<\/p>\n\n\n\n
![\"Clinical](\"https:\/\/www.socra.org\/blog\/wp-content\/uploads\/2019\/10\/iStock-1018676898-1024x576.jpg\")
<\/figure>\n\n\n\nIntroduction<\/strong><\/h2>\n\n\n\nStudy sites are over-reporting adverse events (AEs) and serious\nadverse events (SAEs) for studies conducted under Investigational New Drug (IND)\napplications. IRBs are required by the U.S. Food and Drug Administration (FDA)\nand the Office of Human Research Protections (OHRP) within the Department of\nHealth and Human Services to review \u201cunanticipated problems involving risks to\nparticipants or others.\u201d <\/p>\n\n\n\n
IntegReview IRB is a central\nIRB that reviews many protocols each year, just as institutional IRBs do. In 2016,\nIntegReview IRB saw an increase in the number of IND safety reports and a\nslight decrease in SAE reports. The reason for these changes is unknown. IntegReview\nIRB is seeing about a four-fold increase in IND safety reports, which is far\nabove the increase in business.<\/p>\n\n\n\n
IRBs receive many IND safety\nreports that are not related to the current protocol at the clinical researchsite.\nThe reports could be about something that is happening in Asia or Europe, a\ndifferent use of the drug, or a different research project. These reports must\nbe processed, even though they are not under the jurisdiction of the IRB for the\ncurrent study, creating information overload.<\/p>\n\n\n\n\n\n\n\n
Unanticipated Problems <\/strong><\/h2>\n\n\n\nWhile protecting research subjects\nis paramount, sending IND safety reports to IRBs for issues that do not meet\nthe definition of an unanticipated problem does not accomplish this. Sponsors often\nsend IND safety reports that are not related to the current study to\ninvestigators and instruct the investigators to submit them to the IRB. Some\nIND safety reports only have part of the necessary information because the\nsituation is evolving.<\/p>\n\n\n\n
The OHRP defines an\nunanticipated problem as any outcome or experience that meets three criteria\n(Table 1). The problem must be unexpected given the nature of the protocol and\nthe study population, related or possibly related to the participation in the\nresearch (any reasonable possibility), and suggest that the research places\nresearch subjects or other people at a greater risk of harm. The harm is\nanything that was not previously known or recognized. It could be psychological,\nsocial, economic, or physical. <\/p>\n\n\n\n
Examples of unanticipated\nproblems include information that changes the risk\/benefit ratio of the\nresearch and an unanticipated adverse device effect. Perhaps something happened\nafter implanting the device in a device study that was not in the protocol or other\ninformation provided to the IRB. This problem is unanticipated. Another example\nis the imminent threat of a reportable event that has not yet occurred, such as\na breach of confidentiality. This could occur if an investigator accidentally\nleaves a laptop with study data in a taxi. Another example is a dosing error,\nsuch as giving a subject a dose that is 10 times the study dose. An\nunanticipated problem may not cause an AE right away. In order to be an\nunanticipated problem, however, the problem must also meet the other criteria of\nbeing related or possibly related to the research and increase the risk of\nharm.<\/p>\n\n\n\n
Over-reporting<\/strong><\/h2>\n\n\n\nThere are four reasons for over-reporting:\nThe protocol design, standard operating procedures, protection, and lack of\ntraining\/tools. Protocols often specify that SAEs must be reported to the\nsponsor and the IRB. Standard operating procedures may also specify that IND\nsafety issues be reported to the IRB. No one will ignore requirements stated in\na protocol or standard operating procedure. Clinical research professionals\nmust protect subjects; however, in today\u2019s litigious society, clinical research\nprofessionals also want to protect themselves, which results in over-reporting.<\/p>\n\n\n\n
Lack of training and tools is\nthe last reason for over-reporting. The OHRP has useful decision trees on its\nwebsite for what should be reported. Different IRBs have different reporting\nrequirements. Knowing the IRB\u2019s requirements will help stop over-reporting of\nIND safety issues.<\/p>\n\n\n\n
Change is not easy. People\ntend to go back to what they know and are used to doing. One solution to over-reporting\nis education to ensure that all clinical research sites and investigators, as\nwell as sponsors and contract research organizations, are informed about what\nneeds to be reported. Standard operating procedures should also be updated to\nreflect current federal regulations.<\/p>\n\n\n\n
Regulations <\/strong><\/h2>\n\n\n\nTable 2 highlights FDA\nregulations for sponsors, investigators, and IRBs. The regulations require sponsors\nto ensure \u201cthat FDA and all participating investigators are promptly informed\nof significant new adverse effects or risks with respect to the drug.\u201d For IND\nsafety reports, the sponsor must:<\/p>\n\n\n\n
\u201cPromptly\nreview all information relevant to the safety of the drug obtained or otherwise\nreceived by the sponsor from foreign or domestic sources, including information\nderived from any clinical or epidemiological investigations.\u201d<\/p>\n\n\n\n
Sponsors are specifically\nrequired to notify all participating investigators (and FDA) in a written IND\nsafety report of \u201cany adverse experience associated with the use of the drug\nthat is both serious and unexpected\u201d and \u201cany finding from tests in laboratory\nanimals that suggests a significant risk for human subjects\u201d (\u00a7\n312.32(c)(1)(i)(A),(B)). And, more generally, sponsors are required to \u201ckeep\neach participating investigator informed of new observations discovered by or\nreported to the sponsor on the drug, particularly with respect to adverse\neffects and safe use\u201d (\u00a7 312.55(b)).<\/p>\n\n\n\n
There is no federal\nregulation requiring sponsors or investigators to report IND safety issues to\nthe IRB.<\/p>\n\n\n\n
An investigator must\nimmediately report to the sponsor any SAE whether or not it is considered drug-related,\nincluding those listed in the protocol or investigators brochure. The report\nmust include an assessment of whether there is a reasonable possibility that\nthe drug caused the event. FDA regulations also require the investigator to\nreport to the IRB any changes in research activity and unanticipated problems\ninvolving risk to human subjects or others. There is no federal regulation that\nstates that the investigator should send IND safety reports to an IRB.<\/p>\n\n\n\n
IRBs are required to follow\nwritten procedures to ensure prompt reporting to the IRB, the FDA, and appropriate\ninstitutional officials of any unanticipated problems involving risks to human\nsubjects or others and any instance of serious or continuing non-compliance. The\nregulations do not mention reporting IND safety issues to an IRB. <\/p>\n\n\n\n
Guidance Documents<\/strong><\/h2>\n\n\n\nThe FDA, OHRP, and the\nInternational Conference on Harmonisation (ICH) all have guidance documents\nrelated to safety reporting. Two FDA guidance documents are:<\/p>\n\n\n\n
- Guidance for Clinical\n Investigators, Sponsors, and IRBs: \n Adverse Event Reporting to IRBs \u2013 Improving Human Subject\n Protection<\/em> (January 2009) <\/li>
- Guidance for Industry and\n Investigators: Safety Reporting Requirements for INDs and BA\/BE Studies<\/em> (December 2012). <\/li><\/ul>\n\n\n\n
