Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies
Faculty
Jeffrey D. Dunn, PharmD, MBAChief Clinical Officer/Senior Vice President
VRx Pharmacy ServicesSalt Lake City, Utah
Raymond Cross, MD, MSProfessor of Medicine
Division of Gastroenterology and HepatologyDirector, IBD Program
University of Maryland School of MedicineCo-Director, Digestive Health Center
University of Maryland Medical CenterBaltimore, Maryland
Learning Objectives
• Describe the clinical progression of IBD and the clinical and economic consequences of undertreatment, including hospital and surgery costs
• Outline unmet patient needs and treatment shortfalls of conventional IBD pharmacotherapies
• Evaluate the safety, efficacy, mechanisms of action, and pharmacoeconomic profiles of newer IBD treatment modalities
• Develop or augment health plan policies that improve patient access to individualized IBD care
Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies
Jeffrey D. Dunn, PharmD, MBAChief Clinical Officer/Senior Vice President
VRx Pharmacy ServicesSalt Lake City, Utah
Introduction and Issues
• IBD is a broad disease state that is not often well understood– Huge clinical and financial implications
• IBD biologic class of medication is the #1 specialty spend– Multiple drugs with different MOA, indications, routes of administration
• Contracts are by drug, not disease state
– Price and price increases• Lack of useful guidelines, measures, start/stop rules
• Biosimilars coming to market
• There is a need for education
• New evidence outlining best practices– Data and treatment approaches
– Care coordination
– Benefit design
– Specialty strategies
IBD = inflammatory bowel disease; MOA = mechanism of action.Inflammatory Bowel Disease (IBD), US Centers for Disease Control and Prevention Web site. Available at http://www.cdc.gov/ibd/. Accessed December21, 2015.
IBD vs IBS
• What it is?
• What it is not: IBS– The cause of IBS remains unknown,
although symptoms may be explained, at least in some patients, by
• Alterations in intestinal motility
• Visceral hypersensitivity
• Brain response to visceral stimuli
– Activation of the mucosal immune system increases the number of lymphocytes in the GI tract
• These lymphocytes can release mediators that stimulate the enteric nervous system, increase abdominal pain, and increase inflammation
– Rome III criteria are used to differentiate between IBS and other GI disorders
– There is no gold standard for the treatment of IBS-D
• Treatment is geared toward symptoms
IBS = irritable bowel syndrome; GI = gastrointestinal; IBS-D = irritable bowel disease with diarrhea as the primary bowel dysfunction.Ford AC, et al. Am J Gastroenterol. 2014;109:S2-S26; doi:10.1038/ajg.2014.187.
Rome III Criteria
Recurrent abdominal pain or discomfort for at least 3 days/month in the past 3 months associated with two of the following
• Improvement with defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form (appearance) of stool
Criteria must be fulfilled for the past 3 months with symptom onset at least 6 months prior to diagnosis
Option Quality of Evidence
Nonpharmacologic options (eg, diet and increased fiber)
Range from very low to moderate
Antispasmodics andpeppermint oil
Antispasmodics: Low Peppermint oil: Moderate
AntidepressantsTricyclic antidepressants:High
Loperamide Very low
Serotonergic agents Moderate
IBD: What It Is
UC
• Characterized by recurring episodes of inflammation limited to the mucosal layer of the colon
– Commonly involves the rectum and may extend in a proximal and continuous fashion to involve other parts of the colon
– Associated symptoms: Colicky abdominal pain, urgency, tenesmus
• Patients may also have fever, fatigue, and weight loss
– Associated complications: Severe bleeding, toxic megacolon, perforation, strictures, development of dysplasia and colorectal cancer
• Patients may have a slightly higher mortality vs general population
CD
• A disorder of uncertain etiology characterized by transmural inflammation of the gastrointestinal tract
– May involve the entire gastrointestinal tract from the mouth to the perianal area
– Hallmarks: Prolonged diarrhea with abdominal pain, with or without gross bleeding, fatigue, weight loss
• Patients can present with symptoms secondary to the transmural involvement of the bowel, including fistulas, phlegmon, abscess, perianal disease, and/or malabsorption
• Extraintestinal manifestations, such as arthritis, eye and skin disorders, biliary tract involvement, and kidney stones, may occur and tend to be more frequent with colonic involvement
• Typically involves small and/or large intestine, intermittent exacerbations of symptoms, periods of remission
UC = ulcerative colitis; CD = Crohn’s disease.www.UptoDate.com/IBD. Accessed July 22, 2016.
Clinical Progression of IBD and the Clinical and Economic Consequences of Undertreatment
• Treatment expenses make up a significant portion of the cost of IBD
• Studies show that inappropriate treatment, lack of adherence to therapeutic regimens, or suboptimal treatment increases the cost burden
• Costs for IBD: Hospitalizations, eventual need for surgery due to disease complications, physician visits
• Economic burden makes early diagnosis, coupled with effective treatment at onset, imperative
• Management must evolve beyond symptom control and toward sustained control of GI inflammation
– Measured by endoscopic, radiologic, and laboratoryparameters
• Compared to costs for those with mild or moderateUC, inpatient costs for those withsevere disease were more than 4 times higher
AJMC.com. Report: economic implications of inflammatory bowel disease and its management. Published online March 16, 2016. http://www.ajmc.com/journals/supplement/2016/Importance_of_Selecting_Appropriate_Therapy_Inflammatory_Bowel_Disease_Managed_Care_Environment/Importance_of_Selecting_Appropriate_Therapy_Inflammatory_Bowel_Disease_Managed_Care_Environment_Report_Economic_Implications_IBD/#sthash.MsHkOZ91.dpuf. Accessed July 22, 2016. AJMC.com. Report: economic implications of inflammatory bowel disease and its management, page 3. Published online March 16, 2016. http://www.ajmc.com/journals/supplement/2016/importance_of_selecting_appropriate_therapy_inflammatory_bowel_disease_managed_care_environment/importance_of_selecting_appropriate_therapy_inflammatory_bowel_disease_managed_care_environment_report_economic_implications_ibd/P-3#sthash.yTiHdcJY.dpuf. Accessed July 22, 2016.
