What s New in GCP? FDA Clarifies, Expands Safety Reporting Guidance

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1 Vol. 9, No. 2, February 2013 Happy Trials to You What s New in GCP? FDA Clarifies, Expands Safety Reporting Guidance Reprinted from the Guide to Good Clinical Practice with permission of Thompson Publishing Group, th St., Washington, D.C ; To learn more about the Guide to Good Clinical Practice, visit: FDA Clarifies, Expands Safety Reporting Guidance The FDA s final guidance on reporting clinical trial safety data, released Dec. 20, adds new sections on adverse event reporting to institutional review boards and the duration of safety reporting. The agency said the final guidance contains the definitions used for IND safety reporting, makes recommendations on when and how to submit a safety report, and provides advice on other safety reporting issues that have generated questions from sponsors and investigators. In 2010, the FDA issued a final rule and draft guidance clarifying the reporting of clinical trial safety data. The final rule was intended to improve the utility and quality of safety reports, expedite and strengthen FDA s ability to review critical safety information, and better protect human subjects enrolled in clinical trials. Reporting to IRBs Clarified The final guidance notes that although the rule on IND safety reporting does not directly address safety reporting by investigators to IRBs, questions have arisen about its impact on adverse event reports to IRBs, particularly with respect to the specific adverse events considered to be unanticipated problems that must be reported to the IRB. In general, a report that meets the criteria for reporting in an IND safety report should also be considered an unanticipated problem and reported to the IRB by the investigator. The guidance added that it was important to note that some events that would not meet the criteria for reporting in an IND safety report would be considered unanticipated problems involving risk to human subjects (e.g., informed consent or privacy issues, and certain adverse events that could not be caused by the investigational drug, such as events that occur prior to test article administration as a result of a washout period or due to a screening procedure). As part of their clinical trial monitoring responsibility, sponsors generally require that investigators report such unanticipated problems to them. Sponsors should discuss any significant unanticipated problem with the applicable FDA review division, as the problem may affect trial conduct and subject monitoring, the guidance said. As to the duration of safety reporting, the final guidance said that once clinical sites are no longer enrolling or monitoring patients, safety information is no longer needed. The FDA said the cutoff dates for sending IND safety reports to investigators may be described in the protocol. If no cutoff dates are specified, once a site has been officially closed out, the sponsor usually does not need to continue sending IND safety reports to that site, and an investigator does not need to receive or review them. If the sponsor continues to send IND safety reports to the investigator and the investigator does not wish to continue receiving them, the investigator should contact the sponsor and request that the sponsor stop sending them.

2 However, in unusual cases, safety information related to delayed toxicity may be reported after a site is officially closed out. For example, if a late toxicity is discovered that would affect subjects who received the investigational drug, the investigator should be notified so that patients could be followed up if necessary, the guidance said. Harmonized to a Point Although one of the aims of the final rule was to make the FDA reporting standards more consistent with the International Conference on Harmonization (ICH) standards and to ensure harmonized reporting of globally conducted clinical trials, the final guidance makes clear that there is a difference between this rule and ICH E2A guidance with respect to who is responsible for making the causality judgment. The sponsor is responsible for making the causality judgment for this rule, whereas the ICH E2A guidance recommends that the judgment be based on either the investigator s or the sponsor s opinion. However, the guidance reiterates that the investigator s view is important for the sponsor to consider when assessing the safety of the drug and determining whether to report an event expeditiously to FDA, because the investigator is knowledgeable about the subject s clinical state (e.g., medical history, concomitant medications) and thus may be sensitive to distinctions between events that may be related to the drug versus those due to the underlying disease process and/or concomitant therapies. The guidance notes that when new adverse event information is received, it is the sponsor s responsibility to determine whether the event is unexpected for IND safety reporting purposes. In the clinical trial setting, there has been some confusion with the term expected, as it has been used to mean anticipated for the disease being treated or population being studied rather than listed in the investigator brochure. For example, some adverse events can be anticipated to occur as a result of a disease or in an older population (e.g., cancer-related deaths in a cancer trial, strokes or acute myocardial infarctions in an older population). However, for reporting purposes, these anticipated events are not expected because they are not listed in the investigator brochure (i.e., the test drug is not suspected or known to cause them). The FDA added that the definition of serious in the regulation differs slightly from the ICH E2A guidance in that the FDA definition uses and rather than or in the sentence: Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. We will accept application of either the FDA definition (i.e., and ) or the ICH E2A guidance criteria (i.e., or ) in determining the seriousness of an event, the guidance said. Who Is a Participating Investigator? The final guidance noted that the sponsor is required to notify the FDA and all participating investigators of potentially serious risks from clinical trials or any other source as soon as possible. Participating investigators include all investigators participating in clinical trials under an IND, at U.S. and non-u.s. sites, for the investigational drug, and any investigators conducting a study under their own IND for whom the sponsor provides investigational drug, the agency said. The final guidance emphasizes that the analysis of a suspected adverse reaction in light of previous, similar reports or any other relevant information must include similar reports from all INDs held by the sponsor and any other relevant information known to the sponsor including those that occurred in the placebo or active comparator group. 2

