21 CFR Part 312 Flashcards
21 CFR part 312
Investigational new drug application (IND)
What is 21 CFR part 312 about?
procedures and requirements governing the use of investigational new drugs, procedures and requirements for the submission to, and review by, the FDA of investigational new drug applications (IND’s)
Contract research organization
person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor
Independent ethics committee
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. IRB is one type of IEC
Investigational new drug
a new drug or biological drug that is used in a clinical investigation.
Marketing application
an application for a new drug submitted under section 505(b) of the act or a biologics license application for a biological product submitted under the Public Health Service Act.
Promotion of an investigational new drug
regulations prohibit sponsor from making any claims for safety/ efficacy for drugs under an IND except for professional meetings and trade shows
commercial distribution of an investigational new drug.
A sponsor or investigator shall not commercially distribute or test market an investigational new drug
Prolonging an investigation
A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application.
General criteria for charging
3 criteria
- A sponsor must obtain prior written authorization from FDA to charge for an investigational drug.
- A sponsor must justify the amount to be charged
- FDA will withdraw authorization to charge if it determines that charging is interfering with the development of a drug
Charging in a clinical trial
charging for a drug under an IND is restricted unless previous permission is granted by FDA
Duration of charging in a clinical trial
charging may continue for the length of the clinical trial.
Costs recoverable when charging for an investigational drug.
A sponsor may recover only the direct costs of making its investigational drug available.
Waivers of CFR 312
A sponsor may request FDA to waive applicable requirement under this part.
what is subpart B?
IND application
Requirement for an IND
- A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to 312.
- A sponsor shall not begin a clinical investigation subject t0 312 until the investigation is subject to an IND
- A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent
Phases of an investigation
An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases.
Phase 1
the initial introduction of an investigational new drug into humans.
- closely monitored and may be conducted in patients or normal volunteer subjects.
- designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.
of subjects- range of 20 to 80.
Phase 2
- the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication 2. to determine the common short-term side effects and risks associated with the drug.
- well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.
Phase 3
- expanded controlled and uncontrolled trials. performed after preliminary evidence suggesting effectiveness of the drug has been obtained,
- intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship
- include from several hundred to several thousand subjects.
IND content and format.
11 sections
- Cover sheet (Form FDA-1571)
- A table of contents.
- Introductory statement and general investigational plan
- Investigators Brochure
- Protocols
- Chemistry, manufacturing, and control information.
- Pharmacology and toxicology information.
- Previous human experience with the investigational drug
- Additional information
- Relevant information
Protocol amendments
Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application. Including
- new protocols
- change in protocol
- new investigator
Information amendment
A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report.
Adverse event
any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
Life-threatening adverse event or life-threatening suspected adverse reaction
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death
Serious adverse event or serious suspected adverse reaction
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect
Suspected adverse reaction
any adverse event for which there is a reasonable possibility that the drug caused the adverse event
Unexpected adverse event or unexpected suspected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan
Review of safety information
The sponsor must promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the United States.
IND safety reports
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days
Annual reports
A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation
- study information
- summary all SAEs
- investigational plan
- outstanding business with fda
Withdrawal of an IND
At any time a sponsor may withdraw an effective IND without prejudice.
- If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall be ended, all current investigators notified, and all stocks of the drug returned to the sponsor
- If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all participating investigators, and all reviewing IRB
What is subpart c?
Administrative Actions
clinical hold
an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND
Clinical hold on phase 1 study
- Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury;
- The clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND;
- The investigator brochure is misleading, erroneous, or materially incomplete; or
- The IND does not contain sufficient information required to assess the risks to subjects of the proposed studies.
- The IND is for the study of an investigational drug intended to treat a life-threatening disease or condition that affects both genders, and men or women with reproductive potential
clinical hold on phase 1 or 2 study
- .The expanded access IND or expanded access protocol does not comply with the requirements for expanded access submissions in subpart I of this part.
(ii) Ongoing use. FDA may place an ongoing expanded access IND or expanded access protocol on clinical hold if it is determined that the pertinent criteria in subpart I of this part for permitting the expanded access are no longer satisfied.
When is an IND needed?
5 reasons
- new entity (chemical)
- new unapproved indication (usage)
- new dosage form
- new dosage level
- new drug combination
when is an IND not needed?
drug not intended for human use
approved drug is used within the approved indication
sponsor
responsible for funding a clinical trial (pharmaceutical, device, academic, or government institution)
Emergency use IND
compassionate use
reserved for life threatening situations with no other treatment available and not sufficient time to go through process
Form 1571
for initial IND submission
-contract between sponsor and FDA
Form 1572
contract with the FDA for the conduct of the clinical trial (between PI and FDA)
SAE
serious adverse event
death life threatening hospitalization disability congenital abnormality
What needs to be reported to the FDA?
adverse events and safety reporting
protocol amendments
annual reports
safety reporting regulations
Use MEDWATCH form 3500 Aa to submit to FDA or CIOMs form
- 7 day reporting period for death and life threatening events
- 15 day reporting for SAEs
protocol amendmendments
- protocol changes
- personnel changes
- submit modified 1572 form
- information amendments
investigational brochure (IB)
part of the 1571 IND application- mandatory for all new drugs
- sponsors provide all investigators with the IB
- sponsors provides updates on IB as related to safety and adverse events
IB contents
- table of contents
- summary
- introduction
- physical properties
- non clinical studies
- non clinical pharmacology