Health Plan Paid Costsby Cost-Driver Category and
Pharmacy Costs for Crohn’s Disease
Pharmacy 45.5%
Inpatient Hospital 23.1%
Outpatient Hospital 15.7%
Emergency Department 2.6%
MD Office 8.2%
Home 1.4%
Other 3.2%
Adalimumab 32.5%
Infliximab Injection 27.0%
Certolizumab Pegol 5.9%
Mesalamine 8.3%
Budesonide 3.2%
Other Injectables 3.2%
Infusion Sets 0.9%
Other Drugs 19.0%
Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies
Raymond Cross, MD, MSProfessor of MedicineDirector, IBD Program
University of Maryland School of MedicineCo-Director, Digestive Health Center
University of Maryland Medical CenterBaltimore, Maryland
Goals of Therapy
• Induce clinical remission (absence of symptoms)
• Avoid short- and long-term toxicity of treatment
• Enhance quality of life
• Maintain corticosteroid-free remission
– Avoid repeated courses of corticosteroids!
• Induce “deep” remission
– Biologic remission (normalization of biomarkers)
– Mucosal healing
• Prevent complications and decrease unnecessary healthcare utilization (eg, hospitalizations, surgery)
Step-Up vs Top-Down Approach
TNF = tumor necrosis factor; 5-ASA = 5-aminosalicylic acid.Sandborn WJ. Gastroenterol Hepatol (N Y). 2007;3(1):16-17.
Corticosteroids
Immunesuppressants
Surgery
Anti-integrins
Anti-TNFs
Antibiotics and 5-ASAs
Short-Term and Long-TermResponse to Prednisone: 30-Day Outcomes
Faubion WA, Jr, et al. Gastroenterology. 2001;121(2):255-260.
DiseaseActivity
0 30 Days
Complete Response
CD (n=43) (58%)UC (n=34) (54%)
DiseaseActivity
0 30 Days
DiseaseActivity
0 30 Days
Partial Response
CD (n=49) (26%)UC (n=19) (30%)
Nonresponse
CD (n=42) (16%)UC (n=10) (16%)
Short-Term and Long-TermResponse to Prednisone: 1-Year Outcomes
Faubion WA, Jr, et al. Gastroenterology. 2001;121(2):255-260.
DiseaseActivity
1 Year
DiseaseActivity
1 Year
DiseaseActivity
1 Year
DiseaseActivity
1 Year
Prolonged Response
CD (27/74) (32%)UC (31/63) (49%)
Corticosteroid Dependency
CD (21/74) (28%)UC (14/63) (22%)
Duration of Trial (months)
80
60
40
20
0
Pat
ien
ts N
ot
Fa
ilin
g T
rial
(%
)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
100
58% fail to achieveremission
42%
7%
Efficacy of AZA as Maintenance Therapyin Patients with Active CD
AZA = azathioprine.Candy S, et al. Gut. 1995;37(5):674-678.
AZA 2.5 mg/kg/d (n = 33)
Placebo (n = 30)
P = .001
Moderate-to-Severe CD: Maintenance of Remission with MTX
• Multicenter, randomized,controlled trial
• 76 corticosteroid-dependent patients
• In remission following MTX 25 mgx 16 weeks
• Randomized to MTX15 mg or placebox 40 weeks
MTX = methotrexate.Feagan BG, et al. N Engl J Med. 2000;342(22):1627-1632.
30
0 4 12 2816 208 24 32 36 40
Weeks since Randomization
65% of 45% Responders = 30% Overall
80
70
100
90
60
50
40
Re
mis
sio
n (
%)
MTX
Placebo
n = 40
65%
n = 36
39%
Long-Term Maintenance ofRemission in CD
EOW = every other week; CDAI = Crohn’s disease activity index.Hanauer SB, et al. Lancet. 2002;359(9317):1541-1549. Colombel JF, et al. Gastroenterology. 2007;132(1):52-65. Sandborn WJ, et al. N Engl J Med. 2007;357(3):228-238.
60
40
20
10
0
Pa
tie
nts
(%
)
Reduction(≥70 Patients and≥25% in CDAI)
Response(∆100)
Remission(CDAI <150)
80
Certolizumab 400 mg every 4 weeks (PRECiSE 2) Placebo
27
5150
30
70
Weeks 26-30
26
52
36
63
21
39
17
40
29
48
Infliximab 5 mg/kg (ACCENT I) Adalimumab 40 mg EOW (CHARM)
N = 172 N = 215N = 113 N = 172 N = 215N = 113
51.8
69.4
54.6
18.7
38.8
18.5
43.2
62.0
46.9
Clinical Response, Clinical Remission, and Mucosal Healing Rates at 8 Weeks among Anti-TNFs
Rutgeerts P, et al. N Engl J Med. 2005;353(23):2462-2476. Reinisch W, et al. Gut. 2011;60(6):780-787. Sandborn, WJ, et al. Gastroenterology. 2014;146(1):85-95.
60
40
20
10
0
Pa
tie
nts
(%
)
Response Remission Mucosal Healing
80
IFX ADA Golimumab
50
30
70
Accent II:Fistula Response at Week 54
*P < .05.Sands BE, et al. N Engl J Med. 2004;350(9):876-885.
