Original article
Implications of off-label use: An example from the final results of an observational cohort study on IntrinsaÕ (testosterone patch)
Post Reproductive Health 2014, Vol. 20(2) 48–54 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2053369114535762 prh.sagepub.com
Vicki Osborne1,2, Deborah Layton1,2 and Saad AW Shakir1,2
Abstract Introduction: Off-label use is where a medicinal product is used for a medical purpose not in accordance with the authorised product information. IntrinsaÕ is a transdermal testosterone patch, which is indicated for use in hypoactive sexual desire disorder in bilaterally oophorectomised and hysterectomised women receiving concomitant estrogen therapy. Objectives: To describe the utilization characteristics of patients prescribed testosterone patch (IntrinsaÕ ) and to assess, where possible, if the product is being used according to the authorised product information. Study design: Patients identified from dispensed prescriptions issued by general practitioners for IntrinsaÕ between March 2007 and August 2010. Postal questionnaires were sent to general practitioners six months following the date of the first prescription for IntrinsaÕ for each patient, requesting information including patient demographics and drug utilization. Main outcome measures: Menopausal status and use of concomitant estrogen therapy. Results: The final cohort consisted of 3073 patients; the majority were females (3017, 98.2%). The most commonly reported indication was hypoactive sexual desire disorder in 2324 female patients (77.0%). Only 43.5% female patients (n ¼ 1313) were reported to have been hysterectomised and bilaterally oophorectomised. For 1029 (34.1%) female patients there was no evidence that the patient was using concomitant estrogen therapy. Overall, only 643 patients (20.9%) in the cohort were being prescribed IntrinsaÕ according to the manufacturer’s recommendations. Conclusions: Evidence obtained solely from clinical trials might not be generalisable where off-label prescribing occurs in real-life, so evidence from post-marketing observational studies is important to provide complimentary data on a product’s safety and effectiveness.
Keywords Cohort study, drug utilization, off-label use, testosterone patch
Background According to the European Medicines Agency (EMA) guidelines on good pharmacovigilance practices (GVP), off-label use is where a medicinal product is used for a medical purpose not in accordance with the authorised product information.1 After launch of a medicinal product, it may be used in populations that differ from those examined in clinical trials, including the potential for off-label use.2 Off-label use of testosterone products has been seen previously in the US.3 Where off-label use occurs, it is possible that the population using it has very different characteristics from the clinical trial populations. An example is where products are not licensed for use in children, but children are also
susceptible to the diseases that are the indication for prescribing. As such, children may be prescribed these products off-label, although there are no data on use in children from clinical trials.4–6 Another example is where a drug has a specific indication, but is prescribed for other indications based on clinician experience and 1
Drug Safety Research Unit, Bursledon Hall, Southampton, UK School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK 2
Corresponding author: Vicki Osborne, Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton SO31 1AA, UK. Email: [email protected]
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
Osborne et al.
49
judgement such as prescribing antipsychotics for treatment of neuropsychiatric symptoms in dementia.7,8 Since clinical trials provide the main source of data on safety and efficacy of a medicinal product at the time marketing authorisation is approved, it is important to examine whether these data are generalisable to real-life use. Observational post-marketing studies can be a useful tool for examining real-life use of a medicinal product and whether the populations using it are similar or different to clinical trial populations. IntrinsaÕ (The trade name IntrinsaÕ is used for product identification purposes to distinguish it from other testosterone patch products.) is a transdermal testosterone patch, which is indicated for use in hypoactive sexual desire disorder (HSDD) in bilaterally oophorectomised and hysterectomised (surgically induced menopause) women receiving concomitant estrogen therapy.9 HSDD is where there is a deficiency in sexual desire that is chronic or persistent10 and in MedDRA it is a lower level term mapped to the preferred term ‘libido decreased’. The marketing authorisation for IntrinsaÕ was voluntarily withdrawn by the manufacturer in June 2012 due to commercial reasons.11 However, new testosterone products indicated for use in HSDD are currently under development, such as LibigelÕ for which randomised controlled trials (RCTs) are currently ongoing.12 Additionally, the potential for off-label use (which has been seen previously in the US3) of other testosterone products in HSDD remains, such as use of oral tablets, testosterone injections, testosterone implants and other testosterone patches. Testosterone levels are known to decrease with age in both men and pre-menopausal women, though there is no dramatic decrease in women after the menopause.13–15 Production in pre-menopausal women is estimated to be 100 to 400 mg per day,16 though in women who have undergone a bilateral oophorectomy, serum levels of testosterone fall by 50% in the days after surgery.15,16 Each IntrinsaÕ testosterone patch provides 300 mg testosterone/day, so is consistent with levels produced in pre-menopausal women.9 IntrinsaÕ must be used in conjunction with estrogen therapy and continued use is only recommended while concomitant estrogen is considered appropriate.9 A post-marketing observational cohort study was conducted to assess the utilisation of IntrinsaÕ in England and to quantify the amount of off-label use in real-life clinical practice. The interim results of this study have been published previously.17
Objectives To describe the utilisation characteristics of patients prescribed testosterone patch (IntrinsaÕ ) in England
and to assess, where possible, if the product is being used according to the authorised product information.
Methods An observational post-marketing cohort study (prescription-event monitoring (PEM)) was conducted to monitor the safety of IntrinsaÕ as used in general practice in England. A detailed description of PEM is published elsewhere.18 Briefly, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for IntrinsaÕ , supplied to the DSRU in confidence by the National Health Service Business Services Authority (NHSBSA). The GPs were sent a short postal questionnaire at least six months following the date of the first prescription for IntrinsaÕ for each individual patient between March 2007 and August 2010, requesting information including: start and stop dates of treatment (if stopped), age, gender, reasons for stopping IntrinsaÕ and details of events (An ‘event’ in PEM is defined as: ‘any new diagnosis, any reason for referral to a consultant or admission to hospital, any unexpected deterioration (or improvement) in a concurrent illness, any suspected drug reaction, any alteration of clinical importance in laboratory values, or any other complaint that was considered of sufficient importance to enter in the patient’s notes.’) experienced by patients after starting therapy. GPs were also asked whether the patient was hysterectomised and bilaterally oophorectomised prior to starting IntrinsaÕ , and if not, to specify whether they were hysterectomised only, bilaterally oophorectomised only, naturally menopausal or pre-menopausal. In addition, details of concomitant estrogen products were requested. The information provided for these patients was coded onto a database; events and indication data were extracted according to MedDRA. Analyses were performed using STATA v12 (StataCorp, Texas, USA). Off-label use was examined in respect to: indications other than HSDD, patients not hysterectomised and bilaterally oophorectomised, patients not using concomitant estrogen therapy and any reported use in male patients. Additionally, warnings and precautions for use were examined including use in women aged 60 years, naturally menopausal women and patients using conjugated equine estrogen products.
