT has generally required a total testosterone value, usually ⱕ300 ng/dL on 2 morning samples. This metric has generally been recommended as an eligibility inclusion criteria for clinical studies aimed at attaining a TRT approval from the FDA.6 Once this eligibility has been met, it is generally followed by a required dose titration phase, a stable dose phase, and a safety extension phase, with required measurements of target testosterone values throughout the study that demonstrate predefined pharmacokinetic
jama.com
parameters.Clinicalpracticeguidelinesfortestosteronereplacement,ontheotherhand(eg,theEndocrineSociety),7 donotplaceanabsolutelowervaluetoinitiateTRT,butsuggest measurement of a morning total testosterone (which should be below a defined lower limit with an accurate and reliable assay), followed by a confirmatory value with the possible addition of free or bioavailable testosterone level inwhomthetotaltestosteroneisnearthelowerlimitofnormal and in men for whom alterations of sex hormone binding globulin are possible—and only in men with consistent symptoms and signs suggestive of androgen deficiency. Historically,thepathwaytoapprovalforaTRTrequired pharmacokineticcriteria—notclinicalefficacycriteria,such as improved libido, sexual performance, bone density, and muscular performance, among others. These products were intended as replacement therapies for men who had no endogenous testosterone, due to either testicular failure or absence of testicular tissue and central dysfunction of the hypothalamic-pituitary axis. The benefits of TRT for these indications were well accepted, and no clinical benefit data were required for regulatory approval. Rather, the FDA required pharmacokinetic parameters to be demonstrated by having product administration attain certain average testosterone levels and not exceed certain levelsduringtreatment.Presetefficacyendpointsincluded a requirement that 75% or more of men achieved a level of 300 ng/dL to 1000 ng/dL after therapy started; and limitations on maximum blood testosterone values were required.Routinesafetyparameterswererequired,butclinicalefficacyendpointswereconsideredexploratoryandnot mandatedformarketingauthorization.Implicitinthisregulatoryapprovalprocesswasphysicianintentiontomeasure both basal and during-therapy testosterone values, making the lack of such measurements so concerning.4 This drug approval process was not indicated for agerelatedhypogonadism,orwhathasbecomeknownas“low T” or age-related decline of testosterone. In part, the loopholethatallowedTRTusageinagingmaleswasperhapsenabled by the inclusion in the indication of “idiopathic” hypogonadism and applying that term to age-related decline intestosterone.Thepaneldidnothearanyconvincingdata from well-controlled clinical trials that TRT provided clinical benefit and was safe to administer in the aging male population. The issue of efficacy evaluation is even more complicated,becausesymptomsoftenattributedtohypogonadism may occur with similar frequencies among men with normal testosterone levels and those with subnormal levels. In 2003, an Institute of Medicine (IOM)8 committee urged that research on TRT be conducted in symptomatic men 65 years or older with low testosterone to determine itsbenefits,ifany.AseriesofstudiesweresuggestedtodeterminetheeffectofTRTon“strength/frailty/disability,cognitivefunction,sexualfunction,orvitality/well-being/quality of life.” These ongoing studies may provide some efficacy results in the future. (Reprinted) JAMA February 10, 2015 Volume 313, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Yale University User on 05/17/2015
563
Opinion Viewpoint
For cardiovascular safety, the panel considered several extensive analyses—both observational and meta-analysis. The specific language of the panel summary stated9: . . . there was agreement amongst committee members that a weak signal of cardiovascular risk had emerged from results of recent large epidemiologic studies. Given this signal coupled with biologic plausibility for cardiovascular-related adverse events with testosterone use, committee members believed that the need for additional studies was critical and that some commented that clinical trials for safety would be necessary. . . . The committee commented, however, that safety in higher cardiovascular risk populations, such as older men, those with diabetes, and obese men, had not been adequately studied. Some committee members suggested heightened caution for patients at higher risk for cardiovascular disease. Overall the committee agreed that the potential signal for cardiovascular risk should be added to the labeling. Most committee members recommended cautionary wording that would reflect the known information regarding potential risk, while a few others suggested a boxed warning. The public commentary portion of the advisory meeting was both encouraging and concerning. Benefits to patients with testicular failure syndromes clearly articulated the quality-of-life improvements associated with TRT. On the other hand, 2 men in their 40s reported that shortly after receiving TRT for low T, one developed paralysis from a spinal vessel thrombosis and another had an unexpected myocardial infarction with the implication that exogenous testosterone had contributed in some way to these events. The creation and evolution of the low T disease state and the implication that improved energy, and even improved sexual performance resulting from TRT are instructive. Low T advertising or informational programs (that do not mention a specific product, but rather characterize the condition) that have commonly been seen on television and advertisement campaigns are considered Disease Awareness Campaigns, informational programs that are intended to discuss a particular disease or health state, and cannot mention any specific drug or any suggestion of drug benefit. These ARTICLE INFORMATION Published Online: December 11, 2014. doi:10.1001/jama.2014.17334. Conflict of Interest Disclosures: Dr Garnick has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. He reports being a member of the Joint Advisory Committee that evaluated testosterone replacement therapy. REFERENCES 1. US Food and Drug Administration. 2014 Meeting materials of the Bone, Reproductive, and Urologic Drugs Advisory Committee. http://www.fda.gov/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /ucm404895.htm. Accessed November 20, 2014. 2. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.
