Table 1 Examples of HCs used in Clinical Trials for Approvals by Regulatory Agencies
Drug Candidate | Carglumic Acid or CARBAGLU | Protein C Concentrate (Human) or CEPROTIN | Lepirudin or REFLUDAN | Antithrombin [Recombinant] or ATRYN |
|---|---|---|---|---|
Indication | Hyper-ammonaemia | Protein C deficiency | Immunologic type of Heparin-associated thrombocytopenia | Hereditary anti-thrombin deficient patients |
Prevalence of the disease | < 10 patients (US) < 50 (worldwide) | < 20 patients (US) | N/A | N/A |
Other treatments | No | No | No | No |
Approved | 2010 | 2007 | 1998 | 2009 |
Division | FDA-CDER | FDA-CDER | FDA-CDER | FDA-CDER |
Study Design | Retrospective Case Series | N/A | Uncontrolled study | Two prospective, single-arm, open-label studies |
Number of subjects | 23 subjects | 18 subjects | Two studies with 39 and 33 Subjects | 31 subjects |
Endpoint | Ammonia levels | Response for thromboembolic events | Platelet count recovery | Incidence of thromboembolic events |
Type of HC | Natural history data | N/A | Registry data which PI established | Prospectively designed retrospective chart review |
Source of the HC | Subject at baseline | N/A | Subjects not treated with recombinant hirudin | |
Size of HC | 23 subjects | 21 subjects | 91 subjects | 35 Subjects |
Method of application | Descriptive statistics | Descriptive Statistics | Direct comparison | Matching |
Note | HC was used only for secondary endpoint due to the less availability of platelet data | |||
Drug Candidate | Anagrelide or AGRYLIN | Alglucosidase Alfa or MYOZYME/LUMIZYME | Miglustat or ZAVESCA | Blinatumomab or BLINCYTO |
Indication | Reduction of the elevated platelet count, thrombosis and ameliorate-associated symptoms. | Pompe disease | Type I Gaucher disease | Adults relapsed/refractory Acute Lymphoblastic Leukaemia |
Prevalence of the disease | N/A | 1/40,000 live births | 1/100,000 | 1–2/100,000 adults |
Other treatments | No | No | Available | No |
Approved | 1997 | 2006 | 2003 | 2017 |
Division | FDA-CDER | FDA-CDER | FDA-CDER | FDA-CDER |
Study Design | Self-controlled study | RCT with two dose groups | Self-controlled study | Single arm trial |
Number of subjects | About 300 subjects | 18 (9 subjects per dose group) | Three studies include 28, 18 and 36 subjects | 189 subjects |
Endpoint | N/A | Invasive ventilator-free survival and survival rate | Percentage change from baseline in liver organ volume | Complete remission |
Type of HC | Natural history data at baseline | Natural history data (Cross-sectional NH) | Natural history data at baseline | Several kinds of data |
Source of the HC | Subject at baseline | Natural history data | Subject at baseline | Investigator database |
Size of HC | About 300 subjects | 62 subjects | 82 subjects | 1112 subjects |
Method of application | N/A | Direct comparison for non-inferiority inference. | Descriptive Statistics | HC was used to show the validity of efficacy threshold by meta analytic approach. |
Note | Historical data collected over a 20-year span and time trend observed. | For EMA, analysis with propensity score was also performed. | ||
Drug Candidate | Arsenic trioxide or TRISENOX | Eteplirsen or EXONDYS 51 | Elbasvir and Grazoprevir or ZEPATIER | Nitisinone or ORFADIN |
Indication | Acute promyelocytic leukaemia | Duchenne muscular dystrophy (DMD) | Treatment of Chronic Hepatitis C genotypes 1, 4 or 6 in adults | Hereditary Tyrosinemia 1 |
Prevalence of the disease | 6/10,000,000 per year | 20 / 100,000 | N/A | 1/100000 |
Other treatments | Yes | No | Newly available during the development | No |
Approved | 2010 | 2016 | 2016 | 2002 |
Division | FDA-CDER | FDA-CDER | FDA-CDER | FDA-CDER |
Study Design | Single arm trial | Placebo controlled study followed by extension study | Parallel or single arm study | Single arm study |
Number of subjects | 40 subjects | 12 subjects | 1294 subjects from 3 studies | 207 subjects |
Endpoint | Complete remission | Controlled trial: change from baseline of dystrophin positive fibers Extension study: 6MWT | Sustained virologic response | Survival |
Type of HC | Registry data | Registry data | Previous clinical trial data | Registry data |
Source of the HC | Hospital stored data | Matching from 2 DMD patient registries | Previous clinical trial data | Survey result |
Size of HC | 27 subjects | 13 subjects | Depending on the trials | 108 subjects |
Method of application | Just showed as reference | Direct comparison | One sample testing. HC was used for efficacy threshold. | Just showed as reference |
Note | Initially agency and advisory panel voted against the approval | Not a rare disease. | Large improvement against historical data | |
Drug Candidate | Sodium Ferric Gluconate Complex or FERRLECIT | Sebelipase Alfa or KANUMA | Asfotase Alfa or STRENSIQ | Cerliponase Alfa or BRINEURA |
Indication | Iron deficiency anemia undergoing chronic hemodialysis | Lysosomal acid lipase (Wolman disease) | Hypophosphatasia | late infantile neuronal ceroid lipofuscinosis type 2 |
Prevalence of the disease | N/A | 1/500,000 | 1/100,000 | 1/100,000 |
Other treatments | Yes | No | No | No |
Approved | 2001 | 2015 | 2015 | 2017 |
Division | FDA-CDER | FDA-CDER | FDA-CDER | FDA-CDER |
Study Design | Multiple dose historical control study | Historical control study | Single-arm | Single arm trial |
Number of subjects | 88 subjects from 2 dosing groups | 9 subjects | 70 subjects from 2 studies | 22 subjects |
Endpoint | Change in Hemoglobin | Time to Death | Overall survival | Response rate |
Type of HC | Registry data | Natural history data | Natural history data | Natural history data |
Source of the HC | Subjects with oral Iron | Retrospective clinical chart reviews | Retrospective clinical chart reviews | Natural history cohort |
Size of HC | 25 subjects | 21adjudicated as appropriate for comparison | 48 subjects | 42 subjects |
Method of application | Direct comparison | Direct comparison by survival analysis | Direct comparison by survival analysis | Matched analysis with HC |
Note | Another study also supported the efficacy |