Three clinical trials have been analyzed in order to conduct the evaluation. Other articles have not been taken into account because they had been evaluated in a previous application for marketing (which the company decided to withdraw when the conclusion by the Committee for Medicinal Products for Human Use of the EMA was that there was not enough evidence for its use), because they had used patient populations with a less strict diagnosis of STTI, or because they used doses and frequencies different from those currently studied.

In the EPAR Report by the EMA15 (2015) and the CDER16 Report by the FDA (2014), three clinical trials are mentioned:

• •

  SIMPLIFI (TAR-ORI-SD001)21: A Phase II, multicenter, randomized, double-blind, non-inferiority, parallel clinical trial, with active comparator, on patients with complicated skin and soft tissue infection, assumed or confirmed to be caused by Gram-positive pathogens. In total, 311 patients were included, and 302 of them received the study medication: 100 patients in the arm with daily dose of oritavancin (control arm), 99 in the arm with 1,200 mg single dose, and 103 in the 800 mg arm (+ 400 mg optional). This is a dose-ranging clinical trial which compared 3 different doses of oritavancin. Its outcomes appear on table 1.

  Table 1.

  TAR-ORI-SD001 (SIMPLIFI) trial outcomes20

  Variable evaluated in the study	Oritavancin 1,200 mg single-dose N= 99	Oritavancin 800 mg + 400 (if needed) N= 103	Oritavancin 200 mg/24h 7-10 days (Control arm) N= 100	Difference/ARR/HR (90% CI)		p	NNT (90% CI)
  ITT Population	N=99	N=103	N=87
  Primary outcome - est-of-cure (cure or improvement vs. failure) in the ITT population at the first follow-up visit (at day 21-29)				Ori 1,200 mg vs Ori 200 mg	8.7 (−1.7,17.8)	DK	−
  	72/88 (81.8%)	68/87 (78.2%)	63/87 (72.4%)	Ori 800 mg vs Ori 200 mg	5.1 (−5.8, 14.6)	DK	−
  Population: clinically evaluable	N =81	N =71	N =76
  Primary outcome - test-of-cure (cure or improvement vs. failure) in the clinically evaluable population at the first follow-up visit (at day 21-29)				Ori 1,200 mg vs Ori 200 mg	8.6 (−2.5, 18.2)	DK	−
  	66/81 (81.5%)	55/71 (77.5%)	55/76 (72.4)	Ori 800 mg vs Ori 200 mg	5.2 (−6.8, 15.4)	DK	−
  Population: microbiological ITT	N =61	N =62	N =64
  Secondary outcome - test-of-cure (cure or improvement vs. failure) in the population with microbiological ITT at the first follow-up visit (at day 21-29)				Ori 1,200 mg vs Ori 200 mg	10.1 (−2.7, 20.9)	DK	−
  	49/61 (80.3%)	50/62 (80.6%)	44/64 (68.8%)	Ori 800 mg vs Ori 200 mg	11.1 (−1.5, 21.7)	DK	−
  Population: microbiologically evaluable	N =61	N =62	N =64
  Secondary outcome - test-of-cure (cure or improvement vs. failure) in the microbiologically evaluable population at the first follow-up visit (at day 21-29)				Ori 1,200 mg vs Ori 200 mg	8.5 (−5.2, 20.0)	DK	−
  	46/58 (79.3%)	39/48 (81.3%)	38/55 (69.1%)	Ori 800 mg vs Ori 200 mg	11.0 (−2.9, 22.6)	DK	−

  ITT: Intention to treat.
• •

  SOLO I (TMC-ORI-10-01) AND SOLO II (TMC-ORI-10-02) CLINICAL TRIALS: These are pivotal studies with the same design, on Phase III, multicenter, double-blind, non-inferiority, randomized, comparing a single-dose of IV oritavancin 1,200 mg vs. vancomycin 1g or 15 mg/kg/12h during 7-10 days. The inclusion criteria were: patients ≥ 18 year-old, with informed consent, diagnosed with SSTI on a minimum 75 cm2 surface or knowledge that it had been caused by a Gram-positive pathogen, requiring at least 7 days of IV therapy. Some of the exclusion criteria were: previous systemic or topical treatment with agents active against Gram-positive pathogens 14 days before randomization, associated infections with prosthetic devices, severe sepsis or refractory shock, known or suspected bacteremia at the time of screening, CD4 < 200 cells/µL in HIV patients, neutropenia with an absolute neutrophil count (ANC) < 500 cells/µL, contraindication for administering vancomycin, liver function tests ≥ 3x upper limit of normal (ULN) or total bilirubin ≥ 2x ULN; presence of hyperuricemia or gouty arthritis, or patients not willing to abstain from the chronic use of any medication with antipyretic properties.

