Scientificbasis of European registration of biosimilarinfliximab Dr. Miklos Sebeszta MD PhD SeniorMedicalConsultant
Costs of treatment The average daily treatment cost for a small molecule brand drug is around $1 per day (with small molecule generic drug costing cents per day), fora branded biopharmaceutical is $22 per day a breast cancer patient’s average cost for Herceptin® (trastuzumab) is $37,000, the treatment costs for rheumatoid arthritis or Crohn disease with Humira® (adalimumab) is $50,000 per year This situation is unsustainable and may lead to limited access whereby only the more severely affected patients are treated with these agents when disability might be prevented or limited with earlier intervention. Access for even the current patients treated with biologics can become restricted due to costs. mAbs 3:2, 212-220; March/April 2011
Biosimilars: what clinicians should know Despite an establishedlegal pathway for biosimilars in the EuropeanUnion since 2005and increasingand detailed regulatory guidance on datarequirements for their development andlicensing, many cliniciansare reluctant to consider biosimilarsas a treatment option for theirpatients. A clearunderstandingof the scientific principles ofthe biosimilar concept and access to unbiasedinformationonlicensedbiosimilarsare important for physicians to make informed and appropriatetreatmentchoicesfortheirpatients. BLOOD, 20 DECEMBER 2012 VOLUME 120, NUMBER 26
Quality – differencesneedto be justified Because of inherent variability of the biologic system and themanufacturing process, any resulting biological will display acertain degree of variability (microheterogeneity), even betweendifferent batches of the same product. Because of unavoidabledifferences in the manufacturing processes, a biosimilar and therespective originator product, the reference product, will not beentirely identical. However, the amino acid sequence is expected tobe the same, and only small differences in the microheterogeneitypattern of the molecule may be acceptable. Any differences found willneed to be explained and justified with regard to the potentialimpact on the clinical performance of the biosimilar. A biosimilarneeds to be developed based on a more extensivehead-to-head comparison with the reference product, to ensureclose resemblance in physicochemical and biologic characteristics,safety, and efficacy. European Medicines Agency, Committee for MedicinalProducts for Human Use. Guideline on similar biological medicinal products containingbiotechnology-derived proteins as active substance:quality issues. http://www.ema.europa. eu/pdfs/human/biosimilar/4934805en.pdf.
The comparabilityexercise The concept of comparabilityallows manufacturing changes to occur without having toundertake a completely new product-development program. Comparability protocols were developed in the United States,through guidance, as a mechanism to provide input to theFDA as well as assurance to the sponsor that, should there be amanufacturing change, the FDA could determine whether thepre- and postchange products were sufficiently similar (“highlysimilar,” as described in the BPCIA) for the purposes of ongoingmarketing under the same label. This regulatoryinitiative evolved to become the basis for ICH Q5E, adoptedin the highly regulated markets in the mid-2000s. Biologicsoften have a shelf life of just 1–2 years,the original product could be on the market simultaneously withthe newer one
Comparison of the different pre- and post-change batches of Rituxan/Mabthera. The tested products remained on the marketwith unaltered labels in the tested timeframe, indicating the observed changes werepredicted to not result in an altered clinicalprofile nature biotechnology volume 29 number 4 april 2011
Comparability ICH Guidelinetopic Q5E It should be emphasized that the scientificprinciples underlying the comparability exercise for biosimilarsarethe same as those for changes in the manufacturing process of agiven biological, for which guidance and experience already exist. However, because the biosimilar will be produced by a differentmanufacturer, the data requirements for demonstration of biosimilaritywill usually be more extensive than for demonstration ofcomparability of a given biological before and after manufacturingchanges by the same manufacturer. ICH Guideline topic QE5: Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process. http://www.ich.org/products/guidelines/quality/article/ quality-guidelines.html
