1. European Patients’ Academy on Therapeutic Innovation Ethical and practical challenges of organising clinical trials in small populations

2. European Patients’ Academy on Therapeutic Innovation  There is no common definition of small populations. A ‘small population’ is generally referred to when only a limited overall number of patients with the disease being studied exist.  There is some overlap between small and special populations. Small populations can include:  rare diseases including specific sub-types of more common diseases  children (paediatric patients)  elderly (geriatric patients) Small populations in clinical trials 2

3. European Patients’ Academy on Therapeutic Innovation  30 million people in the EU are affected by rare diseases.  Rare diseases are those occurring in less than 1 in 2,000 people.  Ultra rare disease occurs in less than 1 in 2,000,000 people (suggested prevalence 1 ).  There is limited knowledge on rare diseases, due to less research (limited research interest and funding available)  Rare diseases may show a large variability of disease expression and disease state. Rare and ultra rare diseases 1 Hennekam, R.C. (2011). Care for patients with ultra-rare disorders. European Journal of Medical Genetics, 54(3), 220-224. doi:10.1016/j.ejmg.2010.12.001 3

4. European Patients’ Academy on Therapeutic Innovation  In principle, the development of orphan medicinal products and medicines for children are regarded as standard situations, in other words, guidelines exist to regulate them.  In these situations, medicines development follows the principles of evidence-based medicine, as in common diseases.  The development of orphan medicinal products and medicines for children may limit what is possible and reasonable.  Development may therefore require non-standard solutions. Standard and non-standard situations 4

5. European Patients’ Academy on Therapeutic Innovation  The value of clinical study results should be considered in relation to the levels of evidence, as the results of some kinds of studies are more significant than others: 5 Levels of evidence

6. European Patients’ Academy on Therapeutic Innovation  Key questions:  Is it possible to do a randomised controlled trial (RCT)?  Is a small RCT better than a larger observational study?  Risk of bias?  How accurate will the result be?  What evidence is needed for initial marketing authorisation?  What evidence is needed post-marketing? What level of evidence can you obtain in studies in small populations and in children? 6

7. European Patients’ Academy on Therapeutic Innovation Full development with randomised controlled trials (RCT), compared with placebo and/or reference therapy Common or rare disease, reference therapy available Full development including RCT compared with placebo or standard of treatment Open-label, non-comparative trials? Common or rare disease, no reference therapy available SituationSolution Standard Non- standard 7

8. European Patients’ Academy on Therapeutic Innovation Situations and solutions Small populations Enough for RCT Only small Phase II trials Not enough for RCT Unconventional study design Non-comparator trials Historical control Standard Non- standard 8

9. European Patients’ Academy on Therapeutic Innovation The Committee for Medicinal Products for Human Use (CHMP) has given guidelines for these studies:  small populations (http://www.ema.europa.eu/docs/en_GB/document_library/Scient ific_guideline/2009/09/WC500003615.pdf)http://www.ema.europa.eu/docs/en_GB/document_library/Scient ific_guideline/2009/09/WC500003615.pdf  paediatric population (http://www.ema.europa.eu/docs/en_GB/document_library/Scient ific_guideline/2009/09/WC500002926.pdf)http://www.ema.europa.eu/docs/en_GB/document_library/Scient ific_guideline/2009/09/WC500002926.pdf Availability of guidelines for studies in small populations 9

10. European Patients’ Academy on Therapeutic Innovation  Standardised data collection – planned in advance (prospectively), documented in protocol, and adhered to:  Maximising collection of important information  Keeping study participation burden acceptable  Avoiding loss-to-follow-up  Best use should be made of animal models of disease. Studies in small populations: Key factors (1) 10

11. European Patients’ Academy on Therapeutic Innovation Key factors:  Understanding the natural course of disease, how this may change over time.  Understanding sources of possible misinterpretation of data (confounders).  Understanding sources of variable response to therapy. Studies in small populations: Key factors (2) 11

12. European Patients’ Academy on Therapeutic Innovation  Typically, efficacy is measured in terms of:  Cure  Survival  Time to disease progression  Progression-free survival  Reversal of organ dysfunction  Disease stabilisation  Selection of the most suitable endpoint is crucial. Studies in small populations: Evaluating efficacy (1) 12

13. European Patients’ Academy on Therapeutic Innovation  How is efficacy measured?  Hard endpoints (for instance, survival rates)  Surrogate endpoints (clinical improvement)  Symptom relief  Quality of life  Biomarker, surrogate value unknown Studies in small populations: Evaluating efficacy (2) Often a logical combination of measures pointing to the same conclusion must be considered. 13

14. European Patients’ Academy on Therapeutic Innovation Studies in small populations: Choosing a comparator 14 What is the most appropriate comparator? Placebo or standard of treatment?Available therapy = active comparator? What is an acceptable comparator? Historical control group?No control group? What is the desired outcome? Superior efficacy?Non-inferior efficacy? ‘Clearly effective’ although no control group available

15. European Patients’ Academy on Therapeutic Innovation  Seamless adaptive design:  Phase II and Phase III are combined in one study  design is adapted as trial is ongoing  best dose levels are continued after the interim analyses  Sequential studies:  it enrols patients and analyses until a reliable conclusion is made  effect/outcome emerges rapidly  Modeling:  effect of parameters  relationship efficacy - effects Examples of study designs 15

16. European Patients’ Academy on Therapeutic Innovation  Finding relevant trials can be a challenge  Long commutes to the investigator’s site might be required  Possible relocation of the patient may be required  Financial support and/or access to health care system may be required  Need for language support  Need for teaching/school facilities for children  Reorganisation of family life may be required Practical problems for patients in a rare disease trial 16

17. European Patients’ Academy on Therapeutic Innovation  All measures are taken to protect privacy during clinical trials. However, this is a challenge in rare or ultra rare diseases due to:  smaller patient registries or non-existence of patient registries  risk of being identified in a clinical trial Privacy and transparency 17

18. European Patients’ Academy on Therapeutic Innovation  Benefit-risk assessment due to the life-threatening disease condition  A known effective comparator is often not available  New treatment may not be accessible after the end of the trial  No established process for providing trial results to patients Ethical issues in clinical trials with rare diseases 18

19. European Patients’ Academy on Therapeutic Innovation  Patients may not be able to give informed consent themselves and may rely on the decision of the legal representative who may not always represent the patient’s own opinion.  The decision to participate in the trial is often not really voluntary because there may be no treatment alternative.  Placebo control is a particular problem due to the severity of the disease, requiring that the participant agree to possibly not receiving any treatment during the initial trial phase. Informed consent process 19

20. European Patients’ Academy on Therapeutic Innovation  A balance must be found between what is necessary and what is possible.  Methods are available to show efficacy in clinical trials in small populations.  The development strategy for treatment in small populations should be discussed in advance with regulators in scientific advice/protocol assistance.  Clinical trials in rare or ultra rare diseases present a number of ethical and organisational challenges. Conclusion 20