Final Rule on Safety Reporting Emphasizes Causality, Timeliness

Investigational new drugs, including biologic drugs, will face new safety reporting requirements designed to increase timeliness as well as decrease unnecessary reporting of events not likely to be causal.

The changes bring the Food and Drug Administration’s reporting policies in line with international agencies, including the World Health Organization, in an effort to “help ensure harmonized reporting of globally conducted clinical trials.”

The requirements are the result of a final rule issued by the FDA and published in the Federal Register on Sept. 29.

The rule represents the culmination of work on a proposed rule, issued in 2003, and will go into effect 180 days from its publication, according to Karen Riley, an FDA spokeswoman.

Investigational new drug (IND) applications are submitted to the FDA prior to the onset of clinical trials. IND must be filed for any approval request, regardless of whether it is an application for a wholly novel compound or an application for a new indication of existing drugs, according to the agency.

Safety reports on these INDs must be submitted to the FDA and assessed by institutional review boards before clinical trials can begin.

Under the former rule, “sponsors investigating a drug ... were required to notify FDA and all participating investigators, in a written IND safety report, of any adverse experience associated with the use of the drug that was both serious and unexpected, and any finding from tests in laboratory animals that suggested a significant risk for human subjects.”

This requirement often resulted in reporting of events not likely to be associated with the drug, bogging down the agency and leading to slower recognition of truly causal effects, according to the draft guidance.

According to the new rule, rather than submitting details about all adverse events, applicants may submit only “suspected adverse reactions,” defined as events for which there is “evidence to suggest a causal relationship between the drug and the adverse event,” according to a FDA draft guidance for investigators.

For example, any “single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson syndrome)” would meet this definition, as well as “one or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture),” according to the guidance.

Other reportable findings include data concerning bioequivalence of generic biologic drugs, compared with their name-brand counterparts – for example, differing rates of absorption into the bloodstream.

Another change concerns timeliness of reporting. The new rules clarify that “expedited” reporting must occur within 15 days of the drug sponsor determining that given data meet the qualifications for reporting.

“For a serious and unexpected suspected adverse reaction from a clinical trial, this would be the day the sponsor receives information from the clinical investigator,” states the rule.

Moreover, it clarifies that “If any information necessary to evaluate and report the suspected adverse reaction is missing or unknown, the sponsor should actively seek such information.”

In a press release, Dr. Rachel E. Behrman, the associate director for medical policy at the FDA’s Center for Drug Evaluation and Research (CDER), said, “This final rule will expedite FDA’s review of critical safety information and help the agency monitor the safety of investigational drugs and biologics.”

“These changes will better protect people who are enrolled in clinical trials.”

Disclosures: None was reported.

Investigational new drugs, including biologic drugs, will face new safety reporting requirements designed to increase timeliness as well as decrease unnecessary reporting of events not likely to be causal.

The changes bring the Food and Drug Administration’s reporting policies in line with international agencies, including the World Health Organization, in an effort to “help ensure harmonized reporting of globally conducted clinical trials.”

The requirements are the result of a final rule issued by the FDA and published in the Federal Register on Sept. 29.

The rule represents the culmination of work on a proposed rule, issued in 2003, and will go into effect 180 days from its publication, according to Karen Riley, an FDA spokeswoman.

Investigational new drug (IND) applications are submitted to the FDA prior to the onset of clinical trials. IND must be filed for any approval request, regardless of whether it is an application for a wholly novel compound or an application for a new indication of existing drugs, according to the agency.

Safety reports on these INDs must be submitted to the FDA and assessed by institutional review boards before clinical trials can begin.

Under the former rule, “sponsors investigating a drug ... were required to notify FDA and all participating investigators, in a written IND safety report, of any adverse experience associated with the use of the drug that was both serious and unexpected, and any finding from tests in laboratory animals that suggested a significant risk for human subjects.”

This requirement often resulted in reporting of events not likely to be associated with the drug, bogging down the agency and leading to slower recognition of truly causal effects, according to the draft guidance.