Comparabilityexercisein US The FDA, unlikethe EMA*, does not publicly note the use of comparability in theregulatory record. *European Public Assessment Report In the United States,therefore, patients and their providers may never know that amanufacturing change has occurred, let alone the extent of thechange. Nonetheless, the prechange and postchangeproductscan be assumed to be equally safe, pure, and potent, based onthe FDA review of the analytical data (or any requested preclinicalor clinical studies)that supported the comparabilitydetermination. Therefore, these products are interchangeable, andextrapolation between all indications always occurs irrespectiveof whether themechanism of action is known. Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012
Clinicalaspects of biosimilardevelopment The focus of biosimilardevelopmentis not to establish patient benefit per se- this has already been donefor the originator product - but to convincingly demonstrate highsimilarity to the reference product as basis for relying, in part, on itsefficacy and safety experience. For these reasons, the study design,study population, and/or end points used in studies comparing thebiosimilarwith the reference product may be different from thosepreviously used to establish therapeutic benefit of the reference product Arepetition of the entire development program of thereference product is scientifically not necessary and could even beconsidered unethical. BLOOD, 20 DECEMBER 2012 VOLUME 120, NUMBER 26
Therapeuticequivalence In a statistical and regulatory sense, therapeutic equivalenceinfers that the test drug does not have better or worse efficacy thanthe reference product, thus allowing the use of the same dosage forthe same indication, as is intended for biosimilars. When definingcomparability margins, clinical considerations need to be taken intoaccount; the selected margins should represent the largest differencein efficacy that would not matter in clinical practice.Treatment differences within these margins would thus be acceptablebecause they have no clinical relevance. The principles ofmargin selection are not unique to biosimilar testing but are used inany clinical trial comparing treatment alternatives or prechangeandpostchangeproduct in case a biological has undergone a change in itsmanufacturing process and clinical data are required for assessment ofcomparability.
Immunogenicity Immunogenicity is important for all biologics and is thereforenot a unique issue for biosimilars (and is already a considerationin ICH Q5E). To date, there has been no report ofa biosimilar on the market being associated with any unusualor unexpected adverse events as compared with the relevantreference product Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012
Equivalence study comparing CT-P13 with Infliximab in AS: PLANETASA randomized, double-blind, phase 1 study demonstrates equivalence in pharmacokinetics, safety, and efficacy of CT-P13 and Remicade in patients with AnkylosingSpondylitis (AS)
Analytical Design # confidence interval *Seven patients from fraudulent study center were excluded in all-randomized population *ANCOVA = analysis of covariance; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index
Study Design / Inclusion Criteria • Study population: • Active AS diagnosed by modified 1984 New York criteria for ≥3 months prior to screening Screening, N=370 Randomized, N=250 CT-P13 (5 mg/kg IV), N=125 Infliximab (5 mg/kg IV), N=125 Primary endpoint Week 30 (N=116) Week 30 (N=113) Up to Week 54 (N=104) Up to Week 54 (N=106) Dose loading & maintenance phase Dose loading & maintenance phase • Dose loading phase: Week 1, 2 and 6 • Maintenance phase: Week 14, 22, 30, 38, 46 and 54 • Dose schedule
Pharmacokinetics • Mean serum concentration of CT-P13 and INX vs. time (Week 22) • - Pharmacokinetic Population Infusion for Dose 6 Infusion for Dose 5
Pharmacokinetics • Mean serum concentration of CT-P13 and INX vs. time (dose 1 to 9) • - Pharmacokinetic Population
Efficacy: ASAS20 response rates ITT Population • The proportion of patients achieving ASAS20 responses at Week 14 , 30 and 54 was analysed by a logistic regression approach, with treatment as a fixed effect and region / baseline BASDAI score as covariates. Treatment effect was estimated by calculating the odds ratio and 95% CI.
