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Home , Belinostat, Bortezomib, Brentuximab vedotin, Fludarabine, Idelalisib, Melphalan

CHARACTERISTICS OF NON-RANDOMIZED STUDIES USING COMPARISONS WITH EXTERNAL CONTROLS SUBMITTED FOR REGULATORY APPROVAL IN THE US AND EUROPE: A SYSTEMATIC REVIEW

Supplemental tables

Goring et al. Supplemental file 1 1 Supplemental Table 1: Detailed product indications Active ingredient Indication albutrepenonacog alfa Prophylaxis and treatment of bleeding in all patients with haemophilia B (congenital factor IX deficiency) including control and prevention of bleeding in surgical settings. alglucosidase alpha Infantile-onset Pompe disease patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation of their cardiac or respiratory compromise due to fluid overload, and require additional monitoring autologous CD34+ Treatment of patients with severe combined immunodeficiency due to enriched cell fraction† deaminase deficiency (ADA-SCID), for whom no suitable human leukocyte (HLA)-matched related stem cell donor is available Treatment of relapsed or refractory peripheral T-cell (PTCL) Treatment of Philadelphia negative relapsed of refractory B-precursor acute lymphoblastic leukaemia (ALL). Treatment of adult patients with chronic phase (CP), accelerated phase (AP), and blast phase (BP) positive chronic myelogenous leukaemia (Ph+ CML) previously treated with one or more tyrosine kinase inhibitor(s) and for whom , and are not considered appropriate treatment options (1) Treatment of patients with after failure of ASCT or failure of at least two prior multi-agent regimens in patients who are not ASCT candidates brentuximab vedotin (2) Treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL) Treatment of patients with who have received at least two prior therapies including and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy cholic acid Treatment of inborn errors of primary bile acid synthesis, responsive to treatment with cholic acid, in infants from one month of age for continuous lifelong treatment through adulthood Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response coagulation Factor X Treatment and prophylaxis of bleeding in patients with hereditary factor X deficiency Monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy dasatinib Treatment of adult patients with chronic, accelerated or blast phase chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate; or Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy. Treatment of severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome (SOS), in haematopoietic stem-cell transplantation therapy (HSCT) eculizumab Atypical haemolytic uremic sydrome (aHUS) eftrenonacog alfa Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).

Goring et al. Supplemental file 1 2 Supplemental Table 1: Detailed product indications Active ingredient Indication Pediatric and adult patients with T-cell ALL or T-CELL lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens phosphate The treatment of adult patients with B-cell chronic lymphocytic (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. Treatment of patients with CD33 positive in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy human heterologous cells Treatment of paediatric patients from birth to less than 6 years of age with urea cycle disorders (UCD) caused by carbamoylphosphate synthetase 1 deficiency, ornithine transcarbamylase deficiency, argininosuccinate synthetase deficiency (citrullinaemia type 1), argininosuccinate lyase deficiency (argininosuccinic aciduria), or arginase deficiency (hyperargininaemia). (1) Treatment of adult patients with relapsed or refractory (MCL) ibrutinib (2) Treatment of adult patients with Waldenström macroglobulinaemia who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo- immunotherapy Indolent Non-Hodgkin Lymphoma imatinib Treatment of paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ALL) integrated with chemotherapy Transfusion-dependent due to low or intermediate-1 risk MDS associated with a 5q cytogenetic abnormality with or without additional chromosomal abnormalities lenalidomide Treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) Myeloablative Conditioning in Patients with Multiple Myeloma Undergoing ASCT modified T-cells* Haploidentical haematopoietic stem-cell transplantation (HSCT) Treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin Treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and omacetaxine mepesuccinate Treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI) Treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation OR Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate Treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)