Analysis Summary statistics of the characteristics of the cohort were calculated. The proportion of patients within the cohort using IntrinsaÕ in concordance with prescribing guidelines was summarised through the construction of a simple profile score assembled from the algorithm
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
50
Post Reproductive Health 20(2)
Table 1. Summary of algorithm for determining patient’s profile score and concordance with prescribing guidelines. Sex Female ¼ 1 Male ¼ 0
Indication þ
Menopausal status
HSDD ¼ 1 Others ¼ 0
þ
Hysterectomised and bilaterally oophorectomised ¼ 1 Other ¼ 0
shown in Table 1. A sample size of at least 2000 patients was desirable for this study.
Ethics
þ
Therapy
Total Score
Concomitant estrogen therapy ¼ 1 Other ¼ 0
Maximum ¼ 4
Table 2. Off-label use of IntrinsaÕ .
Off-label use
This study was conducted in accordance with national and international guidelines.19–22 In addition, under Section 251 of the NHS Act 2006, the DSRU have received support from the Ethics and Confidentiality Committee of the National Information Governance Board to gain access to and process patient identifiable information without consent for the purposes of medical research (October 2009).
Quality assurance in PEM Good data management is a high priority in PEM. A number of strategies exist to minimise biased results. Data quality is assured through a number of methods based such as operator training, on screen validation during data entry, adoption of and adherence to study specific data coding conventions, coding and convention meetings, double entry (10%) with error reporting, data cleaning using logical checks and analysis of outliers and a study specific analysis design which includes imputations for missing, illogical and conflicting data as reported on the study questionnaire.
Minimum ¼ 0
Indications other than HSDD Indications other than ‘decreased libido’b Patients not hysterectomised and bilaterally oophorectomisedc Patients not using concomitant estrogen therapy Use in male patients
Number of patientsa
% of female cohort
523 463 1146
17.3 15.3 38.0
1029
34.1
52
N/A
a These data were derived from various variables and the counts are not mutually exclusive. b Includes the MedDRA term for HSDD. c Excluding those that were unspecified.
Table 3. Warnings and precautions for use of IntrinsaÕ . Warnings and precautions for use Use in women aged 60 years Naturally menopausal women Patients using conjugated equine estrogen
Number of patientsa
% of female cohort
383 584 120
12.7 19.4 3.4
a
Results Cohort characteristics and off-label use Of the 5386 eligible patients for whom questionnaires were posted to the prescribing GPs, questionnaires were returned for 3381 (62.8%) patients. Of these, 308 patients (9.1%) were excluded because the GP could find no record of the drug (n ¼ 127), the patient was not registered at the GP’s practice (n ¼ 106), the questionnaire was returned blank (n ¼ 33), IntrinsaÕ was not used by the patient (n ¼ 28), only the covering letter was returned (n ¼ 6), the doctor had moved or could not complete the form (n ¼ 6), the patient was temporary (n ¼ 1) or duplicate information was received (n ¼ 1). Data are presented here for a final cohort consisting of 3073 evaluable patients. Off-label use is summarised in Table 2, warnings and precautions for use are summarised in Table 3.
These data were derived from various variables and the counts are not mutually exclusive.
Age and gender The final cohort comprised 3017 females (98.2% of cohort), 52 males (1.7%) and 4 patients (0.1%) in whom the sex was not specified. The median age of the female patients was 50 years (interquartile range (IQR) 44–55 years) with a range between 25 and 72 years. IntrinsaÕ is only indicated up to the age of 60, due to limited data on its use in patients beyond this age16; however, there were 383 female patients (12.7%) aged 60 years and older identified in the cohort. Of the 52 patients reported to be males, the median age was 60 years (IQR 50–66 years). There is a possibility that these male patients were using another testosterone patch product and as such, male patients and
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
Osborne et al.
51
patients for whom sex was not specified are not discussed further and are not included in the analyses.
Concomitant estrogen therapy
The most commonly reported primary indication was the licensed indication of HSDD in 2324 patients (77.0%). There were 463 patients (15.3%) that specified an indication other than decreased libido. No indication was specified for 170 patients (4.8%).
IntrinsaÕ was only licensed for use in combination with estrogen and GPs were asked to specify if a concomitant estrogen containing product was being used. For 1988 (65.9%) patients there was evidence that the patient had been using concomitant estrogen therapy but in 1029 (34.1%) patients there was no evidence of this. There were 120 patients (3.4%) who had used a concomitant conjugated estrogen product, which is not recommended.16
Menopausal status
Subgroup analysis and total off-label use
In response to the question regarding the patients’ menopausal status prior to starting IntrinsaÕ , 1313 patients (43.5%) were classified as hysterectomised and bilaterally oophorectomised, 378 patients (12.5%) were hysterectomised or bilaterally oophorectomised, 584 patients (19.4%) were naturally menopausal and 184 patients (6.1%) were pre-menopausal. For the remaining 558 patients (18.5%) the menopausal status was unknown.
The cohort was stratified based on the menopausal status of the patients (Tables 4 and 5) and the cohort was further examined to determine the number of patients who met the prescribing guidelines. Only 643 patients (20.9% of cohort, 21.3% of females) were identified that met all of these conditions. However, it must be noted that not all GPs provided a response to all of the questions and this does not take into account the use of conjugated estrogens.
Indication
Table 4. Stratification of characteristics based on hysterectomy and oophorectomy status of patients.
Hysterectomised & bilaterally oophorectomised
Number of female patients
Age Median (IQR), range [mean (s.d.)]
