Clinical Trial Considerations Flashcards
List the types of primary endpoints in clinical trials for neuropsychiatric diseases.
Primary endpoints in clinical trials for neuropsychiatric diseases include:
1 - Cognitive endpoints measured by cognitive tests.
2 - Functional endpoints measured by ability to carry out activities of daily living.
3 - Global endpoints measured by global assessments of overall clinical response.
How is a ‘disease-modifying’ effect proven in clinical trials?
Why is this difficult in neuropsychiatric disease?
- In clinical trials, a ‘disease-modifying’ effect is shown by demonstrating that:
1 - The pharmacological treatment delays the underlying pathophysiological disease process.
2 - This is accompanied by an improvement in clinical signs and symptoms.
- (1) is difficult to prove in neuropsychiatric conditions. This is because the symptoms of a disease depend and the location of the damage rather than the type / cause of the damage. Therefore, different pathophysiological processes can manifest as the same symptoms. Also, brain biopsies cannot be carried out in living subjects.
List 7 common problems with clinical trials for neuropsychiatric diseases.
Common problems with clinical trials for neuropsychiatric diseases:
1 - There is high baseline variability.
2 - There are heterogeneous populations.
3 - Outcomes are not sensitive to early changes.
- E.g. when measuring dementia onset or brain atrophy.
4 - Ceiling effects of assessment tools such as MMSE.
5 - Rarity of proposed outcome.
6 - Excessively long durations between follow up.
7 - There is variable timing in dementia onset between individuals which cannot be accounted for.
Describe the VITACOG trial.
- VITACOG is the only clinical trial to date that produced a successful primary prevention strategy for dementia.
- It involved reducing homocysteine in MCI patients by administration of folate and B vitamins.
- It did not have any prior animal studies because no animal models were available for homocysteine.
- Its endpoints included cognitive measures (CAMCOG) and neuroimaging (to measure the rate of atrophy of the medial temporal lobe), which were both reached successfully.
- The trial reached phase 2 but the National Institute for Health Research (NIHR) did not fund a phase 3 trial.
What is the ethical problem with control groups in clinical trials?
The ethical problem with control groups in clinical trials is that the control group is being deprived of a potentially beneficial treatment.
List 8 ideal characteristics of measurement tools (including cognitive, functional and global tools) in clinical trials for neuropsychiatric diseases.
Ideal characteristics for measurement tools in clinical trials for neuropsychiatric diseases:
1 - Accurately reflect symptomatic severity.
2 - Sensitive to modest changes.
3 - Easy to use.
4 - Possibility of easy combination with other tests (e.g. short duration).
5 - Must be calibrated in relation to various populations.
6 - Must have validated norms available for the interpretation of the results. If not, have a validation plan including a prospective study in an independent population.
7 - Standardised for use in different languages and cultures.
8 - Ideally bears some relevance to existing tools for which historical experience exists.
List 3 factors that increase the required patient numbers in clinical trials for neuropsychiatric diseases.
Factors that increase required patient numbers in clinical trials for neuropsychiatric diseases include:
1 - The high withdrawal rate of patients, which can be up to 27%. This is because of:
- Complex trial protocols.
- Problems with informed consent as disease severity increases over time.
2 - The poor accuracy of diagnosis for neuropsychiatric disease.
3 - The poor quality of biomarkers for neuropsychiatric disease.
List 6 factors that contribute to the cost of clinical trials.
Factors that contribute to the cost of clinical trials:
1 - Recruitment of healthcare workers, administrators and statisticians.
2 - Imaging.
3 - Biomarkers.
4 - Drug development.
5 - Follow-up assessments.
6 - Patient travel.
How many patients are usually in phase 2 and phase 3 trials?
- Phase 2 trials usually involve 80-400 patients.
- Phase 3 trials usually involve 400-1600 patients.
Give an example of an approved biomarker for neuropsychiatric disease.
List 7 putative biomarkers for neuropsychiatric disease.
- There are no approved biomarkers for neuropsychiatric disease. Putative biomarkers include:
1 - Blood / CSF amyloid.
2 - Blood inflammatory markers.
3 - Lymphocyte behaviour.
4 - CSF tau.
5 - CSF cytokines.
6 - Urine neurofilaments.
7 - Imaging (CT or MRI).