Goring et al. Supplemental file 1 3 Supplemental Table 1: Detailed product indications Active ingredient Indication recombinant anti-thrombin Prevention of peri-operative and peri-partum thromboembolic events, in hereditary antithrombin deficient patients Treatment of adult patients with peripheral T-cell lymphoma (PTCL) that has relapsed after or become refractory to at least one prior therapy susoctocog alfa Treatment of bleeding episodes in adult patients with acquired haemophilia caused by antibodies to Factor VIII. taliglucerase alfa Type 1 Gaucher disease triacetate Treatment of hereditary orotic aciduria Treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; Treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor sulfate Treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies Treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. *Modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor and the herpes simplex I virus thymidine kinase

†Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence

Goring et al. Supplemental file 1 4 Supplemental Table 2: Primary and supporting efficacy studies

Active ingredient Main interventional trial(s) on which assessment was based Individual patient-level analysis of external controls blinatumomab 1) Phase II single-arm study (n=189) 2) Phase II single-arm study (n=36) defibrotide 1) Historically controlled multicentre, open-label Phase 3 trial (n=102)

2) Phase II dose-finding trial (ndose1=75; ndose2=74) 3) Expanded access single arm trial (n=351) modified T-cells† 1) Phase I/II single arm trial (n=52); 2) Partially complete Phase III trial (first 17 patients from intervention arm). recombinant anti-thrombin 1) Phase III open-label single-arm study (n = 13) 2) Phase III open-label single-arm study (n = 17; FDA only) 2) Retrospective documentation from compassionate use program (n = 5) Aggregate-level external controls (no individual patient-level data) alglucosidase alpha 1) Phase II/iii randomized (to two different doses) uncontrolled open-label study (n = 18) 2) Phase II open-label single-arm study (n = 21) autologous CD34+ enriched cell 1) Phase I/II single arm trial (n=12) fraction‡ 2) Long-term follow-up of Phase I/II study 3) Pilot single arm trial (n=2) 4) Pilot study (n=1) 1) Phase III open-label single arm non-randomized non-comparative compassionate cholic acid treatment study (EMA: n = 59; FDA: n = 79) 2) Sub-study of 1) extending the investigation to treatment to patients with peroxisomal disorders (n = 20, EMA only) clofarabine 1) Phase II single arm trial (n=49 for FDA; n=61 for EMA) 2) Phase II single arm trial (n=11; EMA only) 3) Phase II single arm trial (n=64; EMA only) 4) Phase II single arm trial (n=41; EMA only) 5) Phase I single arm trial (EMA only) 6) Phase II single arm trial (n=35; FDA only; withdrawn from EMA submission) gemtuzumab ozogamicin 1) Phase II open-label single-arm study (EMA: n=84, FDA: n = 65) 2) Phase II open-label single-arm study (EMA: n=95, FDA: n = 40) 3) Phase II open-label single-arm study (EMA: n=98; FDA: 37) human heterologous liver cells 1) Phase II open-label single-arm study (n = 12) 2) Phase II open-label single-arm study (n = 5) ibrutinib for Waldenström’s 1) Phase II single-arm study (n = 63) macroglobulinaemia imatinib 1) Phase II non-randomized study with 5 imatinib regimen cohorts (n = 160, 92 evaluable) omacetaxine mepesuccinate 1) Phase II Open-Label Study (EMA: n=66;FDA: n=103) 2) Phase II Open-Label Study (EMA: n=65; FDA: n=100) 3) Subset analysis of these two studies (n = 122) 4) EMA only: Phase II open-label study (n=4) pralatrexate 1) Phase II open-label single-arm study (n = 115) romidepsin 1) Single arm open-label phase II trial (n = 131)

Goring et al. Supplemental file 1 5 Active ingredient Main interventional trial(s) on which assessment was based 2) Single arm open-label phase II trial (n=45) taliglucerase alfa 1) Phase III randomized trial of two different doses (n = 33) 2) Phase III switchover study (n=30), controlled by patients historical data on previous treatment 3) Phase III extension trial (n=44; 26 from study 1 and 18 from study 2)

