GBTC 6301 Exam 5 (Clinical Trials for Alzheimer's Disease)

What is compassionate use?

Expanded access of a patented drug to provide for public health needs when no alternative treatment exists

What is a clinical trial?

Testing of an intervention and hypothesis (drug/device-diagnostic tool or method/behavior/exercise)

What is an observational study?

Collection of data

How does the Belmont Report define the term 'research'?

An activity designed to test a hypothesis and permit conclusions to be drawn

How does the FDA define a 'human subject'?

An individual who is or becomes a participant in research, either as a recipient of the test article or as a control... may be either a healthy human or patient

What is the health authority in the USA?

Food and Drug Administration (FDA)

What is the health authority in Europe?

European Medicines Agency (EMA)

What is the health authority in Japan?

Pharmaceuticals and Medical Devices Agency (PMDA)

What is the health authority in Africa?

African Medicines Agency (AMA)

What is the health authority in Australia?

Therapeutic Goods Administration (TGA)

What is the health authority in China?

National Medical Products Administration (NMPA)

How does the EMA define mutual recognition agreements?

When a health authority accepts that the conformity assessment of regulated products from third-country authorities complies with their own processes. Includes mutual recognition of good manufacturing practice (GMP) inspections and batch certification of human and veterinary medicines.

What is IND?

Investigational New Drug

What is IDE?

Investigational Device Exemption

What is the first module for filing an IND or IDE with the FDA?

Administrative, Regulatory, and Regional

What is the second module for filing an IND or IDE with the FDA?

Summary Information

What is the third module for filing an IND or IDE with the FDA?

Manufacturing and Chemistry (drug and placebo)

What is the fourth module for filing an IND or IDE with the FDA?

Pre-clinical Datasets and Reports

What does Module 4 include in an FDA report?

• Pharmacology and Drug Disposition (PK/PD, ADME...)

• Toxicology (in vitro and animals)

What is the fifth module for filing an IND or IDE with the FDA?

Describing the Intent of Human Trial

What does Module 5 include in an FDA report?

• Study Protocol specifying safety assessments

• CVs of investigators (PIs only)

• Form 1572 signed by the investigators (Code of Federal Regulations)

• Informed Consent and IRB Oversight

What is study site accreditation and qualification?

Study/sponsor clinical research organization or independent, non-profit organization

What are other requirements for a clinical trial?

• Secure a funding source (grant, sponsor, investors)

• Assemble study team

• Design the study and write the protocol

• Obtain IRB approval: Trials can't start until IRB approves the study (note: most info similar to IND)

• Compliance (to study protocol + staff training) and monitoring (DSMB, internal monitor(s) or CROs)

• Annual IRB and FDA reports (+ sponsor)

• Safety reports (for potentially serious risks: as soon as possible, but no later than 15 calendar days)

What is the goal of Phase I of a clinical trial?

Determining side effects and metabolic processing

What is the goal of Phase II of a clinical trial?

Determining dosage and effectiveness

What is the goal of Phase III of a clinical trial?

Determining risk/benefit ratio and efficacy

What is the goal of Phase IV of a clinical trial?

Determining rare side effects and cost-effectiveness

What are key parameters to include in study design?

• Study subjects: healthy or diseased? age? sex? number? need for informant? -> study Phase?

• Method(s) of recruitment

• Study site(s) location

• Who perform consenting and where are consent forms stored?

• Intervention: device or drug? comparator? dose(s)/intensity? exposure duration? ratio intervention vs. comparator?

• Type of assessments (i.e., outcomes - contractors?) and frequency of measures

• Optional: follow up period and procedures conducted

• Data analysis

• Reporting (safety, toxicity, and intervention outcomes)

What are the types of clinical trials?

• Single/double/triple-blind vs open label

• Uncontrolled

• Controlled

What are uncontrolled clinical trials?

No placebo

What are the types of controlled trials?

• Placebo concurrent control

• "No treatment" concurrent control

• Active treatment concurrent control

• Dose-comparison concurrent control

• Historical control

What are some examples of clinical trial designs?

• Parallel groups

• Cross over

• Factorial

• Randomized withdrawal

What are parallel groups clinical trials?

Groups receive intervention at the same time

What are cross over clinical trials?

Groups switch intervention

What are factorial clinical trials?

Comparing two or more interventions

What are randomized withdrawal clinical trials?

Open label at first, then only responders move to randomized groups

How are clinical trials reported?

• Annual reports to IRB and FDA (+ sponsor)

• Reports of serious adverse events to IRB and FDA (+ funding source) as soon as possible

• At completion, report results of intervention(s) on regulatory websites (e.g., ClinicalTrials.gov)

• Optional: report results in scientific journals and/or conferences

What are some possible issues during clinical trials?

• Difficulties to source the intervention

• Difficulties to enroll / retain study participants

• Study subjects not compliant with the protocol

• Unexpected toxicities / safety issues

• Study team not following the protocol / compliance issues

• Data breach

• Loss of funding

• Unexpected public health emergency

How many people suffer from Alzheimer's disease in the US?

6 million

How many people suffer from Alzheimer's disease worldwide?

50 million

Why is Alzheimer's disease so dangerous?

Loss of autonomy and personality, care burden, no cure available

What do clinical trials for Alzheimer's disease study?

• Neuronal death

• Amyloid plaques

• Hyperphosphorylated tau tangles

• Chronic inflammation

What are amyloid plaques?

Amyloid β produced by neurons and astrocytes

Where are tau tangles found?

Inside neurons

What causes chronic inflammation?

Microglia and astrocytes

What are the types of interventions used for Alzheimer's disease?

• Small molecule drugs that cross the blood-brain barrier (acts on amyloid, tau, or other targets)

• Antibodies and immunotherapies (e.g., vaccines) against amyloid (Leqembi; Kisunla) and tau

• Light and sound stimulation

• Transcranial electromagnetic devices

• Behavioral and physical therapies

• Cognitive stimulation therapies

What are some specific concerns regarding clinical trials for Alzheimer's disease?

• Demented patient can't consent -> need for legally authorized representative and study partner (must also sign informed consent forms)

• Disease stage: prodromal, mild cognitive impairment, mild, moderate, or severe?

• Frail subjects -> high risk of experiencing adverse events and dropping out

• Pathologies in the brain -> need interventions affecting the brain

• Clinical efficacy is cognition, but most cognitive tests not sensitive to small changes

• Brain pathologies accumulated for a long time (10- 20+ years) -> often long interventions = very costly

• Patients display brain pathology heterogeneity -> need to apply stringent inclusion/exclusion criteria that may not reflect the general population