1313
48 (43–54), 27–74 [48.9 (7.8)] 51 (47–57), 28–74 [51.8 (8.1)] 48 (41–53), 28–67 [47.1 (8.9)]
Hysterectomised only
295
Bilaterally oophorectomised only
83
Proportion with HSDD % (n)
Proportion stoppeda % (n)
Proportion concomitant estrogenb % (n)
75.4 (990)
65.2 (856)
66.0 (867)
80.7 (238)
72.5 (214)
67.1 (198)
67.5 (56)
69.9 (58)
72.3 (60)
a
Did patient stop therapy? ticked ‘Yes’ and/or a reason for stopping specified. Was patient prescribed concomitant estrogen? ticked ‘Yes’ and/or estrogen product specified.
b
Table 5. Stratification of characteristics based on pre-menopausal and naturally menopausal patients. Number of female patients
Age median (IQR), range (mean (s.d.))
Naturally menopausal
584
Pre-menopausal
184
54 (49–58), 18–86 (53.6 (7.6)) 44 (39–48) 21–62 (43.2 (7.2))
Proportion with HSDD % (n)
Proportion stoppeda % (n)
Proportion concomitant estrogenb % (n)
81.0 (473)
65.6 (383)
64.2 (375)
80.4 (148)
73.9 (136)
69.0 (127)
a
Did patient stop therapy? ticked ‘Yes’ and/or a reason for stopping specified. Was patient prescribed concomitant estrogen? Ticked ‘Yes’ and/or oestrogen product specified.
b
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
52
Post Reproductive Health 20(2)
Discussion Post-marketing surveillance provides important information on the real-life use of products, including use in populations that may not have been studied in clinical trials contributing to the pre-marketing development programme.2,18 Examining the characteristics of patients using a product post-marketing is important to establish whether prescribing recommendations are being adhered to. Additionally, differences in the characteristics of the real-life population using a product post-marketing can be explored in relation to the premarketing clinical trials population, to determine if safety and efficacy information are generalisable to the intended target population under conditions of real-life use. Off-label prescribing is known to occur in general practice and is not necessarily inappropriate in all circumstances, which is recognised by regulatory agencies such as the MHRA in the UK.23 It may be that treatment for a specific indication is limited, or that a patient cannot tolerate alternative treatment. However, the implications of off-label use need to be considered, as patients with different risk profiles to those for whom use is actually intended could be at greater risk of adverse events. Such events that occur as the result of off-label use are of interest to regulatory agencies and subject to reporting requirements in the EU.24 In particular, the European Medicines Agency (EMA) definition of an adverse drug reaction was updated in 2010 to state that adverse drug reactions can also occur as the result of off-label use.25 In the example from the IntrinsaÕ cohort, the age range of the patient population was similar to that of the populations studied in the clinical trial phase26–31 and the majority of the cohort was female (98.2%). Off-label use in terms of indication (17.3% women had indications other than HSDD) and no concomitant estrogen therapy (34.1% women) were reported. In terms of menopausal status, IntrinsaÕ was only indicated for women who are hysterectomised and bilaterally oophorectomised; however, 38.0% of women in the cohort were not surgically menopausal. Some women (19.4%) were reported to be naturally menopausal. The manufacturer does not recommend use in naturally menopausal women, since safety in this population has not been established.16 Use of the testosterone patch in naturally menopausal women with HSDD has been explored previously in the ADORE study (randomised placebo-controlled clinical trial), which concluded that the testosterone patch was effective in treating HSDD and improving sexual function in naturally menopausal women using concurrent estrogen therapy.32 Safety in this patient population has not been established though and there are concerns
about breast, ovarian and endometrial cancer with use of testosterone.16,33 There are similar safety concerns with use of IntrinsaÕ in pre-menopausal women and this population was not examined in clinical trials.16 As such, IntrinsaÕ was not licensed for use in premenopausal women. Overall, off-label use defined by the terms of the license was found to be very common in the IntrinsaÕ cohort, with use in patients who were not examined in the clinical trial setting or for which safety and/or efficacy has not been proven in trials. As such, the efficacy and safety information from the clinical trials within the pre-marketing development may not be generalisable to the real-life patients who were using this product in England. Whilst Intrinsa is no longer on the market in the UK, the results from this study may be relevant when considering the implications of off-label use in general, in addition to off-label use of testosterone products in HSDD. A limitation of this study is its potential nonresponse bias though we have no reason to believe that the information reported for patients whose GPs did respond was systematically different from those who did not respond. Another limitation is that under-reporting is possible in PEM studies, as for any other observational study. Also, as with many observational studies, the degree of patient compliance in using the prescribed medication cannot be ascertained, particularly when a product may be used intermittently. While it is not possible to be sure the patient used the medication, it is almost certain that the patient received it. Repeat prescriptions would indicate the patient continued to obtain the medication. Despite these limitations, this analysis provides an important example of off-label use in general practice in England. The patients using IntrinsaÕ in this study were different from patients examined in the clinical trials setting.
Conclusion The study has highlighted that the real-life patient population using a product may have a different risk profile to patients included in clinical trials. Some GPs may prescribe outside the recommended terms of the licence, with this example highlighting that only 643 patients (20.9%) in the cohort were being prescribed IntrinsaÕ according to the manufacturer’s recommendations for the product. Evidence obtained solely from clinical trials might not be generalisable as a result, so evidence from post-marketing observational studies is important to provide complimentary data on a product’s safety and effectiveness in real-life use.
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
Osborne et al.
53
Acknowledgements We would like to thank all the staff at the DSRU who contributed to this study. We would like to thank the help of Mr Shayne Freemantle for his assistance with the analysis. We thank the GPs who have participated in this study, and without whose general support PEM would not be possible. We also thank the NHS Business Services Authority (NHSBSA) for their important participation.
Funding The DSRU receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The DSRU has received financial support from Warner Chilcott, the manufacturer of IntrinsaÕ .
Ethics This study was conducted in accordance with national and international guidelines.19–22 In addition, under Section 251 of the NHS Act 2006, the DSRU have received support from the Ethics and Confidentiality Committee of the National Information Governance Board to gain access to and process patient identifiable information without consent for the purposes of medical research (October 2009).