Investigators are required to\nreport promptly to the IRB all unanticipated problems involving risks to human\nsubjects or others, including adverse events that should be considered\nunanticipated problems. An AE is considered an unanticipated problem, which\nneeds to be reported to the IRB, only if it is<\/p>\n\n\n\n
- unexpected,<\/li>
- serious, and<\/li>
- would have implications for the conduct of the study.<\/li><\/ul>\n\n\n\n
The guidance document uses\nthe example of a research subject who is having liver issues such as hepatic\nnecrosis. The subject never had the underlying disease before, and the protocol\nand investigators brochure do not mention liver issues. This AE is unexpected\nand serious, thus, it must be reported to the IRB.<\/p>\n\n\n\n
The FDA guidance documents\nhave examples of corrective actions for unanticipated problems. The unanticipated\nproblem might require a significant and usually safety-related change in the\nprotocol such as revising the inclusion\/exclusion criteria. Other corrective\nactions for unanticipated problems include new monitoring requirements, revisions\nto the informed consent form, or revisions to the investigators brochure. In\nsome cases, the study might be suspended.<\/p>\n\n\n\n
The OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving\nRisks to Subjects or Others and Adverse Events<\/em> (January 2007) is very\nsimilar to the FDA regulations. Reporting is required for any incident,\nexperience, or outcome that meets all of the following criteria:<\/p>\n\n\n\n- Unexpected (in terms of nature, severity, or frequency) given the\n procedures and characteristics of the subject<\/li>
- Related or possibly related to participation in the research<\/li>
- Places subjects or others at a greater risk of harm (including\n physical, psychological, economic, or social harm) than was previously\n known or recognized.<\/li><\/ul>\n\n\n\n
In November 2016, the ICH\nreleased the Integrated Addendum to ICH\nE6 (R1): Guideline for Good Clinical Practice E6 R2<\/em>. The revision was\nnecessary due to the increasing complexity of research studies because the\noriginal guideline was published in 1996. The revisions do not affect IRBs or safety\nreporting. They focus on quality management, clinical monitoring, and so forth.\n<\/p>\n\n\n\nICHE6 GCP states that the sponsor is responsible for the ongoing\nsafety evaluation of the investigational product(s). The sponsor must promptly\nnotify investigators, institutions, and the regulatory authority(ies) about\nfindings that could adversely affect the safety of subjects, impact the conduct\nof the trial, or alter the IRB\u2019s approval\/favorable opinion to continue the\ntrial. The sponsor must expedite the reporting of all serious and unexpected\nadverse drug reactions to all concerned investigator(s)\/institutions(s), to the\nIRB(s)\/institutional ethics committee(s) where required, and to the regulatory\nauthority(ies). <\/p>\n\n\n\n
The investigator must report\nall SAEs immediately to the sponsor except for those SAEs that the protocol or\nother document (for example, the investigators brochure) identifies as not\nneeding immediate reporting. The investigator should also report unexpected\nserious adverse drug reactions to the regulatory authority(ies), the IRB, and\nthe institutional ethics committee. ICHE6\nGCP does not mention safety reporting to IRBs.<\/p>\n\n\n\n
The Burden of Over-reporting<\/strong><\/h2>\n\n\n\nOver-reporting of IND safety\nissues is a burden on more than clinical research site personnel time. There\nare costs associated with over-reporting, and it is also a burden on IRB time.\nIn 2015, the Clinical Trials Transformation Initiative (CTTI) conducted a study\ncomprised of an online survey of in-depth interviews with 47 principal\ninvestigators and 154 study staff. CTTI develops and drives adoption of\npractices that will increase the quality and efficiency of clinical trials. It comprises\nmore than 80 organizations from across the clinical trial enterprise, including\nrepresentatives of government agencies, industry representatives, patient\nadvocacy groups, professional societies, investigator groups, academic\ninstitutions, and other interested parties.<\/p>\n\n\n\n
The participating principal\ninvestigators and study staff had an average of 10 years of clinical trial\nexperience. Many were working on 30 studies concurrently.1<\/sup> <\/p>\n\n\n\nThe survey assessed the FDA\u2019s\nFinal Rule: Investigational New Drug\nSafety Reporting Requirements for Human Drug and Biological Products and Safety\nReporting Requirements for Bioavailability and Bioequivalence Studies in Humans<\/em>\n(March 2011) to determine whether IND safety reporting by clinical research\nsites had decreased. Table 3 highlights survey results, including the estimated\nnumber of IND safety reports received per month. Over 90% of the clinical\nresearch sites received 10 or more safety reports per month. More principal\ninvestigators than study staff (coordinators) estimated that it took more than\n20 hours per month to manage IND safety reports. Overall, more than 50% of both\nprincipal investigators and study staff estimated that more than 10 hours per\nmonth were spent managing IND safety reports. There is a cost associated with\nthis time.<\/p>\n\n\n\nAnother question asked about\nreasons for not reporting safety issues. The most common reason was that the\nissue did not meet the IRB\u2019s reporting requirements. Other answers were that\nthe issue did not comply with the FDA rules and workload.<\/p>\n\n\n\n
Since the rule became\neffective, the number of reports has not decreased. CTTI reviewed the findings\nand concluded that IND safety reporting still posed a substantial burden on clinical\nresearch sites without enhancing the safety of research subjects. Respondents\nfavored a centralized overall platform-independent system for dissemination of\naggregate safety data, with email alerts to investigators. This would reduce the\nreporting burden on clinical research sites by facilitating only necessary\nreporting.<\/p>\n\n\n\n
In 2015, Jonathon Jarrod and\nSean Khozin at the FDA reviewed a random sampling of 160 expedited safety\nreports. They concluded that 86% of the reports were uninformative or did not\nmeet the criteria for submission. Jarrod and Khozin wrote:<\/p>\n\n\n\n
\u201cMore than half (54%) were expedited reports of\nexpected adverse events, listed in the product labeling of the investigator’s\nbrochure \u2026 of the 38 expedited safety reports that met all three criteria, 16\n(42%) were anticipated.\u201d1<\/sup><\/p>\n\n\n\nThe\nFDA\u2019s efforts not only failed to improve the quality of the reports, but it also\nfailed to reduce the sheer number of expedited reports submitted each year. The\nmain barriers to improving the quality of expedited reports are a \u201clack of\ninternational harmonization for reporting rules, liability risks, and a lack of\nclarity of threshold rules for aggregate reporting.\u201d The FDA is looking into\nways to modernize expedited safety reporting, and has called on sponsors to work\nto identify and address the underlying issues that result in over-reporting.1<\/sup><\/p>\n\n\n\nThe Cost of Over-reporting<\/strong><\/h2>\n\n\n\nAs\nmentioned, over-reporting to the IRB is costly for clinical research sites.\nSay, for example, that a study coordinator spends five minutes submitting the\nIND safety report to the IRB and another five minutes obtaining the principal\ninvestigator\u2019s signature and putting the report in the site file. That is 10\nminutes per IND safety report. If there are 10 IND safety reports per month, each\nstudy coordinator is spending 100 minutes, or 1.5 hours, per month on IND safety\nreports, most of which are not relevant to the study being conducted at the\nclinical research site. If a study is using a central private IRB that charges\n$25 (or more) per IND safety report and these reports are not unanticipated\nproblems and thus, are not required to be submitted to the IRB, then you see\nhow this affects a project\u2019s budget. If there are 100 clinical research sites\nparticipating in a study and each submits two reports each month, the cost of\nreporting could be $5,000 per month. <\/p>\n\n\n\n
