Non-inferiority trials and switch from non-inferiority to superiority

Transcription

1 Non-inferiority trias and switch from non-inferiority to superiority D Costagioa Institut Pierre Louis d épidémioogie et de Santé Pubique Sorbonne Universités, UPMC Univ Paris 06, INSERM

2 Discosures I have received consutancy fees, honoraria, trave grants, and study grants from: HIV board Giead France from 2011 unti december 2015 Consutancy Innavirvax (2015 et 2016) Lectures Janssen-Ciag (2016), Merck-Sharp & Dohme-Chibret (2015) Trave/accommodations/meeting expenses Giead (2014), ViiV(2015), Janssen-Ciag (2014) Grants from Janssen-Ciag (2014), Merck-Sharp & Dohme-Chibret (2017), ViiV (2015)

3 Cinica tria objectives Trias comparing a new treatment (or a strategy) to a reference treatment Showing the superiority of the new treatment Is N better than R? Pre-treated patients with treatment faiure Showing the non-inferiority of the new treatment Is N doing not worse than R? Naive patients Switch studies Showing the equivaence of the new treatment Is N doing as we as (neither better not worse) R? Bio-equivaence (different formuation of the same drug)

4 Definition of non-inferiority N is not doing worse than R L N - R = -10% 0 inferior non-inferior superior

5 Choice of the non-inferiority imit - 1 Cinica decision, not statistica The argest difference cinicay acceptabe < = difference used in superiority trias of the same domain To warrant that the new product is doing better than pacebo in trias with no pacebo

6 A working case in diabetes: HbA1c the risk of death - 1 In diabetes, for new drugs the most common endpoint is HbA1C Non inferiority margin usuay taken as 0.6 % Superiority trias usuay try to demonstrate a 1% difference

7 A working case in diabetes: HbA1c the risk of death - 2 Each 1% reduction in updated mean HbA1c was associated with reductions in risk of 21% for any end point reated to diabetes (95% confidence interva 17% to 24%), 21% for deaths reated to diabetes (15% to 27%), 14% for myocardia infarction (8% to 21%), and 37% for microvascuar compications (33% to 41%). No threshod of risk was observed for any end point. Stratton IM et a. UKPDS 35. BMJ 2000;321:

8 A working case in diabetes: HbA1c the risk of death - 3 Is it possibe to define a non-inferiority imit cinicay acceptabe in this context?

9 Choice of the non-inferiority imit - 2 As defining a non-inferiority imit impies to accept some oss There must be some advantage to use the new product easyness safety costs

10 Choice of the non-inferiority imit - 3 FDA recommendations in HIV 4% in switch studies 10% in naive studies

11 Other issues Interna vaidity Limited protoco deviation, ack of adherence, ost to foow-up, and missing data Because they biased the resut towards no difference Externa vaidity Choice of the reference treatment Known efficacy Pacebo group when possibe Study popuation Same as the one in which the reference treatment was shown efficacious Endpoint(s) Same as the one(s) used to show the reference treatment efficacy Expected efficacy from the reference treatment observed in the current tria

12 Hi A AIDS 2008;22: Sampe size

13 Anaysis pan Resuts Confidence intervas of the difference More rarey a p-vaue Both ITT and per protoco anayses shoud be conducted and give the same resuts As ITT anaysis is no onger conservative Anaysis of compiance to treatment and protoco deviation (+++)

14 The concusion is based on The ower imit of the confidence interva of the estimated difference compared with the non inferiority imit L

15 Definition of non-inferiority N is not doing worse than R L N - R = -10% 0 10% inferior non-inferior superior

16 Interpreting a non-inferiority tria as a superiority tria No majors issues, but is the difference of cinica significance? Depending on The reference treatment The power The effect size The anaysed popuation The tria quaity The p vaue for the superiority test is derived from the ITT anaysis

17 Concusion If one accepts a oss of chance, what is the expected gain? The choice of the non-inferiority imit is critica It is a cinica, not a statistica decision Shoud warrant that the new product is better than pacebo Typicay 4-10% in the recent trias or recommendations in HIV The ITT anaysis is no onger the main anaysis Both ITT and per protoco are important The difference in the number of patients incuded in each anaysis is an indicator of the study quaity No major issues in switching from non-inferiority to superiority However, is the difference cinicay reevant?