Conflict of interest The Drug Safety Research Unit is an independent charity (No. 327206), and is an Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The DSRU has received financial support from Warner Chilcott, the manufacturer of IntrinsaÕ . The DSRU has also received remuneration for attending the meetings of the advisory committee on the safety of IntrinsaÕ .
References 1. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) module VI – management and reporting of adverse reactions to medicinal products, http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2012/06/WC500129135.pdf (2012, accessed 30 April 2014). 2. Martin K, Begaud B, Latry P, et al. Differences between clinical trials and postmarketing use. Br J Clin Pharmacol 2004; 57: 86–92. 3. Snabes M and Simes S. Approved hormonal treatments for HSDD: an unmet medical need. J Sex Med 2009; 6: 1846–1849. 4. Lenk C, Koch P, Zappel H, et al. Off-label, off-limits? Parental awareness and attitudes towards off-label use in paediatrics. Eur J Pediatr 2009; 168: 1473–1478.
5. Lindkvist J, Airaksinen M, Kaukonen A, et al. Evolution of paediatric off-label use after new significant medicines become available for adults: a study on triptans in Finnish children 1994–2007. Br J Clin Pharmacol 2011; 71: 929–935. 6. Pasquali S, Hall M, Slonim A, et al. Off-label use of cardiovascular medications in children hospitalized with congenital and acquired heart disease. Circ Cardiovasc Qual Outcomes 2008; 1: 74–83. 7. Leslie D and Rosenhech R. Off-label use of antipsychotic medications in medicaid. Am J Manag Care 2012; 18: e109–e117. 8. Martinez C, Jones R and Rietbrock S. Trends in the prevalence of antipsychotic drug use among patients with Alzheimer’s disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study. BMJ Open 2013; 3: e002080. 9. Warner Chilcott UK Ltd. Intrinsa: summary of product characteristics. Weybridge: Author, 2009. 10. Rosen R and Goldstein I. Sexual dysfunction. In: Warrell D, Cox T and Firth J (eds) Oxford textbook of medicine. Vol. 2, 4th ed. Oxford: Oxford University Press, 2003, pp.287–294. 11. European Medicines Agency. Public statement on withdrawal of the marketing authorisation for Intrinsa in the European Union, http://www.ema.europa.eu/docs/ en_GB/document_library/Public_statement/2012/06/ WC500128837.pdf (2012, accessed 30 April 2014). 12. BioSante Pharmaceuticals. Safety and efficacy of LibiGelÕ for treatment of hypoactive sexual desire disorder in postmenopausal women, http:// ClinicalTrials.gov/show/NCT00612742 (2012, accessed 30 April 2014). 13. Evans J. Geratology. In: Warrell D, Cox T and Firth J (eds) Oxford textbook of medicine. Vol. 3, 4th ed. Oxford: Oxford University Press, 2003, pp.1375–1394. 14. Somboonporn W and Davis S. Testosterone effects on the breast: implications for testosterone therapy for women. Endocr Rev 2004; 25: 374–388. 15. Krapf J and Simon J. The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. Maturitas 2009; 63: 213–219. 16. Warner Chilcott UK Ltd. Intrinsa: Summary of product characteristics, http://www.medicines.org.uk/EMC/ medicine/19592/SPC/Intrinsaþ300þmicrogramsþ24þ hoursþtransdermalþpatch/(2010, accessed 30 April 2014). 17. Osborne V, Hazell L, Layton D, et al. Drug utilization of Intrinsa (testosterone patch) in England: interim analysis of a prescription-event monitoring study to support risk management. Drug Saf 2010; 33: 1–9. 18. Shakir SAW. Prescription-event monitoring. In: Mann RD and Andrews EB (eds) Pharmacovigilance, 2nd ed. Chichester, UK: John Wiley & Sons Ltd, 2007, pp.307–316. 19. British Medical Association Board of Science, British Medical Association Science & Education.
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
54
20.
21.
22.
23.
24.
25.
Post Reproductive Health 20(2) Repor adverse drug reactions. A guide for healthcare professionals, http://www.bma.org.uk/ap.nsf/Content/ AdverseDrugReactions (accessed 31 May 2006). CIOMS-WHO. International ethical guidelines for biomedical research involving human subjects. Geneva: Switzerland, 2002. General Medical Council. Frequently asked questions supplement to: confidentiality: protecting and providing information. London: General Medical Council, 2004, p.9. Royal College of Physicians of London. Guidelines on the practice of ethics committees in medical research involving human subjects, 3rd ed. London: Royal College of Physicians of London, 1996. Medicines and Healthcare Regulatory Agency. Off-label or unlicensed use of medicines: prescribers’ responsibilities. Drug Saf Update 2009; 2: 6. European Medicines Agency. Guideline on good pharmacovigilance practices. Module VI – management and reporting of adverse reactions to medicinal products. EMA/873138/2011, http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2012/02/ WC500123203.pdf (2012, accessed 20 July 2012). European Medicines Agency. New 2010 EU pharmacovigilance legislation, http://www.ema.europa.eu/ema/ index.jsp?curl¼pages/regulation/general/general_content_ 000492.jsp&mid¼WC0b01ac058033e8ad&jsenabled¼true (2010, accessed 30 April 2014).
26. EMEA. Intrinsa: European public assessment report. London: EMEA, 2006. 27. Braunstein GD, Sundwell DA, Katz M, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women. Arch Intern Med 2005; 165: 1582–1589. 28. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for sexual desire in surgically menopausal women: a randomised trial. Obstet Gynecol 2005; 105: 944–952. 29. Davis SR, Van der Morren MJ, van Lunsen RH, et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause 2006; 13: 387–396. 30. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000; 343: 682–688. 31. Simon J, Braunstein G, Utian W, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005; 90: 5226–5233. 32. Panay N, Al-Azzawi F, Bouchard C, et al. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric 2010; 13: 121–131. 33. Shufelt C and Braunstein G. Safety of testosterone use in women. Maturitas 2009; 63: 63–66.
How To Cite Osborne V, et al. Implications of off-label use: An example from the final results of an observational cohort study on IntrinsaÕ (testosterone patch). Post Reproductive Health 2014; 20(2): 48–54.