40
20
5
0
Pa
tie
nts
(%
)
Fistula Response Complete Response
50
30
10
23
46
35
15
45
25
19
36
*
*
PBO IFX
Factors Contributing to Non-Response or Loss of Response to Treatment
• No inflammation (irritable bowel syndrome, psychiatric disease)
• Complicated disease
• Other factors (bile-salt diarrhea, bacterial overgrowth, loss of ileocecal valve, short bowel syndrome, celiac disease)
• “Different” mechanism of inflammation
• “Deep-seated” or intractable disease
• Smoking
• Under treatment (dose, number of drugs)
• Pharmacokinetic issues
Long-Term Course of CD
N = 2002 patients with CD since diagnosis of the disease. Cosnes J, et al. Inflamm Bowel Dis. 2002;8(4):244-250.
Cu
mu
lati
ve
Pro
ba
bil
ity
(%)
Months
Probability of remaining free of complications
0 24 48 72 96 120 168 192 216 240144
100
90
80
70
60
50
40
30
20
10
0
Penetrating
Stricturing
Probability of Surgeryfor Patients with CD
Munkholm P, et al. Gastroenterology. 1993;105(6):1716-1723.
Years after Diagnosis
Patients (%)
NoSurgery
1Surgery
≥2Surgeries
5 51 37 12
10 39 39 23
15 30 34 36
62.5
18.2
Early Biologic Treatment Results in Higher Rates of Endoscopic Healing at 2 Years
D’Haens G, et al. Lancet. 2008;371(9613):660-667. Baert FJ, et al. Gastroenterology. 2010;138(2):463-468.
60
40
20
0
Pa
tie
nts
(%
)
Top-down
100
Simple Endoscopic Score 0
Simple Endoscopic Score 1-9
80
Complete EndoscopicHealing at 2 Years …and These Patients Did Better
in the Next 2 Years!
73
30
Step-up
P = .0028
60
40
20
0
Pa
tie
nts
in
Re
mis
sio
n (
%)
RemissionOff Corticosteroids
100
8070.8
27.3
Off Corticosteroids,No Anti-TNF
43.9
16.5
30.1
P < .001
P = .02
P = .06
47/10718/109 28/93
Comparative Effectiveness Study in CD (SONIC)
PBO = placebo; IFX = infliximab.Colombel JF, et al. N Engl J Med. 2010;362(15):1383-1395.
60
40
20
0
Pa
tie
nts
(%
)
AZA+
PBO
100
80
Clinical Remission
60
40
20
0
100
80
Mucosal Healing
IFX+
PBO
IFX+
AZA
56.8
30.0
44.4
P < .001
P = .006
P = .02
96/16951/170 75/169
AZA+
PBO
IFX+
PBO
IFX+
AZA
Combination Therapy Achieves High Mucosal Healing Rates in Early CD
*Statistical significance based Bonferroni correction for multiple comparisons (P ≤ .016).Early CD: Disease duration ≤18 months after diagnosis, no previous use of immunosuppressants and biologics, and no fistulas.IMM = immunomodulator; CRP = C-reactive protein.Colombel JF, et al. Aliment Pharmacol Ther. 2015;41(11):1211.
60
40
20
0
Pro
po
rtio
n o
f P
ati
en
ts (
%)
100
Infliximab Monotherapy Combination TherapyAzathioprine Monotherapy
80
Mucosal Healing in IMM andBiologic-Naïve CD Patients
(n=188)
29.6
43.6
65.3
12.9
25.6
52.3
60
40
20
0
100
80
30.8
43.5
70.4
10.0
25.0
64.7
Mucosal Healing inEarly CD
(n=63)
P < .001*
MucosalHealing
54n = 62 72
Clinical Remission+ CRPnorm +
Mucosal Healing
31 43 44
MucosalHealing
13 23 27
Clinical Remission+ CRPnorm +
Mucosal Healing
10 16 17
P < .001*
P = .038
P = .014*
P = .015*
P = .015*
P = .085
P = .037
P = .129
P = .245
P = .501
P = .617
UC SUCCESS: Corticosteroid-free Clinical Remission and Mucosal Healing at Week 16
*P < .05 compared to IS and IFX mono; **P < .05 compared to IS.Panaccione R, et al. Gastroenterology. 2014;146(2):392-400.e3.
70
40
20
10
0
Pa
tie
nts
(%
)
Clinical Remission Mucosal Healing
80
50
30
60
24 22
*40
37
55
**63
AZA + PBO IFX + PBO IFX + AZA
Vedolizumab Selectively Targets Leukocyte Adhesion in the Gut
• Natalizumabblocks both α4β1-and α4β7-mediated trafficking, resulting in systemic effects
• Vedolizumabonly targets α4β7 integrin, blocking lymphocytes trafficking to the gut
Rutgeerts P, et al. Gastroenterology. 2009;136(5):1844.
Vedolizumab
NatalizumabNatalizumabNatalizumab
Natalizumab
MLN-0002
PF-00547659,rhuMab-beta7
Integrins
Addressins
BrainBone MarrowOther Organs Gut
Endothelium
4741
VCAM-1 MadCAM-1
Leukocyte
†
25.6
Vedolizumab in CD: Second Induction Study Clinical Remission (CDAI ≤150) at Week 10
(Secondary Endpoint)
TNF = tumor necrosis factor ; VDZ = vedolizumab.*P < .0001; †P < .0012 based on the Cochran-Mantel-Haenszel chi-square test.Sands BE, et al. Gastroenterology. 2014;147(3):618-627.e3.
