Patient Satisfaction and Therapeutic Adherence Considerations of rhgh Dosing Devices

Patient Satisfaction and Therapeutic Adherence Considerations of rhgh Dosing Devices Robert Lipsy, PharmD Clinical Assistant Professor Department of Pharmacy Practice and Sciences University of Arizona School of Pharmacy

Talking Points Brief overview of the diagnostic criteria for SGA and ISS, including ICD-9 codes for claims submission by providers Review available rhgh administration devices Discuss the availability of dosing administration instructions and support services for the devices Highlight data supporting the value of these devices in promoting patient t satisfaction and therapeutic ti adherence rhgh=recombinant human growth hormone

Diagnosis of GHD in Children and Adolescents: History and Physical Exam Children with suspected GHD should be examined by a pediatric endocrinologist to determine Chronological age Stage of pubescence A complete history, physical examination, and laboratory tests should also be conducted

GHD in Children and Adolescents: Evaluation of Current Growth Rate GHD is likely if an evaluation of the growth rate reveals the child is unlikely to attain an adult height in the normal range (ie, 59 and 63 inches for girls and boys, respectively; growth velocity <25th percentile) In children <3 years, a pretreatment growth velocity <7 cm/year suggests GHD In children 3 years, a growth velocity of <4 cm/year when measured accurately for 1 year is indicative of GHD

Diagnosis of GHD in Children and Adolescents: Laboratory Testing Two pharmacologic provocation tests should be conducted Tests include insulin, clonidine, arginine, levodopa, or glucagon provocation testing GH response to provocation must be <10 ng/ml for both tests Stimulation tests are not a gold standard 6 month trial of GH therapy recommended if Patients fail to meet the <10 ng/ml threshold on both stimulation tests or results are discordant Other criteria for GHD have been met Both IGF-1 and IGFBP-3 are below normal for gender and age Gharib H, et al. Endocr Pract. 2003;9(1):64 76. IGF-1=insulin-like growth factor 1 IGFBP-3= Insulin-like growth factor-binding protein 3

Other Causes of Short Stature Should Be Excluded Before Confirming GHD Diagnosis Conditions dii Associated dwihsh With Short Stature Intracranial tumor Constitutional delay Neuroendocrine disease Inflammatory bowel disease Malnutrition Celiac disease Psychosocial deprivation Bone dysplasia Down's syndrome Familial short stature Chronic disease Hypothyroidism Epiphyseal closure Cook DM, et al. Endocr Pract. 2009;15(Suppl 2):1 29.

Criteria for Deciding to Refer to Endocrinology for Evaluation of Short Stature In the presence of short stature Very Short: height less than 2 SD below the mean Short for Family: height more than 1.5 SD below the midparental height ht Short and Growing Slowly: height <1.7 SD below the mean AND one-year height velocity <-1 SD, or a decrease in height SD >0.5 over one year In the absence of short stature Severe Growth Deceleration: height velocity <-2 SD over one year or <-1.5 SD over two years or decrease in height SD >1 over two years Intracranial Lesion: signs indicative of a brain lesion Pituitary Dysfunction: signs of MPHD Congenital GHD: neonatal symptoms and signs of GHD MPHD=multiple pituitary hormone deficiency Cohen P, et al. J Clin Endocrinol Metab. 2008;93(11):4210 4217. Growth Hormone Research Society. J Clin Endocrinol Metab. 2000;85(11):3990 3993.

Children and Adolescents With Idiopathic Short Stature (ISS): Definition Definition Baseline height >2.25 SD below mean for gender and age (ie, <1.2 percentile) Epiphyses must be open Cohen P, et al. J Clin Endocrinol Metab. 2008;93(11):4210 4217.

Coding for Children and Adolescents With ISS ICD-9: 783.43 ICD-10: E34.3 Short stature due to endocrine disorder R62.52 Short stature (child)

Children Born Small for Gestational Age (SGA): Definition and Diagnosis Definition Birth weight or length 2 SD below the mean for gestational age Child must be at least 3 years old Baseline height must be >2 SD below the mean for gender and age (ie, 2.3 3 percentile) Clayton PE, et al. J Clin Endocrinol Metab. 2007, 92(3):804 810.