Non-defined external controls 1) Phase I/II open-label study, two arms for prophylaxis and on-demand treatment regimen, albutrepenonacog alfa respectively (n = 17) 2) Phase II/III open-label study, two arms for prophylaxis and on-demand treatment regimen, respectively (n = 63) 3) Phase III open-label study, two arms for prophylaxis and on-demand treatment regimen, respectively. Pediatric patients. (n = 27) belinostat 1) Phase II open-label single-arm study (n = 129) 2) Phase II open-label study (PTCL arm n = 24) bosutinib 1) Phase 1/2 open-label study (n = 571) 2) Phase III open-label RCT (bosutinib vs. imatinib)* 3) Patients treated in the compassionate use setting (n = 16; EMA only) brentuximab vedotin for HL 1) Phase II open-label, single-arm study in patients who relapsed after ASCT (n = 102) brentuximab vedotin for sALCL 1) Phase II open-label single arm study (sALCL n=58) 2) Phase II open-label single arm re-treatment study (sALCL n=7; EMA only) carfilzomib 1) Phase II open-label single-arm study (n =266) coagulation factor X 1) Phase III open-label non-randomised prospective study (n = 16) daratumumab 1) Phase II open-label single arm, monotherapy (n=124) 2) Phase I/II first-in-human dose-escalation trial, monotherapy (n=42) dasatinib 1) Phase II open-label single-arm study (PC CML, n = 186) 2) Phase II open-label single-arm study (Ph+ ALL, n = 36) 3) Phase II open-label single-arm study (AP CML, n = 107) 4) Phase II open-label single-arm study (MBP CML, n = 74) 5) Phase II open-label single-arm study ( LP CML, n = 42) 6) Phase I (CP/AP/BP CML and ALL, n = 84) eculizumab 1) Phase II open-label single-arm study (n = 17) 2) Phase II open-label single-arm study (n = 20) 3) Phase II open-label single-arm study (n = 41; EMA only) 4) Phase II open-label single-arm pediatric study (EMA: n = 22; FDA: n = 19) 5) Retrospective study (n = 30; EMA only) 1) Phase III open-label study with different regimens of eftrenonacog alfa in patients ≥12 eftrenonacog alfa years of age (total n = 123) 2) Phase III open-label study of prophylaxis with eftrenonacog alfa in patients <12 years of age (total n = 30) fludarabine phosphate 1) Phase II open-label single-arm study, oral administration (n = 78) 2) Phase II open-label single-arm study, IV administration (n = 48) 3) Phase II open-label single-arm study, IV administration (n =61) 1) Phase II open-label non-randomized study with cohorts assigned based on previous ibrutinib for MCL treatment (R/R MCL) (n = 111) idelalisib 1) Phase 2 single-arm study (n=125 for EMA; n=123 for FDA)

Goring et al. Supplemental file 1 6 Active ingredient Main interventional trial(s) on which assessment was based lenalidomide for transfusion- 1) Phase II open-label single-arm study (n = 148; anemia due to MDS) dependent anemia 2) Phase I/II open-label single-arm study (n = 25; anemia due to MDS) lenalidomide for MCL 1) Phase II open-label single-arm study (n = 134; RR MCL) 1) Published literature, including consensus recommendations from the National melphalan Comprehensive Network (NCCN), the British Society of Hematology, and the European Myeloma Network. 2) Safety: phase II open-label single-arm study nelarabine 1) Phase II open-label single-arm study in patients ≤21 years (n = 70) 2) Phase II open-label single-arm study in patients >16 years (n = 39)

1) Phase II open-label single-arm study, three cohorts based on previous treatment (n = nivolumab 240 total, cohort corresponding to final indication (n = 80)) ofatumumab 1) Phase II single-arm study (n = 154) 1) Phase II randomized (pomalidomide or pomalidomide + ) open-label pomalidomide study (n = 221) 2) Phase II randomized (two concentrations of pomalidomide + dexamethasone) open- label study (n =84) 1) Phase II non-randomized study with cohorts assigned based on disease characteristics ponatinib (n=444) 1)Phase II/III open-label single-arm study and expanded access protocol case series (n = susoctocog alfa 28) uridine triacetate 1) Phase 3 open-label single-arm study (n=4) 2) Retrospective case studies of patients treated empirically with other unapproved uridine formulations (n=18) venetoclax 1) Phase II uncontrolled study (n = 107; safety expansion n =38) 2) Phase I uncontrolled dose escalation study (n = 116)