30
20
10
5
0
Pro
po
rtio
n o
f P
ati
en
tsA
ch
iev
ing
Cli
nic
al
Re
mis
sio
n (
%)
Overall Population
(PBO, n = 207; VDZ, n = 209)
Anti-TNF-Failure Population
(PBO, n = 157; VDZ, n = 158)
35
PBO
VDZ
25
15 13.0
*28.7
12.1
21.6
39.036.4
30.1
43.5 45.5
15.9
31.728.8
14.4
21.4
16.2
GEMINI II: Vedolizumab in CD through Week 52, Maintenance Intention to Treat
Q8W = every 8 weeks; Q4W = every 4 weeks.Sandborn WJ, et al. N Engl J Med. 2013;369(8):711-721.
60
40
20
10
0
Pa
tie
nts
(%
)
ClinicalRemission
CDAI-100Response
Durable ClinicalRemission
80
50
30
70
P < .001
Vedolizumab Q8W (N = 154) Vedolizumab Q4W (N = 154)Placebo (N = 153)
Glucocorticoid-FreeRemission
P = .004
P = .01
P = .005
P = .02
P = .04
Vedolizumab in UC:Clinical Response, Clinical Remission, and
Mucosal Healing at 6 Weeks
CI = confidence interval.Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.
Vedolizumab (n = 225)Placebo (n = 149)
60
40
20
10
0
Pa
tie
nts
(%
)
Clinical Response Clinical Remission Mucosal Healing
80
50
30
70
25.5
47.1
∆ 21.7(95% CI: 11.6, 31.7)
5.4
16.9
∆ 11.5(95% CI: 4.7, 18.3)
24.8
40.9
∆ 16.1(95% CI: 6.4, 25.9)
Vedolizumab in UC:Clinical Outcomes at 52 Weeks by Prior TNF
Antagonist Exposure
Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.
60
40
20
10
0
Pa
tie
nts
(%
)
ClinicalRemission
80
Vedolizumab Q8W Vedolizumab Q4WPlacebo
50
30
70
Prior Anti-TNFAntagonist Exposure
(n = 149)
10.6
36.040.4
19.1
44.0 46.2
Durable ClinicalResponse
60
40
20
10
0Clinical
Remission
80
50
30
70
19.1
45.8 47.9
26.6
63.5
56.2
Durable ClinicalResponse
Patients without TNFAntagonist Exposure
(n = 224)
Historical Management Strategies for IBD Are Flawed
• Non-biologic therapies have not modified the natural history of the disease
• Symptoms do not correlate well with inflammation in patients with CD
• Treatment decisions have been based on symptoms alone
– Adjustments to therapy are delayed and allow progressionof disease
• Step-up approach does not distinguish betweenlow-risk and high-risk patients
AGA Clinical Pathway for CD:Stratifying Patients by Risk for Disabling Course
AGA = American Gastroenterological Association.Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95.
Low Risk
Limited anatomic involvement
Age at diagnosis >30 years
Superficial ulcerations at endoscopy
No prior surgery
Non-stricturing, non-penetrating disease
High Risk
Extensive anatomic involvement
Deep ulcers
Age at diagnosis <30 years
Perianal disease and/or severe rectal disease
History of prior resection
Complicated disease behavior
AGA Clinical Pathway for CD:
Initial Treatment
Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95.
Low-risk Patient
Ileum and/or proximal colon, none to minimal symptoms
Options
• Budesonide 9 mg/d with or without AZA
• Tapering course of prednisone with or without AZA
Diffuse or left colon,none to minimal symptoms
Option
• Tapering course of prednisone with or without AZA
Moderate/High-risk Patient
Options
• Anti-TNF monotherapy over no therapy or thiopurine monotherapy
• Anti-TNF + thiopurine over thiopurine monotherapy or anti-TNF monotherapy
• Methotrexate for patients who do not tolerate purine analog in combination with anti-TNF
AGA Clinical Pathway for UC:
Stratifying Patients by Colectomy Risk
ESR = erythrocyte sedimentation rate; CMV = cytomegalovirus.Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95.
Low Risk
Limited anatomic extent
Mild endoscopic disease
High Risk
Extensive colitis
Deep ulcers
Age <40 years
High CRP and ESR
Corticosteroid-requiring disease
History of hospitalization
Clostridium difficile infection
CMV infection
AGA Clinical Pathway for UC:
Induction and Maintenance Therapy
Dassopoulos T, et al. Gastroenterology. 2015;149:238-245.
• Short course of corticosteroids with initiation of thiopurine or
• Anti-TNF with or without thiopurines
• Vedolizumab with or without immunomodulator
• Oral 5-ASA and/or
• Rectal 5-ASA and/or
• Oral budesonide or prednisone and/or
• Rectal corticosteroids
• Maintenance with oral 5-ASA and/or rectal 5-ASA
• Taper corticosteroid over 60 days
Remission
No remission
Options
• Anti-TNF ± thiopurine
• Thiopurine (optimize 6-TGN concentrations)
• Vedolizumab ±immunomodulator
• Proctocolectomy
Maintenance Options
• Thiopurine and taper corticosteroids over60 days
• Anti-TNF with or without thiopurine
• Vedolizumab with or without thiopurine or methotrexate
No remissionRemission
Low-Colectomy-Risk Patient High-Colectomy-Risk Outpatient
What Are the Risks ofAnti-TNF Therapy?
• Increased risk of serious and opportunistic infection
• Increased risk of paradoxic autoimmune reaction
– Psoriasis
– Lupus-like syndrome
– Multiple sclerosis
• Increased risk of melanoma
• Further increased risk of infection and skin cancer and increased risk of lymphoma when combined with thiopurines
Lichtenstein GR, et al. Am J Gastroenterol. 2012;107(7):1051-1063. Toruner M, et al. Gastroenterology. 2008;134(4):929-936. Siegel CA, et al. Clin Gastroenterol Hepatol. 2009;7(8):874-881. Long MD, et al. Clin Gastroenterol Hepatol. 2010;8(3):268-274. George LA, et al. Dig Dis Sci. 2015;60(11):3424-3430.