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
Implications of off-label use: An example from the final results of an observational cohort study on IntrinsaÕ (testosterone patch)
Post Reproductive Health 2014, Vol. 20(2) 48–54 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2053369114535762 prh.sagepub.com
Vicki Osborne1,2, Deborah Layton1,2 and Saad AW Shakir1,2
Abstract Introduction: Off-label use is where a medicinal product is used for a medical purpose not in accordance with the authorised product information. IntrinsaÕ is a transdermal testosterone patch, which is indicated for use in hypoactive sexual desire disorder in bilaterally oophorectomised and hysterectomised women receiving concomitant estrogen therapy. Objectives: To describe the utilization characteristics of patients prescribed testosterone patch (IntrinsaÕ ) and to assess, where possible, if the product is being used according to the authorised product information. Study design: Patients identified from dispensed prescriptions issued by general practitioners for IntrinsaÕ between March 2007 and August 2010. Postal questionnaires were sent to general practitioners six months following the date of the first prescription for IntrinsaÕ for each patient, requesting information including patient demographics and drug utilization. Main outcome measures: Menopausal status and use of concomitant estrogen therapy. Results: The final cohort consisted of 3073 patients; the majority were females (3017, 98.2%). The most commonly reported indication was hypoactive sexual desire disorder in 2324 female patients (77.0%). Only 43.5% female patients (n ¼ 1313) were reported to have been hysterectomised and bilaterally oophorectomised. For 1029 (34.1%) female patients there was no evidence that the patient was using concomitant estrogen therapy. Overall, only 643 patients (20.9%) in the cohort were being prescribed IntrinsaÕ according to the manufacturer’s recommendations. Conclusions: Evidence obtained solely from clinical trials might not be generalisable where off-label prescribing occurs in real-life, so evidence from post-marketing observational studies is important to provide complimentary data on a product’s safety and effectiveness.
Keywords Cohort study, drug utilization, off-label use, testosterone patch
Background According to the European Medicines Agency (EMA) guidelines on good pharmacovigilance practices (GVP), off-label use is where a medicinal product is used for a medical purpose not in accordance with the authorised product information.1 After launch of a medicinal product, it may be used in populations that differ from those examined in clinical trials, including the potential for off-label use.2 Off-label use of testosterone products has been seen previously in the US.3 Where off-label use occurs, it is possible that the population using it has very different characteristics from the clinical trial populations. An example is where products are not licensed for use in children, but children are also
susceptible to the diseases that are the indication for prescribing. As such, children may be prescribed these products off-label, although there are no data on use in children from clinical trials.4–6 Another example is where a drug has a specific indication, but is prescribed for other indications based on clinician experience and 1
Drug Safety Research Unit, Bursledon Hall, Southampton, UK School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK 2
Corresponding author: Vicki Osborne, Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton SO31 1AA, UK. Email: [email protected]
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
Osborne et al.
49
judgement such as prescribing antipsychotics for treatment of neuropsychiatric symptoms in dementia.7,8 Since clinical trials provide the main source of data on safety and efficacy of a medicinal product at the time marketing authorisation is approved, it is important to examine whether these data are generalisable to real-life use. Observational post-marketing studies can be a useful tool for examining real-life use of a medicinal product and whether the populations using it are similar or different to clinical trial populations. IntrinsaÕ (The trade name IntrinsaÕ is used for product identification purposes to distinguish it from other testosterone patch products.) is a transdermal testosterone patch, which is indicated for use in hypoactive sexual desire disorder (HSDD) in bilaterally oophorectomised and hysterectomised (surgically induced menopause) women receiving concomitant estrogen therapy.9 HSDD is where there is a deficiency in sexual desire that is chronic or persistent10 and in MedDRA it is a lower level term mapped to the preferred term ‘libido decreased’. The marketing authorisation for IntrinsaÕ was voluntarily withdrawn by the manufacturer in June 2012 due to commercial reasons.11 However, new testosterone products indicated for use in HSDD are currently under development, such as LibigelÕ for which randomised controlled trials (RCTs) are currently ongoing.12 Additionally, the potential for off-label use (which has been seen previously in the US3) of other testosterone products in HSDD remains, such as use of oral tablets, testosterone injections, testosterone implants and other testosterone patches. Testosterone levels are known to decrease with age in both men and pre-menopausal women, though there is no dramatic decrease in women after the menopause.13–15 Production in pre-menopausal women is estimated to be 100 to 400 mg per day,16 though in women who have undergone a bilateral oophorectomy, serum levels of testosterone fall by 50% in the days after surgery.15,16 Each IntrinsaÕ testosterone patch provides 300 mg testosterone/day, so is consistent with levels produced in pre-menopausal women.9 IntrinsaÕ must be used in conjunction with estrogen therapy and continued use is only recommended while concomitant estrogen is considered appropriate.9 A post-marketing observational cohort study was conducted to assess the utilisation of IntrinsaÕ in England and to quantify the amount of off-label use in real-life clinical practice. The interim results of this study have been published previously.17
Objectives To describe the utilisation characteristics of patients prescribed testosterone patch (IntrinsaÕ ) in England
and to assess, where possible, if the product is being used according to the authorised product information.
Methods An observational post-marketing cohort study (prescription-event monitoring (PEM)) was conducted to monitor the safety of IntrinsaÕ as used in general practice in England. A detailed description of PEM is published elsewhere.18 Briefly, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for IntrinsaÕ , supplied to the DSRU in confidence by the National Health Service Business Services Authority (NHSBSA). The GPs were sent a short postal questionnaire at least six months following the date of the first prescription for IntrinsaÕ for each individual patient between March 2007 and August 2010, requesting information including: start and stop dates of treatment (if stopped), age, gender, reasons for stopping IntrinsaÕ and details of events (An ‘event’ in PEM is defined as: ‘any new diagnosis, any reason for referral to a consultant or admission to hospital, any unexpected deterioration (or improvement) in a concurrent illness, any suspected drug reaction, any alteration of clinical importance in laboratory values, or any other complaint that was considered of sufficient importance to enter in the patient’s notes.’) experienced by patients after starting therapy. GPs were also asked whether the patient was hysterectomised and bilaterally oophorectomised prior to starting IntrinsaÕ , and if not, to specify whether they were hysterectomised only, bilaterally oophorectomised only, naturally menopausal or pre-menopausal. In addition, details of concomitant estrogen products were requested. The information provided for these patients was coded onto a database; events and indication data were extracted according to MedDRA. Analyses were performed using STATA v12 (StataCorp, Texas, USA). Off-label use was examined in respect to: indications other than HSDD, patients not hysterectomised and bilaterally oophorectomised, patients not using concomitant estrogen therapy and any reported use in male patients. Additionally, warnings and precautions for use were examined including use in women aged 60 years, naturally menopausal women and patients using conjugated equine estrogen products.