3) Phase II uncontrolled open label study (ncohort1=43; ncohort2=21) 4) Phase 1b uncontrolled dose escalation study (n=43) vincristine sulfate 1) Phase II open-label single-arm study (n = 65; FDA only) vorinostat 1) Open-label, single-arm study (n=74) 2) Open-label, non-randomized study of different dosing regimens and no control arm (n=33; FDA only) Abbreviations: ALL = acute lymphoblastic leukemia; CML = chronic myeloid leukemia; EMA =European Medicines Agency; FDA = Food and Drug Administration; MCL = Mantle cell lymphoma; MDS = myelodysplastic syndromes; MM =multiple myeloma; n = number; N/R =not reported; RCT = randomized controlled trial; RR = Relapsed/refractory; VOD = veno-occlusive disease *Enrolled population was in a different indication (first line) and the trial failed to meet its primary endpoint. The trial was used to inform safety assessment, and a subset of patients were used as supportive evidence †Modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor and the herpes simplex I virus thymidine kinase ‡Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence

Goring et al. Supplemental file 1 7

Supplemental Table 3: Description of external control groups: data source and sample size among products presenting well-defined controls (without individual patient level data) Active ingredient Source of external control(s) on which External control(s) sample assessment was based size Aggregate-level external controls (no individual patient-level data) alglucosidase alpha Multinational, multicentre (32 sites from 9 countries, n = 42 for study 1), n = 48 for including one center in Austria, Italy, France, UK, and NL), study 2) historical cohort study based on medical records autologous CD34+ enriched Literature review 1 study (n = 106) cell fraction† cholic acid Literature reviews nSED = 25; nSEDsib = 10; nPD = 29; nnathist = 31 clofarabine Data on survival from German and Dutch cancer registries N/R (EMA submission only) gemtuzumab ozogamicin Literature review N/R human heterologous liver Retrospective non-interventional multicentre historical n = 63 cells control ibrutinib for Waldenström’s Literature review 13 studies of single agent, 7 macroglobulinaemia studies of combination therapy imatinib Aggregate data from previous Pediatric Oncology Group 7 studies studies omacetaxine mepesuccinate Literature review N/R pralatrexate* EMA only: Data from three registries (one from Europe, two European registry: n = 104; US from US) registry 1: n = 50, US registry 2: n = 70 romidepsin Only described in EMA documents: Literature review N/R taliglucerase alfa Literature review 14 studies Abbreviations: EMA = European Medicines Agency; N/R = Not reported *After an initial negative recommendation by the CHMP, the manufacturer re-analyzed the data using a matched approach, and presented the analysis as grounds for re-examination. Few details were available regarding the methodology of the matched analysis. †autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence

Goring et al. Supplemental file 1 8 Supplemental Table 4: Reported effect sizes in intervention groups, external control groups, and treatment effect

Submission product Agency Key Endpoint(s) Response in intervention Response in control group Individual patient-level analysis of external controls blinatumomab EMA CR/CRh 43% 24% EMA Survival Median = 6.1 months Median = 3.3 months defibrotide EMA CR at day 100 23% 9% EMA / FDA Survival at day 100‡ 39% 31% modified T-cells* EMA 1y survival 51% 34 to 40% EMA 1y non-relapse mortality 20 to 23% 42 to 46% recombinant anti-thrombin EMA / FDA Incidence of acute DVT 15.40% N/R Aggregate-level external controls (no individual patient-level data) alglucosidase alpha EMA/FDA Study 1): Ventilator-free survival ( % of 0.938 0.019 patients alive and invasive ventilator-free at 12 months from birth, from the date of onset of first symptoms, and from the diagnosis date) EMA/FDA Study 2): OS 0.73 0.37 autologous CD34+ enriched cell EMA Survival at 6.5y 1 Matched sibling / matched family fraction† donor: 86% / 83%; matched unrelated donor: 67% cholic acid EMA / FDA Effect of treatment on urine bile acid 40% improvement in proportion of N/R (compared worst pre-treatment urine bile patients with elevated lab values acid scores with best post-treatment scores) (50% vs. 10%); 45%-55% increased incidence of normal spectra (15% vs. 60%-70%) clofarabine FDA CR 0.12 N/R FDA CRp 0.08 N/R FDA PR 0.1 N/R EMA Survival Median = 17.7 weeks Median = 9 to 10 weeks gemtuzumab ozogamicin EMA / FDA CR EMA 15%, FDA 16% N/R EMA / FDA OS Median 4.8 months N/R

