Download A description of the circumstances surrounding

A description of the circumstances surrounding pharmaceutical approvals by the FDA and EMA
from 1999 to 2014 made without randomised control trial data
Anthony J Hatswell, Gianluca Baio, Nick Freemantle
Research Report number 327
Department of Statistical Science,
University College London
Date: February 2017
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The vast majority of new medicines licensed for use in the European Union and United States (the
two largest single markets for pharmaceuticals), are granted a marketing authorisation on the basis
of randomised controlled trials (RCTs) (Hatswell et al., 2016). We sought to understand however the
circumstances surrounding approvals which were made without RCT data available at the time of
review by the relevant regulatory agency.
A search of the Food and Drug Administration (FDA) drugs@FDA database, and European Medicines
Agency (EMA) website was conducted for all pharmaceutical approvals granted between 1 January
1999, after the EMA had introduced the ‘centralised authorisation procedure’ (Jefferys and Jones,
1995). Each drug approval was reviewed for the evidence it was based on, with those approved
without RCT data investigated further. The results of this review are described in a peer reviewed
paper in BMJ Open (Hatswell et al., 2016), with a summary of all the treatments submitted and
approved by each of the regulators shown in Figure 1.
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Figure 1: Drugs submitted to the EMA and FDA containing only uncontrolled clinical studies, presented in alphabetical order
Generic name
Condition
Abarelix
Prostate cancer
Alemtuzumab
Chronic lymphocytic leukaemia (CLL)
Alglucosidase Alfa
Pompe disease
Alipogene Tiparvovec
Familial lipoprotein lipase deficiency (LPLD)
Anagrelide
Argatroban
Essential thrombocytopenia
Heparin-induced thrombocytopenia (HIT)
Arsenic Trioxide
Acute promyelocytic leukaemia (APL)
Asparaginase Erwinia
Chrysanthemi
Bendamustine
Hydrochloride
Categorisation
Acute lymphoblastic leukaemia (ALL)
Non-Hodgkin’s Lymphoma
Betaine Anhydrous
Homocystinuria
Bexarotene
Cutaneous T-cell lymphoma (CTCL)
Bortezomib
Multiple myeloma (MM)
Bortezomib
Mantle cell lymphoma (MCL)
Bosutinib
Chronic myeloid leukaemia (CML)
Brentuximab Vedotin
Hodgkin's lymphoma (HL)
Brentuximab Vedotin
Systemic anaplastic large cell lymphoma (sALCL)
Busulfan
Haematopoietic progenitor cell transplantation (HPCT)
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Solid tumour oncology
Haematological
oncology
Rare metabolic
condition
Rare metabolic
condition
Blood count
Blood count
Haematological
oncology
Haematological
oncology
Haematological
oncology
Rare metabolic
condition
Solid tumour oncology
Haematological
oncology
Haematological
oncology
Haematological
oncology
Haematological
oncology
Haematological
oncology
Haematological
oncology
FDA
Status
A
EMA
Status
-
RCT data
available
No
A
A
No
A
A
No
-
A
No
A*
A*
A
-
No
No
A
A
No
A
-
No
A
-
Yes
-
A
No
A
A
No
A
A
No
A
-
Yes
A
A
Yes
A
A
No
A
A
No
A
A
Yes
Carfilzomib
Multiple myeloma (MM)
Carglumic Acid
Chronic hyperammonemia
Ceritinib
Cetuximab
Non-small cell lung cancer
Colorectal cancer
Cholic Acid (Kolbam)
Inborn errors in primary bile acid synthesis
Cholic Acid (Orphacol)
Inborn errors in primary bile acid synthesis
Cladribine
Hairy cell leukaemia
Clofarabine
Acute lymphoblastic leukaemia (ALL)
Crizotinib
Non-small cell lung cancer
Dasatinib
Chronic myeloid leukaemia (CML)
Dasatinib
Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL)
Defibrotide
Dexrazoxane Hydrochloride
Ferric Hexacyanoferrate(Ii)
Gefitinib
Veno-occlusive disease
Anthracycline extravasation
Internal contamination with radioactive caesium or thallium
Non-small cell lung cancer (NSCLC)
Gemtuzumab Ozogamicin
Acute myeloid leukaemia (AML)
Glucarpidase
Hydroxocobalamin
Toxic plasma methotrexate concentrations
Treatment of cyanide poisoning
Ibrutinib
Mantle cell lymphoma (MCL)
Ibrutinib
Chronic lymphocytic leukaemia (CLL)
Imatinib Mesylate
Chronic myeloid leukaemia (CML)
Imatinib Mesylate
Gastrointestinal stromal tumours (GIST)
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Haematological
oncology
Rare metabolic
condition
Solid tumour oncology
Solid tumour oncology
Rare metabolic
condition
Rare metabolic
condition
Haematological
oncology
Haematological
oncology
Solid tumour oncology
Haematological
oncology
Haematological
oncology
Poisoning
Poisoning
Poisoning
Solid tumour oncology
Haematological
oncology
Poisoning
Poisoning
Haematological
oncology
Haematological
oncology
Haematological
oncology
Solid tumour oncology
A
-
No
A
A
No
A
A
A
No
No
-
A
No
-
A
No
-
A
No
A
A
No
A
-
No
A
A
No
A
A
No
A
A
A
A
-
Yes
No
No
No
S
S
No
A
A
S
A
No
No
A
-
No
A
-
No
A
A
No
A
A
No
Imatinib Mesylate
Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with
platelet-derived growth factor receptor (PDGFR) gene re-arrangements
Soft tissue sarcoma - Dermatofibrosarcoma protuberans (DFSP)
Imatinib Mesylate
Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL)
Imatinib Mesylate
Aggressive systemic mastocytosis (ASM)
Imatinib Mesylate
Ixabepilone
Advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic
leukaemia (CEL) with FIP1L1-PDGFR rearrangement
Breast cancer
Lomitapide Mesylate
Familial hypercholesterolemia (HoFH)
Metreleptin
Lipodystrophy due to leptin deficiency
Nelarabine
T-cell acute lymphoblastic leukaemia / lymphoma (T-ALL / T-LBL)
Nilotinib Hydrochloride
Monohydrate
Chronic myeloid leukaemia (CML)
Nitisinone
Hereditary tyrosinemia
Ofatumumab
Chronic lymphocytic leukaemia (CLL)
Imatinib Mesylate
Omacetaxine
Mepesuccinate
Paclitaxel
Pasireotide Diaspartate
Pentetate Calcium
Trisodium
Pentetate Zinc Trisodium
Chronic myeloid leukaemia (CML)
Kaposi's sarcoma
Cushing's disease
Haematological
oncology
Solid tumour oncology
Haematological
oncology
Haematological
oncology
Haematological
oncology
Solid tumour oncology
Rare metabolic
condition
Rare metabolic
condition
Haematological
oncology
Haematological
oncology
Rare metabolic
condition
Haematological
oncology
Haematological
oncology
Solid tumour oncology
Rare metabolic
condition
A
A
Yes
A
A
Yes
A
-
Yes
A
S
Yes
A
A
Yes
A
S
Yes
A
A
No
A
-
No
A
A
No
A
A
No
A
A
No
A
A
No
A
S
No
A
A
Yes
A
A
No
Internal contamination with plutonium, americium, or curium
Poisoning
A
-
No
Internal contamination with plutonium, americium, or curium
Poisoning
Haematological
oncology
Haematological
oncology
A
-
No
A
-
No
A
A
No
Pomalidomide
Multiple myeloma (MM)
Ponatinib Hydrochloride
Chronic myeloid leukaemia (CML)
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Ponatinib Hydrochloride
Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL)
Pralatrexate
Peripheral T-cell lymphoma (PTCL)
Raxibacumab
Anthrax inhalation
Romidepsin
Peripheral T-cell lymphoma (PTCL)
Sodium Ferric Gluconate
Complex
Iron deficiency
Sodium Phenylbutyrate
Urea cycle disorders
Sunitinib Malate
Renal cell carcinoma
Taliglucerase Alfa
Gaucher's disease
Temoporfin
Temozolomide
Head and neck cancer
Anaplastic astrocytoma
Tocofersolan
Vitamin E deficiency due to cholestasis
Tositumomab; Iodine I 131
Tositumomab
Trabectedin
Vismodegib
Non-Hodgkin's lymphoma
Soft tissue sarcoma
Basal cell carcinoma
Vorinostat
Cutaneous T-cell lymphoma (CTCL)
Zinc
Wilson's disease (hepatolenticular degeneration)
A=Approved, A*=Approved prior to 1999, S=Submitted but not approved
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Haematological
oncology
Haematological
oncology
Poisoning
Haematological
oncology
Rare metabolic
condition
Rare metabolic
condition
Solid tumour oncology
Rare metabolic
condition
Solid tumour oncology
Solid tumour oncology
Rare metabolic
condition
Haematological
oncology
Solid tumour oncology
Solid tumour oncology
Haematological
oncology
Rare metabolic
condition
A
A
No
A
S
No
A
-
No
A
S
Yes
A
-
No
A*
A
No
A
-
No
A
S
No
A
A
A
No
Yes
-
A
No
A
-
No
A
A
A
No
No
A
S
No
A*
A
No
As a continuation of this work, below we present further detail of the circumstances around each
application, any commentary given by the regulators on why a given decision was made.
Commentaries are performed by drug, with both FDA and any EMA status discussed, and are listed
in order of FDA submission date (which is before than the EMA submission date in 35/44 cases
where applications have been made to both agencies). A listing of all treatments and page numbers
is provided below
1. Zinc in Wilson's disease (hepatolenticular degeneration) ..................................................................... 9
2. Sodium Phenylbutyrate in Urea cycle disorders .................................................................................... 9
3. Anagrelide in essential thrombocytopenia............................................................................................ 9
4. Paclitaxel in Kaposi's sarcoma (KS) ..................................................................................................... 10
5. Argatroban in heparin-induced thrombocytopenia (HIT) .................................................................... 10
6. Sodium Ferric Gluconate Complex in Iron deficiency........................................................................... 11
7. Busulfan in Haematopoietic progenitor cell transplantation (HPCT) .................................................. 12
8. Temozolomide in Anaplastic astrocytoma .......................................................................................... 12
9. Bexarotene in Cutaneous T-cell lymphoma (CTCL) .............................................................................. 13
10.
Temoporfin in Head and neck cancer.............................................................................................. 13
11.
Gemtuzumab Ozogamicin in Acute myeloid leukaemia (AML) ....................................................... 13
12.
Alemtuzumab in CLL........................................................................................................................ 14
13.
Nitisinone in Hereditary tyrosinemia .............................................................................................. 14
14.
Arsenic Trioxide in Acute promyelocytic leukaemia (APL) .............................................................. 15
15.
Tositumomab; Iodine I 131 Tositumomab in Non-Hodgkin's lymphoma (NHL) .............................. 15
16.
Abarelix in prostate cancer ............................................................................................................. 16
17.
Imatinib Mesylate in Chronic myeloid leukaemia (CML)................................................................. 16
18.
Imatinib Mesylate in Gastrointestinal stromal tumours (GIST) ...................................................... 17
19.
Cetuximab in Colorectal cancer ...................................................................................................... 17
20.
Trabectedin in Soft tissue sarcoma (STS) ........................................................................................ 17
21.
Cladribine in Hairy cell leukaemia ................................................................................................... 18
22.
Gefitinib in Non-small cell lung cancer (NSCLC) .............................................................................. 18
23.
Bortezomib in Multiple myeloma (MM).......................................................................................... 19
24.
Ferric HEXACYANOFERRATE (Ii) in Internal contamination with radioactive caesium or thallium . 19
25.
Clofarabine in Acute lymphoblastic leukaemia (ALL) ...................................................................... 20
26.
Pentetate Calcium Trisodium and Pentetate Zinc Trisodium in Internal contamination with
plutonium, americium, or curium ................................................................................................................ 20
27.
Nelarabine in T-cell acute lymphoblastic leukaemia / lymphoma (T-ALL / T-LBL) .......................... 20
28.
Betaine Anhydrous in Homocystinuria ............................................................................................ 21
29.
Dexrazoxane Hydrochloride in Anthracycline extravasation .......................................................... 21
30.
Alglucosidase Alfa in Pompe disease .............................................................................................. 21
31.
Sunitinib Malate in Renal cell carcinoma (RCC) .............................................................................. 22
32.
Imatinib Mesylate in Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL) ... 23
33.
Imatinib Mesylate in Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with
platelet-derived growth factor receptor (PDGFR) gene re-arrangements ................................................... 23
34.
Imatinib Mesylate in Advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic
leukaemia (CEL) with FIP1L1-PDGFR rearrangement................................................................................... 23
35.
Dasatinib in Chronic myeloid leukaemia (CML) .............................................................................. 24
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36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
(ALL)
70.
71.
72.
73.
Dasatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) .......... 24
Imatinib Mesylate in Aggressive systemic mastocytosis (ASM) ...................................................... 25
Imatinib Mesylate in Soft tissue sarcoma - Dermatofibrosarcoma protuberans (DFSP) ................ 25
Vorinostat in Cutaneous T-cell lymphoma (CTCL) ........................................................................... 25
Bortezomib in Mantle Cell Lymphoma (MCL) ................................................................................. 26
Hydroxocobalamin in Treatment of cyanide poisoning .................................................................. 26
Nilotinib Hydrochloride Monohydrate in Chronic myeloid leukaemia (CML) .................................. 27
Ixabepilone in Breast cancer ........................................................................................................... 27
Tocofersolan in Vitamin E deficiency due to cholestasis ................................................................. 28
Bendamustine Hydrochloride in Non-Hodgkin’s Lymphoma (NHL) ................................................ 28
Romidepsin in Peripheral T-cell lymphoma (PTCL) .......................................................................... 28
Ofatumumab in Chronic lymphocytic leukaemia (CLL) ................................................................... 29
Pralatrexate in Peripheral T-cell lymphoma (PTCL) ........................................................................ 29
Carglumic Acid in Chronic hyperammonemia ................................................................................. 30
Cholic Acid (Orphacol®) in Inborn errors in primary bile acid synthesis .......................................... 30
Omacetaxine Mepesuccinate in Chronic myeloid leukaemia (CML) ............................................... 31
Alipogene tiparvovec in Familial lipoprotein lipase deficiency (LPLD) ............................................ 31
Taliglucerase Alfa in Gaucher's disease .......................................................................................... 32
Asparaginase Erwinia Chrysanthemi in Acute lymphoblastic leukaemia (ALL)............................... 32
Brentuximab Vedotin in Hodgkin's lymphoma (HL) ........................................................................ 33
Brentuximab Vedotin in Systemic anaplastic large cell lymphoma (sALCL) .................................... 33
Crizotinib in Non-small cell lung cancer .......................................................................................... 34
Defibrotide in Veno-occlusive disease ............................................................................................. 34
Glucarpidase in Toxic plasma methotrexate concentrations .......................................................... 35
Carfilzomib in Multiple myeloma (MM) .......................................................................................... 36
Vismodegib in Basal cell carcinoma (BCC) ...................................................................................... 36
Bosutinib in Chronic myeloid leukaemia (CML) ............................................................................... 36
Pasireotide Diaspartate in Cushing's disease .................................................................................. 37
Cholic Acid (cholic Acid FGK®) in Inborn errors in primary bile acid synthesis ................................ 37
Lomitapide Mesylate in Familial hypercholesterolemia (HoFH) ..................................................... 38
Pomalidomide in Multiple myeloma (MM) ..................................................................................... 38
Raxibacumab in Anthrax inhalation................................................................................................ 39
Ponatinib Hydrochloride in Chronic myeloid leukaemia (CML) ....................................................... 39
Ponatinib Hydrochloride in Philadelphia chromosome-positive acute lymphoblastic leukaemia
40
Metreleptin in Lipodystrophy due to leptin deficiency .................................................................... 40
Ibrutinib in Mantle cell lymphoma (MCL) ....................................................................................... 41
Ibrutinib in Chronic Lymphocytic Leukaemia .................................................................................. 41
Ceritinib in Non-small cell lung cancer (NSCLC) .............................................................................. 41
8 / 59
1.
ZINC IN WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION)
Wilson’s disease is a rare inherited disorder where patients lack an enzyme to eliminate copper from
the body (which is absorbed in food). The accumulation of copper in the body causes liver damage
and damage to the nervous system (European Medicines Agency, 2007k).
The product works by blocking the absorption of copper from the gut. It was studied in 225 patients
(64 pre-symptomatic and 191 symptomatic) across four published clinical studies, and a number of
published case series. The main study enrolled 148 patients (31 symptomatic, and 117 presymptomatic). Although the study did not define a primary outcome, patients were assessed for
‘metabolic control’, defined as a series of copper excretion and plasma copper level measures – on
this metric, 20/23 evaluable pre-symptomatic and 91/100 evaluable symptomatic patients achieved
adequate control. Other outcomes reported to have improved with treatment were neurological
outcomes a and liver enzyme scores (European Medicines Agency, 2005j). When the trial was
submitted to the FDA, only data on 86 patients were available from the pivotal study, along with
similar results (Gallo-Torres, 1997).
The product was submitted to the FDA in 1994 and approved in 1997; however, it was not submitted
to the EMA until January 2003 and approved in October 2004 (European Medicines Agency, 2005j).
2.
SODIUM PHENYLBUTYRATE IN UREA CYCLE DISORDERS
Urea cycle disorders are inherited enzyme deficiencies that prevent the body to be able to break
down ammonia to urea. Instead there is a build-up of ammonia in the body, which is highly toxic.
This toxicity causes nerve and metabolic issues, leading to anorexia, lethargy, confusion, brain
damage, and ultimately death (Griebel, 2009).
There are two forms of the disease, neonatal-onset – presenting within the first 28 days of life, and
late-onset, which presents at any time thereafter, there are also three different genetic mutation
that cause the condition – sodium phenylbutyrate was studied in both forms of the disease, and all
three genetic mutations. Prior to the advent of effective therapy, mortality was close to 100% in the
first year of life compared to the sodium phenylbutyrate overall survival of approximately 80%
(European Medicines Agency, 2009). As it is hyperammonemic episodes that lead to the crises
causing deaths, these were also of interest to regulators, of the 148 total evaluable patients from
the main trial, 34 experienced no events causing hospitalisation, with 114 experiencing 1 or more
events (European Medicines Agency, 2006g).
Due to the rarity of the condition, and the ‘devastating consequences’ of the condition, the FDA
approved the product in 1996 (Food and Drug Administration, 1996), and the EMA in 1999
(European Medicines Agency, 2009).
3.
ANAGRELIDE IN ESSENTIAL THROMBOCYTOPENIA
Essential thrombocytopenia is a condition where patients have an excess of platelets, which leads to
the danger of blood clots forming.
The treatment was studied in four uncontrolled studies that enrolled over 4000 patients, with 1446
evaluable for efficacy. The primary outcome of three studies was defined as ‘complete response’, a
9 / 59
return of platelet levels to within the normal range (<600 x 109/l). Across all studies, the complete
response rate was between 60%-70% (European Medicines Agency, 2007b).