Analysis Summary statistics of the characteristics of the cohort were calculated. The proportion of patients within the cohort using IntrinsaÕ in concordance with prescribing guidelines was summarised through the construction of a simple profile score assembled from the algorithm
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
50
Post Reproductive Health 20(2)
Table 1. Summary of algorithm for determining patient’s profile score and concordance with prescribing guidelines. Sex Female ¼ 1 Male ¼ 0
Indication þ
Menopausal status
HSDD ¼ 1 Others ¼ 0
þ
Hysterectomised and bilaterally oophorectomised ¼ 1 Other ¼ 0
shown in Table 1. A sample size of at least 2000 patients was desirable for this study.
Ethics
þ
Therapy
Total Score
Concomitant estrogen therapy ¼ 1 Other ¼ 0
Maximum ¼ 4
Table 2. Off-label use of IntrinsaÕ .
Off-label use
This study was conducted in accordance with national and international guidelines.19–22 In addition, under Section 251 of the NHS Act 2006, the DSRU have received support from the Ethics and Confidentiality Committee of the National Information Governance Board to gain access to and process patient identifiable information without consent for the purposes of medical research (October 2009).
Quality assurance in PEM Good data management is a high priority in PEM. A number of strategies exist to minimise biased results. Data quality is assured through a number of methods based such as operator training, on screen validation during data entry, adoption of and adherence to study specific data coding conventions, coding and convention meetings, double entry (10%) with error reporting, data cleaning using logical checks and analysis of outliers and a study specific analysis design which includes imputations for missing, illogical and conflicting data as reported on the study questionnaire.
Minimum ¼ 0
Indications other than HSDD Indications other than ‘decreased libido’b Patients not hysterectomised and bilaterally oophorectomisedc Patients not using concomitant estrogen therapy Use in male patients
Number of patientsa
% of female cohort
523 463 1146
17.3 15.3 38.0
1029
34.1
52
N/A
a These data were derived from various variables and the counts are not mutually exclusive. b Includes the MedDRA term for HSDD. c Excluding those that were unspecified.
Table 3. Warnings and precautions for use of IntrinsaÕ . Warnings and precautions for use Use in women aged 60 years Naturally menopausal women Patients using conjugated equine estrogen
Number of patientsa
% of female cohort
383 584 120
12.7 19.4 3.4
a
Results Cohort characteristics and off-label use Of the 5386 eligible patients for whom questionnaires were posted to the prescribing GPs, questionnaires were returned for 3381 (62.8%) patients. Of these, 308 patients (9.1%) were excluded because the GP could find no record of the drug (n ¼ 127), the patient was not registered at the GP’s practice (n ¼ 106), the questionnaire was returned blank (n ¼ 33), IntrinsaÕ was not used by the patient (n ¼ 28), only the covering letter was returned (n ¼ 6), the doctor had moved or could not complete the form (n ¼ 6), the patient was temporary (n ¼ 1) or duplicate information was received (n ¼ 1). Data are presented here for a final cohort consisting of 3073 evaluable patients. Off-label use is summarised in Table 2, warnings and precautions for use are summarised in Table 3.
These data were derived from various variables and the counts are not mutually exclusive.
Age and gender The final cohort comprised 3017 females (98.2% of cohort), 52 males (1.7%) and 4 patients (0.1%) in whom the sex was not specified. The median age of the female patients was 50 years (interquartile range (IQR) 44–55 years) with a range between 25 and 72 years. IntrinsaÕ is only indicated up to the age of 60, due to limited data on its use in patients beyond this age16; however, there were 383 female patients (12.7%) aged 60 years and older identified in the cohort. Of the 52 patients reported to be males, the median age was 60 years (IQR 50–66 years). There is a possibility that these male patients were using another testosterone patch product and as such, male patients and
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
Osborne et al.
51
patients for whom sex was not specified are not discussed further and are not included in the analyses.
Concomitant estrogen therapy
The most commonly reported primary indication was the licensed indication of HSDD in 2324 patients (77.0%). There were 463 patients (15.3%) that specified an indication other than decreased libido. No indication was specified for 170 patients (4.8%).
IntrinsaÕ was only licensed for use in combination with estrogen and GPs were asked to specify if a concomitant estrogen containing product was being used. For 1988 (65.9%) patients there was evidence that the patient had been using concomitant estrogen therapy but in 1029 (34.1%) patients there was no evidence of this. There were 120 patients (3.4%) who had used a concomitant conjugated estrogen product, which is not recommended.16
Menopausal status
Subgroup analysis and total off-label use
In response to the question regarding the patients’ menopausal status prior to starting IntrinsaÕ , 1313 patients (43.5%) were classified as hysterectomised and bilaterally oophorectomised, 378 patients (12.5%) were hysterectomised or bilaterally oophorectomised, 584 patients (19.4%) were naturally menopausal and 184 patients (6.1%) were pre-menopausal. For the remaining 558 patients (18.5%) the menopausal status was unknown.
The cohort was stratified based on the menopausal status of the patients (Tables 4 and 5) and the cohort was further examined to determine the number of patients who met the prescribing guidelines. Only 643 patients (20.9% of cohort, 21.3% of females) were identified that met all of these conditions. However, it must be noted that not all GPs provided a response to all of the questions and this does not take into account the use of conjugated estrogens.
Indication
Table 4. Stratification of characteristics based on hysterectomy and oophorectomy status of patients.
Hysterectomised & bilaterally oophorectomised
Number of female patients
Age Median (IQR), range [mean (s.d.)]