Goring et al. Supplemental file 1 9 Submission product Agency Key Endpoint(s) Response in intervention Response in control group human heterologous liver cells EMA Mortality 0 0.22 ibrutinib for Waldenström’s EMA ORR 0.873 51%-76% macroglobulinaemia EMA OS (18 months) 0.952 N/R FDA ORR 0.619 N/R imatinib EMA EFS (4 years) 0.696 0.316 OS (4 years) 0.836 0.448 omacetaxine mepesuccinate MCyR (Chronic phase) 0.205 N/R MaHR (Accelerated phase) 0.268 N/R pralatrexate EMA OS (EU registry) Median 14.5 months 5 year: 34.9%, median 10 months EMA OS (US registry 1) Median 8.7 months EMA OS (US registry 2) Median 6.1 months FDA ORR 0.27 N/R FDA OS median 14.5 N/R romidepsin EMA / FDA CR 0.15 N/R EMA / FDA ORR 0.25 N/R taliglucerase alfa EMA / FDA Change in spleen volume from baseline 27 to 38% decrease 17 to 38% decrease Non-defined external control albutrepenonacog alfa EMA number of breakthrough bleeding episodes Main study (phase I/II): prophylaxis: N/R in subjects receiving a prophylaxis treatment 4.4; on demand: 26.8 regimen with rIX-FP during the last 12 weeks (bleeds/year) FDA annualized spontaneous bleeding rate Main study (phase II/III): N/R prophylaxis: 0.9; on-demand: 14.6 belinostat FDA Response rate (CR + PR) 25%; other trial: 25.8% N/R FDA OS Median 7.9 months N/R bosutinib EMA / FDA MCyR @ 24w 30 to 36% N/R EMA / FDA OHR @ 48w 43% to 64% N/R brentuximab vedotin for HL FDA ORR 73% N/R EMA ORR 75% N/R

Goring et al. Supplemental file 1 10 Submission product Agency Key Endpoint(s) Response in intervention Response in control group brentuximab vedotin for sALCL EMA ORR 91% N/R EMA/FDA ORR 86% N/R carfilzomib FDA ORR 22.90% N/R coagulation Factor X EMA / FDA Proportion reporting "excellent response" 91.40% N/R daratumumab EMA / FDA ORR 29% N/R dasatinib EMA / FDA MCyR (AP CML) 31% N/R EMA / FDA MCyR (MB CML) 30% N/R EMA / FDA MyCR (LB CML) 50% N/R EMA / FDA MCyR (Ph+ ALL) 58% N/R EMA / FDA CHR (AP CML) 33% N/R EMA / FDA CHR (MB CML) 24% N/R EMA / FDA CHR (LB CML) 26% N/R EMA / FDA CHR (Ph+ ALL) 31% N/R eculizumab EMA Normalization of counts (C08- 82% N/R 002A/B) EMA TMA event free stats (C08-003A/B) 80% N/R EMA Complete TMA response (C10-004) 56% N/R eftrenonacog alfa EMA / FDA Number of annual bleeding episodes Pre-study: 5.53; during study: 2.26; N/R RR = 0.42 fludarabine Phosphate FDA ORR 51% N/R ibrutinib for MCL EMA ORR 67.60% N/R EMA OS (1 year) 64.20% N/R FDA ORR 65.80% N/R idelalisib EMA ORR 56.80% N/R EMA OS Median = 20 months N/R FDA ORR 55% N/R lenalidomide for MCL FDA ORR (RR MCL) 26% N/R lenalidomide for transfusion- FDA Transfusion independence (anemia due to 67% N/R dependent anemia MDS) melphalan FDA ORR 95% N/R