When to Operate orStart/Switch Biologics?
Most Patients Require Surgery after Treatment for Complicated CD
Samimi R, et al. Inflamm Bowel Dis. 2010;16(7):1187-1194.
Time (years)
0.60
0.40
0.20
0
Su
rviv
al D
istr
ibu
tio
n F
un
cti
on
0.0 0.5 1.0 1.5 2.0 2.5
1.00
Product-Limit Estimate Curve
Time to Relapse or Surgery
Postoperative complication rate32% in patients exposed to anti-TNF
Censored Observations
0.80
Cumulative Probability of Abscess Recurrencein Medically vs Surgically Treated Patients
Nguyen DL, et al. Clin Gastroenterol Hepatol. 2012;10:400-404.
Time (years)
80
60
40
20
0
Pro
ba
bil
ity
of
Ab
sc
es
s
0 2 4 6 8 10
100
Medical Surgical
Two-thirds of patientshad recurrence in first 30 days
Biologics Decrease Surgery due to“Low-Risk” Strictures in Patients with CD
• Historical cohort study of 241 patients with stricturing CD having computed tomographic enterography or magnetic resonance enterography
• 49% surgery within a median of 1 year
SSS = stricture severity score; AUC = area under the curve.Nepal S, et al. Gastroenterology. 2012;142(5):S190-S191.
• Biologics may reduce the risk of surgery by up to 44% in stricturing CD
• This benefit may be more pronounced in patients with a “low-risk” (SSS = 0) enterographic finding
0 0.5 1.5 2.5
60 34 28 22 14 4 2 0
80
100
60
Su
rger
y-fr
ee (
%)
00 0.5 1.5 2.5
40
20
39 32 30 25 17 9 6 3
1.0 2.0 3.0 3.51.0 2.0 3.0 3.5
60 36 31 23 16 9 7 247 34 26 22 13 9 5 2
Biologics
No Biologics
Years Years
SSS 0
No Biologics
SSS 1-5
Biologics
P = .007 P = .3
Development SSS Score
Internal fistula
Small bowel obstruction
Prox. dilation ≥3 cm
Abdominal mass/abscess
Mesenteric stranding
AUC = .7 for predictingsurgery at 1 year
IFX Reduces PostoperativeRecurrence after Intestinal Resection
Regueiro M, et al. Gastroenterology. 2009;136(2):441-450.
80
40
10
0
Pa
tie
nts
(%
)
Placebo IFX
100
60
20
84.6
9.1
70
30
90
50
Endoscopic Recurrence: Endoscopic Scores of i2, i3, or i4
Summary
• Look beyond symptoms in patients with IBD, particularly those with CD
• Consider early biologic therapy with or without IS in patients at high risk of disability
• Concurrent IS with an anti-TNF results in greatest efficacy
– Avoid combination therapy in older patients, those with comorbidities, and those with recent prior cancer
• Search for a reason for incomplete or loss of response to biologics
• Vedolizumab is an alternative to anti-TNF, particularly when use of anti-TNF is contraindicated or higher risk
Evaluating theCosts and Benefitsof Newer IBD Pharmacotherapies
Jeffrey D. Dunn, PharmD, MBAChief Clinical Officer/Senior Vice President
VRx Pharmacy ServicesSalt Lake City, Utah
Sales of Specialty DrugsContinue to Grow
PMPY = per member per year.Artemetrx. Specialty drug trends across the pharmacy and specialty benefit. 2015. Available at: http://www.artemetrx.com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf.
Spending on Specialty Drugs Projected toSurpass Sales of Traditional Agents by 2018
1200
800
400
200
0
Fo
rec
as
ted
PM
PY
Ne
t D
rug
Sp
en
d (
$)
2012 2015 2018
1800
Traditional Specialty
1000
600
1400
665
290
2014 20172013 2016
1600
675
348
694
425
722
514
751
612
789
722
836
845
Inflammatory Disease Remains a Key Driver of the Specialty Drug Trend
Express Scripts. Drug Trend Report 2015. Available at: http://lab.express-scripts.com/lab/drug-trend-report. Accessed April 11, 2016.
Trend
Rank Therapy Class PMPY Spend ($) Utilization (%) Unit Cost (%) Total (%)
1 Inflammatory conditions 89.10 10.3 14.7 25.0
2 Multiple sclerosis 53.31 3.5 6.2 9.7
3 Oncology 49.62 9.3 14.4 23.7
4 Hepatitis C 38.44 -2.2 9.2 7.0
5Human immunodeficiency virus
31.53 4.6 12.0 16.6
6 Growth deficiency 7.12 2.8 2.8 5.6
7 Cystic fibrosis 6.64 12.5 40.9 53.4
8 Pulmonary hypertension 5.85 13.4 4.8 18.1
9 Hemophilia 5.79 4.9 15.4 20.4
10 Sleep disorders 4.57 5.5 18.5 24.1
Total Specialty $341.21 6.8% 11.0% 17.8%
Inflammatory Disease
• Other class of drugs
– Ustekinumab and apremilast = psoriatic arthritis and plaque psoriasis
– Anakinra = RA
*Also indicated for cancer.RA = rheumatoid arthritis; IL = interleukin; TNF = tumor necrosis factor. FDA.gov. http://www.fda.gov/. Accessed July 21, 2016.