Instead of handling unnecessary IND safety reports,\nstudy coordinators could be working on many other important tasks such as study\nvisits, recruitment, data entry, and answering queries. Monitors could be spending their time\nreviewing studies for non-compliance instead of reviewing IND safety reports. IRBs\nmust review every IND safety report that they receive. This requires resources,\nincluding a scientific reviewer and the time and cost for follow-up if\nnecessary. Often, IRBs do not receive all of the information or the context for\nthe safety reports.<\/p>\n\n\n\n
Identifying Solutions <\/strong><\/h2>\n\n\n\nIt will take time to identify solutions (Table 4).\nClinical research professionals should discuss IND safety reporting for each\nprotocol with the IRB. For example, if the sponsor\u2019s standard operating\nprocedure requires reporting of any event to the IRB, it may be possible to submit\nthese reports to the IRB on a monthly basis or in batches. Another possible\nsolution is to report only risks that were previously unknown or unexpected in\ntype, severity, or frequency of occurrence.<\/p>\n\n\n\n
The IRB\u2019s role is to protect the safety, welfare, and rights of subjects; however, over-reporting does not enhance these goals. Educating sponsors, contract research organizations, and clinical research sites about appropriate IND safety reporting is crucial. Reporting only unanticipated problems to the IRB does protect the safety, welfare, and rights of subjects, and it does not compromise the integrity of the study. Appropriate IND safety reporting improves efficiencies. Following the regulatory requirements will decrease study budgets, reduce IRB processing and reviews, save time for study coordinators and principal investigators, and save money for clinical research sites.<\/p>\n\n\n\n
\n\n\n\nTABLE 1<\/strong><\/h2>\n\n\n\nOHRP\nDefinition of Unanticipated Problem2<\/sup><\/strong><\/p>\n\n\n\nThe\nphrase \u201cunanticipated problems involving risks to subjects or others\u201d is found\nbut not defined in the HHS regulations at 45 CFR part 46. OHRP considers an unanticipated\nproblem<\/em>, in general, to include any incident, experience, or outcome that meets\nall<\/strong> of the following criteria.<\/p>\n\n\n\n- The problem must be unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document, and (b) the characteristics of the subject population being studied.<\/li>
- The problem must be related or possibly related to participation in the research (in this guidance document, possibly related<\/em> means that there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research).<\/li>
- The problem suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.<\/li><\/ul>\n\n\n\n
TABLE 2<\/strong><\/h2>\n\n\n\nRequirements\nof 21 CFR and 45 CFR<\/strong><\/p>\n\n\n\n- Sponsor requirements:
- General responsibilities of sponsors:
- Ensuring that the FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug<\/li><\/ul><\/li>
- IND safety reporting:
- Promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations<\/li><\/ul><\/li>
- Sponsors are specifically required to notify all participating investigators (and the FDA) in a written IND safety report of \u201cany adverse experience associated with the use of the drug that is both serious and unexpected\u201d and \u201cany finding from tests in laboratory animals that suggests a significant risk for human subjects. There is no federal regulation that states that the sponsor should report IND safety reports to an IRB.<\/li><\/ul><\/li>
- Investigator requirements:
- An investigator must immediately report to the sponsor any serious adverse event:
- Whether or not considered drug related, including those listed in the protocol or investigator brochure<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
- Must include an assessment of whether there is a reasonable possibility that the drug caused the event<\/li>
- The investigator shall also ensure that they promptly report to the IRB:
- All changes in the research activity<\/li>
- All unanticipated problems involving risk to human subjects or others<\/li><\/ul><\/li>
- There is no federal regulation that states that the investigator should report IND safety reports to an IRB.<\/li>
- IRB requirements:<\/li>
- Follow written procedures to ensure prompt reporting to: the FDA, Sponsor, and appropriate institutional officials of:
- Any unanticipated problems involving risks to human subjects or others<\/li>
- Any instance of serious or continuing non-compliance<\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 3<\/strong><\/h2>\n\n\n\nCTTI Survey\nResults1<\/sup><\/strong><\/p>\n\n\n\n- Estimated number of IND safety reports received per month for studies at the site:
- More than 20:
- 81.15%<\/li><\/ul><\/li>
- 11-20:
- 10.99%<\/li><\/ul><\/li>
- 1-10:
- 7.85%<\/li><\/ul><\/li><\/ul><\/li>
- Estimated number of staff hours per month required to manage IND safety reports:
- More than 20:
- Staff: 38%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li>
- 11-20:
- Staff: 23%<\/li>
- Principal investigators: 19%<\/li><\/ul><\/li>
- 5-10:
- Staff: 17%<\/li>
- Principal investigators: 24%<\/li><\/ul><\/li>
- Less than 5:
- Staff: 22%<\/li>
- Principal investigators: 14%<\/li><\/ul><\/li><\/ul><\/li>
- Reasons for not reporting safety issues:
- Does not comply with FDA rule
- Staff: 54%<\/li>
- Principal investigators: 33%<\/li><\/ul><\/li>
- Does not meet IRB requirements:
- Staff: 68%<\/li>
- Principal investigators: 78%<\/li><\/ul><\/li>
- Workload:
- Staff: 44%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 4<\/strong><\/h2>\n\n\n\nSolutions\nto Over-reporting<\/strong><\/p>\n\n\n\n- Educate sponsors, contract research organizations, and clinical research sites on the regulatory requirements<\/li>
- Report only risks that were previously unknown or unexpected in type, severity or frequency<\/li>
- Change protocol wording on what to report to IRBs<\/li>
- Revise standard operating procedures<\/li>
- Submit reports to the IRB monthly or in batches<\/li><\/ul>\n\n\n\n
Table 5<\/h2>\n\n\n\n
References<\/strong><\/p>\n\n\n\n- Raymond Perez, MD; on behalf of the \u2018Investigator\u2019 Subgroup: CTTI\n IND Safety Advancement Project Investigator Survey and Interview Data\n [July 21, 2015]<\/li><\/ol>\n\n\n\n
https:\/\/www.ctti-clinicaltrials.org\/files\/ind-expmtg-july2015.pdf<\/a><\/p>\n\n\n\n- OHRP: Unanticipated Problems Involving Risks and adverse events\n guidance [January 15, 2007]<\/li><\/ol>\n\n\n\n
While protecting research subjects\nis paramount, sending IND safety reports to IRBs for issues that do not meet\nthe definition of an unanticipated problem does not accomplish this. Sponsors often\nsend IND safety reports that are not related to the current study to\ninvestigators and instruct the investigators to submit them to the IRB. Some\nIND safety reports only have part of the necessary information because the\nsituation is evolving.<\/p>\n\n\n\n