Goring et al. Supplemental file 1 11 Submission product Agency Key Endpoint(s) Response in intervention Response in control group nelarabine EMA / FDA CR Pediatric: first relapse 42%, at least N/R second relapse: 13%; adults: 18% EMA / FDA survival (1 year) Pediatric: first relapse 33%, at least N/R second relapse: 14%; adults: 31% nivolumab EMA / FDA ORR All: 65.3%; cohort corresponding to N/R final indication: 67.5% EMA OS (6 months) 98.70% N/R ofatumumab FDA ORR 42% N/R EMA Response rate 51% N/R EMA OS 15.4 months N/R pomalidomide FDA ORR Pomalidomide + dexamethasone: N/R 29.2%; FDA ORR Other trial: 34.9% and 34.1% for N/R continuous and intermittent pomalidomide dosing + dexamethasone, respectively ponatinib EMA / FDA CP-CML patients: MCyR 54% N/R FDA AP-CML patients: MaHR 52% N/R EMA AP-CML patients: MaHR 58% N/R EMA / FDA BP-CML: MaHR 31% N/R EMA / FDA Ph+ALL: MaHR 41% N/R susoctocog alfa EMA / FDA Proportion of serious bleeding episodes 100% N/R responsive to Obizur at 24 h after initiation of treatment uridine triacetate FDA For patients switching from oral uridine to 3/4 or 75% N/R oral Xuriden (n=3): Stability of pre-specified, patient-specific hematologic parameter ; for treatment naïve patient (n=1): improvement of pre-specified, patient-specific hematologic parameter venetoclax EMA ORR 75% N/R FDA ORR 82% N/R

Goring et al. Supplemental file 1 12 Submission product Agency Key Endpoint(s) Response in intervention Response in control group vincristine sulfate FDA CR + Cri 15% N/R FDA OS (360 days) 8% N/R vorinostat FDA Objective response rate 24.2% to 29.7% N/R Abbreviations: ALL = acute lymphoblastic leukemia; CHR = complete hematologic response; CML = chronic myeloid leukemia; CR = complete remission; CRh = complete remission with partial hematological recovery; CRp = complete remission in the absence of total platelet recovery; EMA = European Medicines Agency; FDA = Food and Drug Administration; HR = hazard ratio; MCyR = major cytogenetic response; N/A = not applicable ; N/R = not reported; OHR = overall hematological response; ORR = objective response rate ; PFS = progression-free survival; Ph+ ALL = Philadelphia chromosome-positive acute lymphoblastic leukemia; PR = partial response; RR = relative risk; TG = triglyceride; TTP = time to progression *Modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor and the herpes simplex I virus thymidine kinase †Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence ‡Based on observational data

Goring et al. Supplemental file 1 13

Supplemental Table 5: Regulatory approvals and designations/pathways granted by the EMA and FDA

