Although there is still no cure for multiple sclerosis (MS), the introduction of several innovative drugs with modes of action different from that of the existing drug arsenal and the progress in monitoring disease progression by imaging and using biomarkers are currently causing a knowledge surge. This provides opportunities for improving patient disease management. New therapies are also under development and pose challenges to the regulatory bodies regarding the optimal design of clinical trials with more patient-focused clinical endpoints. Moreover, with the upcoming patent expiry of some of the key first-line MS treatments in Europe, regulatory bodies will also face the challenge of recommending marketing authorisation for generic and abridged versions based on appropriate requirements for demonstrating equality/similarity to the innovator’s product.
Objective:
The goal of this article is to improve the understanding of the relevant guidance documents of the European Medicines Agency (EMA) on clinical investigation of medicinal products and to highlight the issues that the agency will need to clarify regarding follow-on products of first-line MS treatments.
Conclusion:
Today, it is clear that close collaboration between patients, healthcare professionals, regulatory bodies and industry is crucial for developing new safe and effective drugs, which satisfy the needs of MS patients.
MattkeSTaylorEAHunterLE. The new neglected diseases? Policy interventions are needed to encourage CNS drugs development. RAND, 2013, pp. 1–14.
2.
HauserSLChanJROksenbergJR. Multiple sclerosis: Prospects and promise. Ann Neurol2013; 74: 317–327.
3.
KobeltGBergJLindgrenP. Costs and quality of life of patients with multiple sclerosis in Europe. J Neurol Neurosurg Psychiatry2006; 77: 918–926.
4.
The first Pan-European multiple sclerosis multi-stakeholder colloquium: Exploring opportunities and challenges for improving multiple sclerosis management. Agenda, http://2014.ms-colloquium.org/programme (2014, accessed 3 December 2015).
5.
The second Pan-European multiple sclerosis multi-stakeholder colloquium: Accelerating adoption of innovation for better care. Agenda, http://ms-colloquium.org/programme (2015, accessed 3 December 2015).
CPMP/EWP/561/98. Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. EMEA, 2006, pp. 1–12.
8.
EMA/CHMP/CNSWP/257565/2011. Concept paper on the need for revision of guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. EMA, 2011, pp. 1–3.
9.
EMA/CHMP/771815/2011. Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. EMA, 2012, pp. 1–19.
10.
EMA/576938/2013. Workshop on multiple sclerosis 17 October 2013. EMA, 2013, pp. 1–12.
11.
EMA/CHMP/771815/2011. Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. EMA, 2015, pp. 1–20.
12.
PolmanCHReingoldSCBarkhofF. Ethics of placebo-controlled clinical trials in multiple sclerosis: A reassessment. Neurology2008; 70: 1134–1140.
13.
BalabanovPHaasMElferinkA. Addressing the regulatory and scientific challenges in multiple sclerosis – A statement from the EU regulators. Mult Scler2014; 20: 1282–1287.
14.
LesaffreE. Superiority, equivalence, and non-inferiority trials. Bull NYU Hosp Jt Dis2008; 66: 150–154.
15.
CohenJAReingoldSCPolmanCH. Disability outcome measures in multiple sclerosis clinical trials: Current status and future prospects. Lancet Neurol2012; 11: 467–476.
16.
CutterGRBaierMLRudickRA. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain1999; 122(Pt 5): 871–882.
17.
RothwellPMMcDowellZWongCK. Doctors and patients don’t agree: Cross sectional study of patients’ and doctors’ perceptions and assessments of disability in multiple sclerosis. BMJ1997; 314: 1580–1583.
18.
Weinges-EversNBrandtAUBockM. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler2010; 16: 1134–1140.
19.
DeloireMSABonnetMCSalortE. How to detect cognitive dysfunction at early stages of multiple sclerosis?Mult Scler2006; 12: 445–452.
20.
BaumstarckKPelletierJButzkuevenH. Health-related quality of life as an independent predictor of long-term disability for patients with relapsing-remitting multiple sclerosis. Eur J Neurol2013; 20: 907–914.
21.
EMEA/CHMP/EWP/139391/2004. Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products. EMEA, 2005, pp. 1–5.
FilippiMPreziosaPCopettiM. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology2013; 81: 1759–1767.
24.
AgostaFRovarisMPaganiE. Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis. Brain2006; 129: 2620–2627.
25.
JacobsenCHagemeierJMyhrKM. Brain atrophy and disability progression in multiple sclerosis patients: A 10-year follow-up study. J Neurol Neurosurg Psychiatry2014; 85: 1109–1115.
