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Randomized trial on the therapeutic equivalence between Eprex ...

  1. 1. NEPHROLOGY 2007; 12, 431–436 doi:10.1111/j.1440-1797.2007.00831.x Original Article Randomized trial on the therapeutic equivalence between Eprex and GerEPO in patients on haemodialysis BAK-LEONG GOH1, LOKE-MENG ONG2, SAROJINI SIVANANDAM3, TECK-ONN LIM3, ZAKI MORAD4, FOR THE BIOGENERIC EPO STUDY GROUP* 1 Department of Nephrology, Serdang Hospital, 2Department of Medicine, Penang Hospital, and 3Clinical Research Centre and 4Department of Nephrology, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia SUMMARY: Aim: Treatment of renal anaemia with epoetin is well established. However, epoetin is expensive. Biogeneric epoetin with proven efficacy would reduce cost and improve access to therapy. We conducted this first ever comparative study of a biogeneric and the original product. Methods: Stable haemodialysis patients with haemoglobin (Hb) of at least 9 g/dL and receiving the human recombinant erythropoietin Eprex were randomized to continue Eprex or convert to GerEPO, a biogeneric epoetin, for 12 weeks. The primary efficacy variable was a change in Hb from baseline. Results: Ninety-three subjects were randomized to each arm. Ninety-two and 87 subjects on the Eprex and GerEPO arms, respectively, completed the trial. Mean Hb in both groups declined over time. The mean decline in Hb was -0.47 g/dL in the Eprex group and -0.45 g/dL in the GerEPO group. The mean difference in the change in Hb from baseline to week 12 between the two groups was 0.02. The 95% confidence interval was -0.42 to 0.46, which lies within the margin of equivalence (10.5 g/dL). The results of intention-to-treat analysis were similar. There were no significant differences in the epoetin dose, iron therapy or iron stores between the groups. Patients receiving GerEPO reported more adverse events. Conclusion: GerEPO was therapeutically equivalent to Eprex with respect to Hb response for patients with Hb in the subtherapeutic target range as is common in this study population. The trial duration was insufficient for safety evaluation, which must await further investigation. More biogeneric products should be subjected to rigorous evaluation. KEY WORDS: anemia, biogeneric, biosimilar, chronic kidney disease, epoetin, follow-on biologic. Correspondence: Dr Teck-Onn Lim, Clinical Research Centre, Kuala Kangar Hospital), 2. Kian Seong Gan, Koh Wei Wong, Thevarajah Barathan (Likas Hospital), 3. Ahmad Ghazali (Selayang Hospital), 4. Lumpur Hospital, Jalan Pahang 50586, Kuala Lumpur, Malaysia. Satwant Singh Gill (Pantai Medical Centre), 5. Lai-seong Hooi (Sul- Email: limto@crc.gov.my tanah Aminah Johor Bharu Hospital), 6. Vaithilingam Indralingam Trial registration: http://clinicaltrials.gov. Identifier: NCT00229099. (Taiping Hospital), 7. Subra Indrawathan (Mawar Haemodialysis Role of the funding source and other parties: NCPC GeneTech Biotech- Centre), 8. Rahmat Korina (Malacca Hospital), 9. Wan-tin Lee (HD nology Co Ltd and its local associate participated in the study design; but Centre Felda Foundation), 10. Boon-seng Liew (HD Clinic, Sabah thereafter were not involved in the collection, analysis, and interpreta- Kidney Society), 11. Butt-chin Ng (Tung Shin Hospital), 12. Jeremiah tion of data; in the writing of the report; and in the decision to submit the Philip (Ampang Puteri Specialist Hospital), 13. Menon Prasad (SP paper for publication. An independent clinical research organization Menon Dialysis Centre), 14. Seman Ramli (Tengku Ampuan Afzan (CRO) managed and monitored the conduct of the trial, undertook data Hospital), 15. Ghazalli Rozina (Penang Hospital), 16. Mohamad Sukeri (Kota Bharu Hospital), 17. Chwee-choon Tan, Shah Firdaus Shahnaz management and safety surveillance. All data on efficacy, safety and other (Tengku Ampuan Rahimah Hospital), 18 Hui Hongu Tan Clare predetermined variables were subjected to verification against source (Sarawak General Hospital), 19. Kah Keong Tan (Asia Renal Care), 20. document. Investigators and biostatisticians of the CRO performed data Wee-meng Tan (Sunway Medical Centre and Kidney Dialysis Centre), analysis jointly. 21. Sue-mei Teo (Ipoh Hospital), 22. Mohd Yusof Wan Shaariah *Biogeneric EPO Study Group (Name of investigators and sites, (Seremban Hospital), 23. Morris Wo (Pontian Rotary HD Centre), in alphabetical order): 1. Chen-Hua Ching (Alor Setar Hospital and 24. Hin-seng Wong (Kuala Lumpur Hospital), 25. Ching King Simon Wong (CHKMUS-MAA Medicare Dialysis Centre and Timberland © 2007 The Authors Medical Centre), 26. Nordin Zawawi (Kuala Terengganu Hospital). Journal compilation © 2007 Asian Pacific Society of Nephrology Accepted for publication 31 May 2007.