Disease Tocilizumab GolimumabCertolizumab
PegolRituximab* Abatacept Adalimumab Etanercept Infliximab Vedolizumab
Tofacitinib Citrate
MOA Anti-IL-6ra Anti-TNF Anti-TNF Anti-B Cells Anti-T Cell Anti-TNF Anti-TNF Anti-TNF Anti-Integrin Anti-TNF
Indications
RA x x x x x x x x x
Juvenile RA x x x x
Psoriatic arthritis x x x x x
Ankylosing spondylitis x x x x x
CD x x x x
Plaque psoriasis x x x
UC x ”Soon” x x x
*Infliximab, adalimumab, golimumab, or other approved anti-TNF therapy.•Anti-TNF agent or vedolizumab.6-MP = 6-mercaptopurine; AZA = azathioprine; anti-TNF = anti-tumor necrosis factor agents.https://www.uptodate.com/contents/search?source=USER_PREF&search=ulcerative+colitis+guidelines+graph&searchType=GRAPHICS.
Example of Guidelines:Corticosteroid-Dependent UC
Check serum biologic levels,check for neutralizing antibodies
RelapseFail Relapse
Low biologic level,no antibodies
Low biologic level,antibodies present
Adequate biologiclevel, no antibodies
Dose escalatebiologic
Switch to a biologicin the same class
Switch to a differentclass of biologic
Wean corticosteroids;maintain 6-MP/AZA
Relapse
FailWell FailResponse tocyclosporine
Response toinfliximab
Wean corticosteroids;maintain biologic•
SurgeryInitiate 6-MP/AZA;wean corticosteroids,
thenwean cyclosporine
Initiate 6-MP/AZA;wean corticosteroids,continue infliximab
Well Allergic; failureCyclosporineor infliximab
Previous/current6-MP/AZA failure/allergy?
Previous/current6-MP/AZA failure/allergy?
No6-MP/AZA Anti-TNF* orvedolizumab
Able/willing to remain on corticosteroids
while slow-acting agent started?
Patient responding to systemic corticosteroids
but unable to wean without relapse
NoYes
No Yes
EntryPoint“A”
Guideline: Changing Paradigm
• Step-up vs top-down therapy
• Better understanding of the disease has led to a more targeted and refined approach to using biologic agents
• Newer evidence suggests a rationale for changing the management of IBD
– Using mucosal healing as an endpoint
– Using immunosuppressive and biologic agents earlier, particularly in CD
Devlin SM, et al. Med Clin North Am. 2010 Jan;94(1):1-18. doi: 10.1016/j.mcna.2009.08.017.Source: Expert Rev Gastroenterol Hepatol © 2010 Expert Reviews Ltd.
Anti-TNF
AZA / MTX
Corticosteroids
5-ASA / SPS
Anti-TNF
AZA / MTX
Combination
Corticosteroids
Step-UpTherapy
Top-DownTherapy
UC: Updated Evidence
• Vedolizumab is effective for induction and maintenance of remission in outpatients with moderate to severe UC or CD who have not responded to conventional and anti-TNF therapy
• Infliximab was statistically superior to adalimumab after induction
• Golimumab was statistically superior to adalimumab for sustained outcomes
Thorlund K, et al. Expert Rev Gastroenterol Hepatol. 2015;9(5):693-700.
CD: Updated Evidence
• Vedolizumab is effective for induction and maintenance of remission in outpatients with moderate to severe UC or CD who have not responded to conventional and anti-TNF therapy
• No comparative trials have evaluated the relative efficacy of infliximab, adalimumab, and certolizumab
Bryant RV, et al. J Crohns Colitis. 2015;9(4):356-366. Behn BW, et al. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006893.
Medication Adherence Factors
• Effectiveness
• Adverse events
• Drug interactions
• Concomitant medications (eg, methotrexate)
• Cost/benefit
– Access to care
• Other factors
– Patient’s age
– Full-time employment
– Male gender
– Discordance between patient and provider
– Complex dosing regimens (three-times-daily dosing or a large number of tablets)
– Disease education
• Lack of counseling to patients and access to care challenges
Bokemeyer B, et al. Aliment Pharmacol Ther. 2007;26:217-225. Jackson CA, et al. Am J Gastroenterol. 2010;105:525-539.
Quality Improvement
• No specific IBD quality measures exist
– Lack of objective, easy-to-use measures
• Education
– Symptoms to“mucosal healing”
• Measures have to be standardized but individualized at thesame time
Kappelman MD, et al. Inflamm Bowel Dis. 2010;16:125-133.
• What dowe want to accomplish
• What changes might be useful
• How will we measure progress
• Carry out the plan
• Document issues
• Record chosen outcomes
• What changes should be made
• How can we improve from past experience
• Analyze data• Where were
effects insufficient• What was
learned
Specialty Pharmacy Strategy:The Equation
Specialty Drug
Manage-ment
Drug Dispensing
Utilization Management
Coordinationof Care
Contracting Activities
BenefitDesign
(Cost Share)and
Formulary
Benefit Design: Multi-Tier Structure
• All specialties are NOT created equal
• 12 of 36 health plans with specialty strategy have multi-tier specialty cost share
– Accounts for 45% of covered lives
• 93% of pharmacy benefits managers plan to increase use of specialty tier in the next 24 months
• Opportunity
– Multi-tier specialty formulary
• Generic specialty tier
• Preferred specialty tier
• Non-preferred specialty tier
• Optional to clients but structure in place for those who want to participate in specialty strategy
AMCP. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.
Multi-Tier Structure
Benefits
• Further differentiation of specialty class
– Cost management
– Ability to manage specialty classes
• Contracting benefits
• Provides a strategy solution for employer groups and health plans
Possible Challenges
• Multiple layers adds confusion
– Client
– Member
– Customer service
– Internal
• More time spent managing the formulary
Managed Care Review Board. An analysis of treatment options, comparative effectiveness research, and benefit designs for rheumatoid arthritis. http://www.impactedu.net/nexusra15/AMCP%20Nexus%202015%20RA%20Satellite%20Symposium%20Slides_Impact%20Education.pdf.