According to the new rule, rather than submitting details about all adverse events, applicants may submit only “suspected adverse reactions,” defined as events for which there is “evidence to suggest a causal relationship between the drug and the adverse event,” according to a FDA draft guidance for investigators.

For example, any “single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson syndrome)” would meet this definition, as well as “one or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture),” according to the guidance.

Other reportable findings include data concerning bioequivalence of generic biologic drugs, compared with their name-brand counterparts – for example, differing rates of absorption into the bloodstream.

Another change concerns timeliness of reporting. The new rules clarify that “expedited” reporting must occur within 15 days of the drug sponsor determining that given data meet the qualifications for reporting.

“For a serious and unexpected suspected adverse reaction from a clinical trial, this would be the day the sponsor receives information from the clinical investigator,” states the rule.

Moreover, it clarifies that “If any information necessary to evaluate and report the suspected adverse reaction is missing or unknown, the sponsor should actively seek such information.”

In a press release, Dr. Rachel E. Behrman, the associate director for medical policy at the FDA’s Center for Drug Evaluation and Research (CDER), said, “This final rule will expedite FDA’s review of critical safety information and help the agency monitor the safety of investigational drugs and biologics.”

“These changes will better protect people who are enrolled in clinical trials.”

Disclosures: None was reported.

Investigational new drugs, including biologic drugs, will face new safety reporting requirements designed to increase timeliness as well as decrease unnecessary reporting of events not likely to be causal.

The changes bring the Food and Drug Administration’s reporting policies in line with international agencies, including the World Health Organization, in an effort to “help ensure harmonized reporting of globally conducted clinical trials.”

The requirements are the result of a final rule issued by the FDA and published in the Federal Register on Sept. 29.

The rule represents the culmination of work on a proposed rule, issued in 2003, and will go into effect 180 days from its publication, according to Karen Riley, an FDA spokeswoman.

Investigational new drug (IND) applications are submitted to the FDA prior to the onset of clinical trials. IND must be filed for any approval request, regardless of whether it is an application for a wholly novel compound or an application for a new indication of existing drugs, according to the agency.

Safety reports on these INDs must be submitted to the FDA and assessed by institutional review boards before clinical trials can begin.

Under the former rule, “sponsors investigating a drug ... were required to notify FDA and all participating investigators, in a written IND safety report, of any adverse experience associated with the use of the drug that was both serious and unexpected, and any finding from tests in laboratory animals that suggested a significant risk for human subjects.”

This requirement often resulted in reporting of events not likely to be associated with the drug, bogging down the agency and leading to slower recognition of truly causal effects, according to the draft guidance.

According to the new rule, rather than submitting details about all adverse events, applicants may submit only “suspected adverse reactions,” defined as events for which there is “evidence to suggest a causal relationship between the drug and the adverse event,” according to a FDA draft guidance for investigators.

For example, any “single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson syndrome)” would meet this definition, as well as “one or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture),” according to the guidance.

Other reportable findings include data concerning bioequivalence of generic biologic drugs, compared with their name-brand counterparts – for example, differing rates of absorption into the bloodstream.

Another change concerns timeliness of reporting. The new rules clarify that “expedited” reporting must occur within 15 days of the drug sponsor determining that given data meet the qualifications for reporting.

“For a serious and unexpected suspected adverse reaction from a clinical trial, this would be the day the sponsor receives information from the clinical investigator,” states the rule.

Moreover, it clarifies that “If any information necessary to evaluate and report the suspected adverse reaction is missing or unknown, the sponsor should actively seek such information.”

In a press release, Dr. Rachel E. Behrman, the associate director for medical policy at the FDA’s Center for Drug Evaluation and Research (CDER), said, “This final rule will expedite FDA’s review of critical safety information and help the agency monitor the safety of investigational drugs and biologics.”

“These changes will better protect people who are enrolled in clinical trials.”

Disclosures: None was reported.