European Patients’ Academy on Therapeutic Innovation Ethical and practical challenges of...

European Patients’ Academy on Therapeutic Innovation

Ethical and practical challenges of organising clinical trials in small populations

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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

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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 prevalence1). 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

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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

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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:

Levels of evidence

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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?

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• 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

Situation Solution

Standard

Non-standard

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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

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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/Scientific_guideline/2009/09/WC500003615.pdf)

paediatric population (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002926.pdf)

Availability of guidelines for studies in small populations

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003615.pdf




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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)

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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)

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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)

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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.

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Studies in small populations: Choosing a comparator

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

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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

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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

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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

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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

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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

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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

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