  2. 2. 432 BL Goh et al. Patients with chronic kidney disease commonly have hyperparathyroidism, malignancy, history of mental illness, drug or anaemia. This is in part due to insufficient production of alcohol abuse and known hypersensitivity to mammalian cell-derived erythropoietin.1 The benefits of treatment with recombi- product or human albumin. nant human epoetin are well documented.2,3 All current guidelines recommend epoetin as the corner stone of Randomization and study therapy therapy for renal anaemia.4,5 Unfortunately, epoetin is costly and consume significant Eligible patients were randomized centrally in a one-to-one ratio to amount of health-care budget. For example, in the USA, receive Eprex or GerEPO. The randomization code was generated sepa- Medicare expenditure for treatment of renal anaemia rately for each participating centre by using the random permuted block amounted to USD 1.2 billion in 2001.6 Even a less wealthy method with randomly varying block size. country such as Malaysia was estimated to spend as much as Patients who were randomized to GerEPO were converted to intra- venous GerEPO in a one-to-one ratio while subjects randomized to USD 11 million in 2004 on epoetin alone (unpublished Eprex continued as usual. While the decision to adjust the dose of data). Clearly, cost of epoetin is a concern7–9 and a signifi- epoetin during the 12 week trial was at the investigators’ discretion, cant barrier to wider access to epoetin therapy. Many they were, however, strongly discouraged from doing that unless a surveys on anaemia management even among developed patient’s Hb declined to 8 g/dL and below or if it is absolutely necessary countries10–13 have consistently shown significant gaps in to eliminate an immediate hazard to the patient. achieving recommended therapeutic targets for renal anaemia. The problem is worse in developing countries. For example, in Malaysia, in spite of having 70–80% if its dialy- Study assessments and end-points sis population on epoetin, the majority of patients still have Study visits occurred at the second week, fourth week, thereafter every haemoglobin (Hb) less than 10 g/dL.14 A cheaper alterna- 4 weeks for efficacy and safety assessments for the duration of the study. tive source of epoetin is therefore needed. With the expiry The primary efficacy variable was change in Hb from baseline to week of the patents for both alpha and beta epoetins in 2004, 12. Safety assessments consisted of monitoring adverse events (AE), biogeneric epoetins may become more widely available regular laboratory monitoring, physical examinations and investigation outside their countries of origin. for pure red cell aplasia when this is suspected. Nevertheless, there are concerns about the quality, clini- cal safety and efficacy of biogeneric products. A recent Statistical methods study15 investigated the pharmaceutical quality of several of these products and found most wanting. Regulatory authori- Sample size was estimated based on the assumption that the standard ties are also raising questions concerning product quality deviation of Hb would be 1.25 g/dL. We accepted the margin of equiva- standards, and clinical safety and efficacy requirements lence of 10.5 g/dL difference in mean change in Hb from baseline to these so-called biosimilar or follow-on biopharmaceutical week 12. For a power of 0.8 and alpha of 0.05 (one sided), the required products must meet.16,17,18 Further, to date, there have not sample size was 78 in each treatment groups. Allowing for 20% drop out been any rigorous comparative efficacy and safety studies rate, the sample size required was therefore 93 per arm. between a biogeneric epoetin and the original product. We The primary end-point was analysed by the mean change in Hb report here one such comparative trial between GerEPO from baseline at the end of the trial. The 95% confidence interval (CI) (NCPC GeneTech Biotechnology Co Ltd, Hebei, China) was used to compare the two treatment groups. The two treatments were considered statistically equivalent if the 95% CI for the difference and Eprex (Janssen Cilag AB, Sollentuna, Sweden). in mean change in Hb from baseline between the two groups was within the range of -0.5 to 0.5 g/dL. Clinical trials of epoetin for renal anaemia19–21 have shown that Hb could be maintained at a level above MATERIALS AND METHODS 10 g/dL in more than 90% of