EMA FDA

Product (active ingredient) Indication

Year Approved Orphan Exceptional circumstances approval Conditional Year Approved Orphan track Fast Breakthrough* review Priority Accelerated approval Individual patient-level analysis of external controls Other hematologic N/A recombinant anti-thrombin 2006  No  No 2009     No conditions * defibrotide Stem-cell transplant 2013 *   No 2016    No  No blinatumomab Hematologic cancer 2015   No  2014   No    modified T-cells** Stem-cell transplant 2016   No  2014 † Aggregate-level external controls (no individual patient-level data) N/A clofarabine Hematologic cancer 2006    No 2004      * alglucosidase alpha Rare metabolic conditions 2007   No No 2006   No No No No N/A gemtuzumab ozogamicin Hematologic cancer 2008 No  No No 2000   No   * N/A pralatrexate Hematologic cancer 2012 No  N/A No 2009   No   * N/A romidepsin Hematologic cancer 2012 †  N/A No 2011   No   * N/A taliglucerase alfa Rare metabolic conditions 2012 No  N/A N/A 2012    No No * omacetaxine mepesuccinate Hematologic cancer 2011‡‡ No No N/A No 2012   No No No  imatinib Hematologic cancer 2013  No‡ No No 2013   No No No No cholic acid Rare metabolic conditions 2015    No 2015   No No  No human heterologous liver cells Rare metabolic conditions 2015 No  N/A N/A

Goring et al. Supplemental file 1 14

EMA FDA

Product (active ingredient) Indication

Year Approved Orphan Exceptional circumstances approval Conditional Year Approved Orphan track Fast Breakthrough* review Priority Accelerated approval ibrutinib for Waldenström’s Hematologic cancer 2015   No No 2015   No   No macroglobulinaemia autologous CD34+ enriched cell Rare metabolic conditions 2016   No No fraction†† Non-defined external controls

‡ N/A dasatinib Hematologic cancer 2006  No No No 2006      * N/A vorinostat Hematologic cancer 2009‡‡ No  N/A 2006     No N/A * N/A nelarabine Hematologic cancer 2007    No 2005      * N/A fludarabine phosphate Hematologic cancer 2007  No No No No * N/A ofatumumab Hematologic cancer 2010   No  2009   No   * Other hematologic N/A Eculizumab 2011   No No 2011   No No  conditions * N/A brentuximab vedotin for HL Hematologic cancer 2012   No  2011   No   * N/A brentuximab vedotin for sALCL Hematologic cancer 2012   No  2011      * vincristine sulfate Hematologic cancer 2012   No No No  lenalidomide for transfusion-dependent Other hematologic N/A 2013  2005      anemia conditions * N/A bosutinib Hematologic cancer 2013   No  2012   No No No * ponatinib Hematologic cancer 2013   No No 2012   No No   pomalidomide Hematologic cancer 2013  No 2013   No No No 

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EMA FDA

Product (active ingredient) Indication

Year Approved Orphan Exceptional circumstances approval Conditional Year Approved Orphan track Fast Breakthrough* review Priority Accelerated approval ibrutinib for MCL Hematologic cancer 2014   No No 2013   No    idelalisib Hematologic cancer 2014  No No No 2014   No No No  belinostat Hematologic cancer 2014   No No   carfilzomib Hematologic cancer 2015  No 2012   No No No  Other hematologic susoctocog alfa 2015    No 2014    No  No conditions uridine triacetate Rare metabolic conditions 2015   No   No lenalidomide for MCL Hematologic cancer 2016  2013    No  No Other hematologic eftrenonacog alfa 2016   No No 2014   No No No No conditions Other hematologic coagulation Factor X 2016   No No 2015    No  No conditions daratumumab Hematologic cancer 2016   No  2015       Other hematologic albutrepenonacog alfa 2016   No No 2016   No No No No conditions venetoclax Hematologic cancer 2016   No  2016   No    melphalan Stem-cell transplant 2016   No No No No nivolumab Stem-cell transplant 2017  No No No 2016   No No No  Legend: Approval status: Green = approved; Red = refused; Grey = Not submitted; Diagonal lines: approval based on RCT evidence; Pathways/designations: Green = pathway/designation assigned; Blank = no pathway/designation assigned; Grey = Not submitted/no information available *Initial negative opinion, but upon re-examination with additional US patient registry data, following that re-examination CHMP gave positive opinion †Application was refused in 2010 and again after a re-examination in 2012 because CHMP felt that lack of comparator group in trial made evaluation of clinical benefit impossible ‡ Previously granted orphan status in Europe for this indication but since withdrawn **Modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor and the herpes simplex I virus thymidine kinase ††Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence ‡‡ Year withdrawn

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