1313
48 (43–54), 27–74 [48.9 (7.8)] 51 (47–57), 28–74 [51.8 (8.1)] 48 (41–53), 28–67 [47.1 (8.9)]
Hysterectomised only
295
Bilaterally oophorectomised only
83
Proportion with HSDD % (n)
Proportion stoppeda % (n)
Proportion concomitant estrogenb % (n)
75.4 (990)
65.2 (856)
66.0 (867)
80.7 (238)
72.5 (214)
67.1 (198)
67.5 (56)
69.9 (58)
72.3 (60)
a
Did patient stop therapy? ticked ‘Yes’ and/or a reason for stopping specified. Was patient prescribed concomitant estrogen? ticked ‘Yes’ and/or estrogen product specified.
b
Table 5. Stratification of characteristics based on pre-menopausal and naturally menopausal patients. Number of female patients
Age median (IQR), range (mean (s.d.))
Naturally menopausal
584
Pre-menopausal
184
54 (49–58), 18–86 (53.6 (7.6)) 44 (39–48) 21–62 (43.2 (7.2))
Proportion with HSDD % (n)
Proportion stoppeda % (n)
Proportion concomitant estrogenb % (n)
81.0 (473)
65.6 (383)
64.2 (375)
80.4 (148)
73.9 (136)
69.0 (127)
a
Did patient stop therapy? ticked ‘Yes’ and/or a reason for stopping specified. Was patient prescribed concomitant estrogen? Ticked ‘Yes’ and/or oestrogen product specified.
b
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
52
Post Reproductive Health 20(2)
Discussion Post-marketing surveillance provides important information on the real-life use of products, including use in populations that may not have been studied in clinical trials contributing to the pre-marketing development programme.2,18 Examining the characteristics of patients using a product post-marketing is important to establish whether prescribing recommendations are being adhered to. Additionally, differences in the characteristics of the real-life population using a product post-marketing can be explored in relation to the premarketing clinical trials population, to determine if safety and efficacy information are generalisable to the intended target population under conditions of real-life use. Off-label prescribing is known to occur in general practice and is not necessarily inappropriate in all circumstances, which is recognised by regulatory agencies such as the MHRA in the UK.23 It may be that treatment for a specific indication is limited, or that a patient cannot tolerate alternative treatment. However, the implications of off-label use need to be considered, as patients with different risk profiles to those for whom use is actually intended could be at greater risk of adverse events. Such events that occur as the result of off-label use are of interest to regulatory agencies and subject to reporting requirements in the EU.24 In particular, the European Medicines Agency (EMA) definition of an adverse drug reaction was updated in 2010 to state that adverse drug reactions can also occur as the result of off-label use.25 In the example from the IntrinsaÕ cohort, the age range of the patient population was similar to that of the populations studied in the clinical trial phase26–31 and the majority of the cohort was female (98.2%). Off-label use in terms of indication (17.3% women had indications other than HSDD) and no concomitant estrogen therapy (34.1% women) were reported. In terms of menopausal status, IntrinsaÕ was only indicated for women who are hysterectomised and bilaterally oophorectomised; however, 38.0% of women in the cohort were not surgically menopausal. Some women (19.4%) were reported to be naturally menopausal. The manufacturer does not recommend use in naturally menopausal women, since safety in this population has not been established.16 Use of the testosterone patch in naturally menopausal women with HSDD has been explored previously in the ADORE study (randomised placebo-controlled clinical trial), which concluded that the testosterone patch was effective in treating HSDD and improving sexual function in naturally menopausal women using concurrent estrogen therapy.32 Safety in this patient population has not been established though and there are concerns
about breast, ovarian and endometrial cancer with use of testosterone.16,33 There are similar safety concerns with use of IntrinsaÕ in pre-menopausal women and this population was not examined in clinical trials.16 As such, IntrinsaÕ was not licensed for use in premenopausal women. Overall, off-label use defined by the terms of the license was found to be very common in the IntrinsaÕ cohort, with use in patients who were not examined in the clinical trial setting or for which safety and/or efficacy has not been proven in trials. As such, the efficacy and safety information from the clinical trials within the pre-marketing development may not be generalisable to the real-life patients who were using this product in England. Whilst Intrinsa is no longer on the market in the UK, the results from this study may be relevant when considering the implications of off-label use in general, in addition to off-label use of testosterone products in HSDD. A limitation of this study is its potential nonresponse bias though we have no reason to believe that the information reported for patients whose GPs did respond was systematically different from those who did not respond. Another limitation is that under-reporting is possible in PEM studies, as for any other observational study. Also, as with many observational studies, the degree of patient compliance in using the prescribed medication cannot be ascertained, particularly when a product may be used intermittently. While it is not possible to be sure the patient used the medication, it is almost certain that the patient received it. Repeat prescriptions would indicate the patient continued to obtain the medication. Despite these limitations, this analysis provides an important example of off-label use in general practice in England. The patients using IntrinsaÕ in this study were different from patients examined in the clinical trials setting.
Conclusion The study has highlighted that the real-life patient population using a product may have a different risk profile to patients included in clinical trials. Some GPs may prescribe outside the recommended terms of the licence, with this example highlighting that only 643 patients (20.9%) in the cohort were being prescribed IntrinsaÕ according to the manufacturer’s recommendations for the product. Evidence obtained solely from clinical trials might not be generalisable as a result, so evidence from post-marketing observational studies is important to provide complimentary data on a product’s safety and effectiveness in real-life use.
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
Osborne et al.
53
Acknowledgements We would like to thank all the staff at the DSRU who contributed to this study. We would like to thank the help of Mr Shayne Freemantle for his assistance with the analysis. We thank the GPs who have participated in this study, and without whose general support PEM would not be possible. We also thank the NHS Business Services Authority (NHSBSA) for their important participation.
Funding The DSRU receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The DSRU has received financial support from Warner Chilcott, the manufacturer of IntrinsaÕ .
Ethics This study was conducted in accordance with national and international guidelines.19–22 In addition, under Section 251 of the NHS Act 2006, the DSRU have received support from the Ethics and Confidentiality Committee of the National Information Governance Board to gain access to and process patient identifiable information without consent for the purposes of medical research (October 2009).
