madman
Super Moderator
Abstract
Objectives: To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria.
Design: Analysis of testosterone prescribing data from PBS and private (non-PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria.
Main outcome measures: New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age-group, indication, and prescriber type. Total national testosterone prescriptions (private plus PBS) were verified from an independent data supplier (IQVIA).
Results: PBS usage peaked in 2014 declining by 30% in 2017-8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017-18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle-aged men without pathological hypogonadism whereas specialist initiations and a prescription for adult hypogonadism or pediatric/ prepubertal indications were largely unaffected.
Conclusions: The tightening of PBS criteria from 1 April 2015 to curb off-label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions. The continuation of off-label testosterone prescribing for unproven indications suggests that long-term androgen dependence is created in men without pathological hypogonadism who commence testosterone. This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long-term androgen dependency when trying to quit.
1 | INTRODUCTION
The remarkable worldwide increase in testosterone prescribing over recent decades despite no new approved indications is well known.1,2 Testosterone product sales increased 100-fold over three decades to reach $US2 billion annually in the early 2010s.3 Globally, a progressive increase in testosterone usage per capita was evident over the first decade of the 21st century in 37 of 41 countries and all regions investigated. This included a 40-fold increase in Canada and 10-fold increases in USA of national testosterone usage per capita.3 After a peak in 2013-14, there is evidence that testosterone prescribing has started to fall in Australia1 and in the USA4 following concerns about cardiovascular safety and lack of efficacy data. These concerns led to regulatory curbs including FDA safety warnings and mandated label changes in 2014-5 5 and tightening of Australian Pharmaceutical Benefits Scheme (PBS) criteria for subsidized testosterone prescribing in 2015.1 As virtually all testosterone prescribing in Australia occurs via the PBS scheme that provides taxpayer subsidy of the drug cost, changes to PBS reimbursement rules have the impact of regulatory changes. While the immediate impact of the changes in PBS rules from 1 April 2015 was reported,1,6 the present study aimed to investigate the longer-term impact of the change over 3 years of the tighter 2015 PBS regulations.
4 | DISCUSSION
The present analysis shows that over the following 3 years, the 2015 tightening of PBS prescribing criteria to valid medical indications, subsidized testosterone prescribing fell from a peak in 2014 to stable lower levels while total national testosterone prescribing was largely unchanged. This demonstrates that effective and selective targeting of PBS prescribing criteria to facilitate valid medical indications while curbing unjustified off-label testosterone prescriptions can be sustained without adversely affecting valid medical applications of testosterone.
A striking finding is that total testosterone prescribing remains largely unchanged at a national level despite restriction of PBS prescribing to valid medical indications. This ongoing testosterone usage involves men whose initiation onto testosterone treatment was not for valid medical indications but who switch to private non-PBS prescriptions after 2015 when subsidized prescriptions were no longer available. The financial burden of this switch is low for this old, long off-patent drug with the daily cost of testosterone products ($1-3/ day) comparable with a cup of coffee, a cigarette, or 1 day's charge for a mobile phone or internet connection. This continued use of testosterone most likely indicates androgen dependence in men who did not have pathological hypogonadism. Rather, they had an intact hypothalamic-pituitary-testicular axis that was suppressed by exogenous testosterone treatment through androgenic negative hypothalamic feedback effects. Hence, when exogenous testosterone intake stops, a transient state of androgen deficiency is created, with withdrawal symptoms lasting months10 until normal reproductive axis function resumes. If men were not androgen deficient before starting off-label testosterone treatment (as usual), they will be androgen deficient when they stop. Such iatrogenic androgen dependence encourages the continuation of testosterone treatment after the man chooses to quit treatment but is then driven to alleviate symptoms of androgen withdrawal. This is despite the fact that testosterone treatment further prolongs suppression of endogenous testosterone thereby delaying ultimate recovery and cessation of pointless testosterone treatment. This cycle of dependency makes it difficult to stop exogenous testosterone in men whose reproductive system was functionally normal when they start unjustified testosterone treatment (ie, without pathological hypogonadism). Such under-recognized iatrogenic androgen dependence may explain the analogous overcoming of previous regulatory curbs such as two episodes in Australia between 1994-6 and 2002-6 7 and in Canada.11
The present analysis by age group and indications confirm the previous profile of patients prescribed testosterone prior to 20151,8 represent predominantly middle-aged men with low circulating testosterone without disorders of the hypothalamus, pituitary or testes (“Low T," also known as “andropause” and late-onset hypogonadism”). These functional states differ from the adult hypogonadism or pediatric/pre-pubertal indications which represent pathological disorders of the male reproductive system (hypothalamus, pituitary, testis), the sole unequivocal and approved indication for testosterone treatment. By contrast, “Low T" represents an ad hoc aggregate of functional states with an adaptive down-turning of male reproductive activity by a healthy hypothalamic-pituitary-testicular axis in response to various systemic illnesses. Whether such adaptive reactions represent a beneficial, neutral, or detrimental response requires rigorous evaluation by well-designed, placebo-controlled clinical trials evaluating efficacy and safety, which are almost entirely lacking.12 The recent NIH-funded Testosterone Trials, a set of seven integrated studies prompted by a 2004 Institute of Medicine (IOM) report,13 showed that for men over 65 years of age with LowT (but no reproductive disorders), daily treatment with testosterone gel compared with placebo produced a modest, transient increase in sexual function but no improvement in physical or cognitive function or vitality14,15; however, it also produced an increase in non-calcified coronary plaque, an unprecedented adverse surrogate marker of coronary disease.16 These efficacy data did not warrant initiating testosterone treatment in older men without pathological hypogonadism17,18 nor did they meet the mandate of the IOM report for sufficient short-term efficacy to warrant public funding for a large-scale clinical efficacy trial compared to the Women's Health Initiative.19 Overall “LowT” remains an invalid indication for testosterone prescription with the present highlighting the under-appreciated possible adverse effect of androgen dependence arising from such unjustified testosterone treatment.
