The Science of Small Clinical Trials Introduction to Small Clinical Trials an Industry Perspective Simon Day, PhD
Confucius (allegedly) When it is obvious that the goals cannot be reached, don t adjust the goals, adjust the action steps. 2
Me a man of numbers(?) One pharmaceutical industry maybe with pharma/biotech sub-groups devices another subgroup, or are they different? Many sizes Many philosophies Many strategic directions One (?) purpose 3
The dirty word Pharma and device companies are there to make money for shareholders I reconcile this with The only way to make money, is to make good medicines, that help patients, and for which those patients (or the payers!) are therefore willing to pay And if I make lots of good medicines and lots of money, I can plough that back into research to find lots more medicines, and make even more money! 4
Industry Perspective 5
Varieties Of companies, approaches, and problems Big companies Stuck in mind-set of non-orphans SOPs inappropriate and infelxible Committees all over the place Databases too big and clumsy Rigid on (apparent) regulatory requirements But very good (sometimes) at turning in NDAs 6
Varieties Of companies, approaches, and problems Small (orphan) companies Stuck in mind-set of orphans SOPs not so well thought out Committees lack of clear structure Databases ad hoc, inefficient, etc. Naïve to regulatory requirements Lack of experience at turning in NDAs 7
Varieties Of companies, approaches, and problems Niche (orphan) companies Keep clear focus on orphans SOPs fit for purpose Committees fit for purpose Databases fit for purpose Experienced in regulatory requirements and options Good (sometimes) at turning in NDAs 8
Data sources Roche Ethics Committee (IRB) Friends and colleagues (EU) regulatory experience ICORD contacts Science of Small Clinical Trials (past years) Note, some examples not licensed, or uses discussed outside approved label 9
Example 1 Cystic Fibrosis Rare disease (of course) In this situation the best that can be achieved is an uncontrolled study of N=100. No justification of why 10
Example 2 Cystic Fibrosis Rare disease (of course) We know this is really stretching the limits of acceptability, but we plan to do a study of n 1 =80 patients on active and n 2 =40 patients on placebo. At least an acknowledgement and apology 11
Examples 1 and 2 Cystic Fibrosis Rare disease (of course) In this situation the best that can be achieved is an uncontrolled study of N=100. Meeting 9:30 11:00 We know this is really stretching the limits of acceptability, but we plan to do a study of n 1 =80 patients on active and n 2 =40 patients on placebo. Meeting 11:00 12:30 On the same day! 12
Example 3 bone marrow disorder Rare disease (of course) Two obvious sub-groups Not enough patients to do one (or more!) trial in each subgroup (maximum reasonable N 240) Run one study, with interim analysis to potentially drop one subgroup if no effect ( adaptive design ) If a subgroup is dropped, continue recruitment in the other subgroup, up to N=240 13
Example 4 cancer of blood cells Rare disease (of course) N 650; largest ever trial in this indication Primary endpoint, overall survival, P 0.10 Median survival 5 8 months Secondary endpoint, PFS, P<0.001 Longer follow-up of OS P=0.03 Median survival 5 8 months Don t file too much risk of failure / company image We ve used up all our alpha (i.e. 5% alpha) 14
Example 5 inflammation of arteries Rare disease (of course) Placebo controlled trial Sample size planned, N=200 Number of centres 120 Number of pages in protocol 120 By the way, there s another Phase II exploratory study of 27 patients being conducted in 1 centre 15
Example 6 inherited metabolic disease Rare disease (of course) Primary endpoint, 6 minute walk test Primary analysis, all patients Additional primary analysis(?) 2 well defined subgroups, because Treatment not expected to benefit all patients on the 6 minute walk test, so Why is that their primary endpoint? Alternative primary endpoint could be discussed 16
One Pharmaceutical Industry But very varied Many sizes Many philosophies Many strategic directions Some consistently make good decisions but don t always succeed Some consistently make bad decisions and sometimes get lucky (or rescued!) 17