patients. Thus the effect size of epoetin is in excess of 5 g/dL. Specification of 0.5 g/dL as the margin of equiva- We conducted a prospective, randomized, open label clinical trial at 26 lence, which is 10% or less of the effect size, is reasonable.22 centres in Malaysia. The study was conducted in accordance with As this is a therapeutic equivalence trial, the primary analysis set is Declaration of Helsinki and Good Clinical Practice requirements. The the per-protocol population in which all subjects had completed the institutional review board of each site approved the protocol, and all trial.23 The analysis was also performed on an intention-to-treat (ITT) patients gave written informed consent. basis. Study patients RESULTS The inclusion criteria were age between 18 and 70 years, medically Two of the 188 patients enrolled into the trial withdrew stable on chronic haemodialysis, receiving intravenous Eprex for renal consent soon after randomization and was thus excluded anaemia and maintaining Hb level of at least 9 g/dL while on a stable from trial. Of the remaining 186 patients, 93 patients were dose and an adequate iron store (serum ferritin more than 100 mg/L randomized to the Eprex arm and the same number to the and/or transferrin saturation more than 20%). The exclusion criteria were pregnant or nursing woman, poorly controlled hypertension (dias- GerEPO arm (Fig. 1). However, only 92 and 87 subjects on tolic blood pressures more than 110 mmHg), history of seizure disorder, the Eprex and GerEPO arms, respectively, completed the active infection or inflammation, any illness that had required hospi- trial. One patient on the Eprex arm died. Six on the talization within previous month, recent blood transfusion, haemato- GerEPO arm were withdrawn. The reasons were death (one logic abnormalities (haemolysis, microcytosis, thrombocytosis), severe patient), decrease in Hb (two patients), severe hypertension © 2007 The Authors Journal compilation © 2007 Asian Pacific Society of Nephrology
  3. 3. Biosimilar epoetin therapeutic equivalence trial 433 Eligible patients n = 188 Received Did not receive Treatment as Treatment as allocated allocated n = 186 n=2 Treatment Eprex Treatment GerEPO n = 93 n = 93 Withdrawn Completed trial Completed trial Withdrawn Fig. 1 Trial profile. n=1 n = 92 n = 87 n=6 Table 1 Demographic and other baseline characteristics of subjects enrolled in the trial Eprex GerEPO Baseline characteristics n = 93 n = 93 No. (%) male 61 (65) 45 (48) Mean age (years) 49 1 13 49 1 12 Mean body weight (kg) 59.8 1 12.8 57.4 1 12.3 Primary renal disease. No. (%) Unknown 36 (39) 42 (45) Diabetes mellitus 26 (28) 16 (17) Glomerulonephritis 15 (16) 20 (21) Hypertension 10 (11) 15 (16) Obstructive nephropathy 5 (5) 3 (3) Median epoetin dose (IQR) (IU/week) 4000 (4000, 6000) 4000 (4000, 6000) Median epoetin dose (IQR) (IU/kg BW week) 66 (53) 75 (40) Mean Systolic blood pressure (mmHg) 132 1 24 138 1 26 Mean Diastolic blood pressure (mmHg) 75 1 14 76 1 13 Mean Haemoglobin (g/dL) 11.7 1 1.7 11.1 1 1.5 Median Ferritin (mg/L) 667 (416, 880) 638 (354, 1179) Median Transferrin saturation (%) 26 (19, 33) 25 (19, 38) Median Intact PTH (pmol/L) 33.1 (10.8, 73.1) 32.3 (12.2, 83.1) Mean Albumin (g/L) 42 1 5 41 1 4 Values expressed as mean 1 standard deviation, median (IQR), or number (%) of patients. BW, body weight; IQR, interquartile range. (one patient), and two for administrative reasons. Thus baseline to week 12 was 0.2 IU/kg per week in the Eprex 186 patients were included in the ITT analysis, group and 0.1 IU/kg per week in the GerEPO group. The while 179 patients who completed the trial were included median serum ferritin levels were also similar in the two in the per-protocol analysis. The characteristics of the study groups (685 mg/L at week 12 in the Eprex group and 668 mg/L population at baseline are shown in Table 1. There were in the GerEPO group); corresponding to median changes no clinically significant differences between the two from baseline to week 12 of 37 mg/L and 25 mg/L, respec- groups. tively. The median change in transferrin saturation was 12% Mean Hb in both treatment groups declined over time in the Eprex group and 9% in the GerEPO group. Similar (Fig. 2). In the per-protocol population, the mean decline in percentages of patients were administered concomitant iron Hb from baseline to week 12 were -0.47 g/dL in the Eprex