21 CFR Part 312

Question 1

When does an investigational product not need an IND?

Answer 1

A drug product lawfully marketed in the USA is exempt from having an IND If:
1) Study is not being reported to FDA for new indication or to support any significant change in drug labeling
2) The drug is lawfully marketed as a prescription and the investigation is not intended to support a significant change in advertising
3) Does not involve a route of administration, dose, or patient population, or other factors that significantly increase risk (or decrease acceptability of the risks)
4) Conducted in compliance with requirements for IRB review and consent
5) It is a diagnostic biological product that is intended to be used in a procedure to confirm a diagnosis made by another medically established diagnostic product/procedure
6) The drug is intended solely for tests in vitro or in laboratory research animals
7) INDs do not apply to use in the practice of medicine for an unlabeled indication

Question 2

What is the topic of 21 CFR Part 312?

Answer 2

INDs

Question 3

Can sponsors charge for investigational drugs?

Answer 3

Yes - under specific circumstances.

Question 4

Can sponsors get waivers for INDs?

Answer 4

Yes - via IND application, IND amendment or, in an emergency, via phone or other rapid communication. Must explain why compliance is unnecessary or cannot be achieved, description of alternative submission, or other information justifying a waiver. FDA may grant if no significant & unreasonable risk to subjects & they agree with the justification.

Question 5

IND requirements

Answer 5

1) the sponsor intends to conduct a clinical investigation with an investigational new drug
2) Sponsor can’t start until the IND is in place
3) Sponsor submits a separate IND for any clinical investigation involving an exemption of informed consent.

Question 6

Phase 1 studies

Answer 6

First in humans. Patients or normal volunteers. Designed to determine metabolism and pharmacologic actions of the drug in humans, side effects associated with increasing dose, and if possible, gain early evidence of effectiveness.

Question 7

How many subjects are generally included in Phase 1 studies?

Answer 7

20-80

Question 8

Phase 2 studies

Answer 8

Evaluate the effectiveness of the drug for a particular indication(s) in pts with the disease or condition under study. Determine short term side effects & risks.

Question 9

How many subjects are generally included in Phase 2 studies?

Answer 9

No more than several hundred

Question 10

Phase 3 studies

Answer 10

Expanded controlled and uncontrolled studies. Performed after preliminary evidence suggests effectiveness of the drug. Intended to gather additional info re: effectiveness & safety to evaluate overall benefit-risk relationship.

Question 11

How many subjects are usually included in Phase 3 studies?

Answer 11

Several hundred to several thousand

Question 12

General principles of IND submission

Answer 12

Assure safety and rights of subjects, & for phase 2 &3 help assure quality of scientific evaluation is adequate to permit eval of effectiveness and safety. Central focus of the initial submission should be on the general investigational plan & protocols for specific human studies. Annual reports serve as the focus for reporting the status of studies being conducted under the IND & the plan for the next year.

Question 13

What are the elements of an IND application?

Answer 13

1. Cover sheet
2. Form FDA 1571
3. Form FDA 1572
4. Introductory statement & general investigational plan
5. Investigator’s Brochure
6. Protocols
7. Chemistry, manufacturing & control info
8. Pharmacology & toxicology info
9. Summary of previous human experience
10. Additional info (Drug dependence & abuse issues, radioactive info, peds safety & effectiveness, etc)
11. Other relevant info requested by FDA

Question 14

How are IND submissions numbered?

Answer 14

Serially using a 3 digit number. Initial submission is 000.

Question 15

When is an IND amendment required for an amended protocol?

Answer 15

If it is a phase 1 study and the amendment significantly affects the safety of subjects. If it is a phase 2 or 3 study and the amendment affects subject safety, scope of investigation, or scientific quality of the study.

Question 16

Timeline for sponsor to release IND safety reports

Answer 16

Sponsor must notify the FDA and all participating investigators via IND safety report of potential serious risks no later than 15 calendar days after the sponsor determines that the information qualifies for reporting. Sponsor must identify all previous reports submitted to the FDA for similar suspected AEs, and analyze the significance of the AE.

Question 17

What are the criteria for requiring an IND safety report?

