Background
The European Commission is responsible for authorizing OMPs in the European Union (EU), after careful evaluation of the OMP’s benefits and risks by the European Medicines Agency. An OMP is a drug that is indicated for the treatment of a rare disease with a prevalence of < 5:10000. A centralized procedure allows applicants to obtain a marketing authorization that is valid throughout the EU as well as in the European Economic Area, and is compulsory for the authorization of OMPs and medicines containing a new active substance to treat cancer [64]. Marketing authorizations may be ‘full’ (sufficient comprehensive data are available), ‘conditional’ (benefit of immediate authorization outweighs the risk of less comprehensive data than normally required, but additional data are expected to be generated in the future) or ‘exceptional’ (authorization is granted even though comprehensive data are not expected to be obtained after authorization) [65]. |
Although OS seems to be the most reliable outcome, other frequently used outcomes include tumor measurements and biomarkers. PFS or DFS may be considered to be of benefit to the patient, but they are often not validated as surrogate outcomes for OS. The validation of tumor measurements and biomarkers as surrogates for survival is difficult. For each indication separately, robust evaluations are needed to investigate whether a correlation exists between effects on survival and tumor measurements or biomarkers. For the sake of clarity, categories of endpoints as used in this manuscript are stated below. 1. Overall survival (OS): Time from randomization until death from any cause. 2. Tumor measurements: Progression-free survival (PFS), disease-free survival (DFS) (=recurrence-free survival (RFS)), time to progression (TTP), time to treatment failure (TTF), objective response rate (ORR). 3. Symptom assessment: Time to progression of cancer symptoms, quality of life (QoL) 4. Biomarker: Characteristic that should be capable of objectively measuring and evaluating a normal biological process, a pathological process or the pharmacological response to a therapeutic intervention. Generally assayed from blood or body fluids. The validity of biomarkers as endpoints in trials remains to be established. |
Methods
Efficacy
Effectiveness
Data analysis
Results
Drug | Generic name | Year of authorization | Type of authorization | Disease | Specification of indication |
---|---|---|---|---|---|
Gliveca | imatinib | 2002 2006 | Exceptional | 1. GIST 2. DFSP | 1. Unresectable or metastatic GISTs. 2. Unresectable or metastatic DFSP, and adults who are not eligible for surgery after disease recurrence. |
Lysodrena | mitotane | 2004 | Full | Adrenocortical carcinoma | Unresectable, metastatic or relapsed adrenocortical carcinoma. |
Sutenta | sunitinib | 2006 2006 | Conditional | 1. GIST 2. RCC | 1. Unresectable or metastatic GISTs. Used after treatment with imatinib has failed. 2. Metastatic RCC. Patients who failed to respond to or relapsed after IFN-a or IL-2 based therapy. |
Nexavara | sorafenib | 2006 2007 2014 | Full | 1. RCC 2. HCC 3. Differentiated thyroid carcinoma | 1. Advanced RCC. Patients who have failed to prior IFN-a or IL-2 based therapy. 2. Not specified. 3. Locally advanced or metastatic differentiated thyroid carcinoma refractory to RAI. |
Torisel | temsirolimus | 2007 | Full | RCC | Advanced RCC. Patients who have not previously received systemic therapy and who have at least 3 of 6 prognostic risk factors. |
Yondelis | trabectedine | 2007 2009 | Exceptional | 1. STS 2. Ovarian cancer | 1. Advanced STS, patients in which anthracyclines and ifosfamide failed, or who are unsuited to receive these agents. 2. Relapsed ovarian cancer, sensitive to platinum-based chemotherapy. Used in combination with pegylated liposomal doxorubicin. |