Immunogenicity * Samples for 1 patient in CT-P13 group and 2 patients in Remicade group were not obtained for immunogenicity at screening visit Assessed by Electrochemiluminescence
Equivalence study comparing CT-P13 with infliximab in active RA: PLANETRAA randomized, double-blind, phase 3 study demonstrates equivalence in pharmacokinetics, safety, and efficacy of CT-P13 and Remicade in patients with active Rheumatoid Arthritis (RA)
Analytical Design # Confidence Interval *Eleven patients from fraudulent study center were excluded in all randomized population
Efficacy: ACR20 Primary endpoint: ACR20 at Week 30 ACR20 at Week 54 Equivalence margin -15 +15 +10 -5 CT-P13 result +13 -3 CT-P13 result (95% CI)
Immunogenicity * Samples for 1 patient in CT-P13 group and 2 patients in INX group were not obtained for immunogenicity at ‘screening visit’
Open label study Extension Study of CT-P13 1. Long term efficacy and safety 2. Comparison of efficacy and safety between - Continuing CT-P13 and - Switching from Infliximab to CT-P13
Trial Profiles: AnkylosingSpondylitis : Randomized (N=250) PLANETAS Study CT-P13 1.1 (54-week main study) CT-P13 (3 mg/kg) (n=125) INX (3 mg/kg) (n=125) Completed (n=106) Completed (n=104) PLANETAS Study CT-P13 1.3 (Extension study) Switched from INX to CT-P13 (n=86) Maintained with CT-P13 (n=88) Completed (n=81) Completed (n=77)
ASAS20 and ASAS40 Maintenance group Switch group Proportion of patient (%) ASAS20 ASAS40 ITT population
Immunogenicity 54-week main Study Extension Study Positive for ADA (%)
Trial Profile: Rheumatoid Arthritis : Randomized (N=606) PLANETRA Study CT-P13 3.1 (54-week main study) CT-P13 (3 mg/kg) (n=302) INX (3 mg/kg) (n=304) Completed (n=233) Completed (n=222) PLANETRA Study CT-P13 3.2 (Extension study) Switched from INX to CT-P13 (n=144) Maintained with CT-P13 (n=158) Completed (n=133) Completed (n=128)
ACR20 Maintenance group Switch group CI: −0.69%, 0.13% CI: −0.10%, 0.09% CI: −0.17%, 0.03% Response rate (%) ITT population CI, 95% Confidence Interval of treatment difference
Immunogenicity 54-week main Study Extension Study Positive for ADA (%) Week ADA, Anti-Drug Antibodies
Adverse Events *Sum of safety population from AS and RA Extension study TEAEs, Treatment-Emergent Adverse Events; TESAEs, Treatment-Emergent Serious Adverse Events
Conclusions • The INX biosimilar, CT-P13, is equivalent to innovator infliximab in pharmacokinetics and efficacy, and comparable in safety issues including immunogenecity in patients with AS and RA • CT-P13 is effective and well-tolerated over 2 years of treatment in patients with AS and RA • Switching from INX to CT-P13 was also effective and well-tolerated during the second year of these study
Uptake of biosimilar has beenslowerthanexpected The members and experts of the WorkingParty on Similar Biologic Medicinal Productsof the European Medicines Agency (EMA) addresstheseissues. Sincetheimplementationof a biosimilar approval pathway in 2005, several biosimilars,including somatropins, filgrastims, and epoetins, have been licensedand become available in the European Union (EU) An EMA – FDA BiosimilarCluster has been established for scientific discussionbetween the FDA and EMA and facilitation of globaldevelopment of biosimilars. However, uptake of biosimilars in theEuropean market has been slower than expected, which may, atleast partly, be attributed to a lack of trust in the efficacy and safetyof biosimilars as well as their interchangeability with the originatorproduct by both patients and clinicians. DrugDiscovToday. 2012;17(1):63-70.
Innovator/originator products are independent or standalone approvals; biosimilar is approval relative to a reference productInnovator/originator products are independent or standalone approvals; biosimilar is approval relative to a reference Innovator/originator products are independent or standalone approvals; biosimilar is approval relative to a reference
Principles of extrapolation Human safety (including immunogenicity) data are alwaysrequired for biosimilars before approval.Extrapolation of efficacy and safety data to other indications ofthe reference product that have not been investigated during theclinical development of the biosimilar always requires convincingscientific justification, which should address the mechanism ofaction, toxicities, and immunogenicity in each indication of use. Decision-making of the regulatory authority is based on thetotality of the evidence provided by the applicant in support ofbiosimilarity. A risk management plan for post-licensing surveillance isroutinely required for all new drugs, including biosimilars.