On the basis of the clinical study results, in 2003 the EMA granted a license under exceptional
circumstances, although only for patients intolerant or having inadequate results on their current
therapy (European Medicines Agency, 2009). The FDA reviewed and approved the product in 1997
(without the restriction of patients intolerant or refractory to their current treatment) (Food and
Drug Administration, 2014b).
4.
PACLITAXEL IN KAPOSI'S SARCOMA (KS)
Kaposi’s sarcoma (KS) was a rare sarcoma until the early 1990s, when a spate of cases began to
occur in young males. It was subsequently discovered that these were due to the spread of Acquired
Immune Deficiency Syndrome (AIDS). Kaposi’s sarcoma is now recognised as a complication of HIV
infection and an AIDS defining illness (Gbabe et al., 1996). First-line treatment for the condition at
the time of licensing was anthracycline chemotherapy, with no second-line treatments available.
Paclitaxel was one of the first drugs trialled for the emerging number of cases.
The history of paclitaxel is equally complex; with extracts from the Yew tree found to be cytotoxic in
1964, early clinical trials (Phase I and Phase II) begun in the 1980s, and the drug was commercialised
in the 1990s. The slow growth of the tree from which it was extracted led to concerns regarding the
possible extinction of the species, before a method of synthesizing the drug was found (Weaver,
2014). On entering clinical trials, it was found to have substantial anti-tumour activity in a variety of
conditions, including breast, ovarian and lung cancers (Mekhail and Markman, 2002). Since this time,
different formulations of the drug have been studied in other conditions, most recently pancreatic
cancer (Von Hoff et al., 2013).
The efficacy of paclitaxel in other tumour types made it an obvious candidate for use in KS. To this
end, 107 patients with previously treated KS were enrolled in a clinical study, with 63 patients
considered resistant to liposomal anthracyclines (the only licensed treatment at the time), with a
primary endpoint of best tumour response according to ACTG criteria (Krown, Metroka and Wernz,
1989). Of the 63 patients, 3 (4.8%) had a complete response and 33 (52.4%) had a partial response
to treatment (Food and Drug Administration, 1998).The EMA states ‘it is unlikely that patients having
failed one or more previous chemotherapeutic regimens would respond simultaneously in the
percentage seen in this study’ (European Medicines Agency, 2005h, p. 8). The EMA also stated that
historical controls could not be used due to the changing nature of both AIDS and AIDS-KS – the
introduction of antiviral therapy, and developments in its usage, greatly reduced the number of
cases over time.
Based on the efficacy results observed in previously treated patients, the FDA approved the product
for use in KS in 1997 (Food and Drug Administration, 1998) and the EMA in 1999 (European
Medicines Agency, 2005a).
5.
ARGATROBAN IN HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)
Patients with heparin-induced thrombocytopenia have a reduced level of platelets, which can lead
to the abnormal formation of blood clots. The aim of treatment with argatroban is to prevent the
10 / 59
formation of these clots, without further depleting platelet count (Food and Drug Administration,
2000a).
The drug was studied in 568 adult patients with HIT, with a composite primary endpoint of death,
amputation, or new thrombosis during the study period (days 0-37). This event rate was compared
with 193 historical controls from a registry based at Loyola University, Chicago. When comparing the
two sources, the event rate was lower with argatroban (43% vs. 34.2%). A second study of 264
patients was also conducted using the same historical control. This also demonstrated a lower rate
of events (43% vs. 33.7%) (Center for Drug Evaluation and Research, 2000a).
Based on this, the FDA gave the drug approval in June 2000 (Center for Drug Evaluation and
Research, 2000a). However, this was not a straightforward approval, as the initial application by the
company in 1998 was rejected due to concerns regarding the applicability of the historical control.
Only with an updated control did the FDA approve the treatment (DeBeau, 1999). Argatroban has
not been reviewed by the EMA; however, it may have been approved in European countries via the
process of mutual recognition.
6.
SODIUM FERRIC GLUCONATE COMPLEX IN IRON DEFICIENCY
Patients with renal failure often suffer from anaemia due to low production of erythropoietin (EPO)
and blood loss from repeated blood testing as well as blood retention in the dialysis machine and
tubing. If untreated, this anaemia can cause not only fatigue but also decreased oxygen delivery and
cardiac problems – ultimately leading to lower survival rates. As a result, patients are often given
supplementary EPO and/or intravenous iron to ensure patients have the correct level of red blood
cells and iron stores (Sizer, 1998).
To demonstrate the efficacy of sodium ferric gluconate, two trials were conducted. One trial (560001) enrolled 83 patients from three centres (including the University of Colorado) randomised to
low- and high-dose sodium ferric gluconate. The results for these patients were compared with 25
historical controls from the University of Colorado, where due to drug unavailability, the 25 patients
did not receive IV iron for 14 months (only oral iron supplementation was available). Due to changes
in EPO dose, only 59 patients met the protocol inclusion criteria for efficacy, with the high-dose
group showing improvements in haemoglobin (the primary endpoint) over the historical control but
no significant difference between the low-dose group and the historical control (Food and Drug
Administration, 1999d).
A second study, Study 5600-03 was also conducted with the primary endpoint of change in
haemoglobin from baseline to last observation (to a maximum of 50 days). Thirty-eight patients
were enrolled in the study, which were compared to the same 25-patient historical control treated
with oral iron. In the resulting analysis, patients treated with sodium ferric gluconate complex
showed a statistically significant larger increased in haemoglobin levels (1.3 g/dL vs. 0.4 g/dL,
p=0.022) (Sizer, 1998).
The FDA judged the provided efficacy data sufficient to issue a license for sodium ferric gluconate for
the treatment of dialysis patients receiving supplemental EPO in February 1999 (Raczkowski, 1999).
The EMA have not received a submission from the manufacturer; however, the French regulatory
agency referred IV iron products to the EMA in 2013 due to concern regarding adverse events. The
11 / 59
EMA were asked to judge whether the benefits of the products outweighed the risks (European
Medicines Agency, 2013i). The EMA reviewed all available products (including sodium ferric
gluconate) and concluded that the risk/benefit of the products was positive; however, the EMA
standardised wording in the labels of all products to ensure that the risk of allergic reaction is
understood and adequately managed (European Medicines Agency, 2013g).
7.
BUSULFAN IN HAEMATOPOIETIC PROGENITOR CELL TRANSPLANTATION (HPCT)
Prior to receiving a stem cell transplant, patients receive ‘conditioning’ therapy, to eliminate the
existing faulty cells. Busulfan can be used as a component of this conditioning therapy (Food and
Drug Administration, 1999b).
Busulfan was studied in two clinical studies, OMC-BUS-3 and OMC-BUS-4, both of them uncontrolled
Phase II studies showing myelosuppression with the drug. OMC-BUS-3 was conducted in autologous
SCT, and OMC-BUS-4 was conducted in allogeneic SCT. The endpoint of both OMC-BUS-3 and OMCBUS-4 were blood markers of myeloablation (a combination of neutropenia, lymphopenia and
thrombocytopenia markers). These markers were met for all evaluable patients (42 and 61)
(European Medicines Agency, 2005f).
Busulfan was approved by the FDA in 1999 (Justice, 1999) for use in allogeneic stem cell
transplantation (on the basis of the OMC-BUCS-4) study (Food and Drug Administration, 1999c) and
was approved by the EMA in 2001 for both allogeneic and autologous SCT (using both OMC-BUCS-3
and OMC-BUCS-4) (European Medicines Agency, 2008).
8.
TEMOZOLOMIDE IN ANAPLASTIC ASTROCYTOMA
Anaplastic astrocytoma is a type of brain cancer. Initial symptoms include headache, depressed
mental state and seizures (Cohen, 1999).
Temozolomide was studied in this population in a single study, Study C194-123, in which 118/162
patients were eligible for assessment. The results from this group were compared to a case series of
historical controls, with the six month event-free survival slightly higher with temozolomide – the
temozolomide response rate was stated as 44%, whilst the historical control rate was not given. The
EMA comment that the confidence intervals of the comparison overlapped (Cohen, 1999; European
Medicines Agency, 2009). Other endpoints reported were partial and complete response based on
MRI scans.
Based on the data, the EMA approved temozolomide in this indication in January 1998 (European
Medicines Agency, 2009) – the decision, however, was based on the similarity to giloblastoma, with
the scientific discussion stating explicitly ‘Based on the non-comparative data alone, the therapeutic
indication of anaplastic AA would not meet the requirements of the CPMP Note for Guidance on the
Evaluation of Anticancer Medicinal Products in Man’ (European Medicines Agency, 2005i, p. 12). The
FDA also approved the drug in August 1998; under the condition that further studies were
conducted (Temple, 1999a). The FDA’s concerns in particular seem to be related to the concern that
measurements of tumour size are susceptible to bias due to measurements taken from different
angles.
12 / 59
9.
BEXAROTENE IN CUTANEOUS T-CELL LYMPHOMA (CTCL)
Cutaneous T-Cell Lymphoma is a rare form of lymphoma (cancer of the lymph tissue), where some
white blood cells grow in the skin, which can also lead to secondary malignancies (European
Medicines Agency, 1999).
Bexarotene was studied in two multi-centre clinical studies, enrolling both early stage and previously
treated patients. The primary endpoint of the trials was the objective response rate, determined by
the response of up to 5 lesions per patient and whether these were deemed to have improved or
worsened by the clinician (on a 7-point scale). The result of these studies were response rates of
36% and 27% – above the 0% stated as the expectation of untreated disease (European Medicines
Agency, 2006a).
Based on these clinical studies (the same data package appears to have been made available to the
EMA and FDA (Food and Drug Administration, 1999a; European Medicines Agency, 2006a), both
agencies approved Bexarotene for patients refractory to at least 1 previous treatment – the FDA in
December 1999 (Temple, 1999b) and the EMA in March 2001 (European Medicines Agency, 1999).
This population constitutes a subgroup of the original clinical studies, and the decisions were
consistent between the EMA and FDA.
10.
TEMOPORFIN IN HEAD AND NECK CANCER
Advanced head and neck squamous cell carcinoma is a type of cancer typically found in the oral
cavity and throat. If the cancer is unable to be removed by surgery, survival is poor (European
Medicines Agency, 2006h).
Temoporfin is a drug that is absorbed by cells and can then be activated by light at a specific
wavelength, where it will react with oxygen with the aim of destroying tumour cells. The drug was
studied in four trials, three supportive studies, and a pivotal study of 220 patients who could not
receive surgery or radiotherapy. At 12-16 weeks after treatment, 28 (22%) of 128 evaluable patients
had an improvement in symptoms, with a quarter of patients also having a decrease in tumour size
(European Medicines Agency, 2006h). The median duration of response was between 57-84 days,
depending on the depth of response (European Medicines Agency, 2009).
The regulatory pathway to approval for temoporfin was not straightforward. Initially it was rejected
by the FDA in September 2000, which caused the share price to halve (Hobson, 2000). The drug was
then rejected by the EMA, which forced the company into administration (BBC, 2001) . The company
appealed the EMA decision, at which point there was a divergent position, with the majority of
members supporting the licensing of temoporfin (which occurred in October 2001); however, a
number of members believed the pivotal study to have design deficiencies, and the duration of
response was not clinically relevant (European Medicines Agency, 2006h). The company was
eventually rescued, with a buyer then taking on the marketing of the product (Sims, 2001).
11.
GEMTUZUMAB OZOGAMICIN IN ACUTE MYELOID LEUKAEMIA (AML)
Acute Myeloid Leukaemia (AML) is a form of blood cancer associated with older adults. If untreated,
too many immature white blood cells are produced, blocking the bone marrow and preventing the
13 / 59
immune system from functioning effectively (thus raising the risk of infections) (Center for Drug
Evaluation and Research, 2000b).
The efficacy of Gemtuzumab was studied in patients who had relapsed after first-line chemotherapy.
This was done in three studies conducted across the USA, Canada, and Europe, with the primary
outcome of complete response, defined as the absence of leukemic blasts from the blood, low levels
(<5%) in the bone marrow, normalisation of blood markers and red blood cell transfusion
independence. Of the 154 patients screened, 104 were enrolled, with a complete response rate of
17%. A further 13% of patients had a ‘Morphologic response’, which was a response lacking the
normalisation of red blood and platelet counts (Center for Drug Evaluation and Research, 2000b).
On reviewing the data, in May 2000 (Temple, 2000a) the FDA approved the drug only in patients
over 60 years of age, in whom treatment options are limited. This was based on the risk/benefit
profile of the drug in younger adults – the company had asked for a license in patients of all ages
(Center for Drug Evaluation and Research, 2000b). The drug was submitted to the EMA in 2005;
however, it was rejected in 2006 and again in 2008 as having insufficient evidence of benefit, and
due to safety concerns in that platelet and red blood cell production can remain permanently
suppressed in a large number of patients (European Medicines Agency, 2008).
12.
ALEMTUZUMAB IN CLL
Alemtuzumab was approved by the EMA and FDA in 2001, on the basis of three uncontrolled studies
in CLL (n=93, n=32, n=24). All studies enrolled patients who had failed on at least first-line therapy
(fludarabine) and received a median of 3 prior therapies (range 1-10), after which no other licensed
treatments were available (Food and Drug Administration, 2001a; Millenium and ILEX Partners,
2001).
Although CLL is a common condition (and the most common adult leukaemia), at later stages of
disease, there are relatively few treatment options, and fewer still that have been adequately
studied. The primary endpoint of the studies was the haematologically defined Overall Response
Rate, which was 33%, 21% and 29% in the three studies, with median progression-free survival of 4,
5 and 7 months (European Medicines Agency, 2005d). The EMA stated that ‘In a population of
heavily pre-treated patients with CLL, MabCampath has shown outstanding anti-leukaemia activity.
The response rate and duration was independent of previous treatment as the molecule has a
completely different mechanism of action’ (European Medicines Agency, 2005d).
Subsequent to the original license, a comparative study was conducted (as part of the postmarketing commitment) in first-line treatment, showing a benefit over standard of care and leading
to an extension of the license in 2005 to first-line CLL (Department of Health and Human Services,
2007; European Medicines Agency, 2008).
13.
NITISINONE IN HEREDITARY TYROSINEMIA
Tyrosinemia is where the body is unable to completely break down the amino acid tyrosine, which
causes a build-up of metabolites in the body, leading to serious liver problems as well as neurological
14 / 59
and kidney problems. The disease is rare, with the first stage in treatment being to limit the intake of
tyrosine, which is normally found in foods rich in protein (European Medicines Agency, 2007g).
The drug nitisinone was originally developed as a herbicide and then trialled as a drug for human
use. The main clinical study enrolled 207 patients in 25 countries, over a period of 6 years. The
results from this study were compared with historical controls from the literature, with the FDA
reviewer stating that ‘There is an obvious improvement in long-term survival in this study, compared
to historical controls’ (Leonardi, 2001). In the historical control, patients aged 0-2 months at
diagnosis had a 29% survival rate at 2 and 4 years, and aged 0-6 months at diagnosis, a survival rate
of 60% at 2 years, and 74% at 4 years. In the nitisinone trial, the survival rate for patients aged 0-2
months was 88% at 2 and 4 years, and aged 0-6 months, 94% at 2 and 4 years.
Based on these results, the drug was approved by the FDA in 2002 (Jenkins, 2002) and the EMA in
2005 (European Medicines Agency, 2009).
14.
ARSENIC TRIOXIDE IN ACUTE PROMYELOCYTIC LEUKAEMIA (APL)
APL is a type of leukaemia, caused by a genetic mutation, which leads to the abnormal accumulation
of immature granulocytes in the blood. Arsenic trioxide was studied in this disease in 52 patients, in
2 uncontrolled clinical studies (n=12, n=40) (European Medicines Agency, 2005e).
In these studies, patients had relapsed after having received between 1-6 prior therapies. After
treatment, 45 of the 52 were deemed to have a complete response, measured by haematological
markers. Eighteen-month survival was given as 66% (Food and Drug Administration, 2000b).
Based on the results of these studies, and a relatively benign safety profile, the FDA approved
arsenic trioxide in September 2000 (Temple, 2000b), and the EMA in March 2002 (European
Medicines Agency, 2009), both for previously treated patients.
Although there were no concerns regarding the efficacy of arsenic trioxide in APL, the company was
sued, and settled for $10.5 million with the US government, over allegations of off-label promotion
(Armstrong and Berens, 2013).
15.
TOSITUMOMAB; IODINE I 131 TOSITUMOMAB IN NON-HODGKIN'S LYMPHOMA
(NHL)
NHL is a type of B-Cell lymphoma, where the body produces excessive numbers of lymphocytes,
which collect in the lymph nodes. Patients are initially treated with chemotherapy (with added
rituximab) (Shastri et al., 2003).
Like rituximab, tositumomab is an anti-CD20 monoclonal antibody; however, tositumomab has a
different mechanism of action – it is radiolabelled, and on attaching to the CD20 receptor (especially
common on lymphocytes), the radioactivity kills the cell. It was studied in 40 patients with FL, whose
disease had not responded to rituximab or who had relapsed soon after a course of at least 4 doses
of rituximab, with further supportive information from 190 patients from 4 other single arm studies
in rituximab refractory patients. Of the 40 patients in the main clinical study, 35 fit the definition of
being rituximab refractory (having had no response or a duration of response <6 months). In these
patients, based on independent chart and radiological review, 29% of patients had a complete
15 / 59
response, with a further 34% of patients having a partial response (Food and Drug Administration,
2003a; Shastri et al., 2003).
Based on the results of the trials, the FDA approved the product in June 2003, with a requirement
for an open-label comparative trial to also be conducted (Masiello and Risso, 2003).
16.
ABARELIX IN PROSTATE CANCER
Abarelix was approved in 2003 by the FDA on the basis of a clinical study enrolling 81 patients with
advanced symptomatic prostate cancer who were at risk of a clinical exacerbation if treated with
standard of care (‘LHRH agonists’). The objective of the study was to demonstrate that patients
could avoid orchiectomy (surgical removal of the testicles) if treated.
Nine patients from the study were excluded due to poor documentation, with 60 of the remaining
72 patients remaining on treatment for the maximum 6-month study duration (at which point they
were enrolled on an extension study). No patients received an orchiectomy, with 68/71 patients
achieving medical castration (defined by a blood testosterone test) by Week 4 (Division of
reproductive and urologic data products, 2003).
The drug has not been assessed by the EMA but may have been approved in European countries via
the process of mutual recognition.
17.
IMATINIB MESYLATE IN CHRONIC MYELOID LEUKAEMIA (CML)
Chronic Myeloid Leukaemia is caused by a translocation of chromosome 9 to chromosome 22. This
causes the production of immature white blood cells, which cause the immune system to stop
working correctly, thus leading to an increased risk of infection. Untreated CML will progress
through the ‘chronic’ phase (CP) in 4-5 years, then with an accumulation of blasts, move into the
‘advanced’ phase (AP) for approximately 1 year, before entering the ‘blast’ phase (BP) where the
bone marrow is overwhelmed by the immature white blood cells (lasting 3-6 months), which causes
death from bone marrow failure. Prior to the licensing of imatinib, patients were treated with
interferon or hydroxyurea (Cohen et al., 2001).
