21 CFR Part 312

Question 1

What does 21 CFR part 312 cover?

Answer 1

INDs (Investigational New Drug Applications)

Question 2

What are the FDAs 2 primary objectives in reviewing an IND?

Answer 2

1) To assure the safety and rights of subjects
2) In Phase 2 & 3 studies - to help assure the quality of studies is adequate to permit an evaluation of the drug’s effectiveness and safety

Question 3

What are the contents of an IND?

Answer 3

1) Cover sheet
2) A table of contents
3) Introductory statement and general investigational plan
4) IB
5) Protocols - A protocol for each planned study
6) Chemistry, manufacturing and control information for the drug product
7) Pharmacology and toxicology information
8) Previous human experience with the investigational drug
9) Additional information on special topics as needed (drug dependence/abuse potential, radioactive drugs, pediatric studies)
10) Other relevant information requested by the FDA

Question 4

If an investigation involves an exception from informed consent, how does this impact the IND submission?

Answer 4

The sponsor shall prominently identify on the cover sheet that the investigation is subject to the requirements of 21 CFR 50.24 (exception from informed consent requirements for emergency research)

Question 5

An investigational new drug for which an IND is in effect may be __________ lawfully for the pruposes of conducting clinical investigations of the drug.

Answer 5

Shipped

Question 6

What are the two requirements for the labeling of an investigational new drug?

Answer 6

1) The label must state, “Caution: New Drug - Limited by Federal (or US) law to investigational use”
2) The label shall not bear any statement that is false/misleading or represents that the drug is safe/effective for the purposes under investigation

Question 7

Which phase of an investigation includes the initial introduction of an investigational new drug into humans?

Answer 7

Phase 1 - designed to determine metabolism and pharmacologic actions of drug in humans & side effects with increasing doses (usually 20 - 80 subjects)

Question 8

Which phase of an investigation includes studies conducted to evaluate the effectiveness of the drug & the common short term side effects and risks for a particular indication?

Answer 8

Phase 2 (usually no more than several hundred subjects)

Question 9

Which phase of an investigation includes studies conducted to evluate the overall benefit-risk relationship of the drug and provide an adequate basis for labeling?

Answer 9

Phase 3 (usually include several hundred to several thousand subjects)

Question 10

A protocol change intended to eliminate an apparent immediate hazard to subjects may be implemented immediately provided the FDA is subsequently notified by protocol amendment and the IRB is notified within ____ working days.

Answer 10

5 WORKING days

Question 11

A sponsor shall notify the FDA of a new investigator within _____ days of the investigator being added to a protocol.

Answer 11

30 days

Question 12

For the purposes of IND safety reporting, what is an Adverse Event?

Answer 12

Any untoward medical occurrence associated with the use of a drug in humans, WHETHER or NOT considered drug related. (This is the same for ICH E2A)

Question 13

For the purposes of IND safety reporting, what is a Serious Adverse Event?

Answer 13

An AE is considered serious if it results in any of the following outcomes:
1) Death
2) Life-threatening outcome
3) Inpatient hospitalization or prolongation of hospitalization
4) Persistent or significant incapacity/disability
5) Congenital anomaly/birth defect
(This is the same for ICH E2A)

Question 14

For the purposes of IND safety reporting, what is a Suspected Adverse Reaction?

Answer 14

Any adverse event for which there is a reasonable possibility that the drug caused the AE (Equivalent to Adverse Drug Reaction in ICH E2A)

Question 15

For the purposes of IND safety reporting, what is an Unexpected AE or Unexpected Suspected Adverse Reaction?

Answer 15

An AE or suspected adverse reaction not listed in the IB or not listed at the specificity or severity that has been observed. (Unexpected Suspected Adverse Reaction = Unexpected Adverse Drug Reaction in ICH E2A)

Question 16

How soon must the sponsor submit an IND safety report to the FDA (and all participating investigators) notifying them of the potential for serious harm?

Answer 16

In no less than 15 CALENDAR days after the sponsor determines that the information qualifies for reporting.

