Pros and cons in MS treatment: Are new drugs safe? Dr. Vladimiro Sinay

Pros and cons in MS treatment: Are new drugs safe? Dr. Vladimiro Sinay

Seguro que nada es seguro (Nothing is safe, for sure)

Reason 1 to prescribe new drugs: An extensive menu allows us to evaluate specific safety risks for each padent according to their safety profile

Reason 2 to prescribe new drugs: Treatments with different mechanisms of acdon give us alternadves to safety issues

Reason 3 to prescribe new drugs: Proven efficacy, MulDple Sclerosis is unsafe

Reason 4 to prescribe new drugs: The future is not safe Variability1,2 Uncertain evolu'on Variable DMD response Imperfect assessment of disability and progression of the disease1,3 EDSS focus on ambula'on Clinical surrogate markers with variable valida'ons Prognos'c factors not completely known1 What is an acceptable relapse rate in DMD treated pa'ents? How many MRI lesions are bad prognos'c factor? Many defini'ons, but we can't feel confident un'l now.1 1. Freedman MS, et al. Curr Med Res Opin. 2009;25:2459-2470. 2. Freedman MS, et al. Can J Neurol Sci. 2004;31:157-168. 3. Rieckmann P, et al. Ther Adv Neurol Dis. 2008;1:181-192. 6

Reason 5 to prescribe new drugs: Every drug may fail, it is unsafe to have no alternadve Up to 74% Up to 74% of pa'ents suffer a clinical relapse during the first 2 years of treatment.1,2,a Relapse s Up to 21% Up to 21% of pa'ents develop at least 1 point of EDSS progression during the first 2 years of treatment.3,4,b EDSS Progression a Datos de ensayos randomizados, doble- ciego, controlados a placebo de 372 (IFNβ Mul'ple Sclerosis Study Group) y 560 (PRISMS Study Group) pacientes con EM a brotes y remisiones (RRMS). b Datos de ensayos randomizados, doble- ciego, controlados a placebo de 301 (Mul'ple Sclerosis Collabora've Research Group) y 251 (Copolymer 1 Study Group) pacientes con RRMS. 1. IFNβ Mul'ple Sclerosis Study Group. Neurology. 1993;43:655-661. 2. PRISMS Study Group. Lancet. 1998;352:1498-1504. 3. Jacobs LD, et al. Ann Neurol. 1996:39:285-294. 4. Johnson KP, et al. Neurology. 1995;45:1268-1276. 7

Reason 6 to prescribe new drugs: It is unsafe if you do not act before a therapeudc failure Treatment failure carries to SP Treatment failure affects survival Goodin DS, et al. Neurology 2012;78:1315 1322. Pfleger CC, et al. Mult Scler 2010; 16:121 126 Trojano M, et al. Ann Neurol. 2007;61:300 306.. Treatment failure affects employment

Reason 7 to prescribe new drugs: It is unsafe not to treat early 100 Time to conversion to EDSS 4 P = 0.74 P < 0.001 75 75 PaDents (%) PaDents (%) Conversion from EDSS 4 to 6 100 RRMS 50 25 50 Progressive MS 25 PPMS RRMS 0 0 10 20 30 Years 40 0 0 5 10 15 20 Years aver EDSS 4 Once EDSS 4 is reached, progression is faster and it is not modified by relapses Confavreux C, et al. N Engl J Med. 2000;343:1430-1438.

Reason 8 to prescribe new drugs: A Dred padent is unsafe Oral drugs Less injections

But, I can hear Dr. Fernandez Liguori s words

Reason 1 not to be concerned about new drugs: Pharmacological research is not what it was

Reason 2 not to be concerned about new drugs: False alarms The number of fake security alerts increases. Every warning needs to be verified by the regulatory authorities. Efficacy results of observational studies should always be checked, but safety reports are not measured by the same yardstick. The burden of proof is reversed

Reason 3 not to be concerned about new drugs: Media bias Public and Medical Press avoid the NO NEWS. An informa'on bias exists and replica'on increases risk percep'on.

Reason 4 not to be concerned about new drugs: They are new and we have learned We have compared them against first generation drugs We have seen what happens if we change from first generation drugs We have used new diagnostic criteria in modern trials We have learned that more is not always better We have adopted safety measures

Reason 5 not to be concerned about new drugs: We know their safety profile and we have adopted prevendve and correcdve measures

Reason 6 not to be concerned about new drugs: Safety programs have been developed Pre-marketing studies are carried out in limited number of patients: The rule of three In order to confirm SAEs that occur as 1 event per 2,000 patients treated we need to treat: 6,000 patients for 1 case 9,600 patients for 2 cases 13,000 patients for 3 cases The number of patients involved in pre-marketing studies has increased, but it is still limited in comparison with the exposure to the drug in the post-marketing phase

Reason 7 not to be concerned about new drugs: Safe drugs obsession, safe drug is not the same as zero risk drug Not even pa'ents seek this Risk acceptance to Natalizumab Montalvan PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82796

However, there is sdll work to do We should improve risk/ benefit measures. And we need to develop decision making guidelines depending on different scenarios. Regulatory authorities should clearly set what is an unacceptable, worrying or negligible risk for each disease. We actually know that patients accept higher risks than we suspect. We have to learn to accept patients decisions and opinions. There is no battle between pharmaceutical companies and regulatory agencies for efficacy against safety. Both owe obligations to the two sides of the same coin.

Pros and cons in MS treatment: Are new drugs safe? Dr. Vladimiro Sinay