Conflict of interest The Drug Safety Research Unit is an independent charity (No. 327206), and is an Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The DSRU has received financial support from Warner Chilcott, the manufacturer of IntrinsaÕ . The DSRU has also received remuneration for attending the meetings of the advisory committee on the safety of IntrinsaÕ .
References 1. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) module VI – management and reporting of adverse reactions to medicinal products, http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2012/06/WC500129135.pdf (2012, accessed 30 April 2014). 2. Martin K, Begaud B, Latry P, et al. Differences between clinical trials and postmarketing use. Br J Clin Pharmacol 2004; 57: 86–92. 3. Snabes M and Simes S. Approved hormonal treatments for HSDD: an unmet medical need. J Sex Med 2009; 6: 1846–1849. 4. Lenk C, Koch P, Zappel H, et al. Off-label, off-limits? Parental awareness and attitudes towards off-label use in paediatrics. Eur J Pediatr 2009; 168: 1473–1478.
5. Lindkvist J, Airaksinen M, Kaukonen A, et al. Evolution of paediatric off-label use after new significant medicines become available for adults: a study on triptans in Finnish children 1994–2007. Br J Clin Pharmacol 2011; 71: 929–935. 6. Pasquali S, Hall M, Slonim A, et al. Off-label use of cardiovascular medications in children hospitalized with congenital and acquired heart disease. Circ Cardiovasc Qual Outcomes 2008; 1: 74–83. 7. Leslie D and Rosenhech R. Off-label use of antipsychotic medications in medicaid. Am J Manag Care 2012; 18: e109–e117. 8. Martinez C, Jones R and Rietbrock S. Trends in the prevalence of antipsychotic drug use among patients with Alzheimer’s disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study. BMJ Open 2013; 3: e002080. 9. Warner Chilcott UK Ltd. Intrinsa: summary of product characteristics. Weybridge: Author, 2009. 10. Rosen R and Goldstein I. Sexual dysfunction. In: Warrell D, Cox T and Firth J (eds) Oxford textbook of medicine. Vol. 2, 4th ed. Oxford: Oxford University Press, 2003, pp.287–294. 11. European Medicines Agency. Public statement on withdrawal of the marketing authorisation for Intrinsa in the European Union, http://www.ema.europa.eu/docs/ en_GB/document_library/Public_statement/2012/06/ WC500128837.pdf (2012, accessed 30 April 2014). 12. BioSante Pharmaceuticals. Safety and efficacy of LibiGelÕ for treatment of hypoactive sexual desire disorder in postmenopausal women, http:// ClinicalTrials.gov/show/NCT00612742 (2012, accessed 30 April 2014). 13. Evans J. Geratology. In: Warrell D, Cox T and Firth J (eds) Oxford textbook of medicine. Vol. 3, 4th ed. Oxford: Oxford University Press, 2003, pp.1375–1394. 14. Somboonporn W and Davis S. Testosterone effects on the breast: implications for testosterone therapy for women. Endocr Rev 2004; 25: 374–388. 15. Krapf J and Simon J. The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. Maturitas 2009; 63: 213–219. 16. Warner Chilcott UK Ltd. Intrinsa: Summary of product characteristics, http://www.medicines.org.uk/EMC/ medicine/19592/SPC/Intrinsaþ300þmicrogramsþ24þ hoursþtransdermalþpatch/(2010, accessed 30 April 2014). 17. Osborne V, Hazell L, Layton D, et al. Drug utilization of Intrinsa (testosterone patch) in England: interim analysis of a prescription-event monitoring study to support risk management. Drug Saf 2010; 33: 1–9. 18. Shakir SAW. Prescription-event monitoring. In: Mann RD and Andrews EB (eds) Pharmacovigilance, 2nd ed. Chichester, UK: John Wiley & Sons Ltd, 2007, pp.307–316. 19. British Medical Association Board of Science, British Medical Association Science & Education.
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
54
20.
21.
22.
23.
24.
25.
Post Reproductive Health 20(2) Repor adverse drug reactions. A guide for healthcare professionals, http://www.bma.org.uk/ap.nsf/Content/ AdverseDrugReactions (accessed 31 May 2006). CIOMS-WHO. International ethical guidelines for biomedical research involving human subjects. Geneva: Switzerland, 2002. General Medical Council. Frequently asked questions supplement to: confidentiality: protecting and providing information. London: General Medical Council, 2004, p.9. Royal College of Physicians of London. Guidelines on the practice of ethics committees in medical research involving human subjects, 3rd ed. London: Royal College of Physicians of London, 1996. Medicines and Healthcare Regulatory Agency. Off-label or unlicensed use of medicines: prescribers’ responsibilities. Drug Saf Update 2009; 2: 6. European Medicines Agency. Guideline on good pharmacovigilance practices. Module VI – management and reporting of adverse reactions to medicinal products. EMA/873138/2011, http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2012/02/ WC500123203.pdf (2012, accessed 20 July 2012). European Medicines Agency. New 2010 EU pharmacovigilance legislation, http://www.ema.europa.eu/ema/ index.jsp?curl¼pages/regulation/general/general_content_ 000492.jsp&mid¼WC0b01ac058033e8ad&jsenabled¼true (2010, accessed 30 April 2014).
26. EMEA. Intrinsa: European public assessment report. London: EMEA, 2006. 27. Braunstein GD, Sundwell DA, Katz M, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women. Arch Intern Med 2005; 165: 1582–1589. 28. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for sexual desire in surgically menopausal women: a randomised trial. Obstet Gynecol 2005; 105: 944–952. 29. Davis SR, Van der Morren MJ, van Lunsen RH, et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause 2006; 13: 387–396. 30. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000; 343: 682–688. 31. Simon J, Braunstein G, Utian W, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005; 90: 5226–5233. 32. Panay N, Al-Azzawi F, Bouchard C, et al. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric 2010; 13: 121–131. 33. Shufelt C and Braunstein G. Safety of testosterone use in women. Maturitas 2009; 63: 63–66.
How To Cite Osborne V, et al. Implications of off-label use: An example from the final results of an observational cohort study on IntrinsaÕ (testosterone patch). Post Reproductive Health 2014; 20(2): 48–54.
Downloaded from min.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on July 19, 2015