Tier Specialty “Opt In” (%) “Opt Out” (%)
4 (generic) 10 20
5 (preferred) 20 20
6 (non-preferred) 40 20
Drug Dispensing
• Site-of-care optimization
MD = medical doctor; HOPD = hospital outpatient department.Internal Utilization and Pricing Data.
Infliximab Site-of-Care Example
Place of ServiceCost per
UnitUnits
Cost per Claim
Claims per Year
Annual Cost
MD office or home infusion
$70 50 $3500 7 $24,500
HOPD (average) $111 50 $5500 7 $38,850
HOPD (highest cost hospital)
$360 50 $18,000 7 $126,000
Utilization Management
• PAs
• Step-therapy
• Quantity limits
• Reporting
PA = prior authorization.EMD Serono Specialty Digest, 9th Edition. Managed Care Strategies for Specialty Pharmaceuticals. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.
83%
85%
74%
72%
75%
68%
71%
78%
79%
78%
72%
74%
70%
68%
13%
7%
17%
16%
9%
14%
11%
11%
9%
7%
11%
9%
12%
10%
GH Disorders
RA/Crohn's Disease (SC)
Hepatitis C (Oral)
MS (Oral)
Hepatitis C (SC)
ESAs
MS (SC)
RA/Crohn's Disease (IV)
Psoriasis
Botulinum Toxins
RSV
MS (IV)
Immune Globulin (IV)
Immune Globulin (SC)
96%
83%
83%
85%
88%
89%
82%
82%
84%
88%
91%
92%
82%
78%
Use of Prior Authorizations by Disease State (%)
50 60 70 80 90 100
2011 % Change from 2011 2012
Utilization Management (cont)
Analysis
• Review specialty database for clinically appropriate quantity limits and PAs
– Opportunities exist to further control utilization by implementing PAs and QLs on medications
• Evaluate effectiveness of PA/step-therapy
Outcomes
• PAs may not help and may increase work and costs to
– Client
– Member
– Customer service
– Internal
• Evaluate requests and approvals/denials/appeals
QL = quantity limits.EMD Serono Specialty Digest, 9th Edition. Managed Care Strategies for Specialty Pharmaceuticals. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.
Care Management
Opportunity
• Costs will continue to increase
– How to get the most out of drug spend
• Fill the specialty pharmacy “gap”
– Education on use
– Education on side effects
– Adherence
– Site-of-care optimization
AMCP. http://www.amcp.org/EMDSeronoSpecialtyDigest9th.pdf. Accessed July 22, 2016.
80
40
10
0
Pla
ns
(%
)
EnsureDose
Accuracy
100
60
20
88
57
70
30
90
50
Specialty Pharmacy Services
Most Valuable Services (top 4+5) Satisfaction with Services (top 4+5)
85
46
76
44
76
61
75
58
75
41
73
50
69
36
ManageDrug
Waste& Abuse
AdherenceMeasurement
LimitedDistribution
DrugAccess
AdherencePrograms
SavingsMeasurement
TrackPatient
Interventions
TrackOutcomesof Patient
Interventions
Specialty Care Management
Program
• Specialty pharmacy medication therapy management
– Integrate with care management
– Coordinate site of care
– Ensure appropriate dosing
– Ensure adherence
– Provide education on use
– Ensure expectation management
– Address barriers
Actions
• Design program workflow and integration with care management
• Analyze utilization to select targeted drugs/disease states
• Train personnel
– Specialty diseases
– Medications
– Site-of-care logistics
Traditional Management Approach
• Many available programs focus on proper utilization and improving the quality of care
– Programs tend to be fragmented with little to no collaboration
Internal Data. VRx.
Chronic
Disease
Management
Acute Care
Management
Medication
Therapy
Management
Utilization
Review
Mental
Health
Management
Integrated Care Management
• Patient care is complex
• Integration
– Unites different viewpoints
– Allows management of every aspect of patient care
MENTALHEALTHCARE
MANAGER
Incorporatessocial
and behavioralcomponents of care
PHARMACISTCARE
MANAGER
Approaches carefrom a treatment-based
perspective focusedon disease and drug
information
NURSE CAREMANAGER
Supports and advocatesfor patients,
helping them navigatethe healthcare system
and obtainappropriate care
Other Strategies for Improving Management, Education, and Adherence
• Encourage pay-for-performance
– Offers incentives for medication compliance
– Can be either patient or provider targeted
• Strengthen patient-provider relationships
– As prescription costs increase, medication underuse increases
– In patients grouped by level of trust for their physician, the low-trust group was less likely to be adherent than the high-trust group
• Empower the patient
– Address the complex interaction of motivations, cues to action, perception of benefits and consequences, expectancies, environmental and cultural influences, self-efficacy, state of readiness to change, ambivalence, and implementation intentions
• Integrate communication channels
– Communicate respect for the patient's perspective of his/her condition
– Provide rationale for any recommended treatment
– Negotiate a plan and anticipate and address problems
– Discuss adherence at every visit in a nonjudgmental way
– Establish a collaborative process of problem-solving
Butterworth SW. J Manag Care Pharm. 2008;14(6)(suppl S-b):S21-S25. Piette JD, et al. Arch Intern Med. 2005;165:1749-1755.