Initially imatinib was studied in patients in CP who had failed interferon-alpha (Study 110, n=532),
patients with AP (Study 109, n=235) and patients with BP (Study 102, n=260). Each of these studies
was a single arm study, treating patients with single agent imatinib. In CP, a major cytogenetic
response (a large fall in the number of Ph+ immature blasts in the bone marrow and blood) was
observed in 49% of patients, with 30% exhibiting a complete cytogenetic response (undetectable
disease and normalisation of blood markers). In AP, major cytogenetic response was observed in
21% of patients, and in BP, major cytogenetic response was observed in 14% of patients (Food and
Drug Administration, 2001b; European Medicines Agency, 2005g).
Based on these efficacy results, the FDA gave a license for imatinib in May 2001 (Temple, 2001), and
the EMA a license in July 2001 (European Medicines Agency, 2009). The license for imatinib was later
amended in both regions to include the results of the ‘IRIS’ study, which included over 1000 patients
randomised 1:1 to either imatinib or interferon-alpha plus low-dose cytarabine. The results of this
study were extremely compelling, with the rate of major cytogenetic response being 84% on
imatinib but only 30% on the comparator (O’Brien et al., 2003).
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18.
IMATINIB MESYLATE IN GASTROINTESTINAL STROMAL TUMOURS (GIST)
Gastrointestinal Stromal Tumour (GIST) is a type of sarcoma found in the digestive system, most
frequently in the stomach. Imatinib works on these tumours by inhibiting tyrosine kinase, though
only if the GIST expresses CD117, a protein made by the gene c-kit – this occurs in the majority of
cases of GIST (Dagher et al., 2002; Food and Drug Administration, 2002a).
Imatinib was studied in 147 patients with metastatic or recurrent malignant GIST expressing CD117.
In the study, 38% of patients achieved an overall objective response rate, higher than the responses
observed with any other therapy in this population, although there was no comparative arm in the
study (Dagher et al., 2002).
Based on this study the FDA extended the license for imatinib, which was already on the market for
CML) in February 2002 (Pazdur, 2002), and the EMA in May 2002 (European Medicines Agency,
2005c).
19.
CETUXIMAB IN COLORECTAL CANCER
Cetuximab is used in the treatment of colorectal cancer, which expresses the EGFR mutation. It was
studied in a randomised trial where patients were randomised to treatment with cetuximab alone or
irinotecan plus cetuximab. Although a randomised trial (n=329), both arms contained cetuximab,
and thus, there was no control arm. It was also studied in two further clinical trials as a single agent
(n=57) or in combination with irinotecan (n=138) (European Medicines Agency, 2006d).
Patients entering the randomised study were refractory to irinotecan and oxaliplatin, and they had
independent confirmation of disease progression. The objective response rate was 23% for
cetuximab with irinotecan, and 11% for cetuximab alone (European Medicines Agency, 2006d).
The drug was initially rejected by the FDA in 2001 with an application based only on small single arm
studies (Pai-Scherf et al., 2010), but approved in February 2004 once the larger trial with patients
randomised between the two arms was available (Weiss, 2004). The EMA approved the product in
June 2004 (European Medicines Agency, 2009) on the same data as the FDA, for the same patient
group –patients with EFGR expressing metastatic colorectal cancer after treatment with irinotecanbased chemotherapy (Food and Drug Administration, 2004; European Medicines Agency, 2009).
The two regulators, however, differed in the exact wording applied to previous treatment, with the
FDA specifying that patients could be intolerant to irinotecan therapy before being treated with
cetuximab as a single agent, whilst the EMA stated that patients should have failed irinotecan
therapy before being administered cetuximab in combination with irinotecan.
20.
TRABECTEDIN IN SOFT TISSUE SARCOMA (STS)
STS is a cancer of soft tissue, a rare cancer which forms lumps in fat and muscle tissue. Patients are
initially treated with chemotherapies; however, approximately half are likely to become refractory
and relapse. If the disease becomes advanced, i.e. spreads, median survival is under 1 year
(European Medicines Agency, 2007i).
The main study for trabectedin compared two doses of the drug in 266 patients – 134 in the highdose group and 132 in the low-dose group, with time to progression being the main outcome. This
17 / 59
was 3.7 months in the high-dose group and 2.3 months in the low-dose group. Median OS was 11.8
months in the low-dose group and 16.7 months in the high-dose group (European Medicines Agency,
2009).
The submitting company, PharmaMar, originally filed the drug for approved in 2001 on the basis of
three single arm studies; however, this was rejected by the EMA in 2003. The company then
conducted a Phase II study, randomising patients between two doses of trabectedin – based on the
results of this study, the EMA approved the product in 2007 at the high dose, although they did state
that they would have preferred to see an internal control arm within the study (European Medicines
Agency, 2007i).
The drug was rejected by the FDA in July 2009 for ovarian cancer (Chustecka, 2009) by vote at the
Oncology Drugs Advisory Committee (Food and Drug Administration, 2009). At present, however,
the drug is not licensed in the US for STS, although a clinical trial is on-going (George et al., 2014).
21.
CLADRIBINE IN HAIRY CELL LEUKAEMIA
Hairy cell leukaemia is a rare type of B-cell malignancy, named due to the appearance of leukemic
cells under a microscope. Like other B-cell leukaemias, if untreated, the disease is fatal (European
Medicines Agency, 2005b; Guest et al., 2009).
Cladribine is a drug that was originally licensed in the US in 1993 (Centre for Drug Evaluation and
Research, 2000) and is widely available in Europe. This version, however, has a more convenient
dosing schedule for patients and a reduced dose. It was studied in 63 patients with hairy cell
leukaemia, 33 of whom were newly diagnosed, and 30 of whom had received previous treatments,
in an open-label single arm study, the SAKK 32/93 study. Of the 63 patients, 61 went on to have a
response (defined by blood measurements) (European Medicines Agency, 2005b, 2009). The sponsor
also provided information on over 1700 historical controls from the literature.
The drug was approved by the EMA in 2004. A subsequent submission to the EMA for Cladribine in
multiple sclerosis was withdrawn by the manufacturer in 2011 (European Medicines Agency, 2011).
Although the original variants of Cladribine are available in the US, this version (Litak®) has not been
reviewed by the FDA.
22.
GEFITINIB IN NON-SMALL CELL LUNG CANCER (NSCLC)
Non-small cell lung cancer is a common yet deadly form of cancer. After first-line treatment,
prognosis is poor, with an untreated median survival of 4-5 months (European Medicines Agency,
2009).
In this population, gefitinib was studied in two trials where patients were randomised to different
doses of the investigational drug (250mg/day or 500mg/day), with no control arm (either active or
placebo). One study (Trial 39) was conducted in 216 patients who were refractory to 2 or more lines
of chemotherapy. In this study, the FDA deemed only 107 patients to be truly eligible given the
inclusion criteria. The overall response rate of the study was 10.2% – results for the eligible patient
population are not reported. A second study, Study 16, was conducted in patients who were
refractory to one or two previous lines of chemotherapy. This study reported a similar response rate
18 / 59
of 18.5% with 39/210 patients showing a response to treatment, although without issues in the
eligibility of patients.
Based on these clinical studies, the FDA approved gefitinib in 2003 (Food and Drug Administration,
2003c; Temple, Robert, 2003) by majority vote. The company (AstraZeneca) did not submit the
product to the EMA until 2008, when comparative data were available. It was approved on this basis
in 2009 (European Medicines Agency, 2009).
23.
BORTEZOMIB IN MULTIPLE MYELOMA (MM)
Multiple myeloma is a cancer of plasma cells in the bone marrow. It is often diagnosed following
routine blood tests, with patients then treated with first-line therapies. If/when they relapse,
patients will be retreated with the same therapy until they become refractory to the treatment, at
which point they move on to the next line in treatment (European Medicines Agency, 2006b).
Bortezomib was initially studied in 202 patients who had been previously treated with at least two
prior therapies (demonstrating disease progression on their last prior therapy); however, the
majority of patients had received more therapies than this (the median was 6). Of the 188 evaluable
patients, there was a 28% overall response rate (determined by an independent review committee,
according to objective criteria around blood tests) (Bross et al., 2003).
Based on this data package, bortezomib was approved by the FDA in May 2003 (Temple, 2003) and
by the EMA in April 2004 (European Medicines Agency, 2009). Since this time, it has been studied
using comparative trials in different lines of therapy within multiple myeloma, from which it now has
multiple indications approved in both Europe and the US (Food and Drug Administration, 2003b;
European Medicines Agency, 2014d).
24.
FERRIC HEXACYANOFERRATE (II) IN INTERNAL CONTAMINATION WITH
RADIOACTIVE CAESIUM OR THALLIUM
Caesium is a radioactive material, with fears it could be used in a ‘dirty bomb’ due to its relatively
widespread availability from a variety of uses (for example industrial and medical radiation uses).
Although not poisonous in itself, the radioactive particles it emits are a serious danger to human
health. Thallium has a different mechanism of harm, in being a highly toxic heavy metal that
circulates through the liver in the same way as caesium (Yaes et al., 2003).
Ferric hexacyanoferrate is a compound that binds to both of these elements, interrupting their
circulation and increasing the rate of faecal elimination, thus reducing exposure within the body. The
evidence for efficacy is mainly taken from an incident of caesium contamination in Brazil, where 249
people were contaminated. Forty-six were treated with ferric hexacyanoferrate, which increased the
rate of elimination. Case series data from the literature (n=34) also show that the rate of elimination
of thallium was increased. However, there have been no prospective studies, and only animal and
anecdotal evidence to support its use for these forms of poisoning have been reported (Food and
Drug Administration, 2003d).
It was approved by the FDA in October 2003 (Houn, 2003) but has not been reviewed by the EMA.
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25.
CLOFARABINE IN ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL)
Acute leukaemia is the most common form of childhood leukaemia, estimated at approximately 30%
of all childhood leukaemias. Patients are commonly offered first-line treatments (which include stem
cell transplantation); however, there remains an unmet need for patients who are refractory to firstline therapies, where the disease is often resistant to existing agents (European Medicines Agency,
2007d).
Clofarabine was studied in paediatric patients with relapsed or refractory ALL. The study included 25
patients (17 with ALL, and 18 with AML). Of the patients studied, 5/25 achieved a complete response
and 3/25 a partial response according to the Children’s Oncology Group response criteria. A second
study was then conducted with the same primary endpoint, in which 12/61 patients achieved
remission and 6/61 a partial response. Ten patients also discontinued clofarabine to receive a stem
cell transplant. This was compared to historical data on patient survival from the German and Dutch
cancer registries (Cohen, Johnson and Sridhara, 2004; European Medicines Agency, 2007d).
Based on this trial data, both the EMA and the FDA granted the drug a license for the treatment of
paediatric ALL (and not paediatric AML) (Food and Drug Administration, 2004; European Medicines
Agency, 2009). The FDA did so in December 2004 (Temple, 2010), and the EMA did so in May 2006
(European Medicines Agency, 2009).
26.
PENTETATE CALCIUM TRISODIUM AND PENTETATE ZINC TRISODIUM IN
INTERNAL CONTAMINATION WITH PLUTONIUM, AMERICIUM, OR CURIUM
These two products have been discussed together, as they are produced by the same manufacturer,
were reviewed together by the FDA (in the same review), and are used for the same condition in
combination.
The products are for internal contamination by the trans-uranium elements plutonium, americium
or curium, all of which are seen in nuclear weapons production, which is the source of the
contamination in all literature cases. The evidence for the efficacy of the compounds in increasing
the rate of excretion by these radioactive elements was entirely from reviews in the literature – 454
patients in total were identified, with 54 papers published between 1954 and 1970, including 70
patients, 60 of whom were treated with these products in combination (Yaes et al., 2004).
The products were judged to work based on the concentration of metals in the urine, as compared
to what this was before the administration of the treatment, known as the ‘Urine Enhancement
Factor’ (Food and Drug Administration, 2004a, 2004b). Based on these data and a commitment from
the manufacturer to collect safety data on the first 20 patients treated, the drugs were approved in
2004 (Beitz, 2004). At the time of writing (October 2014), the EMA had not reviewed the products.
27.
NELARABINE IN T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA / LYMPHOMA (T-ALL
/ T-LBL)
ALL and LBL are aggressive diseases that are rapidly fatal if untreated. First-line therapy consists of
chemotherapy, with a long-term complete response of over 95% in children and 60-80% in adults.
Should a patient relapse, the recommendation is that they receive re-induction with chemotherapy
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and then a bone marrow transplant, although chemotherapy is not always successful or suitable (for
example if a donor cannot be found).
It is in the population who have failed prior chemotherapies that Nelarabine was studied; in 84
paediatric patients (31 after one prior therapy and 39 after two or more therapies) and 39 adult
patients (28 of whom were refractory to two prior therapies or more). In the group of patients who
had relapsed following two prior therapies or more, the response rate (complete response and
complete response without haematologic recovery) was 23% in children and 21% in adults.
Based on these data, both the FDA and the EMA granted the product a license in patients who had
received two or more prior chemotherapies. The FDA license was granted in October 2005 (Pazdur,
2005), and the EMA license was granted in August 2007 (European Medicines Agency, 2009).
28.
BETAINE ANHYDROUS IN HOMOCYSTINURIA
Homocystinuria is an inherited genetic disease where the amino acid methinonine cannot be broken
down fully by the body, leading to an accumulation of homocystine in the blood and urine. This leads
to blood clots, skeletal weakness, and mental retardation (European Medicines Agency, 2007c).
The drug Betaine converts the homocystine back to methinonine, with clinical efficacy data based on
a study conducted in 12 healthy volunteers, and 202 reports in the medical literature, of which 140
could be verified. On this basis, the EMA granted a license for the treatment, subject to patients
being enrolled in a registry (European Medicines Agency, 2007c, 2008).
The drug was reviewed (and approved) by the FDA in 1996, with the label subsequently updated to
include RCT evidence (Food and Drug Administration, 2006, 2010a).
29.
DEXRAZOXANE HYDROCHLORIDE IN ANTHRACYCLINE EXTRAVASATION
Extravasation is the leakage of a fluid, in this case the leakage of cytotoxic drugs from veins to the
surrounding tissue. If these agents are left in situ, they may cause necrosis of tissue requiring
surgical intervention and, potentially, the cessation of chemotherapy treatment (European
Medicines Agency, 2006f).
For this condition, dexrazoxane was studied in two single arm studies, one with 23 patients and one
with 57 patients. Of all the patients treated, only one required surgical intervention. This was
compared with a historical control from published literature, in which 35% of patients required
surgery (100% in biopsy proven cases) (European Medicines Agency, 2006f).
Based on this efficacy data, the EMA approved the product in July 2006 (European Medicines
Agency, 2008). Although there are no approvals on the FDA website, dexrazoxane was approved by
the FDA in 1995 (Food and Drug Administration, 2014a) for use as a cardioprotective agent in
patients receiving doxorubicin (Food and Drug Administration, 2002b). It does not appear to have
been reviewed for the indication for which it is approved in Europe.
30.
ALGLUCOSIDASE ALFA IN POMPE DISEASE
Pompe disease is a rare lysosomal storage disorder, in which a patient lacks a certain enzyme to
break down waste material, and therefore suffers from a build-up of waste material that reaches
21 / 59
toxic levels. In Pompe disease the missing enzyme is called alpha-glucosidase, which breaks down
glycogen (European Medicines Agency, 2007a).
The drug (Myozyme®) is an enzyme that performs the same function as the missing endogenous
enzyme. It was studied in 39 patients (across 2 studies – one in infantile onset, and one in late onset
disease). Neither study had a comparative arm. In infantile onset disease, in the first 18 months of
treatment 7/18 patients required ventilator support, and one of these patients died. The FDA
concluded that the drug was effective by comparing the proportion of patients who died or required
ventilator support with a matched historical cohort, identified by chart review. In this historical
control, by the age of 18 months, only 1/61 patients was alive.
The second study was in late-onset disease, where 5/21 patients were on ventilator support at study
entry, and the primary endpoint was survival at the end of study (52 weeks). At this point 16/21
patients were alive. The results were compared with another historical matched control, which
overlapped in endpoints (European Medicines Agency, 2007a).
A license was therefore granted by the FDA in 2006 for infantile onset disease, with a statement
that, in other forms of the disease, the efficacy has not been adequately studied (Genzyme, 2006).
The EMA also approved the product in 2006, but for both infantile onset and late onset disease
(European Medicines Agency, 2009).
31.
SUNITINIB MALATE IN RENAL CELL CARCINOMA (RCC)
RCC is a malignancy in the kidneys, which comprises approximately 80% of renal malignancies. Initial
treatment would involve surgery; however, if the disease has metastasized before detection or
subsequently returns, then the prognosis is poor, with a 5-year survival of under 10%. First-line
treatment for metastatic RCC prior to sunitinib consisted of cytokines, with a median survival of
under a year (European Medicines Agency, 2007h).
Sunitinib was initially studied in two Phase II trials, A6181006 (n=106) and RTKC-0511-014 (n=63),
with an on-going Phase III trial of sunitinib vs. interferon-alpha, Study A6181034 (aiming to enrol
approximately 750 patients), at the time of regulatory submissions. The primary outcome of both
studies was the overall response rate, according to the RECIST criteria (Eisenhauer et al., 2009),
which was 25.5% and 37% in the two trials. The median duration of response in the two studies was
27.1 weeks and 54.0 weeks, respectively (Goodman and Dagher, 2006).
Based on the level and duration of the responses observed in the single arm study (stated to be
‘impressive’), the FDA approved sunitinib for use in RCC (along with GIST) in January 2006 (Goodman
and Dagher, 2006; Pazdur, 2006). Pfizer submitted to the EMA approximately 6 weeks after the FDA
(28 September 2005 vs. 11 August 2005), and due to the approval process taking longer in Europe,
the interim results of Study A6181034 (i.e. comparative data) were available by the time the license
was granted in July 2007 (European Medicines Agency, 2007h, 2009).
22 / 59
32.
IMATINIB MESYLATE IN PHILADELPHIA CHROMOSOME-POSITIVE ACUTE
LYMPHOBLASTIC LEUKAEMIA (ALL)
ALL is a form of aggressive leukaemia that is caused by the translocation of genes 9 and 22 (the
‘Philadelphia chromosome’). It can be treated by drugs that target this mutation, which is the main
cause of CML.
Imatinib was studied in this population in a Phase II study of 43 patients, 35% of whom achieved a
major cytogenetic response (Cohen and He, 2006). Based on this study, the FDA issued a positive
opinion for imatinib in Ph+ ALL in October 2006 (Justice, 2006a). The EMA also issued a positive
opinion on the same data in 2007 (European Medicines Agency, 2014b).
33.