Requirementsfordataexptrapolation Similarity with the reference product must be convincinglydemonstrated, based on the totality of the evidence from a thoroughcomparability exercise. Clinicians need to be aware that clinicaldata are not the only cornerstone of a biosimilar development to berelied on.Clinicaldataprovide complementary information (eg, regarding the clinicalrelevance of any observed differences and on immunogenicity If clinical similarity can be shown in a key indication,extrapolation of efficacy and safety data to other indication(s) ofthe reference product may be possible (eg, if the relevant mechanismof action and/or the receptor(s) involved in the extrapolatedindications are the same). thesafetyprofile of the biosimilar must have been properly characterized andunacceptable immunogenicity excluded. Extrapolation of immunogenicitydata is only possible from high-risk to low-risk patientpopulationsand clinicalsettings. BLOOD, 20 DECEMBER 2012 VOLUME 120, NUMBER 26
Steps taken for the assessment of the product The Applicant received scientific advices from the CHMP on 24 September 2009 and 17 December 2009. The scientific advices pertained to quality, non-clinical and clinical aspects of the dossier. The application was received by the EMA on 01 March 2012 The final consolidated List of Questions was sent to the Applicant on 20 July 2012. The Applicant submitted the responses to the CHMP consolidated List of Questions on 16 November 2012. During the CHMP meeting on 14-17 January 2013, the CHMP agreed on a list of outstanding issues to be addressed in writing and/or in an oral explanation by the Applicant. The Applicant submitted the responses to the CHMP List of Outstanding Issues on 29 April 2013 During the CHMP meeting on 27-30 May 2013, the CHMP agreed on a second list of outstanding issues to be addressed in writing by the Applicant. The Applicant submitted the responses to the 2nd CHMP List of Outstanding Issues on 5 June 2013 During the meeting on 27 June 2013, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to Remsima.
CHMP recommendation Based on the robust comparisons of the physicochemical and in vitro and ex vivo biological analyses, Remsima/Flammegiswas considered biosimilar to the reference product Remicade. These data, in combination with clinical data demonstrating pharmacokinetic and therapeutic equivalence in rheumatology conditions, allow for extrapolation to all other indications of Remicade. In addition, the Applicant will conduct a randomised, double-blind, parallel-group comparative study between Remsima/Flammegisand Remicade in patients with active Crohn’s disease. The CHMP concluded that the benefit/risk balance of Remsima as a biosimilar product to Remicade is positive. Several post-authorisation studies and registries, as detailed in the risk management plan, will provide further long-term efficacy data, including in the treatment of inflammatory bowel diseases, and further characterise the long-term safety profile of Remsima/Flammegis
Biologicalactivity As part of the comparability exercise it was shown that all major physicochemical characteristics and biological activities of CT-P13were comparable to those of Remicade. The CHMP noted a small difference in the amount of afucosylated infliximab, translating into a lower binding affinity towards specific Fc receptors and a lower ex vivo antibody-dependent cellular cytotoxicity (ADCC) activity in the most sensitive ADCC assay. This difference was, however, not considered clinically meaningful, as it did not affect the activities of CT-P13 in experimental models regarded as more relevant to the pathophysiological conditions in patients.
The FcyRIIIa and ADCC issue The results of the extensive comparability exercise performed by the Applicant show that the only difference between CT-P13 and Remicade is a lower amount of afucosylated species, which results in lower binding to FcγRIIIa and hence lower ADCC activity in the most sensitive experimental in vitro model using NK cells of patients suffering from Crohn disease (CD) and with high affinity genotypes (V/V and V/F). In blood, the physiological environment, the differences in binding to FcγRIIIa and in ADCC activity are abolished. This has been shown by repeating the experiments in the presence of serum of a CD patient, by using peripheral blood mononuclear cells preparations (rather than isolated NK cells) or by using whole blood
Pre- and post-change batches ofRituxan/Mabtherahavedifferentglycan and ADCC profile – no clinicalconsequence The tested products remained on the marketwith unaltered labels in the tested timeframe, indicating the observed changes werepredicted to not result in an altered clinicalprofile nature biotechnology volume 29 number 4 april 2011
Data forextrapolationto IBD The Applicant has provided convincing evidence that the difference detected in the amount of afucosylated species has no clinically relevant impact on the efficacy and safety of CT-P13, in particular in IBD. Additional in vitro data from human intestinal cells are further supporting extrapolation of the clinical data to IBD Extrapolation to IBD of the clinical data collected in AS is further supported by increasing genetic and immunological evidence of a clinical and histological overlap between gut inflammation in spondyloarthropathies and CD. Arthritis occurs in 9%-53% of patients with IBD and subclinical gut inflammation has been described in up to two-thirds of patients with spondyloarthropathies, with histologic gut inflammation found in 30%-60% of cases. Finally, preliminary clinical data from a very small cohort of 23 patientswith CD (15) or UC (8) indicate similar response to CT-P13 compared with historical data on Remicade. The Applicant has extended the enrolment of IBD patients in this post-marketing surveillance study and will conduct an additional comparative trial versus Remicade in active CD.