The driving influences on testosterone prescribing for “LowT” include aggressive direct-to-consumer-advertising,20 permitted in North America but not elsewhere, and disease-mongering clinical guidelines which elastically stretched the boundaries of disease to expand sales of treatments.12 For testosterone, the latter redefined the term “hypogonadism,” defined as pathological disorders of the reproductive system, to encompass any conjunction of ubiquitous, non-specific symptoms with low blood testosterone,21 regardless of the underlying disease causing both and whether there was any causal link between symptoms and blood testosterone levels. In concert, these factors led to phenomenal growth in global testosterone sales and usage.3 This involves large numbers of men without reproductive disorders treated for low serum testosterone (or sexual dysfunction) where efficacy remains unproven and possibly unsafe.16,22,23 Conversely, the more recent abatement of excessive testosterone prescribing has been prompted by reports of possible adverse cardiovascular effects leading to regulatory curbs by the FDA and the PBS.4
It is concluded that the 2015 tightening of the PBS criteria for testosterone prescribing has had sustained, effective, and suitably selective impact to curb unjustified off-label testosterone prescribing while not hindering testosterone prescribing for valid medical indications. The finding that total national testosterone prescribing continued largely unchanged after 2015 for men whose commencement of testosterone treatment was not medically justified is likely a manifestation of iatrogenic androgen dependence ultimately the result of having undertaken unjustified testosterone treatment. This highlights the need to restrict initiation of testosterone prescription to men with reproductive pathology and to exert caution and provide warnings to those with a functionally normal reproductive system which will become subject to iatrogenic, sustained suppression of endogenous testosterone with treatment by exogenous testosterone.
Objectives: To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria.
Design: Analysis of testosterone prescribing data from PBS and private (non-PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria.
Main outcome measures: New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age-group, indication, and prescriber type. Total national testosterone prescriptions (private plus PBS) were verified from an independent data supplier (IQVIA).
Results: PBS usage peaked in 2014 declining by 30% in 2017-8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017-18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle-aged men without pathological hypogonadism whereas specialist initiations and a prescription for adult hypogonadism or pediatric/ prepubertal indications were largely unaffected.
Conclusions: The tightening of PBS criteria from 1 April 2015 to curb off-label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions. The continuation of off-label testosterone prescribing for unproven indications suggests that long-term androgen dependence is created in men without pathological hypogonadism who commence testosterone. This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long-term androgen dependency when trying to quit.
1 | INTRODUCTION
The remarkable worldwide increase in testosterone prescribing over recent decades despite no new approved indications is well known.1,2 Testosterone product sales increased 100-fold over three decades to reach $US2 billion annually in the early 2010s.3 Globally, a progressive increase in testosterone usage per capita was evident over the first decade of the 21st century in 37 of 41 countries and all regions investigated. This included a 40-fold increase in Canada and 10-fold increases in USA of national testosterone usage per capita.3 After a peak in 2013-14, there is evidence that testosterone prescribing has started to fall in Australia1 and in the USA4 following concerns about cardiovascular safety and lack of efficacy data. These concerns led to regulatory curbs including FDA safety warnings and mandated label changes in 2014-5 5 and tightening of Australian Pharmaceutical Benefits Scheme (PBS) criteria for subsidized testosterone prescribing in 2015.1 As virtually all testosterone prescribing in Australia occurs via the PBS scheme that provides taxpayer subsidy of the drug cost, changes to PBS reimbursement rules have the impact of regulatory changes. While the immediate impact of the changes in PBS rules from 1 April 2015 was reported,1,6 the present study aimed to investigate the longer-term impact of the change over 3 years of the tighter 2015 PBS regulations.
4 | DISCUSSION
The present analysis shows that over the following 3 years, the 2015 tightening of PBS prescribing criteria to valid medical indications, subsidized testosterone prescribing fell from a peak in 2014 to stable lower levels while total national testosterone prescribing was largely unchanged. This demonstrates that effective and selective targeting of PBS prescribing criteria to facilitate valid medical indications while curbing unjustified off-label testosterone prescriptions can be sustained without adversely affecting valid medical applications of testosterone.