Answer 17

Suspected adverse reactions if serious and unexpected. AEs if there is evidence to suggest a causal relationship:
A) Single occurrence of an uncommon event strongly associated w/drug exposure
B) 1+ occurrences of an event not commonly associated w/drug exposure but uncommon in the population
C) Aggregate analysis of specific events observed that indicate the events occur more frequently in the tx group than concurrent or historical control group.

Question 18

How are IND safety reports submitted?

Answer 18

Either in narrative format or on FDA Form 3500A (Medwatch Form)

Question 19

Timeline for submitting unexpected fatal or life-threatening suspected adverse reactions?

Answer 19

Sponsor must submit to the FDA as soon as possible but no later than 7 calendar days after sponsor’s initial receipt of the information.

Question 20

Events requiring an IND safety report other than serious and unexpected suspected adverse reactions?

Answer 20

1. Findings from other studies that suggest a significant risk in humans exposed to the drug (would normally result in change of protocol/consent/IB/etc).
2. Findings from animal or in vitro testing that suggest significant risk in humans exposed to the drug.
3. Increased rate of occurrence of serious suspected adverse reactions over that listed in the protocol or IB.

Question 21

Reporting timelines for AEs not previously determined to be reportable but are now reportable

Answer 21

Sponsor must report such suspected adverse reactions in an IND safety report as soon as possible but no later than 15 days after the determination is made.

Question 22

When are IND annual reports due?

Answer 22

Within 60 days of the anniversary date that the IND went into effect.

Question 23

What is the purpose of conducting clinical investigations of a drug?

Answer 23

To distinguish the effects of a drug from other influences, such as spontaneous change in the course of disease, placebo effect, or biased observations

Question 24

Phase IV Clinical trials

Answer 24

Post-approval surveillance

Question 25

How does 21 CFR 312 differ from ICH E6 on the use of CROs?

Answer 25

They both allow delegation (in writing) of sponsor responsibilities to a CRO. ICH specifies though that the sponsor must ensure oversight even if a CRO is used.

If all duties are delegated the FDA allows a general statement to this effect to be used. ICH does not.

Question 26

What does 21 CFR 312 say about sponsor responsibilities for monitoring?

Answer 26

Only that the sponsor is responsible for ensuring proper monitoring of the investigation. ICH E6 is more specific.

Question 27

What is a “cross-reference letter” used for?

Answer 27

Provided by the drug manufacturer, enabling a sponsor-investigator to reference the following technical information from the manufacturer’s IND in the sponsor-investigator’s IND:
- Chemistry, manufacturing, and controls information
- Pharmacology and toxicology information
- Previous human experience with the drug

Question 28

What is a form FDA 1571?

Answer 28

A contractual agreement between a sponsor and the FDA. The sponsor agrees to:
- Not begin clinical investigations until 30 days after FDA receipt of the IND application unless they receive earlier notification
- Not to begin or continue investigations covered by the IND if those studies are placed on a clinical hold
- That an IRB that complies with 21 CFR 56 will be responsible for the trial
- To conduct the study in accordance with all other applicable regulatory requirements

Question 29

How are INDs for marketed products different from INDs for new drugs?

Answer 29

A copy of the approved labeling can be provided for a marketed drug in place of an Investigator Brochure (IB).

Question 30

What types of reports/updates get submitted to the FDA for an IND?

Answer 30

• Protocol Amendments
• Information Amendments (e.g. new toxicology or chemistry information, new technical information, study discontinuation)
• Adverse Events & IND Safety Reports
• Annual Reports
• Final Reports

Question 31

Sponsor-investigator reporting timelines to regulatory authorities and participating investigator for unexpected and serious events?

Answer 31

As soon as possible but no later than 15 calendar days after the sponsor-investigator determines that information received must be reported.

If the event is an adverse reaction that is unexpected, fatal, or life threatening, the timeline is 7 calendar days from learning of the event.

Question 32

When does an AE qualify as an SAE?

Answer 32

When the event results in the following outcomes:
- Death
- Life-threatening adverse drug experience
- Inpatient hospitalization or prolongation of existing hospitalization
- Persistent or significant disability/incapacity
- Congenital anomaly/birth defect