The outcomes of both studies have been published by Corey et al. in two articles22,23 and are summarized in Tables 2 and 3, respectively.

Regarding the validity of clinical trials, the risk of bias has only been analyzed in the pivotal clinical trials, SOLO I and SOLO II, because SIMPLIFI is a dose escalation and determination study.

Besides, there is an indirect comparison available that has been published, where the combined “Test-of-Cure” (cure at 1-2 weeks after completing treatment) for the population clinically assessable included 14 treatments in 20 studies. Only the SOLO I and SOLO II studies were included in order to evaluate the early clinical response in the clinically assessable population. The combined “Test-of-Cure” for the population by Intent to Treat according to FDA standards included five treatments in four studies; while for the clinically assessable population it included eight treatments in seven studies. The conclusions of this network meta-analysis were that oritavancin 1200 mg was considered equivalent to vancomycin. Indirect evidence also suggests that oritavancin 1200 mg has demonstrated equivalence with linezolid (OR 1.55; CrI 95% 0.91-2.57), teicoplanin (OR 0.72; CrI 95% 0.61-1.26), tedizolid (1.51; CrI 95°% 0.82-2.73) and daptomycin (OR = 2.18; 95°% CrI = 0.90-5.42)24.

Overall, oritavancin is a well-tolerated drug, with manageable toxicity. In studies conducted until its marketing, the most common adverse effects were nausea, headache and vomiting; and the most severe, cellulitis and osteomyelitis22,23.

The safety database consisted of 3,017 patients treated with oritavancin, from 22 clinical trials, including four Phase III studies, four Phase II studies, and 14 Phase I studies. The adverse effects of interest in the SOLO trials that appeared to a higher extent in the oritavancin arm than in the vancomycin arm included essentially infection and infestation. There were 40 cases (4%) vs. 31 (3%) respectively. These cases included 4 patients in the oritavancin arm who developed osteomyelitis (in the subsequent review, it was put forward that this could be due to the lack of efficacy of oritavancin in osteomyelitis, or failure to diagnose osteomyelitis at screening). There were a slightly higher number of cases of subcutaneous abscesses in the oritavancin arm, which represents a failure in efficacy, because the infection appeared in the site of the index infection. Cellulitis cases were balanced in both arms, which could indicate lack of efficacy, lack of the adequate incision and drainage for infection control, or recurring infection due to underlying comorbidities.

For those subjects randomized to any of the arms, the highest incidence of drug-related adverse reactions (DRAE) which led to treatment interruption was infections and infestations (1.6% vs. 1.9% respectively). Twenty-one (21) patients (2.2%) in the oritavancin arm and 19 (1.9%) in the vancomycin arm suffered a severe adverse event (AE) which led to treatment interruption. The most common DRAEs in both the oritavancin and the vancomycin arms were nausea (17.7% and 18.3%), headache (12.6% and 11.7%), vomiting (8.2% and 8.2%), diarrhoea (6.6% and 5.7%), cellulitis (6.8% and 5.7%), constipation (6% and 6.7%), and extravasation in the infusion site (6% and 5.9%). The incidence in ALT and AST elevation, cellulitis, abscesses, subcutaneous abscesses, physical integrity of abscesses, and infection on infections and infestation, tachycardia and myalgia, were slightly higher than in patients treated with oritavancin. There were 24 subjects (4.4%) in the oritavancin arm and 11 subjects (1.9%) in the vancomycin arm in the set of SOLO trials (SOLO pool) with the adverse event of tachycardia. No specific conclusions can be drawn from this analysis. There were 27 (2.8%) and 16 (1.6%) patients with elevated ALT in the oritavancin and vancomycin arms, respectively. There were 18 (1.8%) and 16 (1.6%) patients with elevated AST in the oritavancin and vancomycin arms, respectively. Even though the history of hepatitis or liver disease (9 subjects) or the use of intravenous drugs (12 subjects) could predispose subjects to transaminase elevation, there were subjects without this past history where anomalies appeared in their liver function tests. These cases don't seem to be the result of severe sepsis or septic shock. None of the subjects met Hy's Law criteria.25. There was a slightly higher incidence of severe DRAEs in diabetic subjects, with 23/138 (16.7%) in the oritavancin arm versus 18/141 (12.8%) in the vancomycin arm. However, the total number of subjects with >1 DRAE was similar in both arms. In those subjects with creatinine clearance of 30-60ml/min, 12/70 in the oritavancin arm vs. 3/54 in the vancomycin arm presented one severe adverse effect.

Within the set of patients in the SOLO I and II trials, 5 patients died (2 in the oritavancin arm and 3 in the vancomycin arm). There were 5/302 (1.7%) deaths in the SIMPLIFI study (3 in the arm with oritavancin daily dose, 2 in the arm with infrequent dosing, and none in the single-dose arm). None of the deaths seemed to be related to the research medication.