26.
FisherERudickRASimonJH. Eight-year follow-up study of brain atrophy in patients with MS. Neurology2002; 59: 1412–1420.
27.
LukasCSombekkeMHBellenbergB. Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients. Radiology2013; 269: 542–552.
28.
VermerschPBergerTGoldR. The clinical perspective: How to personalise treatment in MS and how may biomarkers including imaging contribute to this?Mult Scler2016; S2: 18–33.
29.
ColesAJTwymanCLArnoldDL. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet2012; 380: 1829–1839.
30.
ColesAJFoxEVladicA. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology2012; 78: 1069–1078.
31.
CostelloeLJonesJColesA. Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis. Expert Rev Neurother2012; 12: 335–341.
32.
EichlerHGOyeKBairdLG. Adaptive licensing: Taking the next step in the evolution of drug approval. Clin Pharmacol Ther2012; 91: 426–437.
33.
CrommelinDBermejoTBissigM. Pharmaceutical evaluation of biosimilars: Important differences from generic low-molecular-weight pharmaceuticals. EJHP-S2005; 11: 11–17.
34.
CHMP/437/04. Guideline on similar biological medicinal products. EMEA, 2005, pp. 1–7.
35.
EMEA/CHMP/BMWP/42832/2005. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues. EMA, 2014, pp. 1–13.
36.
EMA/CHMP/BWP/247713/2012. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). EMA, 2014, pp. 1–9.
37.
SchellekensHKlingerEMühlebachS. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol2011; 59: 176–183.
38.
CrommelinDJAde VliegerJSBWeinsteinV. Different pharmaceutical products need similar terminology. AAPS J2014; 16: 11–14.
39.
BorchardGFlühmannBMühlebachS. Nanoparticle iron medicinal products – Requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies. Regul Toxicol Pharmacol2012; 64: 324–328.
40.
The European commission implementing decision concerning, in the framework of Article 31 of Directive 2001/83/EC of the European Parliament and of the Council, the marketing authorisations of ‘Iron containing intravenous medicinal products’, medicinal products for human use, http://ec.europa.eu/health/documents/community-register/2013/20130913126618/dec_126618_en.pdf (2015, accessed 3 December 2015).
41.
RottembourgJKadriALeonardE. Do two intravenous iron sucrose preparations have the same efficacy?Nephrol Dial Transplant2011; 26: 3262–3267.
42.
ClarkC. Are all parenteral iron sucrose preparations identical or just similar?Hospital Pharmacy Europe, October2011, vol. 58, pp. 1–8.
43.
EMA/CHMP/SWP/100094/2011. Reflection paper on non-clinical studies for generic nanoparticle iron medicinal product applications. EMA, 2011, pp. 1–5.
44.
AharoniR. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun Rev2013; 12: 543–553.
45.
VarkonyHWeinsteinVKlingerE. The glatiramoid class of immunomodulator drugs. Expert Opin Pharmacother2009; 10: 657–668.
46.
JohnsonKP. Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: An update. Expert Opin Drug Metab Toxicol2010; 6: 643–660.
47.
De StefanoNFilippiMConfavreuxC. The results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing-remitting multiple sclerosis. Mult Scler2009; 15: 238–243.
48.
RamotYRosenstockMKlingerE. Comparative long-term preclinical safety evaluation of two glatiramoid compounds (glatiramer Acetate, Copaxone(R), and TV-5010, protiramer) in rats and monkeys. Toxicol Pathol2012; 40: 40–54.
49.
CrommelinDJAShahVPKlebovichI. The similarity question for biologicals and non-biological complex drugs. Eur J Pharm Sci2015; 76: 10–17.
50.
TowficFFuntJMFowlerKD. Comparing the biological impact of glatiramer acetate with the biological impact of a generic. PLoS ONE2014; 9: e83757.
51.
KolitzSHassonTTowficF. Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids. Sci Rep2015; 5: 10191.
52.
SimmonsDLTanSTenenDG. Monocyte antigen CD14 is a phospholipid anchored membrane protein. Blood1989; 73: 284–289.
53.
FDA 2014-P-0933. Citizens petition requesting that FDA refrain from approving any abbreviated new drug application referencing Copaxone® until certain conditions are met, FDA 2014, pp. 1–132, http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0933-0001 (2014, accessed 3 December 2015).
CarráAMacias IslasMATarullaA. Biological and nonbiological complex drugs for multiple sclerosis in Latin America: Regulations and risk management. Expert Rev Neurother2015; 15: 597–600.