Question 17

What 4 circumstances qualify for IND safety reporting?

Answer 17

1) Serious AND unexpected suspected adverse reaction (i.e. evidence to suggest relationship between the drug and the adverse event)
2) Findings from other studies that suggest a significant risk in humans exposed to the drug
3) Findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug
4) Increased rate of occurrence of serious suspected adverse reactions

Question 18

In the event of an Unexpected, Fatal or Life-threatening, Suspected Adverse Reaction, how many days does the sponsor have to notify the FDA after initial receipt of the information?

Answer 18

7 CALENDAR days (same as ICH E2A)

Question 19

Within _____ days of the anniversary date that the IND went into effect, the ________ shall submit a brief annual report to the FDA

Answer 19

60 days

Sponsor

Question 20

An IND goes into effect ____ days after the FDA receives the IND, unless the FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold.

Answer 20

30 days; FDA will notify the sponsor of the date of receipt in writing

This is the same for an expanded access IND

Question 21

A Sponsor may ship an investigational new drug to investigators ____ days after FDA receives the IND

Answer 21

30 days

Question 22

What is the consequence of a clinical hold for a proposed study vs. an ongoing study?

Answer 22

> Proposed study - subjects may not be given the investigational drug
Ongoing study - new subjects may not be recruited & patients already in the study should be taken off therapy unless specifically permitted by the FDA in the interest of patient safety

Question 23

What are the 5 grounds for a clinical hold of a Phase 1 study?

Answer 23

1) Subjects exposed to unreasonable and significant risk
2) Clinical investigators named in the IND are not qualified
3) IB is misleading, erroneuous, or incomplete
4) IND doesn’t contain sufficient info to assess risks
5) If the drug is intended to treat a life-threatening condition and people of reproductive potential are excluded due to potential for reproductive or developmental toxicity

Question 24

What is the additional grounds for a clinical hold of a Phase 2 or 3 study?

Answer 24

The protocol is deficient to meet stated objectives

Question 25

When can an investigation resume after a clinical hold?

Answer 25

After the SPONSOR corrects the deficiencies and the FDA has notified the sponsor that the investigation may proceed.

Question 26

An IND is converted to inactive status after ____ year(s) on clinical hold.

An IND is terminated after ____ year(s) on inactive status.

Answer 26

1+ years

5+ years

Question 27

When can an investigation resume after inactive status?

Answer 27

30 days after the FDA receives a protocol amendment from the Sponsor, unless FDA notifies the sponsor of a clinical hold.

Question 28

What are the SPONSOR’s responsibilities according to 21 CFR 312?

Answer 28

1) Select qualified investigators
2) Provide investigators with info needed to conduct the study
3) Ensure proper monitoring
4) Ensure study is conducted according to the protocol
5) Maintain the IND
6) Promptly notify FDA and investigators of significant new risks

Question 29

An Investigator must update financial disclosure information for ____ year(s) following completion of the study.

Answer 29

1 year (same for 21 CFR 812 - IDEs)

Question 30

If a sponsor determines that an investigational drug presents an unreasonable and significant risk to subjects, the sponsor shall discontinue the investigation as soon as possible and in no event later than ___ days after making the determination.

Answer 30

5 WORKING days

Question 31

How long shall a Sponsor or Investigator retain records and reports required by 21 CFR 312?

Answer 31

For 2 years after
a) a marketing application is approved for the drug
b) shipment and delivery of the drug for investigational use is discontinued (and the FDA is notified)

Question 32

What are the INVESTIGATOR’s responsibilities according to 21 CFR 312?

Answer 32

1) Ensure the study is conducted according to plan and applicable regulations
2) Protect the rights, safety and welfare of subjects
3) Obtaining informed consent
4) Control of the investigational drug(s)

Question 33

In the event of an emergency that requires a patient to be treated before a written submission can be made, the FDA may authorize expanded access use by telephone. In this case the physician or sponsor must agree to submit an expanded access submission within ____ days of the FDA’s authorization of use.

Answer 33

15 WORKING days