The OHRP defines an\nunanticipated problem as any outcome or experience that meets three criteria\n(Table 1). The problem must be unexpected given the nature of the protocol and\nthe study population, related or possibly related to the participation in the\nresearch (any reasonable possibility), and suggest that the research places\nresearch subjects or other people at a greater risk of harm. The harm is\nanything that was not previously known or recognized. It could be psychological,\nsocial, economic, or physical. <\/p>\n\n\n\n
Examples of unanticipated\nproblems include information that changes the risk\/benefit ratio of the\nresearch and an unanticipated adverse device effect. Perhaps something happened\nafter implanting the device in a device study that was not in the protocol or other\ninformation provided to the IRB. This problem is unanticipated. Another example\nis the imminent threat of a reportable event that has not yet occurred, such as\na breach of confidentiality. This could occur if an investigator accidentally\nleaves a laptop with study data in a taxi. Another example is a dosing error,\nsuch as giving a subject a dose that is 10 times the study dose. An\nunanticipated problem may not cause an AE right away. In order to be an\nunanticipated problem, however, the problem must also meet the other criteria of\nbeing related or possibly related to the research and increase the risk of\nharm.<\/p>\n\n\n\n
Over-reporting<\/strong><\/h2>\n\n\n\nThere are four reasons for over-reporting:\nThe protocol design, standard operating procedures, protection, and lack of\ntraining\/tools. Protocols often specify that SAEs must be reported to the\nsponsor and the IRB. Standard operating procedures may also specify that IND\nsafety issues be reported to the IRB. No one will ignore requirements stated in\na protocol or standard operating procedure. Clinical research professionals\nmust protect subjects; however, in today\u2019s litigious society, clinical research\nprofessionals also want to protect themselves, which results in over-reporting.<\/p>\n\n\n\n
Lack of training and tools is\nthe last reason for over-reporting. The OHRP has useful decision trees on its\nwebsite for what should be reported. Different IRBs have different reporting\nrequirements. Knowing the IRB\u2019s requirements will help stop over-reporting of\nIND safety issues.<\/p>\n\n\n\n
Change is not easy. People\ntend to go back to what they know and are used to doing. One solution to over-reporting\nis education to ensure that all clinical research sites and investigators, as\nwell as sponsors and contract research organizations, are informed about what\nneeds to be reported. Standard operating procedures should also be updated to\nreflect current federal regulations.<\/p>\n\n\n\n
Regulations <\/strong><\/h2>\n\n\n\nTable 2 highlights FDA\nregulations for sponsors, investigators, and IRBs. The regulations require sponsors\nto ensure \u201cthat FDA and all participating investigators are promptly informed\nof significant new adverse effects or risks with respect to the drug.\u201d For IND\nsafety reports, the sponsor must:<\/p>\n\n\n\n
\u201cPromptly\nreview all information relevant to the safety of the drug obtained or otherwise\nreceived by the sponsor from foreign or domestic sources, including information\nderived from any clinical or epidemiological investigations.\u201d<\/p>\n\n\n\n
Sponsors are specifically\nrequired to notify all participating investigators (and FDA) in a written IND\nsafety report of \u201cany adverse experience associated with the use of the drug\nthat is both serious and unexpected\u201d and \u201cany finding from tests in laboratory\nanimals that suggests a significant risk for human subjects\u201d (\u00a7\n312.32(c)(1)(i)(A),(B)). And, more generally, sponsors are required to \u201ckeep\neach participating investigator informed of new observations discovered by or\nreported to the sponsor on the drug, particularly with respect to adverse\neffects and safe use\u201d (\u00a7 312.55(b)).<\/p>\n\n\n\n
There is no federal\nregulation requiring sponsors or investigators to report IND safety issues to\nthe IRB.<\/p>\n\n\n\n
An investigator must\nimmediately report to the sponsor any SAE whether or not it is considered drug-related,\nincluding those listed in the protocol or investigators brochure. The report\nmust include an assessment of whether there is a reasonable possibility that\nthe drug caused the event. FDA regulations also require the investigator to\nreport to the IRB any changes in research activity and unanticipated problems\ninvolving risk to human subjects or others. There is no federal regulation that\nstates that the investigator should send IND safety reports to an IRB.<\/p>\n\n\n\n
IRBs are required to follow\nwritten procedures to ensure prompt reporting to the IRB, the FDA, and appropriate\ninstitutional officials of any unanticipated problems involving risks to human\nsubjects or others and any instance of serious or continuing non-compliance. The\nregulations do not mention reporting IND safety issues to an IRB. <\/p>\n\n\n\n
Guidance Documents<\/strong><\/h2>\n\n\n\nThe FDA, OHRP, and the\nInternational Conference on Harmonisation (ICH) all have guidance documents\nrelated to safety reporting. Two FDA guidance documents are:<\/p>\n\n\n\n
- Guidance for Clinical\n Investigators, Sponsors, and IRBs: \n Adverse Event Reporting to IRBs \u2013 Improving Human Subject\n Protection<\/em> (January 2009) <\/li>
- Guidance for Industry and\n Investigators: Safety Reporting Requirements for INDs and BA\/BE Studies<\/em> (December 2012). <\/li><\/ul>\n\n\n\n
Investigators are required to\nreport promptly to the IRB all unanticipated problems involving risks to human\nsubjects or others, including adverse events that should be considered\nunanticipated problems. An AE is considered an unanticipated problem, which\nneeds to be reported to the IRB, only if it is<\/p>\n\n\n\n
- unexpected,<\/li>
- serious, and<\/li>
- would have implications for the conduct of the study.<\/li><\/ul>\n\n\n\n
The guidance document uses\nthe example of a research subject who is having liver issues such as hepatic\nnecrosis. The subject never had the underlying disease before, and the protocol\nand investigators brochure do not mention liver issues. This AE is unexpected\nand serious, thus, it must be reported to the IRB.<\/p>\n\n\n\n
The FDA guidance documents\nhave examples of corrective actions for unanticipated problems. The unanticipated\nproblem might require a significant and usually safety-related change in the\nprotocol such as revising the inclusion\/exclusion criteria. Other corrective\nactions for unanticipated problems include new monitoring requirements, revisions\nto the informed consent form, or revisions to the investigators brochure. In\nsome cases, the study might be suspended.<\/p>\n\n\n\n
The OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving\nRisks to Subjects or Others and Adverse Events<\/em> (January 2007) is very\nsimilar to the FDA regulations. Reporting is required for any incident,\nexperience, or outcome that meets all of the following criteria:<\/p>\n\n\n\n- Unexpected (in terms of nature, severity, or frequency) given the\n procedures and characteristics of the subject<\/li>
- Related or possibly related to participation in the research<\/li>
- Places subjects or others at a greater risk of harm (including\n physical, psychological, economic, or social harm) than was previously\n known or recognized.<\/li><\/ul>\n\n\n\n