Mepact | mifamurtide | 2009 | Full | Osteosarcoma | High-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. Combined with post-operative multi-agent chemotherapy. |
Afinitora | everolimus | 2009 | Full | RCC | Advanced RCC when relapsed after treatment with a VEGF-targeted medicine. |
Cometriq | cabozantinib | 2014 | Conditional | Medullary thyroid cancer | Progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma. |
Lynparza | olaparib | 2014 | Full | Ovarian cancer | Maintenance therapy of adult patients with platinum-sensitive relapsed BRCA-mutated ovarian cancer who are in response to platinum-based chemotherapy. |
Cyramzaa | ramucirumab | 2014 | Full | Gastric cancer | Advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy. Combined with paclitaxel. |
Unituxinb | dinutuximab | 2015 | Full | Neuroblastoma | Patients aged 11 months to 17 years with high-risk neuroblastoma, following myeloablative therapy and ASCT, in combination with GM-CSF, IL-2 and isotretinoin. |
Lenvima | lenvatinib | 2015 | Full | Differentiated thyroid carcinoma | Progressive, locally advanced or metastatic differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to RAI. |
Lartruvo | olaratumab | 2016 | Conditional | STS | Adult patients with advanced STS, not amenable to curative treatment with surgery or radiotherapy and not previously treated with doxorubicin. Used in combination with doxorubicin. |
Onivyde | nanoliposomal irinotecan | 2016 | Full | Pancreatic cancer | Metastatic adenocarcinoma of the pancreas, in combination with 5-FU and LV, in adult patients who have progressed following gemcitabine based therapy. |
Efficacy - COMPASS tool
Drug | Indication | Pivotal study | Primary endpoint | Study phase | Control | Design | Performance status [16] | No. of patients | OS effect in months | QoL effect |
---|---|---|---|---|---|---|---|---|---|---|
Imatinib | GIST | Demetri 2002 [36] DeMatteo 2009 [21] | ORR RFS | II III | Imatinib (different dose) Placebo | Rand. OL Rand. DB | ECOG ≤3 ECOG ≤2 | 147 713 | n/a n/a | NE NE |
Imatinib | DFSP | Heinrich 2008 [39] | ORR | II | None | Single-arm | ECOG ≤2 | 18 | NE | NS |
Mitotane | Adrenocortical carcinoma | Several pivotal studies | OS, PFS, ORR | n/a | n/a | n/a | n/a | > 500 | n/a | n/a |
Sunitiniba | GIST | Demetri 2006 [22] | TTP | III | Placebo | Rand. DB | ECOG ≤1 | 312 | n/a | NE |
Sunitinib | RCC | Motzer 2006 [40] Motzer 2007 [31] | ORR PFS | II III | None IFN-α | Single-arm Rand. OL | ECOG ≤1 ECOG ≤1 | 106 750 | n/a n/a | NE Improved |
Sorafeniba | RCC | Escudier 2007 [24] | OS | III | Placebo | Rand. DB | ECOG ≤1 | 903 | n/a | NS |
Sorafenib | HCC | Llovet 2008 29 | OS, TTP | III | Placebo | Rand. DB | ECOG ≤2 | 602 | 2.8 | NE |
Sorafenib | Thyroid carcinoma | Brose 2014 [20] (DECISION) | PFS | III | Placebo | Rand. DB | ECOG ≤2 | 417 | n/a | NS |
Temsirolimus | RCC | Hudes 2007 [26] (ARCC) | OS | III | IFN-α | Rand. OL | Karnofsky ≥60 (ECOG 1) | 626 | 3.6 | NS |
Trabectedin | STS | Demetri 2009 [35] | TTP | II | Trabectedin (different dose) | Rand. OL | ECOG ≤1 | 266 | 2.1 (NS) | NE |
Trabectedin | Ovarian cancer | Monk 2010 [29] | PFS | III | Single-agent PLD | Rand. OL | ECOG ≤2 | 672 | n/a | NS |
Mifamurtide | Osteosarcoma | Meyers 2005 [28] | EFS | III | Ifosfamide | Rand. OL (factorial) | Not reported | 678 | n/a | NE |
Everolimusa | RCC | Motzer 2008 [30] | PFS | III | Placebo | Rand. DB | Karnofsky ≥70 (ECOG 1) | 416 | n/a | NS |
Cabozantinib | Medullary thyroid cancer | Elisei 2013 [23] | PFS | III | Placebo | Rand. DB | ECOG ≤2 | 330 | n/a | NE |
Olaparib | Ovarian cancer | Ledermann 2012 [37] | PFS | II | Placebo | Rand. DB | ECOG ≤2 | 265 | n/a | NS |