IMATINIB MESYLATE IN MYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASES
(MDS/MPD) ASSOCIATED WITH PLATELET-DERIVED GROWTH FACTOR RECEPTOR
(PDGFR) GENE RE-ARRANGEMENTS
MDS/MPD are a group of myeloproliferative disorders that share two features: the bone marrow
produces blasts that interfere with normal cell development and produces too many white blood
cells (Cohen and He, 2006).
The Phase II clinical trial B2225 enrolled patients with a range of life threatening diseases associated
with Abl, Kit or PDGFR protein tyrosine kinases, who were then treated with imatinib (an inhibitor of
these proteins) (Food and Drug Administration, 2006). This study included 7 patients with
MDS/MPD, with a further 24 patients identified through published case series. Of these 31 patients,
45% reported a complete haematological response (normalisation of blood markers), with 39%
achieving a major cytogenetic response (Cohen and He, 2006).
Based on these data, the FDA extended the label for imatinib to include this population in October
2006 (Justice, 2006a).
34.
IMATINIB MESYLATE IN ADVANCED HYPEREOSINOPHILIC SYNDROME (HES)
AND/OR CHRONIC EOSINOPHILIC LEUKAEMIA (CEL) WITH FIP1L1-PDGFR
REARRANGEMENT
HES is a condition where the blood contains a high number of eosinophils for which no cause can be
determined. It leads to inflammation and organ damage. CEL patients have the same symptoms;
however, the cause of the excess of eosinophils for these patients is a cytogenetic mutation (Cohen
and He, 2006).
The Phase II clinical trial B2225 enrolled patients with a range of life threatening diseases associated
with Abl, Kit or PDGFR protein tyrosine kinases, who were then treated with imatinib (an inhibitor of
these proteins) (Food and Drug Administration, 2006). This study include 14 patients with HES/CEL,
with a further 162 patients identified in 35 published case series. Of the 176 patients, 61% achieved
a complete haematologic response on treatment with imatinib, with a further 23% achieving a
partial haematologic response (Cohen and He, 2006).
Based on these data, the FDA extended the label for imatinib to include this population in October
2006 (Justice, 2006a).
23 / 59
35.
DASATINIB IN CHRONIC MYELOID LEUKAEMIA (CML)
Chronic myeloid leukaemia is a disease of several stages, caused by the translocation of a
chromosome fragment called the Philadelphia chromosome. In the early stages of disease (the
chronic phase, CP), the disease is mostly benign; however, it becomes more aggressive in the
accelerated phase (AP) and ends in the blast phase (BP). In BP, life expectancy is short, and a
patient’s blood is effectively overrun with immature white blood cells (European Medicines Agency,
2006e).
At the time dasatinib was under investigation, imatinib had become firmly established as first-line
therapy, showing clear superiority in the IRIS study (O’Brien et al., 2003). Dasatinib was therefore
studied in patients who had become refractory to imatinib or who were intolerant to imatinib. An
initial Phase I study enrolled patients at all stages of CML and included Philadelphia chromosomepositive ALL (Ph+ ALL), before individual studies were set up for CP, AP, and BP (as well as Ph+ ALL).
Each of these studies was a single arm uncontrolled study; however, a further study was set up in CP
CML, comparing dasatinib to high-dose imatinib – although the full study results were not available
for this trial, the pilot phase, enrolling 24 patients to dasatinib, and 12 to high-dose imatinib, had
been completed and provided comparative results (Brave, Goodman and Kaminskas, 2006; European
Medicines Agency, 2006e).
Based on the studies available, dasatinib was granted a license in CP, AP, and BP CML, in patients
who were refractory or intolerant to imatinib by the FDA in June 2006 (Pazdur, 2006) and by the
EMA in November 2006 (European Medicines Agency, 2009). The AP and BP indications are relevant
to this review as they were granted without controlled trial data (Food and Drug Administration,
2006; European Medicines Agency, 2009).
36.
DASATINIB IN PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC
LEUKAEMIA (PH+ ALL)
ALL is a form of aggressive leukaemia that can be caused by the translocation of chromosomes 9 and
22 to produce what is known as the ‘Philadelphia chromosome’. This translocation is commonly
found in CML, with drugs meant to target it, and therefore likely to show an effect in Ph+ ALL (Brave,
Goodman and Kaminskas, 2006; European Medicines Agency, 2006e).
Imatinib was the first Tyrosine Kinase Inhibitor (TKI) used to treat Ph+ ALL; however, patients can
become refractory to treatment. It is in this population that dasatinib was studied. Eight patients
with Ph+ ALL were included in the CA180002 Phase I study of dasatinib (along with CML patients),
before a Phase II study (CA180015) was set up, which subsequently enrolled 36 patients with Ph+
ALL (34 imatinib resistant, 2 imatinib intolerant). The primary endpoint of the studies was the
cytogenetic response to treatment, with 58% of patients having a major cytogenetic response
(between 0%-35% of cells in bone marrow testing positive for the Philadelphia chromosome) (Brave,
Goodman and Kaminskas, 2006; European Medicines Agency, 2006e).
Based on this efficacy data, dasatinib was granted a license in Ph+ ALL for patients who were
refractory or intolerant to imatinib by the FDA in June 2006 (Pazdur, 2006), and by the EMA in
November 2006 (European Medicines Agency, 2009) at the same time as licenses were issues for the
CML indications for dasatinib.
24 / 59
37.
IMATINIB MESYLATE IN AGGRESSIVE SYSTEMIC MASTOCYTOSIS (ASM)
ASM is a rare form of systemic mastocytosis, where mast cells infiltrate different tissues, causing
severe symptoms of flushing, diarrhoea, pain, organomegaly, organ dysfunction and abnormal blood
values. If untreated, patients risk anaphylactic shock (Cohen and He, 2006).
The Phase II clinical trial B2225 enrolled patients with a range of life threatening diseases associated
with Abl, Kit or PDGFR protein tyrosine kinases, who were then treated with imatinib (an inhibitor of
these proteins) (Food and Drug Administration, 2006). Included in the study were 5 patients with
ASM, who were the efficacy population on which the Novartis submission was based, along with 10
published case reports detailing 23 additional patients treated with imatinib. Of the 28 patients,
when treated with imatinib, 29% achieved a complete haematologic response, and another 32% a
partial haematologic response (Cohen and He, 2006).
Based on these data, the FDA extended the label for imatinib to include this population in October
2006 (Justice, 2006a).
38.
IMATINIB MESYLATE IN SOFT TISSUE SARCOMA - DERMATOFIBROSARCOMA
PROTUBERANS (DFSP)
DFSP is a rare form of sarcoma that develops in the deep layers of the skin, with most caused by a
translocation of chromosomes 17 and 22. This causes a tumour in the skin that can metastasise,
although this happens in fewer than 5% of cases (Cohen and He, 2006).
The Phase II clinical trial B2225 enrolled patients with a range of life threatening diseases associated
with Abl, Kit or PDGFR protein tyrosine kinases, who were then treated with imatinib (an inhibitor of
these proteins) (Food and Drug Administration, 2006). The study included 12 patients with
metastatic DFSP, with 6 further patients identified in 5 published case series. Of the 18 patients
treated with imatinib, 39% achieved a complete response, a further 44% also achieved a partial
response (5 of these 8 patients then had surgery, rendering them disease free). The median duration
of response in the clinical study was 6.2 months.
Based on these data, the FDA extended the label for imatinib to include this population in October
2006 (Justice, 2006a).
39.
VORINOSTAT IN CUTANEOUS T-CELL LYMPHOMA (CTCL)
CTCL is an uncommon subtype of NHL, affecting the T-cells and causing manifestations in the skin,
including patches, plaques and tumours. The disease is diagnosed in adulthood, with a chronic and
relapsing survival pattern. Patients with advanced disease have a median survival of approximately
2.5 years (European Medicines Agency, 2008).
The main studies on the effectiveness of vorinostat were two single arm trials: Protocol 001 (n=74),
and a supportive trial, Protocol 005 (n=65). Both studies had response rate as the primary outcome
(Stevens SR et al., 2002). In Protocol 001, 22/74 patients (30%) had an objective response rate, and
in Protocol 005, 21/65 patients had an objective response rate (32%) (Mann, 2006).
Based on the clinical data presented, the FDA approved the product in October 2006 (Pazdur, 2006).
The company, MSD, also submitted to the EMA in 2007; however, MSD withdrew the submission in
25 / 59
2009 (Merck Sharp & Dohme, 2009). At the time the submission was withdrawn, the EMA was of the
provisional opinion that the drug was not approvable due to concerns regarding the meaningfulness
of a 30% response rate and potential thromboembolic complications (European Medicines Agency,
2008).
40.
BORTEZOMIB IN MANTLE CELL LYMPHOMA (MCL)
Mantle Call Lymphoma (MCL) is caused by excessive immature B-cells in the lymph nodes. It is a
form of non-Hodgkin’s Lymphoma and manifests in this way. However, the differences between the
lymphomas can be seen when the cells are placed under a microscope (Kane, 2006).
There are a range of intensive chemotherapies that represent first-line therapy in MCL. At the time
of licensing, however, there was no established treatment for patients who are refractory to firstline treatment. Bortezomib was already on the market at this point for the treatment of multiple
myeloma, and was investigated in patients with MCL who were refractory to one or more prior
therapy. The study conducted was a single arm study, administering bortezomib alone to 155
patients. In these patients an overall response rate of 31% was achieved, with a median response of
9 months (Kane, 2006).
On the basis of this study, the FDA approved a license extension for bortezomib in December 2006
(Justice, 2006b), which was extended in 2014 to include the results of a first-line open label
randomised study in MCL (Food and Drug Administration, 2014e). Although the EMA have approved
bortezomib in Multiple Myeloma, they have not reviewed it in MCL (European Medicines Agency,
2014d).
41.
HYDROXOCOBALAMIN IN TREATMENT OF CYANIDE POISONING
Cyanide poisoning can occur with inhalation, ingestion or contact with cyanide on the skin or mucus
membranes. If a patient is affected, their blood pressure will drop, and they will struggle to breathe
– ultimately patients would become unconscious and die of cardiovascular collapse or respiratory
arrest (European Medicines Agency, 2007e).
Hydroxocobalamin binds to cyanide ions, with the resulting molecule, cyanocobalamin, being a nontoxic compound that is excreted in urine. It was demonstrated to be effective in 1952 as an antidote
to cyanide; however, no RCT has been conducted due to ethical considerations (European Medicines
Agency, 2007e). To assess the safety and efficacy of the product, a number of studies were
performed. These studies include those in healthy human volunteers who took the drug, to ensure
safety, and efficacy studies conducted in dogs and rabbits. In the dog studies 3/17 dogs survived to
14 days, whilst hydroxocobalamin dogs survival at the rate of 15/19 at a dose of 75mg/kg, and 18/18
at a dose of 150mg/kg. Four studies were also available in the literature that detailed the outcomes
of human patients treated for cyanide poisoning with hydroxocobalamin. In these studies 3/11
patients survived who were discovered in cardiac arrest (and then treated), and 17/22 patients
survived who were not in cardiac arrest when treated (Simone, 2006).
Based on these efficacy data, the FDA approved the drug in December 2006 and the EMA in
November 2007.
26 / 59
42.
NILOTINIB HYDROCHLORIDE MONOHYDRATE IN CHRONIC MYELOID LEUKAEMIA
(CML)
Chronic Myeloid Leukaemia is caused by a translocation of chromosome 9 to chromosome 22, which
is also known as the Philadelphia chromosome. This causes the production of immature white blood
cells (blasts), which in turn interfere with the correct working of the immune system. The disease
follows a defined course, with patients experiencing a ‘chronic’ phase (CP) for several years before
the disease progresses to the ‘advanced’ phase (AP), in which the number of blasts greatly
multiplies, and finally, blast crisis, or blast phase (BP), in which the immature white blood cells
overwhelm the bone marrow, leading to abnormal functioning of the blood (European Medicines
Agency, 2007f).
At the time nilotinib was studied, imatinib had become established as first-line therapy, leading to
nilotinib being studied in patients who were resistant or intolerant to imatinib therapy. One single
arm study was conducted that enrolled 232 patients with CP CML and 105 patients with AP CML. In
patients with CP CML, 40% achieved a major cytogenetic response (28% achieved a complete
cytogenetic response), whilst AP patients had a 26% response rate (18% achieved complete
response) (European Medicines Agency, 2007f).
Given the lack of treatment options for these patients, the FDA granted a license for nilotinib in
October 2007 (Pazdur, 2007b), and EMA in November 2007 (European Medicines Agency, 2007j).
43.
IXABEPILONE IN BREAST CANCER
Brest cancer is a life-threatening cancer and the most common cancer in women. Deaths largely
occur once the disease has metastasised. Patients after frequently diagnosed early in the disease,
although some patients relapse, others present late when the disease has already spread to other
sites. Once the disease has metastasized and become refractory to standard chemotherapy options
including taxanes and anthracyclines, treatment options are limited – it is in this population that
ixabepilone was investigated (European Medicines Agency, 2009).
The clinical study programme for the drug included two trials. One study was conducted in patients
refractory to taxane- and anthracycline-based chemotherapy, where patients were then randomised
to ixabepilone or capecitabine (standard of care at this line of therapy). The second trial was in
patients who had also failed capecitabine, where the drug was studied as monotherapy in a single
arm trial (Lechleider and Kaminskas, 2007). In the monotherapy study, which meets the criteria for
inclusion in this review, 126 patients were treated, and their Objective tumour response was
measured using the RECIST criteria (Eisenhauer et al., 2009). Overall 12.4% of patients showed a
response according to the independent review board (18.3% based on the investigator assessment),
with a mean response duration of 6.3 months (Food and Drug Administration, 2007).
Based on the two studies, the FDA approved the drug in October 2007 for the two indications
(Pazdur, 2007a). However, the EMA issued a negative CHMP opinion in the same month, after which
the submitting company, BMS, withdrew the submission. The reason stated for the negative opinion
was concern regarding adverse events as the risk/benefit of the drug was not positive (European
Medicines Agency, 2009).
27 / 59
44.
TOCOFERSOLAN IN VITAMIN E DEFICIENCY DUE TO CHOLESTASIS
Patients with chronic cholestasis cannot absorb Vitamin E through their gut. This is often due to
genetic flaws causing problems with the flow of bile from the liver. As Vitamin E is key to the
development and maintenance of the nervous system, patients with a chronic deficiency are likely to
experience neurological problems (European Medicines Agency, 2009).
Although the disease is rare, the drug was studied in 130 patients, across 8 published studies – three
of which were trials, and the remaining publications were case studies. The doses for patients were
adjusted until the level of Vitamin E in their blood reached a satisfactory level, which was within 1
month in all cases. Fifty four patients were eligible for efficacy evaluation, with mean neurologic
score abnormally low for 52/54 patients. As patients were treated (for a mean of 2.5 years), 25
patients improved their score, 27 stabilised, and 2 worsened (European Medicines Agency, 2009).
Based on the results of the clinical study, the EMA approved the product in August 2009 (European
Medicines Agency, 2009).
45.
BENDAMUSTINE HYDROCHLORIDE IN NON-HODGKIN’S LYMPHOMA (NHL)
Bendamustine was studied in two B-cell leukaemias simultaneously; a randomised controlled trial
compared to chlorambucil in first-line CLL (Ryan, Kwitkowski and CRNP, 2007), and an uncontrolled
study in NHL in patients refractory to rituximab containing regimens (the first-line treatment option)
(Kwitkowski, 2007).
In the study of 100 NHL patients, the overall haematological response rate was 74%, with a median
duration of response of 9.2 months, determined by independent (blinded) investigators (Food and
Drug Administration, 2008). Based on this study the FDA deemed the response to treatment
clinically important and approved the drug in October 2008 (Food and Drug Administration, 2008);
the CLL indication was approved in March 2008 (Food and Drug Administration, 2008).
The EMA has not reviewed bendamustine for approval, although a challenge was taken to them. The
marketing company for the product applied to the German regulatory bodies for approval through
the decentralised procedure, where approval in one country leads to approval in all countries.
During this process several countries objected to the approval (which also included another
indication of multiple myeloma), and the EMA were asked to arbitrate. The results of this
assessment were that the CHMP agreed with the German regulatory body, and a license was
granted in Germany (and therefore all other member states) for approval in CLL and NHL (European
Medicines Agency, 2010b).
46.
ROMIDEPSIN IN PERIPHERAL T-CELL LYMPHOMA (PTCL)
PTCL is a form of NHL, although with a worse prognosis due to the involvement of T-cells rather than
B-Cells. Patients are often over 60, with common symptoms including rash, fatigue, and painless
swelling in the lymph nodes (Vose et al., 2008).
The drug was studied in two trials, GPI-04-001 (n=96) and NCI 1312 (n=71), with the primary
endpoint being Overall Response Rate (ORR) according to the IWC criteria (Cheson et al., 2007). In
these studies, patients had previously received a mean of 2.7 and 2.4 prior therapies, and had ORRs
of 34% and 35% (Food and Drug Administration, 2009).
28 / 59
Although the FDA Oncology Drugs Advisory Committee had some misgivings regarding the lack of a
randomised controlled trial, they accepted that the drug could be approved without one given the
rarity of the condition and given that the risk/benefit was positive (Ryan and Maher, 2009). As such
the FDA licensed Romidepsin for patients with PTCL who had received one or more prior therapy, in
December 2009 (Pazdur, 2009).
When presented with the same efficacy data, the EMA, however, reached a different opinion, with
concerns raised regarding the benefit seen with the drug beyond the initial response rate, and with
external control data not seen as a sufficient alternative to RCT data (European Medicines Agency,
2012c). As a result the EMA rejected the application in November 2012, despite the company
requesting a license in patients who had received two or more previous treatments (lower in the
treatment pathway than the US license) (European Medicines Agency, 2012h).
47.
OFATUMUMAB IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
CLL is a cancer of the white blood cells, and the most common adult leukaemia. Its prevalence
increases with age, and it is often diagnosed via a routine blood test or due to non-specific
symptoms (such as night sweats). First-line treatment consists of chemotherapy, often combined
with rituximab. Patients will eventually relapse (unless dying from other causes first) (Lemery et al.,
2009).
Ofatumumab was studied in a refractory group of patients, who had all had the preferred first-line
treatment (fludarabine) and who were either ineligible or refractory to the second-line treatment
alemtuzumab (itself studied in a single arm trial). In the study, Hx-CD20-406, of the 154 patients, all
were refractory to fludarabine, and of these, 79 patients were ineligible to receive alemtuzumab due
to bulky lymph nodes, and 59 patients were refractory to alemtuzumab. In the ineligible group, the
drug achieved an overall response rate of 47%, with a response rate of 58% observed in the
refractory group. These results were compared to a historical control from the literature, where
monoclonal antibodies had a 0% response rate and salvage chemotherapy a 20-25% response rate
(European Medicines Agency, 2010a).
Based on the results of the Hx-CD20-406 study, both the FDA (in 2009) and the EMA (in 2010)
granted ofatumumab a license for use in patients refractory to fludarabine and alemtuzumab, but
not for patients ineligible for alemtuzumab due to bulky lymph nodes (Pazdur, 2009; European
Medicines Agency, 2010d).
48.
