21 CFR Part 312 Flashcards
What does 21 CFR Part 312 cover?
Investigational New Drug Application
clinical investigation of a drug product that is lawfully marketed in the US is exempt from the requirements of part 312 if all of the following applies:
1) The investigation is not intended to be reported to the FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling of the drug.
2) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product.
3) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks associated with the use of the drug product.
4) Investigation is conducted in compliance w/ the IRB and appropriately consents.
5) Investigation is conducted in compliance with the requirements.
What products are exempt from requirements of 312?
1) blood grouping serum
2) reagent red blood cells
3) anti-human globulin.
In what setting is a drug exempt from requirements of 312?
drugs intended solely for tests in vitro or in laboratory research animals
A clinical investigation involving use of THIS is exempt from the requirements of 312 if the investigation does not otherwise require submission of an IND
Placebo
Is an Unlabeled indication of drug/device subject to provisions of 320.31? (Applicability of requirements regarding an “Investigational New Drug Application”)
No, does not apply to the use in the practice of medicine for an unlabeled indication of a new drug product
(320.31 applies to bioavailability studies)
Independent ethics committee (IEC)
a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection.
Investigational new drug
a new drug or biological drug that is used in a clinical investigation.
FDA shall provide a written determination within ____ days after receiving IND application
30
Grounds for clinical holds on Phase I studies:
unreasonable risk
unqualified investigators
IB is misleading, inaccurate or incomplete
or IND doesn’t contain sufficient information to assess risk to subjects
Grounds for clinical holds on Phase II or III studies:
deficient protocol to meet stated objectives
When an ongoing study is on a clinical hold can new subjects be enrolled and what happens to subjects currently enrolled and on IP?
no new subjects,
subjects on IP have to stop unless specifically permitted by the FDA
Who can appeal the FDA’s decision for a clinical hold?
Sponsor
How must the FDA notify the sponsor of a clinical hold on an IP?
Can be imposed by telephone, rapid communication or in writing
What is required to resume study after clinical hold on IP?
Cited issues must be resolved and the FDA must notify the sponsor to proceed
Under an IND, if no subjects are entered into a study for 2+ years or if all studies under an IND remain on clinical hold for 1 year+, the IND may be placed on “_____”
Inactive status
INDs that are “Inactive” for ___+ years may be terminated
5
For an IND, how soon should the sponsor report serious unexpected life-threatening safety events to FDA?
7 calendar days.
For an IND, how soon should the sponsor report serious unexpected safety events to FDA when not life-threatening?
15 calendar days.
For an IND, what form is used for the sponsor reporting serious unexpected safety events?
Form FDA 3500A
What does SUSAR stand for?
Suspected unexpected serious adverse reaction
For an IND, when do investigators report serious events to sponsors?
As soon as possible (typically stated in protocol). (15 Days)
For an IND, when is the annual report is provided to the FDA by the sponsor?
60 calendar days from the anniversary of the IND becoming active.
True or False: Reactions which are serious but expected are subject to expedited reporting requirements
False. Reactions that are serious but unexpected are subject to expedited reporting.
For an IND, when do Investigator’s provide annual report to sponsor?
No time criteria, give to sponsor to submit to FDA.
For an IND, when does the Investigator need to submit the final report to the sponsor?
When the study site is finished with the investigation (no specified time constraints).
For emergency use of a drug, where immediate use of the product was required and the patient was not able to be consented, how long does the sponsor have to notify the FDA of the use of the product?
5 working days
Fatal or life-threatening unexpected adverse drug reactions are required to be reported no later than how many days after first knowledge? What about non-life-threatening unexpected ADRs?
Fatal unexpected ADRs: 7 calendar days after first knowledge
Non-fatal serious unexpected ADRs: 15 calendar days after first knowledge
What key data elements should be included in expedited reports for serious adverse drug reactions?
Patient details
Suspected medicinal product
Other treatments patient was receiving
Details of Suspected ADR
Reporter of the event
Sponsor details
When is unblinding inappropriate in the case of a fatal or serious adverse event?
If a fatal or serious outcome is the primary efficacy endpoint, the integrity of the clinical investigation may be compromised if the blind is broken. It may be advantageous to reach an agreement with regulatory authority not to unblind and expedite reporting.
What is form FDA 3500 used for?
Voluntary reporting of an adverse event.
Key Aspects of Pre-clinical studies:
o Help establish boundaries for the safe use of treatment when human testing begins
o Studies designed to evaluate compounds for potential pharmacologic use
o Generally performed in animals
o Evaluate the possibility of long-term, adverse events: onset of cancer, interference with reproduction or the induction of birth defects etc.
o When sufficient data are obtained to warrant study in humans subjects, a sponsor submits an IND
Key aspects of Phase 1 studies:
o Small trials with healthy subjects, purpose is to determine pharmacokinetics and maximum tolerated dose
o Conducted to determine the appropriate dose range with regard to safety and toxicity (not to evaluate efficacy)
o Conducted in a limited number (20-80) of health volunteers or patients (cancer, AIDS)
o Many compounds are abandoned in this phase because of safety/toxicity problems
Key aspects of Phase II studies:
o Initial demonstration of efficacy in patients, short-term safety information
o Conducted in a relatively limited number (100-300) patients who have the disease
o Often involve hospitalized patients who can be closely monitored
o Many focus on dose-response, dosing schedule, or other issues related to preliminary safety and efficacy
o Takes about 1 to 3 years to complete
Key aspects of Phase III studies:
o Use in large numbers of patients, long-term safety data
o Conducted in larger (several hundred to several thousand) and more diverse groups for whom the drug is ultimately intended
o Make comparisons between new treatment and standard therapy or placebo
o Study drug used by practicing physicians in the same manner as it would be used after marketing
o Takes about 2 to 5 years to complete
Key aspects of Phase IV studies:
o Post-marketing, continue assessing therapeutic value and monitor less common adverse events
True or False. FDA Form 1572 is required for all trials.
False. Form 1572 is required for IND studies but not required for IDE. A generic doctor agreement is all that is required for IDE.
What does CAPA stand for?
Corrective and Preventative Action Plans
When a sponsor intends to conduct a clinical investigation with an exception from informed consent for emergency research, what must be done?
Sponsor shall submit a separate IND for such investigation.
The sponsors request for a regulatory hearing must be made within ___ of the sponsors receipt of fda’s notification of nonacceptance
10 days
