The regulator’s perspective: How should new therapies and follow-on products for MS be clinically evaluated in the future?

Abstract

Background:

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.

Keywords

Get full access to this article

View all access options for this article.

References

Mattke

Taylor

Hunter

. The new neglected diseases? Policy interventions are needed to encourage CNS drugs development. RAND, 2013, pp. 1–14.

Hauser

Chan

Oksenberg

. Multiple sclerosis: Prospects and promise. Ann Neurol 2013; 74: 317–327.

Kobelt

Berg

Lindgren

. Costs and quality of life of patients with multiple sclerosis in Europe. J Neurol Neurosurg Psychiatry 2006; 77: 918–926.

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).

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).

The Pan-European multiple sclerosis multi-stakeholder colloquia. Calls to action, https://dl.dropboxusercontent.com/u/7697080/MS%20Colloquium%202015/Calll_to_action2015.pdf (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.

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.

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.

Polman

Reingold

Barkhof

. Ethics of placebo-controlled clinical trials in multiple sclerosis: A reassessment. Neurology 2008; 70: 1134–1140.

13.

Balabanov

Haas

Elferink

. Addressing the regulatory and scientific challenges in multiple sclerosis – A statement from the EU regulators. Mult Scler 2014; 20: 1282–1287.

14.

Lesaffre

. Superiority, equivalence, and non-inferiority trials. Bull NYU Hosp Jt Dis 2008; 66: 150–154.

15.

Cohen

Reingold

Polman

. Disability outcome measures in multiple sclerosis clinical trials: Current status and future prospects. Lancet Neurol 2012; 11: 467–476.

16.

Cutter

Baier

Rudick

. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999; 122(Pt 5): 871–882.

17.

Rothwell

McDowell

Wong

. Doctors and patients don’t agree: Cross sectional study of patients’ and doctors’ perceptions and assessments of disability in multiple sclerosis. BMJ 1997; 314: 1580–1583.

18.

Weinges-Evers

Brandt

Bock

. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler 2010; 16: 1134–1140.

19.

Deloire

MSA

Bonnet

Salort

. How to detect cognitive dysfunction at early stages of multiple sclerosis? Mult Scler 2006; 12: 445–452.

20.

Baumstarck

Pelletier

Butzkueven

. Health-related quality of life as an independent predictor of long-term disability for patients with relapsing-remitting multiple sclerosis. Eur J Neurol 2013; 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.

22.

Filippi

Agosta

. Imaging biomarkers in multiple sclerosis. J Magn Reson Imaging 2010; 31: 770–788.

23.

Filippi

Preziosa

Copetti

. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology 2013; 81: 1759–1767.

24.

Agosta

Rovaris

Pagani

. Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis. Brain 2006; 129: 2620–2627.

25.

Jacobsen

Hagemeier

Myhr

. Brain atrophy and disability progression in multiple sclerosis patients: A 10-year follow-up study. J Neurol Neurosurg Psychiatry 2014; 85: 1109–1115.

26.

Fisher

Rudick

Simon

. Eight-year follow-up study of brain atrophy in patients with MS. Neurology 2002; 59: 1412–1420.

27.

Lukas

Sombekke

Bellenberg

. Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients. Radiology 2013; 269: 542–552.

28.

Vermersch

Berger

Gold

. The clinical perspective: How to personalise treatment in MS and how may biomarkers including imaging contribute to this? Mult Scler 2016; S2: 18–33.

29.

Coles

Twyman

Arnold

. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839.

30.

Coles

Fox

Vladic

. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78: 1069–1078.

31.

Costelloe

Jones

Coles

. Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis. Expert Rev Neurother 2012; 12: 335–341.

32.

Eichler

Oye

Baird

. Adaptive licensing: Taking the next step in the evolution of drug approval. Clin Pharmacol Ther 2012; 91: 426–437.

33.

Crommelin

Bermejo

Bissig

. Pharmaceutical evaluation of biosimilars: Important differences from generic low-molecular-weight pharmaceuticals. EJHP-S 2005; 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.

Schellekens

Klinger

Mühlebach

. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol 2011; 59: 176–183.

38.

Crommelin

DJA

de Vlieger

JSB

Weinstein

. Different pharmaceutical products need similar terminology. AAPS J 2014; 16: 11–14.

39.

Borchard

Flühmann

Mühlebach

. 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 Pharmacol 2012; 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.

Rottembourg

Kadri

Leonard

. Do two intravenous iron sucrose preparations have the same efficacy? Nephrol Dial Transplant 2011; 26: 3262–3267.

42.

Clark

. Are all parenteral iron sucrose preparations identical or just similar? Hospital Pharmacy Europe, October 2011, 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.

Aharoni

. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun Rev 2013; 12: 543–553.

45.

Varkony

Weinstein

Klinger

. The glatiramoid class of immunomodulator drugs. Expert Opin Pharmacother 2009; 10: 657–668.

46.

Johnson

. Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: An update. Expert Opin Drug Metab Toxicol 2010; 6: 643–660.

47.

De Stefano

Filippi

Confavreux

. 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 Scler 2009; 15: 238–243.

48.

Ramot

Rosenstock

Klinger

. Comparative long-term preclinical safety evaluation of two glatiramoid compounds (glatiramer Acetate, Copaxone(R), and TV-5010, protiramer) in rats and monkeys. Toxicol Pathol 2012; 40: 40–54.

49.

Crommelin

DJA

Shah

Klebovich

. The similarity question for biologicals and non-biological complex drugs. Eur J Pharm Sci 2015; 76: 10–17.

50.

Towfic

Funt

Fowler

. Comparing the biological impact of glatiramer acetate with the biological impact of a generic. PLoS ONE 2014; 9: e83757.

51.

Kolitz

Hasson

Towfic

. Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids. Sci Rep 2015; 5: 10191.

52.

Simmons

Tan

Tenen

. Monocyte antigen CD14 is a phospholipid anchored membrane protein. Blood 1989; 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).

54.

FDA 2015-P1050. Citizens petition denial letter from CDER to Teva Pharmaceuticals, FDA 2015, pp. 1–43, http://www.noticeandcomment.com/Citizen-Petition-Denial-Letter-From-CDER-to-Teva-Pharmaceuticals-fn-259296.aspx (2015, accessed 3 December 2015).

55.

Carrá

Macias Islas

Tarulla

. Biological and nonbiological complex drugs for multiple sclerosis in Latin America: Regulations and risk management. Expert Rev Neurother 2015; 15: 597–600.