PRALATREXATE IN PERIPHERAL T-CELL LYMPHOMA (PTCL)
PTCL is a form of NHL, specifically affecting T-cells, which indicates a worse prognosis than B-cell
lymphomas (Vose et al., 2008). At the time Pralatrexate was studied, various multi-agent
chemotherapies were given first-line, with no standard second-line treatment – the only clinical
literature in the disease were a number of Phase I and Phase II studies.
Pralatrexate was studied in 111 patients with refractory PTCL, with a primary endpoint of overall
response rate according to the International Workshop Criteria (Cheson et al., 2007). Of the 109
evaluable patients, 29 (27%) achieved a complete or partial response to treatment, with a median
response of 9.4 months (Food and Drug Administration, 2009).
29 / 59
This data package was submitted to both the FDA in 2009 and the EMA in 2010. The FDA approved
the drug by a 10-4 majority vote (Malik, 2009), but stipulated a number of post-marketing
conditions, including a RCT, when giving the product a marketing authorisation in 2009 (Pazdur,
2009).
The EMA had concerns regarding the uncontrolled trial design, stating that the lack of a ‘dramatic
activity’ made it difficult to conclude that the drug was efficacious, a decision which was ratified on
re-examination. However, there was a divergent position held by a minority of the CHMP, who
stated that given the rarity of the condition and the poor prognosis for patients, the overall response
rate of 30% was comparable to other approved therapies used as single agents, and thus has a
positive risk/benefit balance (European Medicines Agency, 2012g). Since the rejection of the drug in
2012, the company has not re-submitted to the EMA.
49.
CARGLUMIC ACID IN CHRONIC HYPERAMMONEMIA
Carglumic acid is used for the treatment of hyperammonemia (excessive ammonia in the
bloodstream), caused by patients lacking certain enzymes that break down ammonia (European
Medicines Agency, 2006c).
It was studied in a retrospective analysis of 23 patients with abnormal ammonia blood levels. Of the
23 patients, 13 were fully evaluable for efficacy data. Over the first three days of treatment, all 3
patients showed a normalisation of ammonia levels (Elgin and Sile, 2010).
It was approved by the EMA in 2003 (European Medicines Agency, 2009), and by the FDA in 2001
(Beitz, 2010; Food and Drug Administration, 2010b), both for the same indication (hyperammonemia
in patients with deficiency of the hepatic enzyme N-acetylglutamate synthase).
50.
CHOLIC ACID (ORPHACOL®) IN INBORN ERRORS IN PRIMARY BILE ACID
SYNTHESIS
Cholic acid (Orphacol®) is also used for the treatment of inborn errors in primary bile acid synthesis,
and is licensed specifically for patients with 3β-HSD and Δ4-3-oxoR mutations (European Medicines
Agency, 2013o).
The initial application for a license was made by the French pharmaceutical company Cell Therapies
Research & Services in 2009, with a positive CHMP opinion issued on 16 December 2010, based on
single arm efficacy data from the literature, case series, and sibling studies. Other factors in the
decision were the rarity of the condition, ethical concerns in running a trial, and the stipulation for
the continued monitoring of patient safety (European Medicines Agency, 2010c, 2013f).
Typically, after a positive CHMP opinion has been given, approximately 2 months later the
recommendation is transformed by the European Commission into a positive marketing
authorisation. In the case of Orphacol, however, this was not the case. The European Commission
appears to have taken issue with the lack of primary data for the drug and refused to approve the
treatment until ordered to do so by the European Court of Justice (PMLiVE, 2013). The FDA has not
reviewed the product.
30 / 59
51.
OMACETAXINE MEPESUCCINATE IN CHRONIC MYELOID LEUKAEMIA (CML)
CML is caused by a translocation of chromosome 9 to chromosome 22 (the Philadelphia
chromosome). This causes the production of immature white blood cells (blasts), which interfere
with the correct working of the immune system. Patients experience a ‘chronic’ phase (CP) for
several years where they have slightly elevated blast levels, before the disease progresses to the
‘advanced’ phase (AP) where the number of blasts greatly multiplies, and finally blast crisis, or blast
phase (BP), where the immature white blood cells overwhelm the bone marrow, leading to
abnormal functioning of the blood (Alvandi, 2012).
Omacetaxine was studied in two clinical trials, CML-202 (n=66) and CML-203 (n=65), in patients who
had failed multiple TKIs. Of the 76 patients with CP CML, 14 (18.4%) achieved a major cytogenetic
response, for which the mean duration was 12.5 months. In AP CML, 35 patients were included in
the trials, of whom 5 (14.3%) achieved a major haematologic response, with a mean duration of 4.7
months (European Medicines Agency, 2011; Food and Drug Administration, 2012).
The regulatory path to approval for the drug was not straightforward; submissions were made to the
EMA in October 2009 and the FDA in November 2009. Ultimately the company withdrew both of
these submissions in early 2011 (ChemGenex Europe S.A.S., 2011; Alvandi, 2012). At the time of
withdrawal of each submission, the FDA stated that the drug needed a companion diagnostic test to
be approvable (Alvandi, 2012), and the EMA viewed the submission as approvable, stating that the
activity of the drug was ‘low’ and not ‘dramatic’, with concerns regarding the safety of the drug
(European Medicines Agency, 2011).
The company resubmitted to the FDA in March 2012, based on further analysis of the data,
restricted to patients who had failed at least two TKIs. On this basis, the FDA approved the drug in
October 2012 (Pazdur, 2012c). At the time of writing (October 2014), no re-submission had been
made to the EMA.
52.
ALIPOGENE TIPARVOVEC IN FAMILIAL LIPOPROTEIN LIPASE DEFICIENCY (LPLD)
LPLD is an ultra-rare condition affecting approximately 1 in a million people. It is a genetic disease
where patients lack lipase, an enzyme that clears triglycerides from the blood, with problems also
arising from high levels of fat, which accumulates in organs. The consequence of this is that after
eating, patients can have dangerous rises in their triglyceride levels and must be placed on a fat
controlled diet (European Medicines Agency, 2012b).
The treatment is gene therapy and works using a genetically modified virus that replaces the faulty
gene with a functioning version in the muscles. After the initial administration, patients should
require no further treatment. It was studied in three clinical studies enrolling 27 patients. The clinical
studies demonstrated that, after 6 months, all patients had measurable active lipase enzyme, and of
the 12 patients who had previous pancreatitis attacks, the frequency of these was reduced
(European Medicines Agency, 2012b).
Alipogene tiparvovec was licensed by the EMA in 2012 for patients who have pancreatitis attacks,
despite the imposition of a low fat diet. The type of license given was under ‘exceptional
circumstances’, meaning that, due to the rarity of the condition, it was not possible to gather full
information on the efficacy of treatment. The license was also not granted in a ‘straightforward’
31 / 59
manner – initially the marketing authorisation was refused in 2011 due to a lack of evidence of longterm efficacy in both enzyme levels and clinical outcomes (pancreatitis attacks), with concern also
over the safety of the virus delivery mechanism (European Medicines Agency, 2011). The company
requested a re-examination, where by majority vote, the treatment was given a license with a range
of conditions attached, including enrolling patients in a registry (European Medicines Agency, 2012j).
The treatment has not been assessed by the FDA and is therefore not available in the US.
53.
TALIGLUCERASE ALFA IN GAUCHER'S DISEASE
Gaucher’s disease is a rare, autosomal recessive lysosomal storage disorder. If left untreated, lipidengorged macrophages (Gaucher cells) accumulate in the liver, spleen, and bone marrow, leading to
debilitating visceral, haematological, and skeletal complications. In addition to causing pain, these
complications lead to a shortened life expectancy. Patients with GD1 present with a range of
symptoms, including splenomegaly, hepatomegaly, anaemia, growth retardation and osteoporosis
(Epps, 2012).
Taliglucerase is an Enzyme Replacement Therapy (ERT), which is intended to mimic the absent
natural enzyme, relieving symptoms. It was studied in two clinical trials, one with treatment-naïve
patients and one with patients switching from imiglucerase (an existing ERT). In treatment-naïve
patients, 31 patients were randomised to high- and low-dose taliglucerase, with all patients showing
a reduction from baseline in spleen volume and liver volume, as well as improvements in
haemoglobin and platelet count. In the treatment switching study, 25 patients ceased imiglucerase
therapy and began therapy with taliglucerase. After 9 months, spleen volume, liver volume,
haemoglobin level and platelet count were all unchanged (Food and Drug Administration, 2012).
The FDA judged the product to have a similar efficacy and safety profile to existing ERTs, although it
did mandate further data collection as post-marketing commitments when approving the drug in
May 2012 (Beitz, 2012).
The EMA also reviewed taliglucerase; however, the result was a negative recommendation
(European Medicines Agency, 2012e). However, this was not due to concerns regarding the efficacy
of the product, but orphan drug policy – as a previous ERT had been approved by the EMA
(velaglucerase alfa, Vpriv®) from a different manufacturer (Shire), this product received 10 years of
market exclusivity. As taliglucerase was judged to offer no additional benefits, and there were no
supply issues, the CHMP recommended refusal of the marketing authorisation, which the EC ratified
in October 2012 (European Medicines Agency, 2012f).
54.
ASPARAGINASE ERWINIA CHRYSANTHEMI IN ACUTE LYMPHOBLASTIC LEUKAEMIA
(ALL)
The enzyme asparaginase is an enzyme that converts the amino acid L-asparagine to aspartic acid
and ammonia. As leukaemia cells are unable to synthesize the amino acid asparagine, they therefore
require circulating asparagine and will die without this. This mechanism of action is well established,
with asparaginase produced from Escherichia coli for both medical and food uses and with pegylated
32 / 59
asparaginase (pegaspargase). Asparaginase from Erwinia chrysanthemi is produced by a different
process, yet it should have the same effects (Center for Drug Evaluation and Research, 2011).
In the clinical study for the drug, 58 patients were enrolled, all with hypersensitivity to
pegaspargase. Of the 58, 48 were evaluable for efficacy, which was done to test for serum trough
concentration of asparaginase ≥ 0.1 International Units/mL. This was achieved in 100% of patients
48 and 72 hours after dosing (Food and Drug Administration, 2011).
Based on the evidence of the similar enzyme, and comparable effects in this version, the drug was
licensed for use by the FDA in patients with hypersensitivity to pegaspargase or the E. coli derived
version in 2011 (Pazdur, 2011). The EMA have not reviewed the product; however, it may have been
approved in European countries via the process of mutual recognition.
55.
BRENTUXIMAB VEDOTIN IN HODGKIN'S LYMPHOMA (HL)
Hodgkin’s Lymphoma (HL) and Non-Hodgkin’s Lymphoma (NHL) are two diseases that present
similarly, but they have an important difference, the presence of a type of cell called the ReedSternberg cell in HL, which leads to different treatment options (due to the different receptors on
these cells). HL represents around a fifth of lymphoma diagnoses and is usually treated with
chemotherapy. Where chemotherapy fails, or the disease returns, patients are treated with highdose chemotherapy, and/or stem cell transplant (SCT). This leads to a cure for many patients,
although some will relapse (European Medicines Agency, 2012a).
It is following the failure of (or ineligibility for) stem cell transplantation that brentuximab vedotin
was studied. In total, 102 patients with relapsed or refractory HL received the drug, all of whom has
received a prior SCT, and 1-13 prior therapies (a median of 3.5). Patients were assessed by an
independent panel for haematologically defined objective response, with 75% of patients meeting
this criteria and 33% of patients achieving complete remission (de Clare and Kwitkowski, 2011).
Based on this evidence, both the EMA and FDA granted licenses in October 2012 and August 2011,
respectively (Pazdur, 2011; European Medicines Agency, 2012k), for brentuximab vedotin in patients
who had either failed SCT or who had received two prior therapies and were ineligible for SCT (Food
and Drug Administration, 2011; European Medicines Agency, 2012k).
56.
BRENTUXIMAB VEDOTIN IN SYSTEMIC ANAPLASTIC LARGE CELL LYMPHOMA
(SALCL)
sALCL is a rare form of NHL, often diagnosed by enlarged lymph nodes. If left untreated, the body
will eventually become overwhelmed by the proliferation of white blood cells and susceptible to
infection. Approximately 40-65% of patients are expected to relapse following first-line treatment, at
which point existing therapies have been exhausted (European Medicines Agency, 2012a; Pro et al.,
2012).
It is in this patient population that brentuximab vedotin was studied; 58 patients received the drug
in a multi-centre study. Patients were scored by an independent review centre, against a set of
objective review criteria. Of the 58 patients, 34 were judged to have had a complete response, and a
further 17 had a partial response, for an overall response rate of 86%. Subsequent to treatment, 16
patients were then able to receive a SCT (de Clare and Kwitkowski, 2011).
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Based on this clinical study, both the EMA in October 2012 (European Medicines Agency, 2012k) and
the FDA in August 2011 (Pazdur, 2011) granted a license for brentuximab vedotin in previously
treated sALCL.
57.
CRIZOTINIB IN NON-SMALL CELL LUNG CANCER
Non-small cell lung cancer makes up the majority of lung cancers (85%), which is amongst the most
lethal types of cancer, with a 5-year survival rate under 20%. First-line treatment generally consists
of platinum-based chemotherapy, which has an overall response rate of 15-32% and a median
progression-free survival of 3-6 months, with median overall survival of 8-12 months (European
Medicines Agency, 2012i).
Crizotinib was initially studied in two single arm trials, in patients with advanced or metastatic ALKpositive NSCLC who had received previous chemotherapy. The primary endpoint in both studies was
the overall response rate according to the RECIST criteria (Eisenhauer et al., 2009), measured both
by the investigator and an independent panel. Over the two studies, according to the investigator
measurements of the 255 patients, 140 patients had either a complete or partial response (Food and
Drug Administration, 2011). At the time of the regulatory submissions, a comparative RCT was also
on-going, comparing crizotinib to standard of care second-line chemotherapy (pemetrexed or
docetaxel). The results of this study, when available, showed a benefit in objective response rate for
crizotinib of 65% vs. 20%, progression-free survival (7.7 vs. 3.0 months) based on 173 and 174
patients in each arm (European Medicines Agency, 2012l) .
Based on these clinical results, the FDA approved crizotinib in August 2011 via an accelerated
approval (Pazdur, 2011), and the EMA approved the product in November 2012 via a conditional
marketing authorisation, at which point results from the comparative study were available and
present in the scientific discussion of the EMA (European Medicines Agency, 2012i, 2012l).
58.
DEFIBROTIDE IN VENO-OCCLUSIVE DISEASE
Veno-occlusive disease (VOD) is a condition where some of the smaller veins in the liver are
obstructed, which can be a complication of high-dose chemotherapy (as given before stem cell
transplant) (European Medicines Agency, 2013b).
Defibrotide was studied in this population, in a single arm study that enrolled 102 patients (against
an initial target of 80), of whom 40 (40%) responded to treatment. This was intended to be a
historically controlled trial, with a historical cohort identified through patient notes (n=80 planned).
However, at an interim analysis of the 86 patients identified in the historical control, 54 were
excluded by a medical review committee for having different diagnoses to the inclusion criteria,
leaving only 32 patients. Using the 32-patient historical control, the response rate was 23.5%, whilst
using the 86 patients it was 40.8% (which would mean no benefit from using the drug). The EMA had
severe concerns regarding this study and the lack of safety comparison for the product, stating on
page 46 of the assessment report
“There are serious methodological flaws in this study that make it extremely difficult to
quantify the benefits. This study is severely compromised by the changing of the HC group
and therefore the efficacy data as presented by the applicant cannot be considered as
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robust evidence for an effect in the treatment indication for VOD.”
(European Medicines Agency, 2013b)
In addition to the problems with the historically controlled trial, a proposed second prophylactic
indication, which had a randomised element, also had methodological problems. Based on these
concerns, the CHMP issued a negative opinion for defibrotide in May 2013 (European Medicines
Agency, 2013j).
The company (Gentium S.p.A.) asked the CHMP to reconsider their decision, providing further data
from a US registry, which showed a likely survival advantage for defibrotide. In the trial, patients
treated with defibrotide showed a survival rate of 38%; the historical control had a survival rate of
25%; and data from a US registry of over 8000 patients, with 99 eligible for analysis, showed a
survival rate of 22%. Based on this additional data, the EMA granted a licensed for the use of
defibrotide restricted to severe patients with multi-organ failure only, in October 2013 (European
Medicines Agency, 2013m).
The FDA has not reviewed the product, although an investor statement in July 2014 discussed the
possibility of an FDA filing (Jazz Pharmaceuticals, 2014).
59.
GLUCARPIDASE IN TOXIC PLASMA METHOTREXATE CONCENTRATIONS
High-dose methotrexate is a therapy often used in malignant conditions. If a patient develops renal
insufficiency after the administration of methotrexate, this is a serious problem, as the drug is
metabolised through the kidneys. The drug, glucarpidase, is an enzyme that metabolises the
methotrexate to non-toxic metabolites (European Medicines Agency, 2008).
The efficacy of glucarpidase was studied in two trials, Trial 006, which enrolled 184 patients, with
149 dosed and 22 eligible for efficacy assessment, and Trial 016, which enrolled 244 patients, with
171 receiving treatment. In both trials all patients were treated with glucarpidase, with no
comparative arm included. The primary endpoint of the study was the reduction in methotrexate
level below 1 μmol/L (beyond which toxicity occurs). Of the 22 evaluable patients, 10 had a rapid
reduction in methotrexate concentration (all subsequent blood samples). Two more patients failed
this criterion on the test performed 15 minutes post glucarpidase administration. All patients
demonstrated a greater than 95% reduction in methotrexate concentration in the 8 days after
treatment.
Based on these results, the FDA approved the product in January 2012. The EMA received a
submission from the manufacturer in 2007, which was given a negative CHMP opinion (European
Medicines Agency, 2008), although the company withdrew the submission before a final decision
was issued (Protherics PLC, 2007). The difference in the data package presented to regulatory was
the lack of Trial 006 and Trial 016 in the EMA package – the studies relied on a previous trial that had
been completed, but with a different formulation of the drug, which was identified as an
insurmountable problem by the EMA (and FDA, who opted not to include this trial in their efficacy
assessment) (Dinndorf, Demko and Keegan, 2011).
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60.
CARFILZOMIB IN MULTIPLE MYELOMA (MM)
As stated for bortezomib, multiple myeloma is a cancer of bone marrow cells. Carfilzomib was
approved by the FDA for the treatment of multiple myeloma in 2012 (Pazdur, 2012a) for patients
who had received at least two prior therapies (including bortezomib) (Food and Drug Administration,
2012). It had not been reviewed by the EMA.
The drug was studied in 266 patients with multiple myeloma who had received at least two prior
therapies (including bortezomib and thalidomide or lenalidomide). The primary endpoint was the
overall response rate, determined by haematological criteria – 61 patients (22.9%) showed an
overall response. Of the responders, the median duration of complete response was 7.8 months
(Herndon, 2012).
It was licensed by the FDA in 2012 (Pazdur, 2012a) but has not been submitted to the EMA.
61.