Ramucirumab | Gastric cancer | Wilke 2014 [34] (RAINBOW) Fuchs 2014 [25] (REGARD) | OS OS | III III | Placebo Placebo | Rand. DB Rand. DB | ECOG ≤1 ECOG ≤2 | 665 355 | 2.2 1.4 | NS NS |
Dinutuximaba | Neuroblastoma | Study not yet published [19] | EFS | III | Isotretinoin | Rand. OL | Karnofsky ≥50 (ECOG 2) | 230 | n/a | NE |
Lenvatinib | Thyroid cancer | Schlumberger 2015 [32] | PFS | III | Placebo | Rand. DB | ECOG ≤3 | 392 | n/a | NE |
Olaratumab | STS | Tap 2016 [38] | PFS | Ib/II | Doxorubicin | Rand. OL | ECOG ≤2 | 133 | 11.8 | NE |
Nanoliposomal irinotecan | Pancreatic cancer | Wang-Gillam 2016 [33] | OS | III | Fluorouracil and folinic acid | Rand. OL | Karnofsky ≥70(ECOG 1) | 417 | 1.9 | NS |
Efficacy - ESMO-MCBS
Drug | Indication | Score ESMO-MCBS | Median OS of standard of care (before authorization) | Median OS of OMP (after authorization) | OS gain (before authorization vs after authorization) |
---|---|---|---|---|---|
Imatinib | GIST | A | 9 – 22 months | 41.1 months | ≥3 months |
Imatinib | DFSP | n.a. | 3-year OS rate 66% | 3-year OS rate 60 – 77% | No gain |
Mitotane | Adrenocortical carcinoma | n.a. | 3 – 9 months | No post-marketing studies | n.a. |
Sunitinib | GIST | 3 | 9 – 22 months | 14.1 – 17.6 months | Gain of unknown magnitude |
Sunitinib | RCC | 4 | 10 – 13 months | 18.2 – 27.2 months | ≥3 months |
Sorafenib | RCC | 3 | 10 – 13 months | 17.8 – 29.3 months | ≥3 months |
Sorafenib | HCC | 3 | < 6 months | 5 – 10.2 months | ≥3 months |
Sorafenib | Thyroid carcinoma | 2 | 2.5 – 3.5 years | 2.4 – 4.7 years | Gain of unknown magnitude |
Temsirolimus | RCC | 4 | 6 – 12 months | 11.6 – 18 months | ≥3 months |
Trabectedin | STS | 1 | 6 months | 11.9 – 19.3 months | ≥3 months |
Trabectedin | Ovarian cancer | 2 | > 30 months | 16.3 – 22.2 months | No gain |
Mifamurtide | Osteosarcoma | C | 13 – 28 months | No post-marketing studies | n.a. |
Everolimus | RCC | 2 | 5-year survival rate 9.5% | 14.8 – 32 months | n.a. |
Cabozantinib | Medullary thyroid cancer | 3 | 10-year survival rate < 40% | No post-marketing studies | n.a. |
Olaparib | Ovarian cancer | 2 | 5-year OS 44% for BRCA1 carriers, 52% for BRCA2 carriers | No post-marketing studies | n.a. |
Ramucirumab | Gastric cancer | 2 | 12 months | No post-marketing studies | n.a. |
Dinutuximab | Neuroblastoma | A0 | EFS rates are 30 - 40% for children with high-risk neuroblastoma | No post-marketing studies | n.a. |
Lenvatinib | Thyroid cancer | 2 | 2.5 – 3.5 years | No post-marketing studies | n.a. |
Olaratumab | STS | 4 | 11 – 15 months | No post-marketing studies | n.a. |
Nanoliposomal irinotecan | Pancreatic cancer | 2 | < 12 months | No post-marketing studies | n.a. |
Effectiveness – OS gain in the real-world setting
Efficacy-effectiveness gap
Determinants of a clinically relevant gain in OS in the real world
Effectiveness | ||||
---|---|---|---|---|
Survival benefit > 3 months | Survival benefit < 3 months, unknown magnitude or no benefit | Total | ||
ESMO-score | Score A, B, 5 or 4 | 3 | 0 | 3 |
Score C, 1, 2 or 3 | 3 | 4 | 7 | |
Total | 6 | 4 | 10 |
Effectiveness | ||||
---|---|---|---|---|
Survival benefit > 3 months | Survival benefit < 3 months, unknown magnitude or no benefit | Total | ||
Primary endpoint | OS or surrogate endpoint for OS | 3 | 1 | 4 |
PFS, RFS, TTP, ORR | 3 | 3 | 6 | |
Total | 6 | 4 | 10 |
Effectiveness | ||||
---|---|---|---|---|
Survival benefit > 3 months | Survival benefit < 3 months, unknown magnitude or no benefit | Total | ||
Authorization | Full | 3 | 1 | 4 |
Conditional or exceptional | 3 | 3 | 6 | |
Total | 6 | 4 | 10 |
Effectiveness | ||||
---|---|---|---|---|
Survival benefit > 3 months | Survival benefit < 3 months, unknown magnitude or no benefit | Total | ||
Study power | Adequately powered | 6 | 2 | 8 |
Underpowered | 0 | 2 | 2 | |
Total | 6 | 4 | 10 |