Compassionate Use Navigator – Safety reports requirements
FDA requires all sponsors of IND applications, including physicians who administer an investigational drug to a patient, to report adverse events.
See the Reporting Requirements Chart
What to report?
As a treating physician, you must report any suspected adverse reaction to treatment that is both serious and unexpected in an IND Safety Report. Before submitting an IND Safety Report, you need to ensure the event meets all three of the definitions:
• Suspected adverse reaction;
• Serious;
• Unexpected.
If the adverse event does not meet all three of the definitions, it should not be submitted as an IND Safety Report.
Adverse reaction is an adverse event where there is a reason to conclude that the drug caused the event. A suspected adverse reaction is an adverse event for which there is a reasonable possibility that it is caused by the drug. For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event.
Serious adverse event refers to an event that results in the following outcomes:
• death;
• a life-threatening adverse event (places the patient at immediate risk of death);
• in-patient hospitalization or prolongation of an existing hospitalization;
• a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.
Unexpected adverse event refers to an event that is not consistent with previously described risk information, or occurs at a specificity or severity that has not been previously observed. This definition is also used in the absence of an investigator’s brochure in which observed adverse events are described.
Deciding whether an adverse event meets the definition of a suspected adverse reaction can be difficult, but this decision is critical to avoid the submission of uninformative IND safety reports. You should evaluate the available information and decide whether there is a reasonable possibility that the drug caused the adverse event.
Any relevant additional information which becomes available and is necessary to evaluate the suspected adverse reaction that pertains to a previously submitted IND safety report must be submitted as a Follow-up IND Safety Report.
When to report?
• Serious and unexpected adverse events that are fatal or life-threatening must be reported to FDA as soon as possible, and no later than 7 days after they occur.
• Suspected adverse reactions or other safety information that are not serious or life-threatening must be reported no later than 15 calendar days after the event.
• A Follow-Up IND Safety Report should be submitted as soon as new information is available, and no later than 15 calendar days after you receive the information. If the safety report submitted within 7 calendar days is complete, an additional submission within 15 days from day zero is not required.
• At the conclusion of treatment, you must provide FDA with a written summary of the results of the expanded access use, including adverse effects, the patient’s response, drug disposition, and other relevant information. When submitting this summary report, you may request FDA to close the IND application.
• If the investigational treatment continues for a year or longer, there is a requirement to submit an annual report to FDA for any year during which your patient has received the investigational drug. You will need to submit a brief report of the progress within 60 days of the anniversary from the date when the original IND application went into effect.
Who to report to?
In addition to reporting to the FDA, you need to report to the drug company and your IRB.
The FDA believes that the pharmaceutical company is better positioned than the individual investigator to assess the overall safety of the investigational drug because it has access to serious adverse event reports from multiple study sites and multiple studies and is able to aggregate and analyze these reports. The company is also more familiar with the drug’s mechanism of action, class effects, and other information. For these reasons, investigators must immediately report any serious adverse event to the company, whether or not the investigator considers the event to be drug related. Drug companies can impose additional reporting requirements when they provide the drug.
You might also have an obligation to report adverse events to your IRB. In general, when an adverse event meets the criteria for reporting it to FDA, it should also be considered an “unanticipated problem” and reported to the IRB.
How to report?
Safety reports to FDA must be submitted by email, fax or telephone to the Review Division that authorized the expanded access request. Use FDA Form 3500A together with Form 1571. See Instructions for completing Form 3500A and Instructions for completing Form 1571.
Protocol amendments
After an IND application has gone into effect, you may amend the application as needed. You are expected to submit protocol amendments for new protocols or changes to existing protocols before implementation of any changes. Amendments could include any increase in drug dosage or duration of therapy beyond that described in the current protocol, change in the design of a protocol, addition or elimination of a test or procedure, or addition of a new investigator. If the amendment concerns change in application sponsor or addition of a new investigator, Form 1572 should be included in addition to Form 1571.
More information
Please use the Reporting Requirements Chart for links to reporting forms and deadlines.
For detailed explanation of the definitions, requirements, and procedures related to IND application safety reports and the responsibilities of IND applications sponsors with regard to such reporting, see Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies (PDF).
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