In November 2016, the ICH\nreleased the Integrated Addendum to ICH\nE6 (R1): Guideline for Good Clinical Practice E6 R2<\/em>. The revision was\nnecessary due to the increasing complexity of research studies because the\noriginal guideline was published in 1996. The revisions do not affect IRBs or safety\nreporting. They focus on quality management, clinical monitoring, and so forth.\n<\/p>\n\n\n\nICHE6 GCP states that the sponsor is responsible for the ongoing\nsafety evaluation of the investigational product(s). The sponsor must promptly\nnotify investigators, institutions, and the regulatory authority(ies) about\nfindings that could adversely affect the safety of subjects, impact the conduct\nof the trial, or alter the IRB\u2019s approval\/favorable opinion to continue the\ntrial. The sponsor must expedite the reporting of all serious and unexpected\nadverse drug reactions to all concerned investigator(s)\/institutions(s), to the\nIRB(s)\/institutional ethics committee(s) where required, and to the regulatory\nauthority(ies). <\/p>\n\n\n\n
The investigator must report\nall SAEs immediately to the sponsor except for those SAEs that the protocol or\nother document (for example, the investigators brochure) identifies as not\nneeding immediate reporting. The investigator should also report unexpected\nserious adverse drug reactions to the regulatory authority(ies), the IRB, and\nthe institutional ethics committee. ICHE6\nGCP does not mention safety reporting to IRBs.<\/p>\n\n\n\n
The Burden of Over-reporting<\/strong><\/h2>\n\n\n\nOver-reporting of IND safety\nissues is a burden on more than clinical research site personnel time. There\nare costs associated with over-reporting, and it is also a burden on IRB time.\nIn 2015, the Clinical Trials Transformation Initiative (CTTI) conducted a study\ncomprised of an online survey of in-depth interviews with 47 principal\ninvestigators and 154 study staff. CTTI develops and drives adoption of\npractices that will increase the quality and efficiency of clinical trials. It comprises\nmore than 80 organizations from across the clinical trial enterprise, including\nrepresentatives of government agencies, industry representatives, patient\nadvocacy groups, professional societies, investigator groups, academic\ninstitutions, and other interested parties.<\/p>\n\n\n\n
The participating principal\ninvestigators and study staff had an average of 10 years of clinical trial\nexperience. Many were working on 30 studies concurrently.1<\/sup> <\/p>\n\n\n\nThe survey assessed the FDA\u2019s\nFinal Rule: Investigational New Drug\nSafety Reporting Requirements for Human Drug and Biological Products and Safety\nReporting Requirements for Bioavailability and Bioequivalence Studies in Humans<\/em>\n(March 2011) to determine whether IND safety reporting by clinical research\nsites had decreased. Table 3 highlights survey results, including the estimated\nnumber of IND safety reports received per month. Over 90% of the clinical\nresearch sites received 10 or more safety reports per month. More principal\ninvestigators than study staff (coordinators) estimated that it took more than\n20 hours per month to manage IND safety reports. Overall, more than 50% of both\nprincipal investigators and study staff estimated that more than 10 hours per\nmonth were spent managing IND safety reports. There is a cost associated with\nthis time.<\/p>\n\n\n\nAnother question asked about\nreasons for not reporting safety issues. The most common reason was that the\nissue did not meet the IRB\u2019s reporting requirements. Other answers were that\nthe issue did not comply with the FDA rules and workload.<\/p>\n\n\n\n
Since the rule became\neffective, the number of reports has not decreased. CTTI reviewed the findings\nand concluded that IND safety reporting still posed a substantial burden on clinical\nresearch sites without enhancing the safety of research subjects. Respondents\nfavored a centralized overall platform-independent system for dissemination of\naggregate safety data, with email alerts to investigators. This would reduce the\nreporting burden on clinical research sites by facilitating only necessary\nreporting.<\/p>\n\n\n\n
In 2015, Jonathon Jarrod and\nSean Khozin at the FDA reviewed a random sampling of 160 expedited safety\nreports. They concluded that 86% of the reports were uninformative or did not\nmeet the criteria for submission. Jarrod and Khozin wrote:<\/p>\n\n\n\n
\u201cMore than half (54%) were expedited reports of\nexpected adverse events, listed in the product labeling of the investigator’s\nbrochure \u2026 of the 38 expedited safety reports that met all three criteria, 16\n(42%) were anticipated.\u201d1<\/sup><\/p>\n\n\n\nThe\nFDA\u2019s efforts not only failed to improve the quality of the reports, but it also\nfailed to reduce the sheer number of expedited reports submitted each year. The\nmain barriers to improving the quality of expedited reports are a \u201clack of\ninternational harmonization for reporting rules, liability risks, and a lack of\nclarity of threshold rules for aggregate reporting.\u201d The FDA is looking into\nways to modernize expedited safety reporting, and has called on sponsors to work\nto identify and address the underlying issues that result in over-reporting.1<\/sup><\/p>\n\n\n\nThe Cost of Over-reporting<\/strong><\/h2>\n\n\n\nAs\nmentioned, over-reporting to the IRB is costly for clinical research sites.\nSay, for example, that a study coordinator spends five minutes submitting the\nIND safety report to the IRB and another five minutes obtaining the principal\ninvestigator\u2019s signature and putting the report in the site file. That is 10\nminutes per IND safety report. If there are 10 IND safety reports per month, each\nstudy coordinator is spending 100 minutes, or 1.5 hours, per month on IND safety\nreports, most of which are not relevant to the study being conducted at the\nclinical research site. If a study is using a central private IRB that charges\n$25 (or more) per IND safety report and these reports are not unanticipated\nproblems and thus, are not required to be submitted to the IRB, then you see\nhow this affects a project\u2019s budget. If there are 100 clinical research sites\nparticipating in a study and each submits two reports each month, the cost of\nreporting could be $5,000 per month. <\/p>\n\n\n\n
Instead of handling unnecessary IND safety reports,\nstudy coordinators could be working on many other important tasks such as study\nvisits, recruitment, data entry, and answering queries. Monitors could be spending their time\nreviewing studies for non-compliance instead of reviewing IND safety reports. IRBs\nmust review every IND safety report that they receive. This requires resources,\nincluding a scientific reviewer and the time and cost for follow-up if\nnecessary. Often, IRBs do not receive all of the information or the context for\nthe safety reports.<\/p>\n\n\n\n
Identifying Solutions <\/strong><\/h2>\n\n\n\nIt will take time to identify solutions (Table 4).\nClinical research professionals should discuss IND safety reporting for each\nprotocol with the IRB. For example, if the sponsor\u2019s standard operating\nprocedure requires reporting of any event to the IRB, it may be possible to submit\nthese reports to the IRB on a monthly basis or in batches. Another possible\nsolution is to report only risks that were previously unknown or unexpected in\ntype, severity, or frequency of occurrence.<\/p>\n\n\n\n