Oritavancin does not require dose adjustment in patients with mild or moderate renal or liver impairment, and it has not been researched in paediatric patients.

There are four published pharmacoeconomic studies available; of these, three are budgetary impact studies and one is a cost-minimization study.

• •

  The study by Wu26 analyzed a theoretical model on the economic impact represented by the inclusion of oritavancin in a U.S.A. hospital for SSTI treatment. An analytical decision making model was designed, based on current clinical practice guidelines, limiting the use of oritavancin to patients with moderate-severe SSTI (Eron Classes II and III) at risk of MRSA. The model simulated a cohort of 1,000 patients with SSTI. The base case shows the mean national use of antibiotics active against MRSA (vancomycin 92%, linezolid 2%, daptomycin 6 %, oritavancin 0%). In the hypothetical case, it was assumed that oritavancin will be used for 25.75% of patients (5% in hospitalized patients, 15% in ER/outpatient unit, and 80% in observation units), replacing vancomycin but not the rest of antibiotics. As a result of this change, fewer patients were treated as hospitalized, and there was an increase in the use of observation units. Direct costs were taken into account: medication, administration, monitoring, hospital stay and others. According to this model, there would be savings of 2,752 $ per patient; most of it would be caused by a reduction in the number of hospitalizations and the use of observation units, cheaper than traditional hospitalization units.

• •

  The study by Jensen27 analyzed a theoretical model on the economic impact represented by the inclusion of oritavancin in a U.S.A. hospital for SSTI treatment, identically to the previous study 43, but it evaluated two scenarios: hospital with outpatient services and without them. The results were that the use of oritavancin in 26% of patients instead of vancomycin would represent total savings of 13% from the hospital perspective, or approximately 1,235 $ per patient. In the model of economic impact on a hospital without outpatient services, the use of oritavancin in 26% of patients would also represent savings, though lower (9%, or approximately 634 $ per patient).

• •

  Another study by Wu28 repeated the model of the two previous studies, but applied to a hospital in the United Kingdom. In this case, it was assumed that oritavancin would be used in 3.6% of patients; and the conclusion was that its use would represent total savings by 0.63% from the hospital perspective, or 29.23£ per patient.

• •

  The study by Lodise29 developed a cost-minimization model in order to compare the costs of patients on treatment with vancomycin while hospitalized vs. those with oritavancin administered as outpatient regimen, in patients with SSTI and few or no comorbidities (Charlson Comorbidity Index [CCI] 0 or 1). The costs associated with the use of oritavancin in the Emergency Unit (3,409.46 $) and in the observation unit (4,220.27 $) were lower to those for vancomycin in hospitalized patients (5,972.73-9,885.33 $). To switch a hospitalized patient on vancomycin to outpatient treatment with oritavancin could save 1,752.46-6,475.87 $ depending on the CCI, presence of systemic symptoms, and the use of the observation unit. If all patients hospitalized on vancomycin were treated with oritavancin at the Emergency Unit, savings per patient could be of 3,102.43 $. Assuming that some patients could be admitted to hospital after receiving treatment with oritavancin in the Emergency Unit, it is expected that savings with oritavancin in the observation unit vs. treatment hospitalized with vancomycin will be 2,291.62 $.

The limitations of these studies lie essentially in: a) the difficulty to extrapolate data from models based on U.S.A. data to our country, and even to Europe; b) the lower prevalence of MRSA in Europe; c) the lower impact in Spain of hospitalization and drug administration costs than in other countries; d) the risky assumption that all patients treated with oritavancin can be treated as outpatients, and those patients treated with alternative options (vancomycin, linezolid, teicoplanin, etc.) must be hospitalized.

We have conducted our own comparison of the cost of the treatment evaluated vs. those alternative options currently available in Spain (Table 4). Given that these are equivalent treatments, an incremental cost-efficacy analysis is not adequate, and a cost-minimization analysis should be conducted, considering oritavancin as a therapeutic alternative vs. the rest of drugs considered for the indication under study.

On September, 1st, 2016, oritavancin had not been yet approved by the AEMPS; therefore, its price in U.S.A. has been used for its economic evaluation: 1 vial 400 mg = 1,035 $ = 973.5 €.

For the estimation of the overall economic impact at national level, there are no data available about the prevalence of SSTI in Spain. It is known that in U.S.A. there are 500 episodes per 10,000 persons and per year30. According to the January, 2015 census by the National Statistics Institute, there were 46.449.565 inhabitants in Spain; applying the American prevalence, this would represent a figure of 2.322.478 episodes per year. If we take the proportion of patients who required hospitalization for treatment in the SOLO I trial (19%)22, we would have 441.270 patients. For an oritavancin introduction rate of 2.5% per year (11,032 patients), on the first year we would have costs of 32,411,023€.