3 In addition to updating the investigator brochures with new safety information, as was stated in the draft guidance, sponsors also should update the protocol and informed consent forms, the final guidance said. The guidance noted that 21 C.F.R (c)(1)(ii) requires the sponsor to report findings from other studies that suggest a significant risk in humans, whether or not conducted under an IND and whether or not conducted by the sponsor. Therefore, as long as the sponsor maintains an open IND for a drug marketed or approved in the United States, safety information from foreign and domestic studies, including non-ind studies, must be reported to the IND and in accordance with the postmarketing requirements, if it meets the criteria for reporting. For example, if an applicant of a drug marketed or approved in the United States sponsors a multicenter, multinational clinical trial for a new indication, where the domestic sites are included in an IND, adverse events from the clinical trial, whether or not the foreign sites are also conducted under the IND, must be promptly evaluated and reported if they qualify for reporting under 21 C.F.R and the postmarketing requirements, the guidance said. If the same applicant or sponsor receives a spontaneous report of an adverse event from U.S. or foreign commercial marketing experience for a drug that is also under investigation, the report would not need to be reported to the IND because it is not a suspected adverse reaction observed in a study, but would need to be reported in accordance with the postmarketing reporting requirements if it meets the criteria for reporting. Investigator Causality Assessments The final guidance also provides more detail on sponsor reviews of investigator causality assessments. For serious events that are unexpected, the sponsor considers the investigator s causality assessment but submits an IND safety report only for those events for which the sponsor determines there is a reasonable possibility that the drug caused the event, regardless of the investigator s causality assessment. (See chart below that clarifies sponsor and investigator responsibilities for reporting.) The agency provided two examples: The sponsor would not report events for which the investigator s assessment is positive for causality, but where the sponsor s evaluation did not find evidence to suggest a causal relationship between the drug and the event. The sponsor would report events for which the investigator s assessment is negative for causality, but where the sponsor s evaluation found evidence to suggest a causal relationship between the drug and the event. The investigator s assessment of causality should be included in the report submitted to the sponsor, the guidance said. If the investigator fails to provide a causality assessment and the sponsor is unable to obtain it, or if the investigator assesses the causality as unknown, the sponsor should evaluate the event without the investigator s assessment. As for investigator reporting, the FDA said that it recognizes that it may take the investigator a short period of time (i.e., a day) to compile information about the event, but then expects the information to be immediately reported to the sponsor. Investigators are not required to determine whether an event is unexpected, as defined in 21 C.F.R (a). This is a sponsor responsibility. The guidance added that although it is the exception, immediate reporting of all serious adverse events to the sponsor may not be necessary in certain trials if the events are expected and well-defined. For example, many oncologic clinical trials use drugs with known serious hematologic adverse reactions and immediate reporting of each serious adverse 3

4 event may not be useful. In these cases, the sponsor may propose an alternative reporting arrangement by identifying and describing the alternative reporting arrangement in the protocol or by requesting a waiver. The review division that has responsibility for the IND must agree to any alternative reporting arrangements (21 C.F.R (c)(3) and 21 C.F.R ). Reporting Responsibilities of Investigators under 21 C.F.R (b) and Sponsors under 21 C.F.R (c)(1)(i) for Serious and Unexpected Suspected Adverse Reaction 4