treatment in each group (91% in the Eprex and 85% for group while Hb of patients on GerEPO declined by -0.45 g/ GerEPO group). The cumulative mean iron dose was 4062 dL. The mean difference in change in Hb from baseline and 4084 mg in the Eprex and GerEPO groups, respectively. between the two groups was 0.02. The 95% CI of the mean Only four and three patients on Eprex and GerEPO, respec- difference was -0.42 to 0.46, which lies entirely within the tively, had intravenous iron therapy in the course of the trial. prespecified margin of equivalence (Fig. 3). The results of No patient from either group received blood transfusion ITT analysis were similar (Fig. 3). throughout the trial. Nineteen and 17 patients on Eprex Median dose of epoetin at the end of the trial was 4000 IU and GerEPO, respectively, were on angiotensin-converting in both groups. The median change in epoetin dose from enzyme inhibitors, while four and 12 patients, respectively, © 2007 The Authors Journal compilation © 2007 Asian Pacific Society of Nephrology
  4. 4. 434 BL Goh et al. 12.5 Table 2 Adverse events occurring in greater than 1% of patients Eprex GerEPO 10.5 11 11.5 12 n = 93 n = 93 Mean Hb level Adverse events No. (%) No. (%) Hb declined more than 25 (27) 30 (32) 1 g/dL from baseline Hb declined more than 11 (12) 11 (12) 2 g/dL from baseline Hb declined more than 5 (5) 5 (5) 10 3 g/dL from baseline 0 2 4 6 8 10 12 Hypertension or Blood 19 (20) 10 (11) Week pressure increased Hypotension 4 (4) 0 (0) Fig. 2 Mean (95% confidence interval, CI) Hemoglobin levels Hyperkalaemia 4 (4) 2 (2) (g/dL) by treatment group over time (per-protocol population). Headache 0 (0) 5 (5) ( ) Mean for Eprex, ( ) mean for GerEPO, ( ) Pyrexia 0 (0) 3 (3) 95% CI for Eprex, ( ) 95% CI for GerEPO. Influenza like illness 0 (0) 3 (3) Pruritus 0 (0) 3 (3) Back pain 0 (0) 2 (2) Dyspnoea 0 (0) 2 (2) Cough 0 (0) 2 (2) Fatigue 0 (0) 2 (2) ITT 0.01 [–0.42, 0.44] Palpitations 0 (0) 2 (2) Vomiting 0 (0) 2 (2) pyrexia, flu-like illness and pruritus. On the other hand, PP 0.02 [–0.42, 0.46] more patients on Eprex were reported to have increased blood pressure, hypotension and hyperkalemia. One patient on Eprex died of acute myocardial infarction while another patient on GerEPO died of acute pulmonary oedema. In the GerEPO group, one patient each developed pneumonia, –1 –0.5 0 0.5 1 Mean change in Hb from baseline at week 12 venous occlusion, atrial fibrillation and hypertensive crisis, low Hb and platelet count. In the Eprex group, one patient Fig. 3 Treatment group difference in mean change in Hb from each developed cerebrovascular accident, acute cholecysti- baseline (95% confidence interval) over time. Dotted line indi- tis and pleural effusion. cates the prespecified margin of equivalence (10.5 g/dL Hb). Data for per-protocol population (n = 179) and ITT population (n = 186). DISCUSSION This study has shown that GerEPO was statistically equiva- lent to Eprex in terms of Hb response on treatment. To our were on angiotensin receptor blockers during the trial. No knowledge this is the first ever published comparative trial patients were on ascorbic acid or pentoxyfylline. between a biogeneric product and its innovator counterpart There were a total of 115 AE reported in the trial. The to demonstrate therapeutic equivalence. The design and most common AE were increase blood pressure (29 events, conduct of such a trial has been challenging, and high- 15.6%), hyperkalaemia (six events, 3.2%), hypotension lighted several difficult issues. (five events, 2.7%) followed by headache (five events, There was concern regarding equitable recruitment of 2.7%). A total of 9.6% of events were reported as related trial subjects as economically disadvantaged patients might (causal relationship reported as ‘very likely’, ‘likely’ or ‘pos- be unduly influenced to participate in the trial. To minimize sibly’) to the study treatment and 90.4% as not related. this, the consent process was closely monitored and ethical Table 2 summarizes the commoner reported AE. A approval for conducting the trial was obtained from ethics similar number of patients in each treatment group had review board of each institution. experienced decline in Hb during the course of the trial. Another unexpected challenge was the observed decline However, two patients on GerEPO were withdrawn due to in Hb in both arms of the trial. We had originally surmised the decline in Hb level but none in the Eprex group. More that in the event a biogeneric epoetin is not therapeutically patients on GerEPO had reported AE such as headache, equivalent to Eprex on a unit-to-unit basis, this would show © 2007 The Authors Journal compilation © 2007 Asian Pacific Society of Nephrology
