L8: Drug Approvals Flashcards
what is included in phase 3 clinical trials
- Randomized control trials
- Usually just one dose (guided by phase 2 data)
- Thousands of patients
- Less monitoring, more “real world” to see how the drug interferes
- Duration (detect more safety events)
- Efficacy and safety
what does the FDA/health canada consider when an NDA is filed?
File an NDA to FDA
they look at the:
– For intended use
– In intended patient population
– and relies mainly on Phase 3 clinical trial data
- this will help them consider if they will approve the drug
Risk decisions:
– How safe is safe enough?
– Population
– individual
what criteria does health canada evaluate? (3)
- safety
- efficacy
- Quality of data (study design, statistics)
- TPD assesses the potential benefits and risks of the drug using the above
what are the two options of the review process by health Canada and how are they determined?
Option one: Decision to approve:
* Benefits outweigh the risks
* Risks can be dealt with
* Drug issued a Notice of Compliance
* Drug issued a Drug Identification Number (DIN); drug is officially approved in Canada
Option two: Deny approval:
* Sponsor can supply additional information
* Sponsor can re-submit later with additional data
* Sponsor can appeal decision
what is an example of how external pressure changes the drug development process? ie. explain the first AIDS drug development
Ex of when public pressure works: Rapid, effective development of the first AIDS drugs
- during the first years of deadly HIV epidemic (1980s)
- Patients frustrated with slow pace of research into treatments
- HIV related AIDS lethal
- “FDA not meeting the needs of people with AIDS” – presidential report, 1988
- Months later….
- ACT UP (AIDS Coalition To Unleash Power) closes down the FDA outside of Washington, DC.
- More than 1,000 activists stage a series of demonstrations which result in almost 180 arrests.
- The event receives international press coverage.
- A historical event, shutting down the FDA represents to a vast audience the lethargy of this dysfunctional bureaucracy, which is in charge of testing and approving possible AIDS treatments
explain the ways the citizens protested for the AIDS protest
- so many banners and signs
- hating the FDA for their slow development
- tombstones and where protesters lie dead
- vito russo calls for faster testing – uses language about clinical trials and states how other countries can approve drugs faster– why does it take so long for the FDA
what were some specific demands from the aids activists? (4)
- shorten the drug approval process
- immediate free access to drugs when safe and effective – as soon as phase 1 trials are completed
- no more double blind placebo trials as giving a placebo to someone with a life threatening disease is unethical – FDA shall not accept placebo data. Instead –> new drugs measured against:
- other approved drugs or
- different doses of the same drug or
- against what is already known of the natural progression of AIDS or
- experimental therapies (when no other approved drugs are present) - include people from all affected populations at all stages of HIV infection in clinical trials
- If a trial requires a homogeneous population, parallel trials must be conducted in other affected populations.
consequences of political action from the ACT UP demonstration (7)
- 8 days later: FDA announced new regulations that would accelerate the approval of drugs for the treatment of AIDS
- many hurdles to clinical testing were lifted
- community groups participated in research
- feb 1989 - FDA approval of drug for AIDS related pneumonia
- august 1989 AZT clinical results: slow the progression of AIDS in HIV positive individuals who displayed no symptoms
- oct 1989 - second drug made available even though clinical trials were not complete
- april 1993- 15 pharmaceutical organizations formed coalition to speed development of HIV antiviral drugs
what was one of the main results of the protest? what does this result consist of
ACT UP caused the FDA and Health canada to fast-track drug approval pathways
Priority Review Process
* Faster review for drugs for life-threatening or severe conditions
– E.g. cancer, AIDS, Parkinsons’
– Especially if there are few effective drugs on the market
why is a phase 4 trial needed? why aren’t the other three sufficient?
- demonstrate efficacy with statistical confidence
- provide sufficient information of risk-benefit without unnecessarily taxing time or resources and limiting patient access to medications
- uses thousands of patients
other three trials arent significant because they are limited in scope:
Populations evaluated are restricted, excluding:
◗ Young and old
◗ Mild or very severe disease/condition
◗ Significant co-morbidities (e.g., renal dysfunction)
◗ Pregnant or lactating women
◗ Different ethnicities may not be adequately represented
More intensive monitoring vs. real world
◗ Compliance assessed through e.g., pharmacokinetic samples, tablet counts
◗ More frequent medical visits and assessments
what are phase 4 clinical trials
- Any study performed after drug approval and related to the approved indication (not off-label use)
- Post-market evaluation permits:
– Assessment in “real-world” setting
– Identification of less common side effects. Are these drug- related? - These studies may involve thousands of people.
- Phase IV studies look at safety over time, and other aspects of the treatment, such as quality of life or cost effectiveness.
what are drug recalled – phase 4
The FDA can recall drugs due to:
* Drug manufacturing/purity
* Drug causes mild side effect
* Drug causes major side effects, including death
- A drug can be on the market for many years and still be recalled
what is the emergency use authorization in the FDA
During an emergency (e.g. current pandemic)
- Increases the availability of an unapproved medication or vaccine
- Increases the availability of an approved medication for unapproved uses
- Not the same as a full FDA approval
- “FDA also expects manufacturers who receive an EUA to continue their clinical trials to obtain additional safety and effectiveness information and pursue licensure (approval).”
what are off label use of medications
Means prescribing a drug product in a way that is inconsistent with the approved label, for example:
– Outside the condition/ indication
– Different population
– At different dosages or frequencies
– Modifying duration of treatment
– Using alternate routes of administration
- Differs from experimental use (e.g., as part of a trial)
- Common in some indications or populations, e.g.,
– Oncology
– Pediatrics
– Elderly - Estimated that 40%-60% of prescriptions in the U.S. are for off-label use (American Medical Association)