VISMODEGIB IN BASAL CELL CARCINOMA (BCC)
BCC is a type of slow growing malignant skin tumour. If detected early, it is easily resected, with a
high cure rate. However, a small number are undetected / untreated until they have metastasized,
or alternatively spread after surgery. Although rare in these cases the condition is serious, causing
morbidity and tissue loss, with median survival of 8-10 months (European Medicines Agency, 2013c).
In this population, vismodegib was studied in two clinical trials – one dose-finding study with 68
patients (33 with advanced BCC and 35 with metastatic BCC) and an efficacy study with 103 patients
(71 with advanced BCC and 33 with metastatic BCC). In this second study, the primary outcome was
the objective response rate (Eisenhauer et al., 2009), according to the independent review facility. In
advanced BCC, 13/63 patients had a complete response, and 14/63 had a partial response, for an
objective response rate of 27/63 (43%). In metastatic BCC, no patients had a complete response, and
10/33 had an objective response, for an objective response rate of 30% (Axelson, 2012; European
Medicines Agency, 2013r).
Based on the results of the clinical study, the FDA approved the drug in November 2012 (Pazdur,
2012b) and the FDA in July 2013 (European Medicines Agency, 2013c).
62.
BOSUTINIB IN CHRONIC MYELOID LEUKAEMIA (CML)
Chronic Myeloid Leukaemia is caused by an abnormal chromosome, where DNA from chromosome 9
translocates to chromosome 22. This leads to a proliferation of myeloid blasts in the blood, which
are immature white blood cells – these abnormal white blood cells do not function correctly and
lead to an increased risk of infection (European Medicines Agency, 2013a).
The disease has three stages (all within CML), the chronic phase (CP), where the disease is slowly
increasing, likely with only mild symptoms. The disease can then move to the advanced phase (AP),
where there is likely to be spleen enlargement and weight loss, along with highly increased white
blood cell production. The final stage of the disease is known as the blast phase (BP), where the
leukaemia cells have spread around the body; patients will experience severe symptoms and spleen
enlargement. At the time of licensing, imatinib was the standard first-line therapy, with two
treatments (dasatinib and nilotinib) licensed for second-line therapy – all of these treatments being
tyrosine kinase inhibitors [TKIs]).
36 / 59
Bosutinib was initially studied in newly diagnosed CML, in a head to head study vs. imatinib (n=502).
This study shows numerically worse complete cytogenetic response but numerically better major
molecular responses for Bosutinib, although neither result reached statistical significance (the study
did not reach its primary endpoint of superiority to imatinib). This study was described by the EMA
as “not approvable” (European Medicines Agency, 2013a) and by the FDA as a “failed study”
(McGinn, 2012). A second study was also conducted; an uncontrolled study in previously treated
CML. This enrolled patients who had previously been treated with imatinib (n=266), imatinib and
dasatinib/nilotinib (n=110), and accelerated (n=69) or blast phase (n=54) CML.
On the basis of this second study, Bosutinib was licensed by the EMA in March 2013 (European
Medicines Agency, 2013l) and the FDA in September 2012 (Pazdur, 2012d) for previously treated
CML, at all stages of disease (CP, AP, and BP). Whilst the FDA only specified that patients must have
been previously treated (Food and Drug Administration, 2012), the EMA were more specific in
stating that patients must have been treated with a TKI but must also be unsuitable for treatment
with imatinib, dasatinib or nilotinib (European Medicines Agency, 2013l).
63.
PASIREOTIDE DIASPARTATE IN CUSHING'S DISEASE
Cushing’s disease is caused by a tumour of the pituitary gland, which stimulates the production of
cortisol. This leads to problems with blood sugars and swollen features, similar to the more common
Cushing’s syndrome, where patients are taking steroids on a long-term basis (Lowy, 2012).
The first-line treatment for Cushing’s disease is surgery to remove the tumour. Should surgery fail,
the options are further attempts at surgery, irradiation, or off-label therapies. Pasireotide was
studied in a 6-month trial of 162 patients for whom surgery was not indicated or had refused
surgery. The primary endpoint of the study was the 24 hour free cortisol results, at the 6 month time
point with patients randomised 1:1 to two doses of the study drug. The primary endpoint was
achieved by 12/82 patients at the power dose and 21/80 patients at the higher dose, with secondary
endpoints showing patients having mean decreases in blood pressure, weight, body mass index and
waist circumference, although it was noted that, due to the single arm design, it is difficult to
conclude these were directly the result of drug treatment (Food and Drug Administration, 2012).
Based on the results on the clinical study, pasireotide was approved by the EMA in April 2010
(European Medicines Agency, 2012d) and the FDA in October 2012 (Rosebraugh, 2012) for patients
in whom surgery is not an option or has not been curative.
64.
CHOLIC ACID (CHOLIC ACID FGK®) IN INBORN ERRORS IN PRIMARY BILE ACID
SYNTHESIS
Cholic acid is a bile acid produced by the liver, which aids in the breakdown of fat for absorption by
the body. Children with inborn errors in acid synthesis (which are rare) are not able to create this
acid and thus break down fats in their diet – the EMA approval states the condition to be lethal if
untreated (European Medicines Agency, 2014a).
The drug was studied in 28 patients with five types of inborn error. Case series were also available
on 43 patients treated with cholic acid in the literature (European Medicines Agency, 2014c). The
efficacy of the drug was determined by the increase in cholic acid available, using the patients as
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their own controls, in addition to several published sibling studies, where the untreated sibling was
used as a control (European Medicines Agency, 2014a).
The EMA stated that the data for the treatment was limited but that the use of cholic acid was
established in the literature to avoid death in children, and as such approved cholic acid under
exceptional circumstances in 2014. Cholic acid FGK, however, did not have a straightforward
approval process due to concerns regarding the similarity with Cholic acid (Orphacol®), which is
discussed below, and was under review at the same time, and approval as Cholic acid FGK was still
under review. As a result of discussions with the EMA, the company withdrew the application for
two types of inborn error (3β-HSD and Δ4-3-oxoR), resulting in the product being approved for three
specific genetic mutations in CTX, AMACR and CYP7A1 that cause issues with cholic acid production
(European Medicines Agency, 2013k). The FDA has not reviewed the product.
65.
LOMITAPIDE MESYLATE IN FAMILIAL HYPERCHOLESTEROLEMIA (HOFH)
HOFH is an inherited disease that causes high blood levels of cholesterol. The severity of cholesterol
levels means that untreated patients do not survive beyond 30. The first stage of treatment is to
restrict the amount of dietary fat consumed by patients; however, should this fail to be successful
(for example cholesterol is also made by the liver), then there are few treatment options (European
Medicines Agency, 2013e).
It is in this patient population that lomitapide was studied, in an open-label single arm pivotal trial of
29 patients. In the study, after 2 weeks of treatment, there was a mean decrease of 9% in
cholesterol levels, and at week 56, the mean decrease in cholesterol level was 44% (Food and Drug
Administration, 2012; Smith, 2012).
Based on this efficacy data, lomitapide was approved by the FDA in December 2012 (Nguyen, 2012)
and the EMA in July 2013 (European Medicines Agency, 2013n).
66.
POMALIDOMIDE IN MULTIPLE MYELOMA (MM)
Multiple myeloma is a cancer of plasma cells in the bone marrow. It is often diagnosed due to nonspecific symptoms or following routine blood tests, after which patients receive first-line therapies.
After relapse, patients would be retreated with the same regimen until becoming refractory, at
which point they would receive an alternative therapy (European Medicines Agency, 2013h).
Pomalidomide was initially studied in patients who were refractory to their last MM therapy (relapse
within 60 days of treatment) and had received both lenalidomide and bortezomib (two of the main
treatments in the disease area at the time). Two trials were conducted – one of pomalidomide
monotherapy, and one of pomalidomide in combination with dexamethasone. In both trials, the
primary endpoint was the overall response rate according to the International Myeloma Working
Group criteria (Durie et al., 2006). In the studies, the overall response rate for pomalidomide
monotherapy was 9/108 (7.4%), and in combination with dexamethasone, it was 33/113 (29%)
(Ayache, 2012; Food and Drug Administration, 2013).
Based on the response rates, the FDA approved the drug in February 2013 (Pazdur, 2013). The
manufacturer, Celgene, had the results of an RCT become available whilst the product was under
review, which comparing pomalidomide + dexamethasone to dexamethasone monotherapy in the
38 / 59
same population as the uncontrolled studies. Using this data, the drug was then approved in Europe
in August 2013 (European Medicines Agency, 2013p), with the FDA label subsequently updated to
include this trial (Kane, 2014).
67.
RAXIBACUMAB IN ANTHRAX INHALATION
Anthrax is a type of bacteria known to be deadly for humans and animals and follows the same
pattern of infection – spores come into contact with an animal and are activated, infecting the host.
Eventually the animal will be overwhelmed and die, then becoming a source of further spores. Death
rates in humans are estimated to be in excess of 95% (Yasinskaya and Alexander, 2012).
Due to the ethical concerns of denying patients access to a potentially beneficial treatment, the
majority of clinical evidence for the product is taken from animal studies. In rabbits exposed to
anthrax, 24/37 treated with antibacterials survived, compared to 32/39 treated with antibacterials
and raxibacumab, monkeys show 69% survival when given the treatment immediately postexposure. In post-exposure prophylaxis, the drug was compared with placebo in both rabbits and
monkeys – at 14 days 0/17 rabbits survival with placebo, compared to 5/18 on low-dose
raxibacumab and 8/18 on high-dose raxibacumab. At 28 days, 0/24 rabbits and 0/12 monkeys
survived, whereas with low-dose raxibacumab 7/14 monkeys survived (there were no rabbits at this
dose), and with high-dose raxibacumab 11/24 rabbits and 9/14 monkeys survived (Food and Drug
Administration, 2012).
Based on the severity of the condition, the FDA concluded that the mechanism of action was similar
in all mammals, that the results of animal experiments could be extrapolated directly to humans,
and that the benefits of the product outweighed any risks for infected persons. The drug was
therefore approved in December 2012 (Cox, 2012). It has not been reviewed by the EMA.
68.
PONATINIB HYDROCHLORIDE IN CHRONIC MYELOID LEUKAEMIA (CML)
CML causes the production of immature white blood cells. Patients experience a ‘chronic’ phase (CP)
for several years where they will not have major symptoms as the number of blasts increases, before
the disease progresses to the ‘advanced’ phase (AP) where there is a marked increase in the number
of blasts, and finally the blast phase (BP), where the bone marrow becomes saturated by immature
blasts, causing death.
At the time ponatinib was licensed, imatinib, nilotinib and dasatinib were established as first- and
second-line therapies; however, if patients develop genetic mutations, these drugs can be
ineffective. The most common individual mutation is the T315I mutation, on which the development
of ponatinib was focussed (European Medicines Agency, 2013d). The main study for ponatinib was
study 10-201, which enrolled 449 patients, of whom 444 could be assessed for efficacy. Of the
patients, approximately 270 were in CP, 85 in AP, and 62 in BP, with approximately a third of
patients having a T315I mutation. The primary endpoint was major cytogenetic response, which was
listed for resistant/intolerant patients and T315I patients separately – in CP these were 49% / 70%,
in AP 55% /39%, and in BP 32% /29% (de Claro, 2012). The EMA listed slightly different figures
(European Medicines Agency, 2013d) as the FDA choosing to reclassify some patients as nonresponders due to missing data or reanalysis of baseline data.
39 / 59
Based on the results of the clinical study, both the FDA and EMA granted similar licenses to
ponatinib, for patients who were refractory to imatinib, nilotinib or dasatinib or alternatively who
have a T315I mutation. However, there was a difference in that the FDA approved ponatinib in
refractory/intolerant patients as early as second line (patients resistant to any prior therapy),
whereas the EMA specified that patients must have tried (or be ineligible for) therapy with nilotinib
or dasatinib, in addition to imatinib – a third-line license. These differing decisions were made on the
same available data from Study 10-201 – in the study population, 7% had received 1 prior TKI, 35%
had received 2 prior TKIs, and 58% had received 3 or more TKIs.
The licenses were granted by the FDA in December 2012 (Pazdur, 2012b) and the EMA in July 2013
(European Medicines Agency, 2013q).
69.
PONATINIB HYDROCHLORIDE IN PHILADELPHIA CHROMOSOME-POSITIVE ACUTE
LYMPHOBLASTIC LEUKAEMIA (ALL)
Ph+ ALL is ALL caused by the same mutation (the Philadelphia Chromosome) that causes CML. As a
result, the treatments for CML are often studied and effective in this condition.
The main pivotal trial for ponatinib, Study 10-201, also enrolled a minority of Ph+ ALL patients. Of
the 444 patients eligible for assessment, 32 had Ph+ ALL with the haematological response rate as
the primary endpoint. Of the 32 patients, 10 were refractory or intolerant to first-line therapy and
had a response rate of 50%, whilst 22 had mutation T315I, which causes existing TKIs to be
ineffective – in these patients, the response rate was 36%.
As in CML, the EMA and the FDA gave similar but slightly different licenses: the FDA specified that
patients must have failed or be intolerant to a single previous therapy (or have the T315I mutation),
and the EMA stated that patients must have failed one prior therapy and be inappropriate to receive
a second prior therapy (or have the T315I mutation). The FDA also issued their decision earlier than
the EMA, in December 2012 (Pazdur, 2012b), compared to July 2013 (European Medicines Agency,
2013q).
70.
METRELEPTIN IN LIPODYSTROPHY DUE TO LEPTIN DEFICIENCY
Leptin is a hormone that plays an important role in energy production and storage. Patients with
leptin deficiency can have varying levels of deficiency, and thus varying levels of lipodystrophy. The
consequence of lipodystrophy (loss of adipose tissue) can be fat stored in the muscles and liver,
which results in metabolic disorders such as diabetes and hypertriglyceridemia (Golden, 2014).
Metreleptin is a recombinant form of the human hormone leptin, which was studied in a single arm
trial of 48 patients. At baseline, 77% of the patients had high HbA1c values (>7%), 69% had fasting
plasma glucose of 126mg/dL or greater, and 35% fasting triglyceride values of 500mg/dL of greater.
After treatment, patients had mean reductions of 2% HbA1c, 49mg/dL fasting glucose, and a
reduction of 184mg/dL in fasting triglyceride level (Food and Drug Administration, 2014d; Golden,
2014).
Based on these efficacy results, the FDA approved metreleptin (Parks, 2014). At the time of the
review, it had not been reviewed by the EMA.
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71.
IBRUTINIB IN MANTLE CELL LYMPHOMA (MCL)
Mantle Cell Lymphoma (MCL) is a rare type of non-Hodgkin’s Lymphoma, a cancer of the lymphatic
system. The disease is caused by a proliferation of immature B-Cells, which cause swelling in the
lymph nodes and spread around the body, hampering the immune system. Patients are treated first
line with chemotherapy (although there is no single established standard of care) (McGinn, 2013).
Ibrutinib was studied in patients who had relapsed after first-line chemotherapy, where no standard
treatment exists and prognosis is poor – with a median expected OS of 1-2 years. Trial 1104 (n=111)
was the main study that investigated the use of ibrutinib. The primary outcome of the study was the
Overall Response Rate – a combination of haematological markers (Cheson et al., 2007). This
outcome was achieved by 65.8% of patients, with a median duration of response of 17.5 months.
Based on these data, the FDA approved ibrutinib in November 2013 (Food and Drug Administration,
2014c). At the time the EMA website was searched (May 2014), the EMA had not reviewed the
product.
72.
IBRUTINIB IN CHRONIC LYMPHOCYTIC LEUKAEMIA
CLL has had a number of treatments approved without uncontrolled studies, including alemtuzumab
and ofatumumab.
In CLL ibrutinib was studied in 48 previously treated patients, 28 of whom achieved a partial
response with no complete responses (Food and Drug Administration, 2014c).
The submission to the FDA was made on the same dat as the application for an approval in MCL,
however the CLL approval was not granted until 3 months afterwards. At the time of the review, the
product was not approved by the European Medicines Agency.
73.
CERITINIB IN NON-SMALL CELL LUNG CANCER (NSCLC)
Ceritinib is used for the treatment of ALK-positive Non-Small Cell Lung Cancer. The ALK mutation in
the DNA of the cancer is the target for the drug and is the biological basis for treatment (Khozin and
Zhang, 2014).
It was studied in a multi-centre study where 163 patients were treated with ceritinib and assessed
for efficacy by both the investigator and a blinded independent review committee. The primary
endpoint of the study was the overall response rate, according to objective criteria, the RECIST
criteria (Therasse et al., 2000). In the trial, 89/163 patients showed a response according to the
investigators and 79/163 in the blinded assessment (Food and Drug Administration, 2014f).
Based on these results, the drug was given a license by the FDA in April 2014 (Pazdur, 2014). It has
not been reviewed by the EMA.
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Alvandi, F. (2012) ‘Clinical Review 203585/0’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203585Orig1s000MedR.pdf.
Armstrong, K. and Berens, M. J. (2013) ‘Part 2: Orphan drug earns millions | Pharma’s Windfall’, The Seattle
Times, 9 November. Available at: http://apps.seattletimes.com/reports/pharma-windfall/2013/nov/9/seattlebiotech-orphan-drug/ (Accessed: 7 October 2014).
Axelson, M. (2012) ‘Clinical and Statistical Review’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203388Orig1s000MedRpdf.pdf.
Ayache, S. (2012) ‘Clinical Review for Pomalidomide’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204026Orig1s000MedR.pdf.
BBC (2001) ‘Scotia calls in administrators’, BBC, 30 January. Available at:
http://news.bbc.co.uk/1/hi/business/1143869.stm (Accessed: 29 October 2014).
Beitz, J. (2004) ‘NDA 21-749 NDA 21-751’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/21749,21751ltr.pdf.
Beitz, J. (2010) ‘NDA Approval NDA 022562’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/022562s000ltr.pdf.
Beitz, J. (2012) ‘NDA 022458’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/022458s000ltr.pdf.
Brave, M., Goodman, V. and Kaminskas, E. (2006) ‘Clinical review 21-986’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021986s000_Sprycel__MedR.pdf.
Bross, P., Kane, R., Farrell, A., Wang, Y.-C. and Chen, G. (2003) ‘Clinical review - NDA 21-602 - Bortezomib’.
Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21602_Velcade_medr.pdf.
Center for Drug Evaluation and Research (2000a) ‘Medical Officer’s Review - Argatroban’. Food and Drug
Administration.
Center for Drug Evaluation and Research (2000b) ‘NDA Medical Review NDA 21-174’. Center for Drug
Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21174_MYLOTARG_medr.pdf.
Center for Drug Evaluation and Research (2011) ‘Division Director Summary Review - BL STN 12539/0’.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125359Orig1s000SumR.pdf.
Centre for Drug Evaluation and Research (2000) ‘Cladribine Approval Letter, Application number 75405’. Food
and Drug Administration.
ChemGenex Europe S.A.S. (2011) ‘Withdrawal of TEKINEX (omacetaxine mepesuccinate) 5mg, powder for
solution for injection’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/01/WC500101410.pdf.