The IRB\u2019s role is to protect the safety, welfare, and rights of subjects; however, over-reporting does not enhance these goals. Educating sponsors, contract research organizations, and clinical research sites about appropriate IND safety reporting is crucial. Reporting only unanticipated problems to the IRB does protect the safety, welfare, and rights of subjects, and it does not compromise the integrity of the study. Appropriate IND safety reporting improves efficiencies. Following the regulatory requirements will decrease study budgets, reduce IRB processing and reviews, save time for study coordinators and principal investigators, and save money for clinical research sites.<\/p>\n\n\n\n
\n\n\n\nTABLE 1<\/strong><\/h2>\n\n\n\nOHRP\nDefinition of Unanticipated Problem2<\/sup><\/strong><\/p>\n\n\n\nThe\nphrase \u201cunanticipated problems involving risks to subjects or others\u201d is found\nbut not defined in the HHS regulations at 45 CFR part 46. OHRP considers an unanticipated\nproblem<\/em>, in general, to include any incident, experience, or outcome that meets\nall<\/strong> of the following criteria.<\/p>\n\n\n\n- The problem must be unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document, and (b) the characteristics of the subject population being studied.<\/li>
- The problem must be related or possibly related to participation in the research (in this guidance document, possibly related<\/em> means that there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research).<\/li>
- The problem suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.<\/li><\/ul>\n\n\n\n
TABLE 2<\/strong><\/h2>\n\n\n\nRequirements\nof 21 CFR and 45 CFR<\/strong><\/p>\n\n\n\n- Sponsor requirements:
- General responsibilities of sponsors:
- Ensuring that the FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug<\/li><\/ul><\/li>
- IND safety reporting:
- Promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations<\/li><\/ul><\/li>
- Sponsors are specifically required to notify all participating investigators (and the FDA) in a written IND safety report of \u201cany adverse experience associated with the use of the drug that is both serious and unexpected\u201d and \u201cany finding from tests in laboratory animals that suggests a significant risk for human subjects. There is no federal regulation that states that the sponsor should report IND safety reports to an IRB.<\/li><\/ul><\/li>
- Investigator requirements:
- An investigator must immediately report to the sponsor any serious adverse event:
- Whether or not considered drug related, including those listed in the protocol or investigator brochure<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
- Must include an assessment of whether there is a reasonable possibility that the drug caused the event<\/li>
- The investigator shall also ensure that they promptly report to the IRB:
- All changes in the research activity<\/li>
- All unanticipated problems involving risk to human subjects or others<\/li><\/ul><\/li>
- There is no federal regulation that states that the investigator should report IND safety reports to an IRB.<\/li>
- IRB requirements:<\/li>
- Follow written procedures to ensure prompt reporting to: the FDA, Sponsor, and appropriate institutional officials of:
- Any unanticipated problems involving risks to human subjects or others<\/li>
- Any instance of serious or continuing non-compliance<\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 3<\/strong><\/h2>\n\n\n\nCTTI Survey\nResults1<\/sup><\/strong><\/p>\n\n\n\n- Estimated number of IND safety reports received per month for studies at the site:
- More than 20:
- 81.15%<\/li><\/ul><\/li>
- 11-20:
- 10.99%<\/li><\/ul><\/li>
- 1-10:
- 7.85%<\/li><\/ul><\/li><\/ul><\/li>
- Estimated number of staff hours per month required to manage IND safety reports:
- More than 20:
- Staff: 38%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li>
- 11-20:
- Staff: 23%<\/li>
- Principal investigators: 19%<\/li><\/ul><\/li>
- 5-10:
- Staff: 17%<\/li>
- Principal investigators: 24%<\/li><\/ul><\/li>
- Less than 5:
- Staff: 22%<\/li>
- Principal investigators: 14%<\/li><\/ul><\/li><\/ul><\/li>
- Reasons for not reporting safety issues:
- Does not comply with FDA rule
- Staff: 54%<\/li>
- Principal investigators: 33%<\/li><\/ul><\/li>
- Does not meet IRB requirements:
- Staff: 68%<\/li>
- Principal investigators: 78%<\/li><\/ul><\/li>
- Workload:
- Staff: 44%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 4<\/strong><\/h2>\n\n\n\nSolutions\nto Over-reporting<\/strong><\/p>\n\n\n\n- Educate sponsors, contract research organizations, and clinical research sites on the regulatory requirements<\/li>
- Report only risks that were previously unknown or unexpected in type, severity or frequency<\/li>
- Change protocol wording on what to report to IRBs<\/li>
- Revise standard operating procedures<\/li>
- Submit reports to the IRB monthly or in batches<\/li><\/ul>\n\n\n\n
Table 5<\/h2>\n\n\n\n
References<\/strong><\/p>\n\n\n\n- Raymond Perez, MD; on behalf of the \u2018Investigator\u2019 Subgroup: CTTI\n IND Safety Advancement Project Investigator Survey and Interview Data\n [July 21, 2015]<\/li><\/ol>\n\n\n\n
https:\/\/www.ctti-clinicaltrials.org\/files\/ind-expmtg-july2015.pdf<\/a><\/p>\n\n\n\n- OHRP: Unanticipated Problems Involving Risks and adverse events\n guidance [January 15, 2007]<\/li><\/ol>\n\n\n\n
Table 2 highlights FDA\nregulations for sponsors, investigators, and IRBs. The regulations require sponsors\nto ensure \u201cthat FDA and all participating investigators are promptly informed\nof significant new adverse effects or risks with respect to the drug.\u201d For IND\nsafety reports, the sponsor must:<\/p>\n\n\n\n
\u201cPromptly\nreview all information relevant to the safety of the drug obtained or otherwise\nreceived by the sponsor from foreign or domestic sources, including information\nderived from any clinical or epidemiological investigations.\u201d<\/p>\n\n\n\n
Sponsors are specifically\nrequired to notify all participating investigators (and FDA) in a written IND\nsafety report of \u201cany adverse experience associated with the use of the drug\nthat is both serious and unexpected\u201d and \u201cany finding from tests in laboratory\nanimals that suggests a significant risk for human subjects\u201d (\u00a7\n312.32(c)(1)(i)(A),(B)). And, more generally, sponsors are required to \u201ckeep\neach participating investigator informed of new observations discovered by or\nreported to the sponsor on the drug, particularly with respect to adverse\neffects and safe use\u201d (\u00a7 312.55(b)).<\/p>\n\n\n\n
There is no federal\nregulation requiring sponsors or investigators to report IND safety issues to\nthe IRB.<\/p>\n\n\n\n
An investigator must\nimmediately report to the sponsor any SAE whether or not it is considered drug-related,\nincluding those listed in the protocol or investigators brochure. The report\nmust include an assessment of whether there is a reasonable possibility that\nthe drug caused the event. FDA regulations also require the investigator to\nreport to the IRB any changes in research activity and unanticipated problems\ninvolving risk to human subjects or others. There is no federal regulation that\nstates that the investigator should send IND safety reports to an IRB.<\/p>\n\n\n\n
IRBs are required to follow\nwritten procedures to ensure prompt reporting to the IRB, the FDA, and appropriate\ninstitutional officials of any unanticipated problems involving risks to human\nsubjects or others and any instance of serious or continuing non-compliance. The\nregulations do not mention reporting IND safety issues to an IRB. <\/p>\n\n\n\n
Guidance Documents<\/strong><\/h2>\n\n\n\nThe FDA, OHRP, and the\nInternational Conference on Harmonisation (ICH) all have guidance documents\nrelated to safety reporting. Two FDA guidance documents are:<\/p>\n\n\n\n