564
programs and advertisements are not under the jurisdiction of FDA regulations, but rather the Federal Trade Commission. In contrast, specific product claims and promotional materials are under FDA regulation. Claims of efficacy ascribed to a particular product but not supported by labeling and data are regulated under the Federal Food, Drug, and Cosmetic Act and the FDA can issue warnings to the offending manufacturer. In practice, manufacturers of TRT products may have exploited this separation of regulatory authority by introducing the low T disease concept followed by carefully scripted portrayals of actual products that address symptoms of low T. The advisory panel also deliberated on the appropriateness of the current indication and labeling of TRT products. There was overwhelming support that the use of TRT should exclude men with agerelated testosterone decline. The panel voted 20 to 1 in favor of revising the current indication by limiting TRT to those with classic hypogonadism, and including in the label the potential for cardiovascular risk, the need for testosterone monitoring, and a statement that both the safety and efficacy of TRT in age-related hypogonadism had not been established. A 20 to 1 vote in favor of the need for additional studies to assess cardiovascular risk was also recorded. Less clear was the assignment of responsibility (both operational and financial) for the conduct of such studies. Subsequent to the advisory panel, the American Urological Association published a position paper10 emphasizing support for the panel’s findings, emphasizing the cardiovascular and other safety considerations of TRT, the need for testosterone monitoring both at baseline and during therapy, and the need for additional educational awareness—for both clinicians and patients. The emergence of TRT as a multibillion-dollar industry without appropriate supporting data or oversight of its proper usage emphasizes the need for stricter controls as well as reassessment of approval pathways when the usage is not consistent with approved labeling. However, this advisory committee meeting represented a remarkable convergence of many disciplines—academics, industry, regulatory scientists,expertpanel,andthepublic—thatcollaborativelyandeffectively charted a blueprint for better controls, further study, and educational outreach to both physicians and patients for this important class of drugs. The safety of the public was well served by this process.
3. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of nonfatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1);e85805. 4. Mohamoud MA, Chai G, Staffa J. Drug use review. http://www.fda.gov /downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /UCM412536.pdf. Accessed December 8, 2014. 5. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465-1466. 6. Hirsch MS, Nguyen CP, Joffe HV. Testosterone replacement therapy. http://www.fda.gov /downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /UCM412536.pdf. Accessed December 8, 2014. 7. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen
deficiency syndromes. J Clin Endocrinol Metab. 2010;95(6):2536-2559. 8. Blazer DG, Barrett-Connor E, Brody BA, et al. Testosterone and aging:clinical research directions. http://www.iom.edu/~/media/Files/Report %20Files/2003/Testosterone-and-Aging-Clinical -Research-Directions/testosteroneonepagerFINAL .pdf. Accessed December 9, 2014. 9. Bhatt K, Johnson J. Summary minutes of the joint meeting of the Bone, Reproductive, and Urologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee. http://www.fda.gov /downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /ReproductiveHealthDrugsAdvisoryCommittee /UCM418144.pdf. Accessed December 8, 2014. 10. American Urological Association. AUA position statement on testosterone therapy. http://www .auanet.org/about/testosterone-therapy.cfm. Accessed December 2, 2014.
JAMA February 10, 2015 Volume 313, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Yale University User on 05/17/2015
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