Cheson, B. D., Pfistner, B., Juweid, M. E., Gascoyne, R. D., Specht, L., Horning, S. J., Coiffier, B., Fisher, R. I.,
Hagenbeek, A., Zucca, E., Rosen, S. T., Stroobants, S., Lister, T. A., Hoppe, R. T., Dreyling, M., Tobinai, K., Vose,
J. M., Connors, J. M., Federico, M., Diehl, V. and International Harmonization Project on Lymphoma (2007)
‘Revised response criteria for malignant lymphoma’, Journal of Clinical Oncology: Official Journal of the
American Society of Clinical Oncology, 25(5), pp. 579–586. doi: 10.1200/JCO.2006.09.2403.
Chustecka, Z. (2009) Trabectedin for Ovarian Cancer Rejected by FDA Committee. Available at:
http://www.medscape.com/viewarticle/706350 (Accessed: 5 November 2014).
42 / 59
de Clare, R. A. and Kwitkowski, V. (2011) ‘Clinical review - BLA STN 125388/0’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125388Orig1s000MedR.pdf.
de Claro, R. A. (2012) ‘Clinical Review NDA 203469’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf.
Cohen, M. H. (1999) ‘Medical Officer Review of Temodal Trademark’. Center for Drug Evaluation and Research.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21029_Temodar_medr_P1.pdf.
Cohen, M. H. and He, K. (2006) ‘Clinical and Statistical Review NDA 21-588 SE1’. Center for Drug Evaluation and
Research. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021588_s011_gleevec.pdf.
Cohen, M. H., Johnson, J. R. and Sridhara, R. (2004) ‘NDA 21-673: ClolarTM (clofarabine) for IV infusion’. Food
and Drug Administration. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21673_Clolar_medr.PDF.
Cohen, M. H., Johnson, J. R., Williams, G., Duan, J., Gobburu, J., Rahman, A., Kwang Kim, S., Wood, R., Benson,
K., Leighton, J., Rothmann, M., Chen, G., Maung, K., Gensinger, G., Staten, A. and Pease, D. (2001) ‘Medical
Officer Review of NDA 21-335’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-335_Gleevec_medr_P1.pdf.
Cox, E. (2012) ‘BLA 125349/0 BLA Approval - Animal Efficacy’. Center for Drug Evaluation and Research.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/125349Orig1s000ltr(r).pdf.
Dagher, R., Cohen, M. H., Rothmann, M., Chen, G. and Griebel, D. (2002) ‘Clinical Review Application 21335/S01’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-335S001_Gleevec_Medr_P1.pdf.
DeBeau, J. (1999) ‘Submissions to the NDA: File 20-833’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20-883_Acova_corres.pdf.
Department of Health and Human Services (2007) ‘Our STN: BL 103948/5070’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/103948s5070lt.pdf.
Dinndorf, P., Demko, S. and Keegan, P. (2011) ‘Clinical Review BLA 125327’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125327Orig1s000MedR.pdf.
Division of reproductive and urologic data products (2003) ‘Medical Officer’s Review of NHA - Abarelix’. Food
and Drug Administration.
Durie, B. G. M., Harousseau, J.-L., Miguel, J. S., Bladé, J., Barlogie, B., Anderson, K., Gertz, M., Dimopoulos, M.,
Westin, J., Sonneveld, P., Ludwig, H., Gahrton, G., Beksac, M., Crowley, J., Belch, A., Boccadaro, M., Turesson,
I., Joshua, D., Vesole, D., Kyle, R., Alexanian, R., Tricot, G., Attal, M., Merlini, G., Powles, R., Richardson, P.,
Shimizu, K., Tosi, P., Morgan, G. and Rajkumar, S. V. (2006) ‘International uniform response criteria for multiple
myeloma’, Leukemia, 20(9), pp. 1467–1473. doi: 10.1038/sj.leu.2404284.
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S.,
Gwyther, S., Mooney, M., Rubinstein, L., Shankar, L., Dodd, L., Kaplan, R., Lacombe, D. and Verweij, J. (2009)
‘New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)’, European Journal of
Cancer (Oxford, England: 1990), 45(2), pp. 228–247. doi: 10.1016/j.ejca.2008.10.026.
Elgin, V. and Sile, H. (2010) ‘Clinical review - NDA 22-562’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022562s000medr.pdf.
Epps, C. (2012) ‘Clinical Review NDA 022-458’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022458Orig1s000MedR.pdf.
43 / 59
European Medicines Agency (1999) ‘Summary of product characteristics - Bexarotene’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000326/WC500034208.pdf.
European Medicines Agency (2005a) ‘Background Information on the Procedure - Paclitaxel’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Procedural_steps_taken_before_authorisation/human/000216/WC500038971.pdf.
European Medicines Agency (2005b) ‘Cladribine scientific discussion’. European Medicines Agency, London,
UK.
European Medicines Agency (2005c) ‘Procedural steps taken after granting the Marketing Authorisation’.
European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Steps_taken_after_authorisation_when_a_cutoff_date_has_been_used/human/000406/WC500022205.pdf.
European Medicines Agency (2005d) ‘Scientific Discussion - Alemtuzumab’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000353/WC500025264.pdf.
European Medicines Agency (2005e) ‘Scientific discussion - Arsenic trioxide’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000388/WC500042839.pdf.
European Medicines Agency (2005f) ‘Scientific discussion - Busulfan’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000472/WC500052062.pdf.
European Medicines Agency (2005g) ‘Scientific discussion - Imatinib’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000406/WC500022203.pdf.
European Medicines Agency (2005h) ‘Scientific Discussion - Paclitaxel’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000216/WC500038970.pdf.
European Medicines Agency (2005i) ‘Scientific Discussion - Temozolomide’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000229/WC500035617.pdf.
European Medicines Agency (2005j) ‘Scientific Discussion - Wilzin’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000535/WC500040791.pdf.
European Medicines Agency (2006a) ‘Scientific discussion - Bexarotene’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000326/WC500034204.pdf.
European Medicines Agency (2006b) ‘Scientific discussion - Bortezomib’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000539/WC500048467.pdf.
European Medicines Agency (2006c) ‘Scientific discussion - Carglumic acid’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000461/WC500021582.pdf.
44 / 59
European Medicines Agency (2006d) ‘Scientific discussion - Cetuximab’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000558/WC500029113.pdf.
European Medicines Agency (2006e) ‘Scientific discussion - Dasatinib’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000709/WC500056995.pdf.
European Medicines Agency (2006f) ‘Scientific discussion - dexrazoxane’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000682/WC500049099.pdf.
European Medicines Agency (2006g) ‘Scientific Discussion - Sodium Phenylbutrate’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000219/WC500024748.pdf.
European Medicines Agency (2006h) ‘Scientific Discussion - Temoporfin’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000318/WC500024394.pdf.
European Medicines Agency (2007a) ‘Scientific Discussion - Aglucosidase Alfa’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000636/WC500032128.pdf.
European Medicines Agency (2007b) ‘Scientific discussion - Anagrelide’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000480/WC500056554.pdf.
European Medicines Agency (2007c) ‘Scientific discussion - Betaine anhydrous’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000678/WC500037401.pdf.
European Medicines Agency (2007d) ‘Scientific discussion - Clofarabine’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000613/WC500031194.pdf.
European Medicines Agency (2007e) ‘Scientific Discussion - Hydroxocobalamin’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000806/WC500036364.pdf.
European Medicines Agency (2007f) ‘Scientific discussion - nilotinib’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000798/WC500034398.pdf.
European Medicines Agency (2007g) ‘Scientific Discussion - Nitisinone’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000555/WC500049192.pdf.
European Medicines Agency (2007h) ‘Scientific Discussion - Sunitinib’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000687/WC500057733.pdf.
European Medicines Agency (2007i) ‘Scientific discussion - trabectedin’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion/human/000773/WC500045836.pdf.
45 / 59
European Medicines Agency (2007j) ‘Summary of Product Characteristics - Nilotinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000798/WC500034394.pdf.
European Medicines Agency (2008) ‘MapCampath-H-C-353-II-30 : EPAR - Scientific Discussion - Variation’.
European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion__Variation/human/000353/WC500025271.pdf.
European Medicines Agency (2008) ‘Refusal assessment report for mylotarg’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/000705/WC500070677.pdf.
European Medicines Agency (2008) ‘Summary of product characteristics - Betaine anhydrous’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000678/WC500037404.pdf.
European Medicines Agency (2008) ‘Summary of product characteristics - Busulfan’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000472/WC500052066.pdf.
European Medicines Agency (2008) ‘Summary of product characteristics - dexrazoxane’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000682/WC500049102.pdf.
European Medicines Agency (2008) ‘Withdrawal assessment report for Voraxaze’. European Medicines
Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010
/01/WC500068409.pdf.
European Medicines Agency (2008) ‘Withdrawal Assessment Report for Vorinostat MSD 100 mg hard capsules
(Vorinostat)’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010
/01/WC500063049.pdf.
European Medicines Agency (2009) ‘Assessment report for Iressa’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/001016/WC500036361.pdf.
European Medicines Agency (2009) ‘CHMP Assessment report for Vedrop’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/000920/WC500047922.pdf.
European Medicines Agency (2009) ‘Cladribine summary of product characteristics’. European Medicines
Agency, London, UK.
European Medicines Agency (2009) ‘Questions and answers on the withdrawal for the marketing authorisation
for Ixempra’. European Medicines Agency, London, UK.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Aglucosidase alfa’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000636/WC500032125.pdf.
46 / 59
European Medicines Agency (2009) ‘Summary of Product Characteristics - AMMONAPS’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000219/WC500024753.pdf.
European Medicines Agency (2009) ‘Summary of product characteristics - Anagrelide’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000480/WC500056557.pdf.
European Medicines Agency (2009) ‘Summary of product characteristics - Arsenic trioxide’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000388/WC500042844.pdf.
European Medicines Agency (2009) ‘Summary of product characteristics - Bortezomib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000539/WC500048471.pdf.
European Medicines Agency (2009) ‘Summary of product characteristics - Carglumic acid’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000461/WC500021584.pdf.
European Medicines Agency (2009) ‘Summary of product characteristics - Cetuximab’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000558/WC500029119.pdf.
European Medicines Agency (2009) ‘Summary of product characteristics - Clofarabine’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000613/WC500031191.pdf.
European Medicines Agency (2009) ‘Summary of product characteristics - Dasatinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000709/WC500056998.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Gefitinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/001016/WC500036358.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Imatinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000406/WC500022207.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Nelarabine’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000752/WC500027918.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Nitisinone’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000555/WC500049195.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Sunitinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000687/WC500057737.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Temoporfin’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000318/WC500024398.pdf.
47 / 59
European Medicines Agency (2009) ‘Summary of Product Characteristics - Temozolomide’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000229/WC500035621.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Tocofersolan’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000920/WC500047919.pdf.
European Medicines Agency (2009) ‘Summary of Product Characteristics - Trabectedin’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000773/WC500045832.pdf.
European Medicines Agency (2009) ‘Withdrawal Assessment Report for Ixempra’. European Medicines Agency,
London, UK.
European Medicines Agency (2010a) ‘CHMP Assessment Report for Arzerra’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/001131/WC500093094.pdf.
European Medicines Agency (2010b) ‘Questions and answers on Levact and associated names (bendamustine
hydrochloride, 2.5 mg/ml, powder for concentrate for solution for infusion)’. European Medicines Agency,
London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Levact_29/WC500075906.p
df.
European Medicines Agency (2010c) ‘Summary of opinion (initial authorisation) - Orphacol’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion__Initial_authorisation/human/001250/WC500099932.pdf.
European Medicines Agency (2010d) ‘Summary of Product Characteristics - Ofatumumab’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/001131/WC500093091.pdf.
European Medicines Agency (2011) ‘Refusal of the marketing authorisation for Glybera (alipogene tiparvovec) Outcome of re-examination’. European Medicines Agency, London, UK.
European Medicines Agency (2011) ‘Withdrawal Assessment Report for Tekinex’. European Medicines Agency,
London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2011
/03/WC500103707.pdf.
European Medicines Agency (2011) ‘Withdrawal of the marketing authorisation application for Movectro
(cladribine)’. European Medicines Agency, London, UK.
European Medicines Agency (2012a) ‘Assessment report - Brentuximab’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002455/WC500135054.pdf.
European Medicines Agency (2012b) ‘Assessment report - Glybera’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002145/WC500135476.pdf.
48 / 59
European Medicines Agency (2012c) ‘Assessment report - Istodax’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002122/WC500140233.pdf.
European Medicines Agency (2012d) ‘Assessment Report - Signifor’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002052/WC500128058.pdf.
European Medicines Agency (2012e) ‘Background information on the procedure - Taliglucerase’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002250/WC500135112.pdf.
European Medicines Agency (2012f) ‘Refusal of the marketing authorisation for Elelyso (taliglucerase alfa)’.
European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion__Initial_authorisation/human/002250/WC500129076.pdf.
European Medicines Agency (2012g) ‘Refusal of the marketing authorisation for Folotyn (pralatrexate) Outcome of re-examination’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion__Initial_authorisation/human/002096/WC500125706.pdf.
European Medicines Agency (2012h) ‘Refusal of the marketing authorisation for Istodax (romidepsin) Outcome of re-examination’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion__Initial_authorisation/human/002122/WC500134835.pdf.
European Medicines Agency (2012i) ‘Scientific discussion - Crizotinib’. European Medicines Agency, London,
UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002489/WC500134761.pdf.
European Medicines Agency (2012j) ‘Summary of product characteristics - Alipogene tiparvovec’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002145/WC500135472.pdf.
European Medicines Agency (2012k) ‘Summary of product characteristics - Brentuximab’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002455/WC500135055.pdf.
European Medicines Agency (2012l) ‘Summary of product characteristics - Crizotinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002489/WC500134759.pdf.
European Medicines Agency (2013a) ‘Assessment report - Bosulif’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002373/WC500141745.pdf.
European Medicines Agency (2013b) ‘Assessment report - Deftelio’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002393/WC500153152.pdf.
European Medicines Agency (2013c) ‘Assessment report - Erivedge’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002602/WC500146820.pdf.
49 / 59
European Medicines Agency (2013d) ‘Assessment report - Iclusig’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002695/WC500145648.pdf.
European Medicines Agency (2013e) ‘Assessment report - Lojuxta’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002578/WC500148551.pdf.
European Medicines Agency (2013f) ‘Assessment report - Orphacol’. European Medicines Agency, London, UK.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/001250/WC500131542.pdf.
European Medicines Agency (2013g) ‘Assessment report for: Iron containing intraveneous (IV) medicinal
products’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/IV_iron_31/WC500150771.p
df.
European Medicines Agency (2013h) ‘Assessment report Pomalidomide Celgene’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002682/WC500147721.pdf.
European Medicines Agency (2013i) ‘New recommendations to manage risk of allergic reaction with
intraveneous iron-containing medicines’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/IV_iron_31/WC500151308.p
df.
European Medicines Agency (2013j) ‘Refusal of the marketing authorisation for Defitelio (defibrotide)’.
European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion__Initial_authorisation/human/002393/WC500140667.pdf.
European Medicines Agency (2013k) ‘Summary of opinion (initial authorisation) - Cholic acid FGK’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion__Initial_authorisation/human/002081/WC500155422.pdf.
European Medicines Agency (2013l) ‘Summary of product characteristics - Bosutinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002373/WC500141721.pdf.
European Medicines Agency (2013m) ‘Summary of product characteristics - Defibrotide’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002393/WC500153150.pdf.
European Medicines Agency (2013n) ‘Summary of product characteristics - Lomitapide’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002578/WC500148549.pdf.
European Medicines Agency (2013o) ‘Summary of product characteristics - Orphacol’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/001250/WC500150993.pdf.
European Medicines Agency (2013p) ‘Summary of Product Characteristics - Pomalidomide’. European
Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002682/WC500147717.pdf.
50 / 59
European Medicines Agency (2013q) ‘Summary of Product Characteristics - Ponatinib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002695/WC500145646.pdf.
European Medicines Agency (2013r) ‘Summary of Product Characteristics - Vismodegib’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002602/WC500146817.pdf.
European Medicines Agency (2014a) ‘Assessment report - cholic acid FGK’. European Medicines Agency,
London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002081/WC500165386.pdf.
European Medicines Agency (2014b) ‘Glivec - Procedural steps taken and scientific information after the
authorisation’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Procedural_steps_taken_and_scientific_information_after_authorisation/human/000406/WC500022206.pdf.
European Medicines Agency (2014c) ‘Summary of product characteristics - Kolbam’. European Medicines
Agency, London, UK. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002081/WC500165383.pdf.
European Medicines Agency (2014d) ‘Velcade - Procedural steps taken and scientific information after the
authorisation’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Procedural_steps_taken_and_scientific_information_after_authorisation/human/000539/WC500048470.pdf.
Food and Drug Administration (1996) ‘Prescribing Information - BUPHENYL’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020572s016,020573s015lbl.pdf.
Food and Drug Administration (1998) ‘Prescribing Information - Paxene’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20262slbl.pdf.
Food and Drug Administration (1999a) ‘Clinical review - Bexarotene’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21055_Targretin_medr_P1.pdf.
Food and Drug Administration (1999b) ‘NDA Medical Review - Busulfex’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20954_medr_P1.pdf.
Food and Drug Administration (1999c) ‘Prescribing Information - Busulfan’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20954lbl.pdf.
Food and Drug Administration (1999d) ‘Prescribing Information - FERRLECIT’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20955lbl.pdf.
Food and Drug Administration (2000a) ‘ACOVATM (argatroban) Injection’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20883lbl.pdf.
Food and Drug Administration (2000b) ‘TRISENOXTM (arsenic trioxide) injection’. Food and Drug
Administration. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/21248lbl.pdf.
Food and Drug Administration (2001a) ‘Complete review: BLA 99-0786 Campath’. Food and Drug
Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/103948_0000_Campath_Medr.pdf.
Food and Drug Administration (2001b) ‘Prescribing Information - GLEEVEC’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/21335lbl.pdf.
51 / 59
Food and Drug Administration (2002a) ‘Prescribing Information - GLEEVEC (imatinib mesylate)’. Food and Drug
Administration. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21335se8Gleevec_lbl.pdf.
Food and Drug Administration (2002b) ‘ZINECARD® (dexrazoxane for injection) - FDA Approved Labelling for S006’. Food and Drug Administration.
Food and Drug Administration (2003a) ‘Prescribing Information - BEXXAR’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/tosicor062703LB.pdf.
Food and Drug Administration (2003b) ‘Prescribing Information - Bortezomib’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021602lbl.pdf.
Food and Drug Administration (2003c) ‘Prescribing Information - IRESSA’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021399lbl.pdf.
Food and Drug Administration (2003d) ‘Prescribing information - RADIOGARDASE’. Food and Drug
Administration. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#
labelinfo.
Food and Drug Administration (2004a) ‘NDA 21-751 Pentetate calcium trisodium injection - Package Insert Instruction for Use’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021749lbl.pdf.