- Guidance for Clinical\n Investigators, Sponsors, and IRBs: \n Adverse Event Reporting to IRBs \u2013 Improving Human Subject\n Protection<\/em> (January 2009) <\/li>
- Guidance for Industry and\n Investigators: Safety Reporting Requirements for INDs and BA\/BE Studies<\/em> (December 2012). <\/li><\/ul>\n\n\n\n
Investigators are required to\nreport promptly to the IRB all unanticipated problems involving risks to human\nsubjects or others, including adverse events that should be considered\nunanticipated problems. An AE is considered an unanticipated problem, which\nneeds to be reported to the IRB, only if it is<\/p>\n\n\n\n
- unexpected,<\/li>
- serious, and<\/li>
- would have implications for the conduct of the study.<\/li><\/ul>\n\n\n\n
The guidance document uses\nthe example of a research subject who is having liver issues such as hepatic\nnecrosis. The subject never had the underlying disease before, and the protocol\nand investigators brochure do not mention liver issues. This AE is unexpected\nand serious, thus, it must be reported to the IRB.<\/p>\n\n\n\n
The FDA guidance documents\nhave examples of corrective actions for unanticipated problems. The unanticipated\nproblem might require a significant and usually safety-related change in the\nprotocol such as revising the inclusion\/exclusion criteria. Other corrective\nactions for unanticipated problems include new monitoring requirements, revisions\nto the informed consent form, or revisions to the investigators brochure. In\nsome cases, the study might be suspended.<\/p>\n\n\n\n
The OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving\nRisks to Subjects or Others and Adverse Events<\/em> (January 2007) is very\nsimilar to the FDA regulations. Reporting is required for any incident,\nexperience, or outcome that meets all of the following criteria:<\/p>\n\n\n\n- Unexpected (in terms of nature, severity, or frequency) given the\n procedures and characteristics of the subject<\/li>
- Related or possibly related to participation in the research<\/li>
- Places subjects or others at a greater risk of harm (including\n physical, psychological, economic, or social harm) than was previously\n known or recognized.<\/li><\/ul>\n\n\n\n
In November 2016, the ICH\nreleased the Integrated Addendum to ICH\nE6 (R1): Guideline for Good Clinical Practice E6 R2<\/em>. The revision was\nnecessary due to the increasing complexity of research studies because the\noriginal guideline was published in 1996. The revisions do not affect IRBs or safety\nreporting. They focus on quality management, clinical monitoring, and so forth.\n<\/p>\n\n\n\nICHE6 GCP states that the sponsor is responsible for the ongoing\nsafety evaluation of the investigational product(s). The sponsor must promptly\nnotify investigators, institutions, and the regulatory authority(ies) about\nfindings that could adversely affect the safety of subjects, impact the conduct\nof the trial, or alter the IRB\u2019s approval\/favorable opinion to continue the\ntrial. The sponsor must expedite the reporting of all serious and unexpected\nadverse drug reactions to all concerned investigator(s)\/institutions(s), to the\nIRB(s)\/institutional ethics committee(s) where required, and to the regulatory\nauthority(ies). <\/p>\n\n\n\n
The investigator must report\nall SAEs immediately to the sponsor except for those SAEs that the protocol or\nother document (for example, the investigators brochure) identifies as not\nneeding immediate reporting. The investigator should also report unexpected\nserious adverse drug reactions to the regulatory authority(ies), the IRB, and\nthe institutional ethics committee. ICHE6\nGCP does not mention safety reporting to IRBs.<\/p>\n\n\n\n
The Burden of Over-reporting<\/strong><\/h2>\n\n\n\nOver-reporting of IND safety\nissues is a burden on more than clinical research site personnel time. There\nare costs associated with over-reporting, and it is also a burden on IRB time.\nIn 2015, the Clinical Trials Transformation Initiative (CTTI) conducted a study\ncomprised of an online survey of in-depth interviews with 47 principal\ninvestigators and 154 study staff. CTTI develops and drives adoption of\npractices that will increase the quality and efficiency of clinical trials. It comprises\nmore than 80 organizations from across the clinical trial enterprise, including\nrepresentatives of government agencies, industry representatives, patient\nadvocacy groups, professional societies, investigator groups, academic\ninstitutions, and other interested parties.<\/p>\n\n\n\n
The participating principal\ninvestigators and study staff had an average of 10 years of clinical trial\nexperience. Many were working on 30 studies concurrently.1<\/sup> <\/p>\n\n\n\nThe survey assessed the FDA\u2019s\nFinal Rule: Investigational New Drug\nSafety Reporting Requirements for Human Drug and Biological Products and Safety\nReporting Requirements for Bioavailability and Bioequivalence Studies in Humans<\/em>\n(March 2011) to determine whether IND safety reporting by clinical research\nsites had decreased. Table 3 highlights survey results, including the estimated\nnumber of IND safety reports received per month. Over 90% of the clinical\nresearch sites received 10 or more safety reports per month. More principal\ninvestigators than study staff (coordinators) estimated that it took more than\n20 hours per month to manage IND safety reports. Overall, more than 50% of both\nprincipal investigators and study staff estimated that more than 10 hours per\nmonth were spent managing IND safety reports. There is a cost associated with\nthis time.<\/p>\n\n\n\nAnother question asked about\nreasons for not reporting safety issues. The most common reason was that the\nissue did not meet the IRB\u2019s reporting requirements. Other answers were that\nthe issue did not comply with the FDA rules and workload.<\/p>\n\n\n\n
Since the rule became\neffective, the number of reports has not decreased. CTTI reviewed the findings\nand concluded that IND safety reporting still posed a substantial burden on clinical\nresearch sites without enhancing the safety of research subjects. Respondents\nfavored a centralized overall platform-independent system for dissemination of\naggregate safety data, with email alerts to investigators. This would reduce the\nreporting burden on clinical research sites by facilitating only necessary\nreporting.<\/p>\n\n\n\n
In 2015, Jonathon Jarrod and\nSean Khozin at the FDA reviewed a random sampling of 160 expedited safety\nreports. They concluded that 86% of the reports were uninformative or did not\nmeet the criteria for submission. Jarrod and Khozin wrote:<\/p>\n\n\n\n
\u201cMore than half (54%) were expedited reports of\nexpected adverse events, listed in the product labeling of the investigator’s\nbrochure \u2026 of the 38 expedited safety reports that met all three criteria, 16\n(42%) were anticipated.\u201d1<\/sup><\/p>\n\n\n\nThe\nFDA\u2019s efforts not only failed to improve the quality of the reports, but it also\nfailed to reduce the sheer number of expedited reports submitted each year. The\nmain barriers to improving the quality of expedited reports are a \u201clack of\ninternational harmonization for reporting rules, liability risks, and a lack of\nclarity of threshold rules for aggregate reporting.\u201d The FDA is looking into\nways to modernize expedited safety reporting, and has called on sponsors to work\nto identify and address the underlying issues that result in over-reporting.1<\/sup><\/p>\n\n\n\nThe Cost of Over-reporting<\/strong><\/h2>\n\n\n\nAs\nmentioned, over-reporting to the IRB is costly for clinical research sites.\nSay, for example, that a study coordinator spends five minutes submitting the\nIND safety report to the IRB and another five minutes obtaining the principal\ninvestigator\u2019s signature and putting the report in the site file. That is 10\nminutes per IND safety report. If there are 10 IND safety reports per month, each\nstudy coordinator is spending 100 minutes, or 1.5 hours, per month on IND safety\nreports, most of which are not relevant to the study being conducted at the\nclinical research site. If a study is using a central private IRB that charges\n$25 (or more) per IND safety report and these reports are not unanticipated\nproblems and thus, are not required to be submitted to the IRB, then you see\nhow this affects a project\u2019s budget. If there are 100 clinical research sites\nparticipating in a study and each submits two reports each month, the cost of\nreporting could be $5,000 per month. <\/p>\n\n\n\n
