L6/7/8: Clincal Trials Flashcards
who conducts clinical trials? where are these clinical trials conducted? what is a main role needed in clinical trials?
who?
- sponsorship by the company developing the drug
–> ex. pfizer
—> ex. biotech company
where?
- universities and hospital research institutes (30% of the time)
- private clinical research organizations (70% of the time)
- may have many locations/countries involved
main role:
Principal investigator = supervises the trial
* Usually a medical doctor
* Usually lots of expertise in that area
how do you participate in a clinical trial
added info from slide 36
three steps
Initially…
- contact a family doctor
- they can refer a site investigator that you can call
Then…
- go through with a Telephone Interview
- Goal: to see if you are eligible to participate, broadly (eligibility and inclusion criteria)
Next….
Screening Visit
- go to a scheduled screening visit, detailed assessment (may include physical exam and testing)
- if you are accepted you may be asked if you want to enter the trial there
- you get accepted based on eligibility on the strict inclusion and exclusion criteria (entry requirements)
- get an information package (which includes the informed consent form)
- review the document and talk to the nurse
- consider how the trial will affect you and choose to accept or not: ie effect your lifestyle, consider the known/potential risks and benefits
how do you decide if you want to participate in a clinical trial
what should you consider? added info from slide 32
- Discuss with doctor, friends, family
- Contact previous trial participants
Consider all the factors:
*Time commitment
* Risks
* Benefits
consider:
* costs (Expenses, loss of wages, Time off work, Transportation costs, Daycare/babysitting costs, pharmacy dispensing fee)
! trial may have funds to help with costs
* possible sickness (tell staff immediately, 24 toll free number for doctors, access to emergency room with trial info)
* getting off certain drugs (due to drug-drug interactions)
how can you find out about clinical trials? how do you start possible participation in a phase 1 trial?
- canada has open sources – even about cancer trials – where you can find and register for clinical trials
for a phase 1 trial you contact either:
* the contract research organization (CRO)
* or hospital
to see where the trial is being conducted
what is the design of a phase 1 clinical trial
(what is phase 1 trials called, how is its content guided, what are the two types of doses it could follow?)
- First-in-human (first test in humans)
- Dosing guided by preclinical animal studies, multiplied by safety factor to be conservative
Test doses are given in ascending order:
* Single ascending dose study
(one dosage level, once ex. 100 mg)
* Multiple ascending dose study
(Tests one dosage level over many days - tests for accumulation)
Subjects in phase 1 clinical trials? and why are these subjects chosen?
what is an exception?
- usually healthy volunteers
- trial chooses healthy volunteers because they want to test the best case scenario of the drug – asking the question on if it is safe?
exception: oncology (cancer) drugs
why: ethics issue
- These drugs may have a risk-benefit ratio that makes them too risky and ethically unacceptable for healthy volunteers (no benefit).
- Thus some phase 1 clinical trials in oncology have study participants who are cancer patients, not healthy volunteers (e.g. First in Human film)
what are the phase 1 research questions?
- What doses can be tolerated?
- What doses are safe?
- How does the drug move in the body? (aka absorption, distribution, metabolism, elimination)
- The results guide dosing in phase 2
what are two ways someone can check if a drug is safe?
- clinical signs (aka medical symptoms)
- how the patient reports to feel - biomarkers (aka medical signs)
- objective indication of the medical state not by the patient themself
what are biomarkers (3 definitions) and what are they used for?
- objectively measured and evaluated characteristic that is an indicator of biological processes
- a substance, structure or process that is measured in the body or its products
- indirect markers of internal state
used to
- classify people (health/disease)
- objectively measure success of drug (in clinical trial)
what are some examples of biomarkers
- Blood pressure
- Temperature
- Cholesterol level
- Medical image / scan
- Level of virus
- DNA test
- Pharmacogenetic test
- Lung cancer breathalyzer test (new)
- Drug concentration in urine (sports, employer)
- Blood sugar level
what are qualities of a good biomarker? (3)
Sensitivity
* Should be able to indicate the fraction of persons with disease (aka are sick) by the biomarker test – should be sensitive
Specificity
* Should be able to indicate the fraction of persons without disease (aka are healthy) by the biomarker test – should be specific.
- Biomarkers are imperfect and have <100% sensitivity and <100% specificity
- good biomarkers have low false negative and false positive results
- false negative = when a person has a condition but the test indicates that they dont
- false positive = when a person does not have a condition but the test says they do
how do we know if a drug is effective in phase 2 trials? use ex. explain with HIV/AIDS disease
use biomarkers
since phase 2 trials are relatively short, biomarkers fit this timeframe
ex. HIV/AIDS
One biomarker: Viral load (blood test)
- High viral load = virus is replicating quickly in the body
- Low viral low = body is keeping the virus replication in check
(Can occur with or without a drug treatment)
Another biomarker: CD4 cell count
- Indicates the number of immune system cells that have CD4 receptors
- Low or falling CD4 count = HIV disease is progressing (since HIV infects and destroy CD4 cells)
what are adverse events (AEs) and serious AEs
Adverse Event
* Any undesirable experience associated with the use of a medical product in a patient.
* Serious AE’s are a subset of Adverse events
Serious AE
* The event is serious and should be reported to FDA when the patient outcome is:
* Death
* Life-threatening
* Hospitalization (initial or prolonged)
* Disability or Permanent Damage
* Congenital Anomaly/Birth Defect
* Required Intervention to Prevent Permanent Impairment or Damage Other Serious (Important Medical Events)
ex. for the last point
- a serious problem with breathing seizures/convulsions that do not result in hospitalization.
- development of drug dependence or drug abuse
how do we test pharmacokinetics in phase one trials?
- Frequent blood and urine tests to measure drug concentration in bodily fluids
- Gives an indication of where the drug is moving, how quickly it is being absorbed, and how quickly it is being eliminated
explain the phase 1 clinical trial disaster of 2016 – Bilal trial
- Investigational drug BIA 10-2474 – under development for treating anxiety
- July 2015 - October 2015: single ascending dose (SAD) study for 64 volunteers
- Doses increasing from 0.25 to 100 milligrams.
- November 2015: a series of multiple ascending dose (MAD) trials began, each enrolling eight subjects. The first group received 2.5 milligrams daily, the second 5 milligrams, and so on; the accident happened in the fifth group, which received 50 milligrams daily, the highest dose.
- One person brain-dead
- 5 in hospital
what was the reasoning and consequences of this 2016 clinical trial phase 1 disaster?
- due to gradual accumulation in the brain
- likely require new best practice codes for all future drugs to reduce these effects
- the authors urged for a tougher selection process for volunteers as the dead man has previously suffered head injury and the other victims had history of hypertension