Food and Drug Administration (2004b) ‘NDA 21-751 Pentetate zinc trisodium injection - Package Insert Instruction for Use’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021751lbl.pdf.
Food and Drug Administration (2004) ‘Prescribing Information - CLOLAR’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021673lbl.pdf.
Food and Drug Administration (2004) ‘Prescribing Information - ERBITUX’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/125084lbl.pdf.
Food and Drug Administration (2006) ‘NDA 20-576/S-008’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/020576s008ltr.pdf.
Food and Drug Administration (2006) ‘Prescribing Information - GLEEVEC’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021588_s011_gleevec.pdf.
Food and Drug Administration (2006) ‘Prescribing Information - SPRYCEL’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021986lbl.pdf.
Food and Drug Administration (2007) ‘Prescribing Information - IXEMPRA’. Food and Drug Administration.
Food and Drug Administration (2008) ‘NDA Approval NDA 22-203’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/022303s000ltr.pdf.
Food and Drug Administration (2008) ‘NDA Approval NDA 22-249’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/022249s000ltr.pdf.
Food and Drug Administration (2008) ‘Prescribing Information - Bendamustine’. Food and Drug Administration.
Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#
apphist.
52 / 59
Food and Drug Administration (2009) ‘FDA Briefing Document - Oncology Drugs Advisory Comittee Meeting NDA 22-447 Yondelis (Trabectedin)’. Food and Drug Administration. Available at:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dru%20gs/OncologicDru
gsAdvisoryCommittee/UCM171149.pdf.
Food and Drug Administration (2009) ‘Prescribing Information - FOLOTYN’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022468lbl.pdf.
Food and Drug Administration (2009) ‘Prescribing Information - ISTODAX’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022393lbl.pdf.
Food and Drug Administration (2010a) ‘Prescribing Information - Betaine anhydrous’. Food and Drug
Administration. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#
apphist.
Food and Drug Administration (2010b) ‘Prescribing Information - CARBAGLU’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022562lbl.pdf.
Food and Drug Administration (2011) ‘Prescribing Information - ADCETRIS’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125388s000,125399s000lbl.pdf.
Food and Drug Administration (2011) ‘Prescribing Information - Asparaginase Erwinia chrysanthemi’. Food and
Drug Administration. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125359lbl.pdf.
Food and Drug Administration (2011) ‘Prescribing Information - XALKORI’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202570s000lbl.pdf.
Food and Drug Administration (2012) ‘Prescribing Information - BOSULIF®’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf.
Food and Drug Administration (2012) ‘Prescribing Information - Carfilzomib’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf.
Food and Drug Administration (2012) ‘Prescribing Information - ELELYSO’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022458lbl.pdf.
Food and Drug Administration (2012) ‘Prescribing Information - LOJUXTA’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203858s000lbl.pdf.
Food and Drug Administration (2012) ‘Prescribing Information - RAXIBACUMAB’. Food and Drug
Administration. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125349s000lbl.pdf.
Food and Drug Administration (2012) ‘Prescribing Information - SIGNIFOR’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf.
Food and Drug Administration (2012) ‘Prescribing Information - SYNRIBO’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203585lbl.pdf.
Food and Drug Administration (2013) ‘Prescribing Information - POMALYST’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204026lbl.pdf.
Food and Drug Administration (2014a) Drug Details - Zinecard. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails (Accessed:
9 October 2014).
53 / 59
Food and Drug Administration (2014b) Drugs @ FDA Anagrelide hydrochloride. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#
labelinfo (Accessed: 10 June 2014).
Food and Drug Administration (2014c) ‘Prescribing Information - IMBRUVICA’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/205552Orig1s000ltr.pdf.
Food and Drug Administration (2014d) ‘Prescribing Information - MYALEPT’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125390s000lbl.pdf.
Food and Drug Administration (2014e) ‘Prescribing Information - VELCADE’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021602s040lbl.pdf.
Food and Drug Administration (2014f) ‘Prescribing Information - ZYKADIA’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205755s000lbl.pdf.
Gallo-Torres, H. E. (1997) ‘Division of Gastrointestinal and Coagulation Drug Products - Medical Officer’s
Review - NDA 20-458-BM’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020458ap.pdf.
Gbabe, O. F., Okwundu, C. I., Dedicoat, M. and Freeman, E. E. (1996) ‘Treatment of severe or progressive
Kaposi’s sarcoma in HIV-infected adults’, in Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd.
Available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003256.pub2/abstract (Accessed: 28
October 2014).
Genzyme (2006) ‘Text Labelling of the drug - Myozyme® (aglucosidase alfa)’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/125141LBLini.pdf.
George, S., Demetri, G. D., Maki, R. and Savarese, D. M. (2014) UpToDate: Systemic treatment of metastatic
soft tissue sarcoma. Available at: http://www.uptodate.com/contents/systemic-treatment-of-metastatic-softtissue-sarcoma#H23 (Accessed: 5 November 2014).
Golden, J. K. (2014) ‘Clinical review BLA 125930’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125390Orig1s000MedR.pdf.
Goodman, V. and Dagher, R. (2006) ‘Clinical Review NDA 21-968’. Center for Drug Evaluation and Research.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021938_S000_Sutent_MedR.pdf.
Griebel, D. (2009) ‘NDA 20-576/S-016 NDA 20-573/S015’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/020572s016,020573s015ltr.pdf.
Guest, J. F., Smith, H., Sladkevicius, E. and Jackson, G. (2009) ‘Cost-effectiveness of pentostatin compared with
cladribine in the management of hairy cell leukemia in the United Kingdom’, Clinical Therapeutics, 31, pp.
2398–2415. doi: 10.1016/j.clinthera.2009.11.016.
Hatswell, A. J., Baio, G., Berlin, J. A., Irs, A. and Freemantle, N. (2016) ‘Regulatory approval of pharmaceuticals
without a randomised controlled study: analysis of EMA and FDA approvals 1999–2014’, BMJ open, 6(6), p.
e011666.
Herndon, T. M. (2012) ‘Clinical review - Carfilzomib’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000MedR.pdf.
Hobson, R. (2000) ‘Scotia slumps on Foscan setback’, Citywire Money, 26 September. Available at:
http://citywire.co.uk/money/scotia-slumps-on-foscan-setback/a213047 (Accessed: 29 October 2014).
Houn, F. (2003) ‘NDA 21-626’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-626_Radiogardase_Approv.pdf.
54 / 59
Jazz Pharmaceuticals (2014) ‘Agreement to acquire rights to defibrotide in the Americas’. Jazz Pharmaceuticals.
Available at: http://phx.corporateir.net/External.File?item=UGFyZW50SUQ9MjQxMDc1fENoaWxkSUQ9LTF8VHlwZT0z&t=1.
Jefferys, D. B. and Jones, K. H. (1995) ‘EMEA and the new pharmaceutical procedures for Europe. European
Medicines Evaluation Agency’, European Journal of Clinical Pharmacology, 47(6), pp. 471–476.
Jenkins, J. (2002) ‘NDA 21-232’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21232ltr.pdf.
Justice, R. L. (1999) ‘NDA 20-954’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1999/20954ltr.pdf.
Justice, R. L. (2006a) ‘NDA 21-588/S011, S012, S013, S014, S017’. Center for Drug Evaluation and Research.
Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021588s011,%20s012,%20s013,%20s014,%2
0s017ltr.pdf.
Justice, R. L. (2006b) ‘NDA 21-602/S-010’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021602s010ltr.pdf.
Kane, R. (2006) ‘Clinical Review NDA 21-602’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021602_s010_velcade.pdf.
Kane, R. (2014) ‘NDA 204026/S-003 Supplement Approval Fullfillment of postmarketing requirement’. Center
for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/204026Orig1s003ltr.pdf.
Khozin, S. and Zhang, L. (2014) ‘Clinical/ Statistical Review - NDA 205755’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000MedR.pdf.
Krown, S. E., Metroka, C. and Wernz, J. C. (1989) ‘Kaposi’s sarcoma in the acquired immune deficiency
syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group
Oncology Committee’, Journal of Clinical Oncology: Official Journal of the American Society of Clinical
Oncology, 7(9), pp. 1201–1207.
Kwitkowski, V. (2007) ‘Clinical review - Bendamustine - Rituximab-refractory, Indolent NHL’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022303s000_MedR.pdf.
Lechleider, R. J. and Kaminskas, E. (2007) ‘Clinical Review NDA 22-065’. Center for Drug Evaluation and
Research.
Lemery, S., Gootenberg, J., Keegan, P., Chiang, R., Zhang, J., Rothmann, M. and Chakaravarty, A. (2009) ‘Clinical
Review and Evaluation - Clinical Studies - Ofatumumab’. Center for Drug Evaluation and Research.
Leonardi, R. G. (2001) ‘Application number 21-232 Medical Review(s)’. Center for Drug Evaluation and
Research. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21232_ORFADIN_medr.pdf.
Lowy, N. (2012) ‘Clinical review NDA 200,677’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/200677Orig1s000MedR.pdf.
Malik, S. (2009) ‘Clinical Review 022468 Folotyn (Pralatrexate)’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022468s000_MedR.pdf.
Mann, B. S. (2006) ‘Clinical & Statistical Review NDA 021991’. Center for Drug Evaluation and Research.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021991s000_Zolinza_MedR_P1.pdf.
55 / 59
Masiello, S. A. and Risso, S. T. (2003) ‘Our STN: BL 125011/0’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/125011s000_Approv.pdf.
McGinn, K. (2012) ‘Clinical review - NDA 203341 - Bosutinib’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf.
McGinn, K. (2013) ‘Clinical review - New Molecular Entity - 205552’. Center for Drug Evaluation and Research.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000MedR.pdf.
Mekhail, T. M. and Markman, M. (2002) ‘Paclitaxel in cancer therapy’, Expert Opinion on Pharmacotherapy,
3(6), pp. 755–766. doi: 10.1517/14656566.3.6.755.
Merck Sharp & Dohme (2009) ‘Withdrawal of Marketing Authorisation for Vorinostat MSD, 100 mg hard
capsules (EMEA/H/C/947)’. European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500063050.pdf.
Millenium and ILEX Partners (2001) ‘Final Draft Package Insert - Alemtuzumab’. Food and Drug Administration.
Nguyen, C. (2012) ‘NDA 203858 NDA Approval’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/203858Orig1s000ltr_replace.pdf.
O’Brien, S. G., Guilhot, F., Larson, R. A., Gathmann, I., Baccarani, M., Cervantes, F., Cornelissen, J. J., Fischer, T.,
Hochhaus, A., Hughes, T., Lechner, K., Nielsen, J. L., Rousselot, P., Reiffers, J., Saglio, G., Shepherd, J.,
Simonsson, B., Gratwohl, A., Goldman, J. M., Kantarjian, H., Taylor, K., Verhoef, G., Bolton, A. E., Capdeville, R.
and Druker, B. J. (2003) ‘Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed
Chronic-Phase Chronic Myeloid Leukemia’, New England Journal of Medicine, 348(11), pp. 994–1004. doi:
10.1056/NEJMoa022457.
Pai-Scherf, L. H., Thornton, M., Andrich, M., Mills, G. and Keegan, P. (2010) ‘Clinical Review - NDA 22-562’.
Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/bla/2004/125084_ERBITUX_MEDR_P1.PDF.
Parks, M. H. (2014) ‘BLA 125390/0 BLA Approval’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/125390Orig1s000ltr.pdf.
Pazdur, R. (2002) ‘NDA 21-335/S-001’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21335s001ltr.pdf.
Pazdur, R. (2005) ‘NDA 21-877’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021877ltr.pdf.
Pazdur, R. (2006) ‘NDA 21-938 NDA 21-968’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021938s000ltr.pdf.
Pazdur, R. (2006) ‘NDA 21-986’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021986s000ltr.pdf.
Pazdur, R. (2006) ‘NDA 21-991’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021991s000ltr.pdf.
Pazdur, R. (2007a) ‘NDA 22-065 NDA Approval’. Center for Drug Evaluation and Research.
Pazdur, R. (2007b) ‘NDA 22-068’. Office of Oncology Drug Products. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/022068s000ltr.pdf.
Pazdur, R. (2009) ‘NDA 022-393 NDA Approval’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022393s000ltr.pdf.
56 / 59
Pazdur, R. (2009) ‘NDA 022468’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022468s000ltr.pdf.
Pazdur, R. (2009) ‘Our STN: BL 125326/0 BLA Accelerated Approval’. Center for Drug Evaluation and Research.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/125326s000ltr.pdf.
Pazdur, R. (2011) ‘BLA Accelerated Approval BL 125388/0 BL 125399/0’. Food and Drug Administration.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/125388s000,125399s000ltr.pdf.
Pazdur, R. (2011) ‘BLA Approval BL 12539/0’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/125359s000ltr.pdf.
Pazdur, R. (2011) ‘NDA 202570 Accelerated Approval’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/202570s000ltr.pdf.
Pazdur, R. (2012a) ‘Accelerated Approval NDA 202714’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1999/20954ltr.pdf.
Pazdur, R. (2012b) ‘NDA 203469 Accelerated Approval’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/203469Orig1s000ltr.pdf.
Pazdur, R. (2012c) ‘NDA 203585 Accelerated Approval’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/203585Orig1s000ltr.pdf.
Pazdur, R. (2012d) ‘NDA APPROVAL, NDA 203341’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/203341Orig1s000ltr.pdf.
Pazdur, R. (2013) ‘NDA 204026 Accelerated Approval’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/204026Orig1s000ltr.pdf.
Pazdur, R. (2014) ‘NDA 205755 Accelerated Approval’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/205755Orig1s000ltr.pdf.
PMLiVE (2013) Court orders EC to approve rejected orphan medicine. Available at:
http://www.pmlive.com/pharma_news/court_orders_ec_to_approve_rejected_orphan_medicine_488555
(Accessed: 7 October 2014).
Pro, B., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M.,
Connors, J. M., Yang, Y., Sievers, E. L., Kennedy, D. A. and Shustov, A. (2012) ‘Brentuximab Vedotin (SGN-35) in
Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study’,
Journal of Clinical Oncology, 30(18), pp. 2190–2196. doi: 10.1200/JCO.2011.38.0402.
Protherics PLC (2007) ‘Withdrawal of Vorazaze powder for solution for injection 1000 Units (glucarpidase)’.
European Medicines Agency, London, UK. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500068411.pdf.
Raczkowski, V. F. (1999) ‘NDA 20-955’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1999/20955ltr.pdf.
Rosebraugh, C. J. (2012) ‘NDA 200677 NDA Approval’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/200677Orig1s000ltr.pdf.
Ryan, Q., Kwitkowski, V. and CRNP (2007) ‘Clinical review - Bendamustine - treatment for CLL’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P1.pdf.
Ryan, Q. and Maher, V. E. (2009) ‘Clinical review NDA 22393’. Center for Drug Evaluation and Research.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022393s000_MedR.pdf.
57 / 59
Shastri, K., Jerian, S., Mills, G. and Keegan, P. (2003) ‘Clinical Review BLA 125011’. Center for Drug Evaluation
and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/125011s000_MedR_P1.pdf.
Simone, A. (2006) ‘Clinical review NDA 21-041’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/022041s000_MedR_p1.pdf.
Sims, C. (2001) ‘New buyer to safeguard Scotia’s Foscan production’, Herald Scotland, 17 August. Available at:
http://www.heraldscotland.com/sport/spl/aberdeen/new-buyer-to-safeguard-scotia-s-foscan-production1.176780 (Accessed: 29 October 2014).
Sizer, K. (1998) ‘Division of gastrointestinal and coagulation drug products medical officer’s review NDA 20995’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20955_Ferrlecit_medr.pdf.
Smith, J. P. (2012) ‘Clinical Review NDA 203858’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf.
Stevens SR, Ke MS, Parry EJ, Mark J and Cooper KD (2002) ‘Quantifying skin disease burden in mycosis
fungoides–type cutaneous t-cell lymphomas: The severity-weighted assessment tool (swat)’, Archives of
Dermatology, 138(1), pp. 42–48. doi: 10.1001/archderm.138.1.42.
Temple, R. (1999a) ‘NDA 21-029’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1999/21029ltr.pdf.
Temple, R. (1999b) ‘NDA 21-055’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1999/21055ltr.pdf.
Temple, R. (2000a) ‘NDA 21-174’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/21174ltr.pdf.
Temple, R. (2000b) ‘NDA 21-248 - Approval Letter’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-248_Trisenox_Approv.pdf.
Temple, R. (2001) ‘NDA 21-335’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2001/21335ltr.pdf.
Temple, R. (2003) ‘NDA 21-602’. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21055_Targretin_medr_P1.pdf.
Temple, R. (2010) ‘NDA 21-673’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/021673ltr.pdf.
Temple, Robert (2003) ‘NDA 21-399’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-399_IRESSA_Approv.pdf.
Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., Verweij, J., Glabbeke, M.
V., Oosterom, A. T. van, Christian, M. C. and Gwyther, S. G. (2000) ‘New Guidelines to Evaluate the Response to
Treatment in Solid Tumors’, Journal of the National Cancer Institute, 92(3), pp. 205–216. doi:
10.1093/jnci/92.3.205.
Von Hoff, D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M., Seay, T., Tjulandin, S. A., Ma, W.
W., Saleh, M. N., Harris, M., Reni, M., Dowden, S., Laheru, D., Bahary, N., Ramanathan, R. K., Tabernero, J.,
Hidalgo, M., Goldstein, D., Van Cutsem, E., Wei, X., Iglesias, J. and Renschler, M. F. (2013) ‘Increased survival in
pancreatic cancer with nab-paclitaxel plus gemcitabine’, The New England Journal of Medicine, 369(18), pp.
1691–1703. doi: 10.1056/NEJMoa1304369.
58 / 59
Vose, J., Armitage, J., Weisenburger, D. and International T-Cell Lymphoma Project (2008) ‘International
peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes’, Journal of
Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 26(25), pp. 4124–4130. doi:
10.1200/JCO.2008.16.4558.
Weaver, B. A. (2014) ‘How Taxol/paclitaxel kills cancer cells’, Molecular Biology of the Cell, 25(18), pp. 2677–
2681. doi: 10.1091/mbc.E14-04-0916.
Weiss, K. D. (2004) ‘BL 125084/0’. Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/bla/2004/125084_ERBITUX_APPROV.PDF.
Yaes, R. J., Welch, M., Sancho, A., Kasliwal, R., Laniyonu, A. and Stewart, P. (2004) ‘Medical Officer Review CaDTPA and ZN-DTPA’. Center for Drug Evaluation and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21749_Pentetate%20Calcium%20and%20Zinc_medr_P1.pdf.
Yaes, R. J., Welch, M., Sancho, A., Place, D., Hussong, D., Laniyonu, A. and Stewart, P. (2003) ‘Medical Officer
Review - Prussian Blue’. Food and Drug Administration.
Yasinskaya, Y. and Alexander, J. (2012) ‘Clinical Review BLA Resubmission 125349’. Center for Drug Evaluation
and Research. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125349Orig1s000MedR.pdf.
59 / 59