  5. 5. Biosimilar epoetin therapeutic equivalence trial 435 up as decline in Hb in the course of the trial. This is pre- jected to the ultimate test in the clinics. Manufacturers of mised on patients being on stable epoetin dose with a stable biogenerics should be more forthcoming to subject their Hb. Clearly, this was not to be. As a group, patients in this products to the test, and manufacturers of innovator product trial reflected the real-life resource limited setting where ought to be more cooperative. epoetin dosing is subtherapeutic (median dose was 4000 IU/ In conclusion, this trial has successfully demonstrated week), well below the dosing levels prevailing in developed therapeutic equivalence between a biogeneric epoetin, countries.10–13 The objective of anaemia therapy in this GerEPO and Eprex with respect to Hb response for patients setting is primarily to avoid blood transfusion rather than with Hb in the subtherapeutic target range as is common in any expectation of deriving the full benefits of epoetin this study population. therapy. Many of these patients would be dosed erratically However, while the results are convincing with respect and would require ‘booster’ epoetin dose from time to time to efficacy measured in terms of Hb response to epoetin, the to avoid blood transfusion. This was discouraged by the trial duration of trial treatment was only 3 months, which is protocol. Add to that the inherent substantial variability in insufficient for safety evaluation. Following demonstration Hb among haemodialysis patients24 and the effect of regres- of equivalent efficacy, we have just initiated a long-term sion to the mean25 which will be observed in subsequent cohort safety and efficacy study where 2000 subjects will be repeat measurements when patients are selected based on enrolled and treated for up to 5 years to track the occurrence Hb above a threshold, their combined effect is the observed of pure red cell aplasia and other AE, to track batch-to- decline in Hb in both treatment groups. batch variability in product quality and efficacy, and to The manufacturer of GerEPO and the study sponsors also demonstrate the ability to reach recommended therapeutic have issues concerning the trial design. Although blinding target. using the double dummy technique would be highly desir- able for this trial, we were unable to obtain placebo prefilled syringes from the manufacturer of the innovator product. ACKNOWLEDGEMENTS This did not affect our primary end-point, Hb level, as the determination was performed by a central laboratory The authors thank NCPC GeneTech Biotechnology Co. blinded to treatment allocation. However, the lack of blind- Ltd and its local associate for providing the study medica- ing may have introduced bias in dosing decisions, safety tions and an unrestricted grant to support this research. reporting and patient withdrawal, which potentially could We thank the Department of Nephrology Kuala Lumpur invalidate the trial or render its results not interpretable. Hospital for supporting this work; and the Clinical Research Some of these biases were borne out in practice. More Centre of the Health Ministry for its role as the independent patients on GerEPO in the trial had reported AE due to clinical research organization for this trial. We also wish to subjective symptoms, and more patients were withdrawn thank the Director-General of Health Malaysia for encour- from the GerEPO arm on account of AE or decreased Hb aging the work and for granting permission to publish this when objectively, both arms showed similar decline in Hb. paper. We had anticipated this potential for bias. Throughout the trial, Hb response was closely monitored centrally, and REFERENCES investigators were actively discouraged from increasing patients’ epoetin dose or to withdraw patients. As a result, 1. Eschbach JW. The anaemia of chronic renal failure: Pathophysi- we had an acceptably low rate of withdrawal even on the ology and the effects of recombinant erythropoietin. Kidney Int. 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