HTA and innovative treatments evaluation: the case of metastatic castration-resistant prostate cancer

Figures & data

Table 1 Methods used for the assessment of each HTA dimension

Dimension	Sub-dimension	Quantitative and qualitative metrics for the evaluation
General relevance	Target population eligible to AA+P or ENZA treatment	mCRPC prevalence and incidence rate of the Italian male population, derived from scientific evidence^Citation3,Citation37,Citation40,Citation41
Safety	Rate of mild, moderate and severe adverse events	% incidence of adverse events, derived from literature evidence, whose clinical management and treatment were economically valorized.^Citation13,Citation14
	Qualitative perception on the real-world safety profile	The 10 mCRPC experts involved in the analysis, completed a comparative qualitative questionnaire, based on a 7-item Likert scale (ranging from −3 to +3), considering the following items, thus retrieving a country-oriented safety indicator: i) development of severe drug-related adverse events; ii) development of mild and moderate drug-related adverse events; iii) development of drug interactions; iv) overall degree of safety and tolerability of hormone therapy; v) impact of the hormone therapy on pain perceived by the patient; vi) impact of side effects related to the use of prednisone; vii) impact of the hormone therapy on the increase systemic exposure, in association with food.
Efficacy	Efficacy indicators	Overall survival (OS) and radiographic progression-free survival (rPFS) rates, derived from randomized clinical trials on the topic, comparing AA+P or ENZA with placebo.^Citation13,Citation14
	Qualitative perception on the real-world effectiveness profile	The 10 mCRPC experts involved in the analysis, completed a comparative qualitative questionnaire, based on a 7-item Likert scale (ranging from −3 to +3), considering the following items, thus retrieving a country-oriented effectiveness indicator: i) improvement in patient reported outcomes; ii) improvement in the overall survival; iii) improvement in the progression-free survival; iv) decrease in the tumor mass; v) time to start treatment with cytotoxic chemotherapy; vi) prostate specific antigen response, in terms of a reduction equal to ≥50% with respect to the baseline; vii) time to prostate specific antigen progression.
Economic and financial impact	Activity Based Costing Analysis	Economic evaluation of the clinical pathway of mCRCP patients assuming AA+P or ENZA.
	Cost-effectiveness analysis	Cost-effectiveness value, calculated as clinical pathway costs divided by efficacy data (OS), derived from literature evidence.^Citation13,Citation14
	Budget impact analysis	The above-mentioned clinical pathway cost per patient was multiplied by the total number of patients diagnosed with mCRPC, thus comparing a baseline with an innovative scenario.
Equity impact	Equity perceived aspects	The 10 mCRPC experts involved in the analysis, completed a comparative qualitative questionnaire, based on a 7-item Likert scale (ranging from −3 to +3), considering the following items: i) access to care at a local level; ii) access to care for person of a legally protected status; iii) impact on the hospital waiting lists; iv) generation of health migrations; v) presence of factors influencing the patient’s ability and autonomy; vi) protection of persons of a legally protected status; vii) level of iniquity.
Social and ethical impact	Social and ethical perceived aspects	The 10 mCRPC experts involved in the analysis completed a comparative qualitative questionnaire, based on a 7-item Likert scale (ranging from −3 to +3), in accordance with the following aspects: i) ability of the drug to protect the patients’ autonomy; ii) ability of the drug to protect the human rights; iii) ability of the drug to protect the patients’ integrity; iv) ability of the drug to protect the patients’ dignity; v) the use of the drug guarantees the social values and the willingness to pay of the patient; vi) impact of the drug on social costs; vii) patients and citizens can have a good level of understanding of the drug; viii) impact of the drug on patients’ satisfaction; ix) impact of the drug on the patient’s perceived quality of life; x) impact of the drug on the care giver’s life and perception; xi) impact of the drug on the patient’s functional state; xii) ease of swallowing the tablet; xiii) impact on the daily intake of the drug, in terms of number of pills.
	Quantitative social costs	Definition of the number of hospital accesses for monitoring activities.
Legal impact	Legal perceived aspects	The 10 mCRPC experts involved in the analysis completed a comparative qualitative questionnaire, based on a 7-item Likert scale (ranging from −3 to +3). In accordance with the following aspects: i) authorization level (national/European/international); ii) need to insert the technology into the registry at National and/or European level; iii) fulfillment of the safety requirements; iv) infringement of intellectual property rights; v) need to regulate the technology acquisition; vi) legislation covers the regulation of technology for all categories of patients.
Organizational impact	Organizational perceived aspects	The 10 mCRPC experts involved in the analysis completed a comparative qualitative questionnaire, using a 7-item Likert scale (ranging from −3 to +3), in accordance with the following aspects. i) additional staff; ii) training course for the clinicians of reference; iii) training course for the healthcare professionals involved in the pathway; iv) hospital meetings required; v) impact of the drug on patient’s management, in terms of follow-up monitoring activities; vi) impact of the drug on hospital waiting lists; vii) impact of the drug on treatment duration; viii) impact of the technology on the hospital purchasing processes; ix) impact of the drug on the internal processes; x) impact of the drug on the patient’s clinical pathway.
	Organizational quantitative aspects	Definition of the time spent for AA+P and ENZA monitoring activities.