5 Aggregate Analysis Discussed Under its discussion of aggregate analysis of specific events, the agency added: 21 C.F.R (c)(1)(i)(C) requires reporting in an IND safety report when an aggregate analysis of specific events observed in a clinical trial indicates those events occur more frequently in the drug treatment group than in a concurrent control group. In cases where a randomized comparison is not available, the estimate of whether the rate is greater than in a control population would have to be based on some other group not receiving the drug, such as the general population or populations similar to the drug population with respect to demographics and disease state but not receiving the test drug (e.g., a historical control). An aggregate analysis of specific events should reflect information from all relevant studies. Therefore, it should be performed both for individual studies (if there are enough events to be informative) and across all studies, including across INDs of the drug, to determine whether they meet the criteria for expedited reporting. The guidance also clarified that some serious adverse events can be anticipated to occur. Such anticipated events include known consequences of the underlying disease or condition under investigation, events anticipated from any background regimen, events common in the study population, or re-emergence or worsening of a condition relative to pretreatment baseline, the guidance said. The final guidance added that the fact that an event is not identified in the protocol does not mean that the sponsor must report a single occurrence of the event expeditiously. (The draft guidance used should ). However, FDA will accept expedited reports for individual cases of unexpected serious adverse events that are not study endpoints and are not specified in the protocol as anticipated (e.g., they are known consequences of the disease being treated or common in the study population) to address concerns expressed by sponsors about not expeditiously reporting such cases. The final guidance also notes that the trial blind should ordinarily be broken for IND safety reports submitted to FDA and all participating investigators The agency does not believe that unblinding single or small numbers of serious and unexpected adverse event cases will compromise the integrity of the study, in part because such unblinding should be infrequent. For example, because the requirement under 21 C.F.R (c)(5) specifically describes different reporting requirements for study endpoints, in a trial evaluating death, myocardial infarctions, and strokes as endpoints, a case of liver injury, if unblinded, would have no effect on overall study integrity. The guidance added that to comply with the requirements for IND safety reports based on data in the aggregate, the sponsor should have in place a systematic approach for evaluating the accumulating safety data. A data monitoring committee or an independent sponsor safety team could perform this function. FDA Answers Questions for Small Entities The agency also released a short guidance on small entity compliance that emphasized that safety reporting requirements apply to sponsor-investigators as well as sponsors. The compliance guide answers eight frequently asked questions including: How does a sponsor or sponsor-investigator conducting one trial comply without access to all of the safety data from other entities? The FDA recognizes that a sponsor or sponsor-investigator may not have access to the complete safety data maintained by a commercial sponsor, but sponsors and sponsor-investigators are required to evaluate all safety information that is available to them to determine whether the information qualifies for reporting. For example, sponsors and sponsorinvestigators should examine reports in the scientific literature and perform literature 5

6 searches to actively seek new safety information about the drug under investigation. To protect human subjects, the agency recommends that entities that provide drug to or receive drug from other entities share safety information with each other. How do sponsors comply with the aggregate reporting requirement (21 C.F.R (c)(1) (i)(c))? In general, sponsors should have a predefined safety monitoring plan that includes processes and procedures for the review, evaluation, and management of safety information. For reporting events in the aggregate, sponsors should perform an aggregate analysis of specific events both for individual studies and across all studies, including across INDs of the drug, to determine whether they meet the criteria for expedited reporting under 21 C.F.R (c)(1)(i)(C) or 21 C.F.R (c)(1)(iv). As discussed in the previous question, the sponsor should perform these analyses on the data available to them. The guidance also provides more detailed guidance regarding the submission of an IND safety report and notes the format for the report is based on the type of expedited report individual cases, aggregate reports, and other reports. To Find Out More The small entity compliance guide is available at s/ucm pdf. Other Recent Developments in the Guide to Good Clinical Practice Empirical Data Needed To Assess Research Enterprise Sponsors Need To Address Compassionate Use IOM Workshop Considers Large, Simple Trials 6