Coding for Children Born SGA ICD-9: 764.00 ICD-10: P05.1 codes, broken out by weight P05.10, Unspecified weight P05.11, Less than 500 grams P05.12, 500 749 grams P05.13, 750 999 grams P05.14, 1000 1249 grams P05.15, 1250 1499 grams P05.16, 1500 1749 grams P05.17, 1750 1999 grams P05.18, 2000 2499 grams

FDA-approved rhgh Treatment Options Growth Hormone Manufacturer Pediatric Genotropin Humatrope Norditropin Nutropin Omnitrope Saizen Tev-Tropin i Valtropin GHD Indications ISS SGA Pfizer Eli Lilly Novo Nordisk Genentech Sandoz EMD Serono Gate/Teva Biopartners

FDA-approved rhgh Dosing Growth Hormone Genotropin Humatrope Norditropin Nutropin Omnitrope Saizen Tev-Tropin i Valtropin Pediatric GH Idiopathic Short Small for Deficiency i Staturet Gestational ti lage (mg/kg/week) (mg/kg/week) (mg/kg/week) 0.16 0.24 0.47 0.48 0.18 0.30 0.22 0.37 0.25 0.47 0.17 0.24 0.47 0.3 0.7 0.3 0.16 0.24 0.23 0.47 0.24 0.48 0.18 0.3 0.17 0.3

GH Therapy Is Cost-effective in Children With GHD Discounted Cost US Dollars) Incremental (2005 I $50,000 $40,000000 $30,000 $20,000000 $10,000 $0 5 16 Years Old 3 18 Years Old $42,556 $36,995 $8,909 $9,277 Cost per NHY Gained Cost per QALY Gained Treatment e t of GHD (somatropin op 0.030 030 mg/kg/day g/day vs no treatment) e t) was assessed using decision analytic modeling in two hypothetical cohorts of children: 1) 5 to 16 years, 2) 3 to 18 years. NHY=normal height years QALY=quality-adjusted life-years Joshi AV, et al. Curr Med Res Opin. 2006;22(2):351 357.

GH Treatment Is Most Cost-effective When Children With High Growth Potential Are Targeted Estimated Incremental e Cost per Child and Incremental e Growth per Child Average cost/child ($) Incremental growth/child (in) Incremental cost/inch ($) Height monitoring (no GH treatment) Standard GH treatment (0.37 mg/kg/week) 248 100,207 1.9* 52,634 Earlier age at initiation of GH therapy led to an improved cost per inch. Alternate treatment strategies such as increased duration of GH treatment and high pubertal dosing of GH did not substantially improve the cost-effectiveness ratio. Targeting GH therapy to children most likely to respond is an important treatment strategy for improving cost-effectiveness. *Mean growth per child was assumed to be 2.8 in for children who completed 5 years of GH treatment, the mean incremental height gain for the entire cohort was lower (1.9 in) because of early discontinuation of GH treatment in 30% of the cohort. Lee JM, et al. Arch Pediatr Adolesc Med. 2006;160(3):263 269.

rhgh Is Available in a Variety of Forms Growth Hormone Genotropin Packaging Vial Pen Pre-Filled Pen Needleless Disposable Humatrope Norditropin Nutropin Omnitrope Disposable Disposable Saizen easypod Tev-Tropin i Valtropin

Examples of Currently Available rhgh Administration Devices Growth Hormone Genotropin Humatrope Norditropin Nutropin and AQ Omnitrope i Saizen Device Pen 5 and Pen 12, MiniQuick premixed HumatroPen with cartridges, vial NordiFlex, FlexPro, and NordiPen with cartridges Nutropin AQ Pen with cartridges, AQ NuSpin, vial Pen 5 and Pen 10, vial cool.click needle-free injector system, one.click auto-injector pen, and easypod needle injector system Tev-Tropin Tropin Tev-TropinT vial and needle-free T-Jet

Growth Hormone Administration Devices

Growth Hormone Administration Devices (cont.)

Growth Hormone Administration Devices (cont.)

Storage Requirements for rhgh Growth Hormone Genotropin : pen with cartridge disposable pen Humatrope : vial pen with cartridge Refrigerate Before Use Yes Yes Yes Yes Refrigerate After First Use, Days Yes, 21 No, 90 after dispensing (Disposable pen use within 24 hrs after reconstitution) Yes, 14 Yes, 28 Norditropin : pen with cartridge No, 21* Yes disposable pen Yes, 28 Nutropin : pen with cartridge and AQ prefilled disposable, vials Yes Yes, 28 Omnitrope : vial No Yes, 21 pen No Yes, 28 Saizen : vial pen, easy pad No No Yes, 14 Yes, 21 Tev-Tropin vials Yes Yes, 14 Valtropin vial No, 90 Yes, 21 *The Norditropin Nordiflex pen can stay out of the refrigerator for 21 days, which can improve compliance and adherence.

Patient Support Options Provided by the Manufacturers of rhgh Growth Hormone Live Nurse Insurance Financial Web Training Patient Support Hormone Training Coverage/PA Assistance Genotropin Video and text Yes Patient Care Consultant, device and Tx support Bridge Program Endocrine Care Humatrope Video Yes Yes Yes Norditropin Text In office Case manager NordiCare NordiCare Nutropin Video for NuSpin Nurse hotline Nutropin Access Solution Omnitrope Video Yes OmniSource Assistance Saizen Video Tev-Tropin Video for needle free Connections for growth, device, and insurance Yes Copay assist Copay assist Copay assist Yes Growth Solutions Yes Yes Valtropin

Preferred Features of an rhgh Administration Device Patient preferences for rhgh injection include Reliability Ease of use Lack of pain during injection Safety on use and in storage Number of steps in preparation before, during, and after use Dumas H, et al. BMC Endocr Disord. 2006;6:5.