A striking finding is that total testosterone prescribing remains largely unchanged at a national level despite restriction of PBS prescribing to valid medical indications. This ongoing testosterone usage involves men whose initiation onto testosterone treatment was not for valid medical indications but who switch to private non-PBS prescriptions after 2015 when subsidized prescriptions were no longer available. The financial burden of this switch is low for this old, long off-patent drug with the daily cost of testosterone products ($1-3/ day) comparable with a cup of coffee, a cigarette, or 1 day's charge for a mobile phone or internet connection. This continued use of testosterone most likely indicates androgen dependence in men who did not have pathological hypogonadism. Rather, they had an intact hypothalamic-pituitary-testicular axis that was suppressed by exogenous testosterone treatment through androgenic negative hypothalamic feedback effects. Hence, when exogenous testosterone intake stops, a transient state of androgen deficiency is created, with withdrawal symptoms lasting months10 until normal reproductive axis function resumes. If men were not androgen deficient before starting off-label testosterone treatment (as usual), they will be androgen deficient when they stop. Such iatrogenic androgen dependence encourages the continuation of testosterone treatment after the man chooses to quit treatment but is then driven to alleviate symptoms of androgen withdrawal. This is despite the fact that testosterone treatment further prolongs suppression of endogenous testosterone thereby delaying ultimate recovery and cessation of pointless testosterone treatment. This cycle of dependency makes it difficult to stop exogenous testosterone in men whose reproductive system was functionally normal when they start unjustified testosterone treatment (ie, without pathological hypogonadism). Such under-recognized iatrogenic androgen dependence may explain the analogous overcoming of previous regulatory curbs such as two episodes in Australia between 1994-6 and 2002-6 7 and in Canada.11
The present analysis by age group and indications confirm the previous profile of patients prescribed testosterone prior to 20151,8 represent predominantly middle-aged men with low circulating testosterone without disorders of the hypothalamus, pituitary or testes (“Low T," also known as “andropause” and late-onset hypogonadism”). These functional states differ from the adult hypogonadism or pediatric/pre-pubertal indications which represent pathological disorders of the male reproductive system (hypothalamus, pituitary, testis), the sole unequivocal and approved indication for testosterone treatment. By contrast, “Low T" represents an ad hoc aggregate of functional states with an adaptive down-turning of male reproductive activity by a healthy hypothalamic-pituitary-testicular axis in response to various systemic illnesses. Whether such adaptive reactions represent a beneficial, neutral, or detrimental response requires rigorous evaluation by well-designed, placebo-controlled clinical trials evaluating efficacy and safety, which are almost entirely lacking.12 The recent NIH-funded Testosterone Trials, a set of seven integrated studies prompted by a 2004 Institute of Medicine (IOM) report,13 showed that for men over 65 years of age with LowT (but no reproductive disorders), daily treatment with testosterone gel compared with placebo produced a modest, transient increase in sexual function but no improvement in physical or cognitive function or vitality14,15; however, it also produced an increase in non-calcified coronary plaque, an unprecedented adverse surrogate marker of coronary disease.16 These efficacy data did not warrant initiating testosterone treatment in older men without pathological hypogonadism17,18 nor did they meet the mandate of the IOM report for sufficient short-term efficacy to warrant public funding for a large-scale clinical efficacy trial compared to the Women's Health Initiative.19 Overall “LowT” remains an invalid indication for testosterone prescription with the present highlighting the under-appreciated possible adverse effect of androgen dependence arising from such unjustified testosterone treatment.
The driving influences on testosterone prescribing for “LowT” include aggressive direct-to-consumer-advertising,20 permitted in North America but not elsewhere, and disease-mongering clinical guidelines which elastically stretched the boundaries of disease to expand sales of treatments.12 For testosterone, the latter redefined the term “hypogonadism,” defined as pathological disorders of the reproductive system, to encompass any conjunction of ubiquitous, non-specific symptoms with low blood testosterone,21 regardless of the underlying disease causing both and whether there was any causal link between symptoms and blood testosterone levels. In concert, these factors led to phenomenal growth in global testosterone sales and usage.3 This involves large numbers of men without reproductive disorders treated for low serum testosterone (or sexual dysfunction) where efficacy remains unproven and possibly unsafe.16,22,23 Conversely, the more recent abatement of excessive testosterone prescribing has been prompted by reports of possible adverse cardiovascular effects leading to regulatory curbs by the FDA and the PBS.4
It is concluded that the 2015 tightening of the PBS criteria for testosterone prescribing has had sustained, effective, and suitably selective impact to curb unjustified off-label testosterone prescribing while not hindering testosterone prescribing for valid medical indications. The finding that total national testosterone prescribing continued largely unchanged after 2015 for men whose commencement of testosterone treatment was not medically justified is likely a manifestation of iatrogenic androgen dependence ultimately the result of having undertaken unjustified testosterone treatment. This highlights the need to restrict initiation of testosterone prescription to men with reproductive pathology and to exert caution and provide warnings to those with a functionally normal reproductive system which will become subject to iatrogenic, sustained suppression of endogenous testosterone with treatment by exogenous testosterone.
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