Figure 1 Prisma flow chart.

Table 2 Qualitative and quantitative assessment of scientific evidence included in the HTA report

Qualitative assessment – New Castle–Ottawa Scale^Citation28	Selection	Comparability	Outcome
Ryan et al, 2015	4/4	2/2	3/3
Beer et al, 2017	4/4	2/2	3/3
Loriot et al, 2015	4/4	2/2	3/3
Quantitative assessment - IMPAQHTA model^Citation29	Quality	Replicability	Completeness
Ryan et al, 2015	4	4	4
Beer et al, 2017	4	4	4
Loriot et al, 2015	3	4	3

Table 3 Rate and economic evaluation of drug-related adverse events

Adverse events	Economic evaluation	Rate of adverse events AA+P	Rate of adverse events ENZA	Economic evaluation of AA+P adverse events	Economic evaluation of ENZA adverse events
Acute renal failure	3,826.57€	–	1.00%	–	38.27€
Adrenocortical insufficiency	3,529.64€	0.40%	-	14.12€	–
Asthenia/Fatigue	315.29€	1.90%	2.30%	5.99€	7.25€
Alanine Transferase increased	364.56€	5.30%	0.20%	19.32€	0.73€
Aspartate Aminotransferase  increased	364.56€	2.70%	–	9.84€	–
Atrial fibrillation	2,407.28€	1.60%	0.20%	38.52€	4.81€
Back pain	527.90€	–	1.70%	–	8.97€
Cardiac events	4,700.00€	6.60%	1.70%	310.20€	79.90€
Dyspnea	1,484.00€	2.10%	0.40%	31.16€	5.94€
Edema	487.30€	0.30%	0.10%	1.46€	0.49€
Fall	4,441.90€	–	1.10%	–	48.86€
Hematuria	336.73€	1.10%	0.90%	3.70€	3.03€
Hyperglycemia	1,491.62€	5.60%	-	83.53€	–
Hypertension	963.00€	3.40%	5.00%	32.74€	48.15€
Hypokalemia	1,809.96€	2.40%	-	43.42€	–
Joint swelling	5,636.42€	1.80%	1.10%	39.28€	24.00€
Lower respiratory tract infection	447.97€	–	1.00%	–	4.48€
Lymphopenia	5,636.42€	7.50%	–	422.73€	–
Non- pathological fracture	2,571.63€	–	1.40%	–	36.00€
Posterior Reversible Encephalopathy Syndrome (PRES)	2,077.00€	–	0.10%	–	2.08€
Seizure	3,289.00€	–	0.10%	–	3.29€
Total cost related to the management of drug-related adverse events				1,056.02€	316.25€