15
10
5
0Pat
ien
ts w
ith
Co
st-R
elat
ed U
nd
eru
se (
%)
<$51
35
25
$51-$100
High-Trust Group (n=557)
Low-Trust Group (n=355)
Monthly Prescription Cost
30
20
>$100
Comparative Effectiveness Research
• Pharmacists, physicians, payers, policy makers, and patients most often rely on incomplete data when making healthcare decisions
• Lack of head-to-head comparisons of competing treatment alternatives can lead to a “trial-and-error” approach todecision-making
• If effectively designed and conducted, CER can help fill data gaps
– Used to compare drug therapies in the absence of head-to-head data
– Applicable to a variety of practice settings and diversity of patients
CER = comparative effectiveness research.Brixner DI, et al. J Manag Care Pharm. 2012;18(Suppl 4-a):S3-S4.
Benefit Design
Formulary Positioning
Coverage Decisions
CAN IT WORK? DOES IT WORK? IS IT WORTH IT?
RandomizedControlled Trials
AccumulatedEvidence
Health TechnologyAssessments
ComparativeEffectiveness
Research
Informed Decision Making
Clinical GuidelinesTreatment Pathways
CER Used to Differentiate the Effectiveness vs Efficacy of Treatment Alternatives
Drummond MF, et al. Int J Technol Assess Health Care. 2008;24:244-258.
CER in Formulary and Benefit Design: How to Evaluate without Head-to-Head Trials
• Identify and target key trials with similar patient characteristics, outcome measures, inclusion/exclusion criteria, etc
• Evaluate drug benefit minus placebo benefit over defined time frame of defined and appropriate outcome measure(s)
• Determine appropriate costs over same period
• Divide cost into drug benefit
• Compare cost to achieve predefined response
– “How much do we pay for an outcome with all of the drugs?”
• Hold industry accountable
Diagnosis Criteria: CDAI
• CDAI scores are frequently used to assess disease severity
– Score 0 to >600 based on a diary of symptoms kept by the patient for 7 days
• Remission: <150
• Response: Decrease >70
– >100 in recent clinical trials
• Mild disease: 150-220
• Moderate to severe disease: 220-450
• Severe disease: >450
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0048967/. Accessed July 22, 2016.
Variable Scale Weight
Liquid or very soft stool
Daily stool count is summed for 7 days 2
Abdominalpain
Sum of 7 days of daily ratings as 0=None, 1=Mild, 2=Moderate, 3=Severe
5
General well-being
Sum of 7 days of daily ratings as 0=Generally well, 1=Slightly below par, 2=Poor, 3=Very poor, 4=Terrible
7
Features of extraintestinal disease
Presence of any of the following in the previous 7 days
• Arthritis or arthralgia• Skin or mouth lesions (erythema nodosum,
aphthous ulcers, pyoderma gangrenosum)• Iritis or uveitis• Anal fissures, fistulas, perianal abscess• Other external fistulas• Fever >100˚F
20each
Opiates for diarrhea
0=No, 1=Yes 30
Abdominal mass
0=None, 2=Questionable, 5=Definite 10
HematocritMen 47% hematocritWomen 42% hematocrit
6
Body weight 100 x [1-(body weight/standard weight)] 1
Summary of Clinical Trials: UC
Note: Values in parentheses indicate placebo values.SQ = subcutaneous; EOW = every other week; BIW = biweekly; W = week.FDA.gov. http://www.fda.gov/. Accessed July 21, 2016. Reinisch W, et al. Gut. 2011;60(6):780-787. Sandborn WJ, et al. Gastroenterology. 2012;142:257-265.
Parameter Adalimumab Etanercept Infliximab Golimumab Vedolizumab
Dose40 mg SQ
EOW 25 mg SQ
BIW5 mg/kg IVevery 8 W
100 mg SQevery 4 W
300 mg IVevery 8 W
Clinicalremission at 8 weeks
18.5%(9.2%)
Not indicated34%(6%)
18%(6%)
17%(5%)
Clinical remission at 8 and52 weeks
16.5%(9.3%)
Not indicated35%
(17%)28%
(16%)42%
(16%)
Summary of Clinical Trials: CD
Note: Values in parentheses indicate placebo values.FDA.gov. http://www.fda.gov/. Accessed July 21, 2016.
Parameter Adalimumab Etanercept Infliximab Certolizumab Vedolizumab
Dose40 mg SQ
EOW 25 mg SQ
BIW5 mg/kg IVevery 8 W
400 mg SQevery 4 W
300 mg IVevery 8 W
Clinicalremission at 4 weeks
36%(12%)
Not indicated22%
(17%)15%(7%)
Clinical remission at 26 weeks
40%(17%)
Not indicated39%
(25%)29%
(18%)
Clinical remission at 52 weeks
36%(12%)
Not indicated NR39%
(22%)
CER in Formulary and Benefit Design: How to Evaluate without Head-to-Head Trials (Recap)
• Identify and target key trials with similar patient characteristics, outcome measures, inclusion/exclusion criteria, etc
– CDAI: Choose appropriate studies
• Evaluate drug benefit minus placebo benefit over defined time frame of defined and appropriate outcome measure(s)
• Determine appropriate costs over same period
– Rebates
• Divide cost into drug benefit
• Use comparative effectiveness research
• Compare cost to achieve predefined response
– “How much do we pay for an outcome with all of the drugs?”
Biologic = Specialty Drug
Close, but… What have we learned in 8 years?
What is abiosimilar?
Biosimilar Issues
• Cost
• Rating / interchangeability
– States to determine
– Batch variance???
– Naming?
• Data extrapolation/ indications
• Safety
• Manufacturing
• Provider acceptance
– Depends on disease state
– Risk (financial vs clinical)
• Experience
– In Europe since 2006
Biosimilar Pipeline
www.biopharma.com/biosimilars/pipeline.pdf.
Summary
• IBD is a significant cost driver
• Education is needed
• Strategies to improve cost and care include
– Utilization management
– Site-of-care/channel management
– Coordinated and integrated care management
• Contracting and pricing have to change
• Biosimilars may play an important role
– But are we ready?
Questions?