Variables Impacting Long-term Adherence to GH Therapy Variable 0per Week Frequency of Missed Injections Up to 1 per Week >1 2 per Week >2 per Week Age of patient 12.3 11.9 11.9 14.2 Duration of GH therapy (yrs) 1.6 1.8 2.8 4.4* Patient allowed to use their preferred administration i ti 81 68 58 23* device (%) Short duration of GH Rx (<4 wks/rx) 10 6 27 50* n=75 Mean age=12.3 years Cross sectional data Mean duration of GH treatment=1.9 t t years GH dose=0.8 mg/kg/day GH devices included automatic injection devices (n=38), manual injection pen devices (n=33), and needle-free injection devices (n=4). *P<0.005 Kapoor RR, et al. Arch Dis Child. 2008;93(2):147 148.

Greater Number of Missed Injections Associated With Lower Growth Rate ocity* ar) Height Vel (SDS/ye 05 0.5 047 0.47 047 0.47 0.4 03 0.3 0.2 01 0.1 0.42 0.05 0 0/Week 1/Week >1 2/Week >2/Week Frequency of Missed Injections/Week n=75 Mean age=12.3 years Cross sectional data Mean duration of GH treatment=1.9 years GH dose=0.8 mg/kg/day. 36% (27/75) missed 0 injections/week; 25% (19/75) missed 1/week; 16% (12/75) missed >1 2/week; 23% (17/75) missed >2 injections/week. *Adjusted for age and duration of GH P<0.05therapy Kapoor RR, et al. Arch Dis Child. 2008;93:147 148.

Ease of Use Can Impact Therapeutic Adherence rhgh often must be either parent-administered administered (in the case of small children) or self-administered, often for several years 1 Adherence to therapy can be negatively affected by the time required to prepare and administer the drug 1,2 Easier-to-use administration devices require less training 1,2 1. Wickramasuriya BP, et al. Horm Res. 2006;65(1):18 22. 2. Dumas H, et al. BMC Endocr Disord. 2006;6:5.

Usability and Acceptability of Pen Devices Rated High by GHD Patients 21 item questionnaire completed by 70 GHD patients (10 to <18 years) receiving daily treatment with selfinjectable GH Asked to evaluate usability and acceptability of the Norditropin FlexPro pen and NovoFine needles 97% rated attachment of the needle, priming the device, dialing the dose, and reading the scale as very or quite easy 99% rated pushing the dose button and giving the injection as very or quite easy 100% said hearing the click was very or quite easy This research and its publication were funded by Novo Nordisk, Inc. Fuchs GS, et al. Clin Ther. 2009;31(12):2906 2914.

Reduced Administration Times With Newer Devices Nursing time and motion study comparing 4 devices Norditropin NordiFlex disposable prefilled pen Norditropin NordiPen prefilled cartridges Genotropin Pen two-chamber mixing cartridge HumatroPen This research and its publication were funded by Novo Nordisk, Inc. Nickman NA, et al. BMC Nurs. 2010;9:6.

Comparison of Time Required to Learn How to Use Common Administration Devices Learning Ti ime (min) 30 25 20 15 10 5 15.83 16.17 24.00 26.00* 0 NNF NNP HTP GTP NNF=Norditropin Nordiflex 5 mg NNP=Norditropin NordiPen 5 mg HPT=HumatroPen 6 mg GTP=Genotropin Pen 5.8 mg N=6 nurses; each nurse completed 5 simulations for the 4 pen devices resulting in a total t number of 30 observations each device across 2 dosing simulations (ie, n=60 observations per pen device). *P<0.05 vs NNF Nickman NA, et al. BMC Nurs. 2010;9:6.

Comparison of Time Required to Prepare Common Devices to Deliver a Single Dose Prepa aration Tim me (min) 1.4 1.2 1 08 0.8 0.6 0.4 0.2 0 1.30* 0.86 0.92 0.94 NNF NNP HTP GTP NNF=Norditropin Nordiflex 5 mg NNP=Norditropin NordiPen 5 mg HPT=HumatroPen 6 mg GTP=Genotropin Pen 5.8 mg N=6 nurses; each nurse completed 5 simulations for the 4 pen devices resulting in a total t number of 30 observations each device across 2 dosing simulations (ie, n=60 observations per pen device). *P<0.05 vs NNF Nickman NA, et al. BMC Nurs. 2010;9:6.

rhgh Administration: Summary GHD is likely if a child is unlikely to attain an adult height in the normal range Several rhgh preparations p are FDA-approved for use in GHD, ISS, and SGA Ease of use, reliability, safety, and amount of preparation required all influence patient satisfaction with the administration device Patient satisfaction can influence adherence to GH therapy Higher adherence is associated with greater height velocity