Table 4 Qualitative dimensions evaluation

Effectiveness profile	AA+P	ENZA
Improvement in patient reported outcomes	1.25	1.25
Improvement in the overall survival	1.75	1.75
Improvement in the progression-free survival	1.25	2.00
Decrease in the tumor mass	1.25	1.25
Time to start treatment with cytotoxic chemotherapy	1.25	1.75
Prostate specific antigen response, in terms of a reduction equal to ≥50% with respect to the baseline	0.75	1.00
Time to prostate specific antigen progression	1.25	1.00
Average value for the effectiveness profile	1.25	1.43
Safety profile	AA+P	ENZA
Development of severe drug-related adverse events	0.00	0.25
Development of mild and moderate drug-related adverse events	−0.50	−0.25
Development of drug interactions	0.50	0.50
Overall degree of safety and tolerability of hormone therapy	0.75	1.25
Impact of the hormone therapy on pain perceived by the patient	1.50	0.75
Impact of side effects related to the use of prednisone	−0.50	0.00
Impact of the hormone therapy on the increase systemic exposure, in association with food	−0.25	0.00
Average value for the safety profile	0.21	0.36
Ethical and social aspects	AA+P	ENZA
Ability of the drug to protect the patients’ autonomy	1.75	1.75
Ability of the drug to protect the human rights	2.25	2.25
Ability of the drug to protect the patients’ integrity	2.5	2.5
Ability of the drug to protect the patients’ dignity	1.5	1.5
The use of the drug guarantees the social values and the willingness to pay of the patient	−0.5	−0.5
Impact of the drug on social costs	1.5	1.5
Patients and citizens can have a good level of understanding of the drug	2.5	2.5
Impact of the drug on patients’ satisfaction	2	2.5
Impact of the drug on the patient’s perceived quality of life	2	1.75
impact of the drug on the care giver’s life	1.75	1.75
Impact of the drug on the patient’s functional state	1	1
Ease of swallowing the tablet	1	−1
Impact of technology on the daily intake of the drug (number of pills)	0	0
Average value for ethical and social aspects	1.48	1.35
Legal aspects	AA+P	ENZA
Authorization level (national/European/international)	0	0
Need to insert the technology into the registry at national and/or European level	0	0
Fulfillment of the safety requirements	2.75	2.75
Infringement of intellectual property rights	0	0
Need to regulate the acquisition of technology	−1.25	−1.25
The legislation covers the regulation of technology for all categories of patients	2.5	2.5
Average value for legal aspects	0.67	0.67
Equity aspects	AA+P	ENZA
Access to care on local level	0.75	0.75
Access to care for person of a legally protected status	1.5	1.5
Access to care for person with comorbidities	−1	2
Impact on hospital waiting lists	0	0
Generation of health migrations	0.25	0.5
Existence of factors influencing the patient’s ability and autonomy	0	0
Protection of persons of a legally protected status	0.75	0.75
Level of iniquity	−0.25	0
Average value for equity aspects	0.25	0.69
Organizational aspects	AA+P	ENZA
Additional Staff	0	0
Training course for the clinicians of reference	1	1
Training course for the healthcare professionals	1	0.75
Hospital meetings required	0	0
Impact of the drug on patients management in terms of follow-up monitoring activities	−0.75	2.25
Impact of the drug on hospital waiting lists	0	0
Impact of the drug on treatment duration	1.25	1.25
Impact of the technology on the hospital purchasing processes	1	1.5
Impact of the drug on the internal processes	0.25	0.25
Impact of the drug on the patient’s clinical pathway	0.75	1.25
Average value for organizational perception	0.45	0.83

Abbreviations: AA+P, abiraterone acetate + prednisone; ENZA, enzalutamide.

Figure 2 Gamma distributions of AA+P and ENZA in terms of clinical pathway cost

Table 5 Economic evaluation of mCRPC patient clinical pathway

Phase	AA+P	ENZA	p-Value
Urology clinic	127.01 €	127.01 €	Not significant, >0.05
Radiological staging	383.34 €	383.34 €	Not significant, >0.05
Medical oncology	8,096.63 €	8,096.63 €	Not significant, >0.05
Hormonal pharmacological treatment of new generation	41,749.50 €	40,861.59 €	0.00
Follow-up	352.77 €	204.80 €	0.00
Total	50,709.25 €	49,673.37 €	0.00

Figure 3 Beta distributions of AA+P and ENZA in terms of overall survival.

Table 6 Cost-effectiveness analysis

	AA+P	ENZA
Clinical pathway	50,709.25 €	49,673.37 €
Overall survival rate (12-month time horizon)	88%	91%
Cost effectiveness value	57,624.15	54,586.12
ICER (incremental cost-effectiveness value)	−34,529.3

Figure 4 Gamma distributions of AA+P and ENZA in terms of cost-effectiveness value

