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
conclusion of phase 1 trials and exception of the bilal trial?
- Phase 1 trials are generally safe and the Bial trial disaster is unusual
- There is always a level of risk in a first-in- human trial and the precise level of risk is unknown
what is the goal of phase 2 and phase 3 trials
efficacy testing
phase 2: look for side effects
phase 3: long term testing
what are the potential benefits of participating in a clinical trial (ex. HIV/AIDS)?
(4)
- among the first to benefit in an experimental therapy that is effective
- having your health monitored more often
- being a part of the process that develops new drugs for other patients
- altruism (helps others even if it doesn’t help yourself)
what are the potential risks of participating in a clinical trial (ex. HIV/AIDS)?
(7)
- no guarantee of personal benefit
- experience possible side effects that: could be dangerous, worsen your health, cause you to be admitted in a hospital
- having to stop taking other meds that work well
- not be eligible for future trials
- not knowing if you are receiving the experimental or controlled drug
- lifestyle changes (meds at certain times, not eating some food)
- potential for stigma or discrimination?
possible questions to have answered when deciding to participate in a clinical trial:
- purpose of trial?
- who is participating?
- effectiveness of treatment?
- any side effects or safety issues?
- chances of getting placebo?
- duration of trial?
- expectation of participants?
- who is in charge of medical care?
when you sign the consent form, what are the expectations of the investigators?
- consent is an ongoing PROCESS
- investigators have the responsibility to continue to inform you of:
- Any new information about the drug you are taking
- Any information that would influence your decision to participate in the trial
- The investigator needs your consent that you wish to CONTINUE to participate
- right of withdrawal whenever
what are inclusion criteria? use an example of inclusion criteria for an HIV/AIDs study
- ensure that relatively similar people take part in a trial
- Allows for reliable comparison about the way that the experimental drug works
ex. inclusion criteria for an HIV/AIDS drug study:
* must be HIV positive
* must have a CD4 count (white blood cells) between 100 and 300
what are exclusion criteria?
- Protect people who might be harmed by the study drug
- People with active infections
- Pregnant women
what occurs right before the beginning of a clinical trial?
- you are randomly assigned to a study group
- there is a waiting period between enrollment and beginning of study
- known as washout period: may be asked to stop taking a medication and wait for a period of time to let the body get rid of the meds and avoid harmful drug-drug interactions
- during this period your health is monitored
what occurs during the clinical trial?
during the clinical trial includes the treatment period
- length of time that the investigators plan to have you on a treatment before they evaluate whether it works
- usually 12, 24, or 48 weeks
follow up visits
- regular clinic visits
- ex. once a month for six months or more frequent
use an at home pregnancy test as an example to describe biomarkers with desirable factors
- Pregnancy test measures level of a pregnancy hormone called human chorionic gonadotropin (hCG) in urine.
- The biomarker is reliably present in people with the condition but is very rarely present in people without the condition
- The biomarker is present in an easily accessible bodily fluid such as urine
- The biomarker is readily detected with a reliable and valid standardized test that is simple to perform correctly
what is included in a phase 2 trial?
what is a placebo, what are placebo effects
placebo-controlled designs
- Placebo = the drug-appearing substance (pill, etc). A physical object.
- Placebo effects = a combination of physiological (how the body works) and psychological (how the mind works) effects related to anticipation.
what is the treatment vs placebo effects?
treatment:
- response due to the combination of psychosocial factors and treatment
placebo
- response due to the combination of psychosocial factors
how do you think about placebo effects quantitivley
the placebo response should be lower than the treatment response.
the overlapping response is the response due to placebo effects.
the extended response is the genuine response to the drug
what are the patients responsibilities during the trial
- Understand the rules of the trial
- Realistic – follow the rules
- Keep appointments
- Follow the drug schedule
- Trials have strict guidelines
- If you don’t follow the trial rules, you will be withdrawn from the trial
what are the subjects family doctor’s responsibilities during the trial? what happens if the family doctor is involved in the clinical trial?
- Since you are a clinical trial participant, your health will be monitored at the trial site
- check-ups, lab tests from family doctor
- responsiblity for family doctor to evaluate general medical care of trial participants (not clinical researcher)
- Family doctors and site investigators communicate to share results of overlapping medical tests
Ethical guidelines and conflict of interest:
* If family doctor is a trial investigator, someone aside from the family doctor (e.g. another doctor) should conduct the interview and obtain consent
* If the family doctor is the trial doctor, then the trial participant can remain in the trial, but should see another doctor for regular care during the trial
* Avoid conflict-of-interest for enrolling clinical trial participants
what happens after the trial?
- The study ends when ALL participants have completed the drug treatment
- If you are one of the first participants in the study, you will be “in the study” for longer than someone who joined later
- exit interview
- MAY be told what treatment (drug/placebo) you were receiving
- The results/code in double-blind trials isn’t broken until EVERYONE has completed the trial
- When the trial is finished, you should expect to receive the results of the trial overall
- A two-year trial may take a long time if enrolment is staggered (e.g. 50 patients per year for a total of 500 patients) since the LAST person must have been in the study for two years for the study
- You need to keep in touch with the investigators after the trial ends (to report long term side effects, so researchers can let you know of any new information)
phase 2 clinical trial case study: Lurasidone
what is it, where does it target, mechanism?
- the drug: Lurasidone
- this drug acts on two different targets: dopamine D2 receptor, and the serotonin receptor
- percise mechanism of the action on the receptors are unknown (okay, the board doesnt need to know the exact bindement of the drug)
- Clinical effects thought to be due to antagonist actions at both receptors
what medical conditions has Lurasidone been approved?
Schizophrenia
* Indicated for schizophrenia
Bipolar Depression
* Monotherapy
* Indicated as monotherapy for adults with major depressive episode associated with bipolar I disorder (bipolar depression)
Adjunctive therapy
* Indicated as adjunctive therapy for major depressive episodes associated with bipolar I disorder with lithium or valproate
what are unmet medical needs for bipolar disorder and schizophrenia
Bipolar disorder
* Lifelong, chronic mood disorder
* Brain disease that causes mood swings that vary in length
* 12 million patients US (3% of population), 60 million world
* Half of patients first experience their BD at ages 15-25
Schizophrenia
* Affects 1% of the population yearly
* Onset common in late teens/early 20s
what are the varying conditions of each phase 2 trial of Lurasidone
Sample, doses, primary endpoint, number of patients per sample
all: 18-64 year olds that has schizophrenia for over a year
doses: all different but all include a placebo
the primary endpoint: the same ending point to understand the effect of the drug (here it was change in brief psychiatric rating scale)
patients: increased per trial (50, 70, 90)
what were the results of the clinical trials for lurasidone
the lurasidone groups had a greater decrease in schizophrenia in comparison to the placebo - placebo decreased, but the doses of lurasidone did more
- Lurasidone better than placebo in 2 of the 3 phase 2 trials
- Endpoint: improvement in symptom rating score
what was the inclusion criteria of the lurasidone trial
- not preganent, no nursing, not planning pregnancy in the study
- Females agree to remain abstinent or use adequate and reliable contraception throughout the study and for at least 30 days after
- Good physical health on the basis of medical history, physical examination, and laboratory screening
what was the exclusion criteria of the lurasidone trial
exclude people who:
- Subject is considered by the investigator to be at imminent risk of suicide
or injury to self, others, or property. - Any chronic organic disease of the CNS (other than Bipolar I Disorder).
- Hospitalization for a manic or mixed episode within the past two months.
- Used investigational compound within past 6 months.
- Clinically significant history of alcohol or substance abuse within the past 3 months or alcohol or substance dependence within the past 12 months
