Product licences for alemtuzumab and multiple sclerosis

Abstract

Alemtuzumab was licensed for the treatment of active relapsing-remitting multiple sclerosis in the European Union on Sept 17, 2013; and, to date, in at least three other countries (Canada, Australia, and Mexico) with several other applications pending. On Nov 13, 2013, the US Food and Drug Administration (FDA) Advisory Committee voted by a majority that there is sufficient evidence for superiority of alemtuzumab over interferon beta-1a and that the safety profile of the drug does not preclude its approval. But on Dec 27, 2013, the US FDA decided not to license alemtuzumab on the basis that the sponsor, Genzyme, had not submitted evidence from adequate and well-controlled studies demonstrating that the putative benefits of alemtuzumab outweigh its adverse effects.We write as clinicians who, since 1991, have assessed alemtuzumab as a potential treatment for multiple sclerosis, and as investigators based outside the USA participating in the clinical trials programme from 2002. We have complete confidence in the results of the phase 2 CAMMS223 study and phase 3 CARE-MS1 and CARE-MS2 studies, published in The New England Journal of Medicine and The Lancet.1Coles AJ Compston DA Selmaj KW et al.Alemtuzumab vs interferon beta-1a in early multiple sclerosis.N Engl J Med. 2008; 359: 1786-1801Crossref PubMed Scopus (828) Google Scholar, 2Cohen JA Coles AJ Arnold DL et al.Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.Lancet. 2012; 380: 1819-1828Summary Full Text Full Text PDF PubMed Scopus (858) Google Scholar, 3Coles AJ Twyman CL Arnold DL et al.Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.Lancet. 2012; 380: 1829-1839Summary Full Text Full Text PDF PubMed Scopus (859) Google Scholar The FDA considers the decision not to mask patients with respect to randomisation, relying solely on rater-blinding for assessment, to have biased results in favour of alemtuzumab versus interferon beta-1a thereby undermining all clinical and radiological outcomes in each of these clinical trials. The FDA was informed from the outset that their recommendation of a double-dummy design with effective double-blinding is not possible for alemtuzumab because of its well-publicised and predictable acute infusion reactions.4Moreau T Coles A Wing M et al.Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis.Brain. 1996; 119: 225-237Crossref PubMed Scopus (246) Google Scholar Almost no clinical trial in multiple sclerosis is effectively double-blinded and reliance on rater-blinding is routine in this context.5US, FDA2013 Meeting Materials, Peripheral and Central Nervous System Drugs Advisory Committee.http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm346581.htmDate: November 13, 2013Google Scholar Many commentators accept that alemtuzumab has easily cleared a hurdle that no other agent has even attempted, demonstrating superiority versus an active comparator in one phase 2 and two phase 3 clinical trials.The decision made by the FDA now prevents patients in the USA from access to an important treatment option in multiple sclerosis that offers high efficacy with infrequent dosing; it risks those who obtain treatment outside the USA not benefiting from the effective and well-rehearsed risk management scheme; and it is likely to demotivate clinician scientists and the pharmaceutical industry from committing to future long-term multiple sclerosis research programmes in the USA if the Agency cannot be trusted to judge evidence objectively and in the interests of patients with a potentially disabling disease.We would be surprised if people with multiple sclerosis living in the USA and their professional representatives acquiesce with insistence on trial design that cannot be applied with integrity to the treatment of multiple sclerosis with alemtuzumab, and we doubt whether they will leave unchallenged a decision that sidelines doctors and US citizens from taking informed decisions on treatment options for a disease that still has important unmet therapeutic needs. We urge the FDA to re-evaluate and revoke this decision.ACol and ACom have received honoraria and travelling expenses for speaking at Genzyme-sponsored meetings. Genzyme have partly funded their research and made a donation to the University of Cambridge. Alemtuzumab was licensed for the treatment of active relapsing-remitting multiple sclerosis in the European Union on Sept 17, 2013; and, to date, in at least three other countries (Canada, Australia, and Mexico) with several other applications pending. On Nov 13, 2013, the US Food and Drug Administration (FDA) Advisory Committee voted by a majority that there is sufficient evidence for superiority of alemtuzumab over interferon beta-1a and that the safety profile of the drug does not preclude its approval. But on Dec 27, 2013, the US FDA decided not to license alemtuzumab on the basis that the sponsor, Genzyme, had not submitted evidence from adequate and well-controlled studies demonstrating that the putative benefits of alemtuzumab outweigh its adverse effects. We write as clinicians who, since 1991, have assessed alemtuzumab as a potential treatment for multiple sclerosis, and as investigators based outside the USA participating in the clinical trials programme from 2002. We have complete confidence in the results of the phase 2 CAMMS223 study and phase 3 CARE-MS1 and CARE-MS2 studies, published in The New England Journal of Medicine and The Lancet.1Coles AJ Compston DA Selmaj KW et al.Alemtuzumab vs interferon beta-1a in early multiple sclerosis.N Engl J Med. 2008; 359: 1786-1801Crossref PubMed Scopus (828) Google Scholar, 2Cohen JA Coles AJ Arnold DL et al.Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.Lancet. 2012; 380: 1819-1828Summary Full Text Full Text PDF PubMed Scopus (858) Google Scholar, 3Coles AJ Twyman CL Arnold DL et al.Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.Lancet. 2012; 380: 1829-1839Summary Full Text Full Text PDF PubMed Scopus (859) Google Scholar The FDA considers the decision not to mask patients with respect to randomisation, relying solely on rater-blinding for assessment, to have biased results in favour of alemtuzumab versus interferon beta-1a thereby undermining all clinical and radiological outcomes in each of these clinical trials. The FDA was informed from the outset that their recommendation of a double-dummy design with effective double-blinding is not possible for alemtuzumab because of its well-publicised and predictable acute infusion reactions.4Moreau T Coles A Wing M et al.Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis.Brain. 1996; 119: 225-237Crossref PubMed Scopus (246) Google Scholar Almost no clinical trial in multiple sclerosis is effectively double-blinded and reliance on rater-blinding is routine in this context.5US, FDA2013 Meeting Materials, Peripheral and Central Nervous System Drugs Advisory Committee.http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm346581.htmDate: November 13, 2013Google Scholar Many commentators accept that alemtuzumab has easily cleared a hurdle that no other agent has even attempted, demonstrating superiority versus an active comparator in one phase 2 and two phase 3 clinical trials. The decision made by the FDA now prevents patients in the USA from access to an important treatment option in multiple sclerosis that offers high efficacy with infrequent dosing; it risks those who obtain treatment outside the USA not benefiting from the effective and well-rehearsed risk management scheme; and it is likely to demotivate clinician scientists and the pharmaceutical industry from committing to future long-term multiple sclerosis research programmes in the USA if the Agency cannot be trusted to judge evidence objectively and in the interests of patients with a potentially disabling disease. We would be surprised if people with multiple sclerosis living in the USA and their professional representatives acquiesce with insistence on trial design that cannot be applied with integrity to the treatment of multiple sclerosis with alemtuzumab, and we doubt whether they will leave unchallenged a decision that sidelines doctors and US citizens from taking informed decisions on treatment options for a disease that still has important unmet therapeutic needs. We urge the FDA to re-evaluate and revoke this decision. ACol and ACom have received honoraria and travelling expenses for speaking at Genzyme-sponsored meetings. Genzyme have partly funded their research and made a donation to the University of Cambridge. Supplementary Material Download .pdf (.06 MB) Help with pdf files Supplementary appendix Download .pdf (.06 MB) Help with pdf files Supplementary appendix FDA's rejection of alemtuzumab divides neurologistsHas the US Food and Drug Administration asked for an impossible trial, or protected patients with multiple sclerosis from a drug with unknown benefits and clear risks? Asher Mullard investigates. Full-Text PDF