Table 7 Budget impact analysis results

Budget impact analysis, considering a treatment duration of 16.6 months, considering 11,116 patients
		Baseline scenario		Innovative scenario	Difference (€)			Difference (%)
12-month time-horizon		479,747,585 €		473,036,612 €	−6,710,973 €			−1.40%
24-month time-horizon		661,315,466 €		647,471,008 €	−13,844,458 €			−2.09%
36-month time-horizon		660,420,244 €		651,735,450 €	−8.684.794 €			−1.32%
Total		1,801,483,295 €		1,772,243,070 €	−29,240,225 €			−1.62%
Budget impact analysis, considering a treatment duration of 13.8 months, considering 11,116 patients
		Baseline scenario	Innovative scenario			Difference (€)	Difference (%)
12-month time-horizon		479,747,585 €	473,036,612 €			−6,710,973 €	−1.40%
24-month time-horizon		549,374,363 €	540,135.475 €			−9,238,888	−1.68%
36-month time-horizon		549,024,059 €	541,804.170 €			−7.219,889	−1.32%
Total		1,578,146,007 €	1,554,976,257 €			−23,169,750 €	−1.47%
Budget impact analysis, considering a treatment duration of 16.6 months, considering 9,902 patients
	Baseline scenario		Innovative scenario			Difference (€)	Difference (%)
12-month time-horizon	427,353,418 €		421,375,363 €			−5,978,055 €	−1.40%
24-month time-horizon	589,091,916 €		576,759,439 €			−12,332,478 €	−2.09%
36-month time-horizon	588,294,464 €		580,558,153 €			−7,736,311 €	−1.32%
Total	1,604,739,798 €		1,578,692,955 €			−26,046,843 €	−1.62%
Budget impact analysis, considering a treatment duration of 13.8 months, considering 9,902 patients
	Baseline scenario		Innovative scenario			Difference (€)	Difference (%)
12-month time-horizon	427,353,418 €		421,375,363 €			−5,978,055 €	−1.40%
24-month time-horizon	489,376,119 €		481,146,228 €			−8,229,891 €	−1.68%
36-month time-horizon	489,064,072 €		482,632,681 €			−6,431,391 €	−1.32%
Total	1,405,793,609 €		1,385,154,272 €			−20,639,337 €	−1.47%
Budget impact analysis, considering a treatment duration of 16.6 months, considering 11,354 patients
	Baseline scenario		Innovative scenario			Difference (€)	Difference (%)
12-month time-horizon	490,019,259 €		483,164,600 €			−6,854,659 €	−1.40%
24-month time-horizon	675,474,613 €		661,333,738 €			−14,140,876 €	−2.09%
36-month time-horizon	674,560,224 €		665,689,484 €			−8,870,741 €	−1.32%
Total	1,840,054,096 €		1,810,187,822 €			−29,866,274 €	−1.62%
Budget impact analysis, considering a treatment duration of 13.8 months, considering 11,354 patients
	Baseline scenario		Innovative scenario			Difference (€)	Difference (%)
12-month time-horizon	490,019,259 €		483,164,600 €			−6,854,659 €	−1.40%
24-month time-horizon	561,136,786 €		551,700,088 €			−9,436,698 €	−1.68%
36-month time-horizon	560,778,982 €		553,404,511 €			−7,374,471 €	−1.32%
Total	1,611,935,027 €		1,588,269,199 €			−23,665,828 €	−1.47%

Table 8 Follow-up monitoring activities

Follow-up monitoring activities	AA+P			ENZA
	N	Duration (minutes)	Total duration (minutes)	N	Duration (minutes)	Total duration (minutes)
Number of specialist visits within the first three months after starting therapy	6	15	90	3	15	45
Number of specialist visits between month 4 and month 12	3	15	45	2	15	30
Number of diagnostic and blood exams within the first three months after starting therapy	6	85	510	3	85	255
Number of diagnostic and blood exams between month 4 and month 12	2	85	170	2	85	170
Total number of activities	17			10
Total minutes spent for monitoring activities	815			500

Table 9 Multi-criteria decision analysis

Dimensions	Standardized dimensions		Normalized prioritization value	Final value
	AA+P	ENZA		AA+P	ENZA
General relevance	0.875	0.875	0.10	0.09	0.09
Safety	0.531	0.750	0.19	0.10	0.15
Efficacy	0.719	0.969	0.22	0.16	0.22
Economic and financial impact–	0.396	0.563	0.14	0.05	0.08
Equity aspects	0.563	0.813	0.12	0.07	0.10
Ethical and social Impact	0.542	0.750	0.10	0.06	0.08
Organizational impact	0.594	0.906	0.08	0.05	0.07
Legal impact	0.625	0.625	0.04	0.03	0.03
Total	4.845	6.251		0.60	0.79

Abbreviations: AA+P, abiraterone acetate + prednisone; ENZA, enzalutamide.

Figure 5 Gamma distributions of AA+P and ENZA in terms of MCDA final value

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