Instead of handling unnecessary IND safety reports,\nstudy coordinators could be working on many other important tasks such as study\nvisits, recruitment, data entry, and answering queries. Monitors could be spending their time\nreviewing studies for non-compliance instead of reviewing IND safety reports. IRBs\nmust review every IND safety report that they receive. This requires resources,\nincluding a scientific reviewer and the time and cost for follow-up if\nnecessary. Often, IRBs do not receive all of the information or the context for\nthe safety reports.<\/p>\n\n\n\n
Identifying Solutions <\/strong><\/h2>\n\n\n\nIt will take time to identify solutions (Table 4).\nClinical research professionals should discuss IND safety reporting for each\nprotocol with the IRB. For example, if the sponsor\u2019s standard operating\nprocedure requires reporting of any event to the IRB, it may be possible to submit\nthese reports to the IRB on a monthly basis or in batches. Another possible\nsolution is to report only risks that were previously unknown or unexpected in\ntype, severity, or frequency of occurrence.<\/p>\n\n\n\n
The IRB\u2019s role is to protect the safety, welfare, and rights of subjects; however, over-reporting does not enhance these goals. Educating sponsors, contract research organizations, and clinical research sites about appropriate IND safety reporting is crucial. Reporting only unanticipated problems to the IRB does protect the safety, welfare, and rights of subjects, and it does not compromise the integrity of the study. Appropriate IND safety reporting improves efficiencies. Following the regulatory requirements will decrease study budgets, reduce IRB processing and reviews, save time for study coordinators and principal investigators, and save money for clinical research sites.<\/p>\n\n\n\n
\n\n\n\nTABLE 1<\/strong><\/h2>\n\n\n\nOHRP\nDefinition of Unanticipated Problem2<\/sup><\/strong><\/p>\n\n\n\nThe\nphrase \u201cunanticipated problems involving risks to subjects or others\u201d is found\nbut not defined in the HHS regulations at 45 CFR part 46. OHRP considers an unanticipated\nproblem<\/em>, in general, to include any incident, experience, or outcome that meets\nall<\/strong> of the following criteria.<\/p>\n\n\n\n- The problem must be unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document, and (b) the characteristics of the subject population being studied.<\/li>
- The problem must be related or possibly related to participation in the research (in this guidance document, possibly related<\/em> means that there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research).<\/li>
- The problem suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.<\/li><\/ul>\n\n\n\n
TABLE 2<\/strong><\/h2>\n\n\n\nRequirements\nof 21 CFR and 45 CFR<\/strong><\/p>\n\n\n\n- Sponsor requirements:
- General responsibilities of sponsors:
- Ensuring that the FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug<\/li><\/ul><\/li>
- IND safety reporting:
- Promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations<\/li><\/ul><\/li>
- Sponsors are specifically required to notify all participating investigators (and the FDA) in a written IND safety report of \u201cany adverse experience associated with the use of the drug that is both serious and unexpected\u201d and \u201cany finding from tests in laboratory animals that suggests a significant risk for human subjects. There is no federal regulation that states that the sponsor should report IND safety reports to an IRB.<\/li><\/ul><\/li>
- Investigator requirements:
- An investigator must immediately report to the sponsor any serious adverse event:
- Whether or not considered drug related, including those listed in the protocol or investigator brochure<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
- Must include an assessment of whether there is a reasonable possibility that the drug caused the event<\/li>
- The investigator shall also ensure that they promptly report to the IRB:
- All changes in the research activity<\/li>
- All unanticipated problems involving risk to human subjects or others<\/li><\/ul><\/li>
- There is no federal regulation that states that the investigator should report IND safety reports to an IRB.<\/li>
- IRB requirements:<\/li>
- Follow written procedures to ensure prompt reporting to: the FDA, Sponsor, and appropriate institutional officials of:
- Any unanticipated problems involving risks to human subjects or others<\/li>
- Any instance of serious or continuing non-compliance<\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 3<\/strong><\/h2>\n\n\n\nCTTI Survey\nResults1<\/sup><\/strong><\/p>\n\n\n\n- Estimated number of IND safety reports received per month for studies at the site:
- More than 20:
- 81.15%<\/li><\/ul><\/li>
- 11-20:
- 10.99%<\/li><\/ul><\/li>
- 1-10:
- 7.85%<\/li><\/ul><\/li><\/ul><\/li>
- Estimated number of staff hours per month required to manage IND safety reports:
- More than 20:
- Staff: 38%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li>
- 11-20:
- Staff: 23%<\/li>
- Principal investigators: 19%<\/li><\/ul><\/li>
- 5-10:
- Staff: 17%<\/li>
- Principal investigators: 24%<\/li><\/ul><\/li>
- Less than 5:
- Staff: 22%<\/li>
- Principal investigators: 14%<\/li><\/ul><\/li><\/ul><\/li>
- Reasons for not reporting safety issues:
- Does not comply with FDA rule
- Staff: 54%<\/li>
- Principal investigators: 33%<\/li><\/ul><\/li>
- Does not meet IRB requirements:
- Staff: 68%<\/li>
- Principal investigators: 78%<\/li><\/ul><\/li>
- Workload:
- Staff: 44%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 4<\/strong><\/h2>\n\n\n\nSolutions\nto Over-reporting<\/strong><\/p>\n\n\n\n- Educate sponsors, contract research organizations, and clinical research sites on the regulatory requirements<\/li>
- Report only risks that were previously unknown or unexpected in type, severity or frequency<\/li>
- Change protocol wording on what to report to IRBs<\/li>
- Revise standard operating procedures<\/li>
- Submit reports to the IRB monthly or in batches<\/li><\/ul>\n\n\n\n
Table 5<\/h2>\n\n\n\n
References<\/strong><\/p>\n\n\n\n- Raymond Perez, MD; on behalf of the \u2018Investigator\u2019 Subgroup: CTTI\n IND Safety Advancement Project Investigator Survey and Interview Data\n [July 21, 2015]<\/li><\/ol>\n\n\n\n
https:\/\/www.ctti-clinicaltrials.org\/files\/ind-expmtg-july2015.pdf<\/a><\/p>\n\n\n\n- OHRP: Unanticipated Problems Involving Risks and adverse events\n guidance [January 15, 2007]<\/li><\/ol>\n\n\n\n
Investigators are required to\nreport promptly to the IRB all unanticipated problems involving risks to human\nsubjects or others, including adverse events that should be considered\nunanticipated problems. An AE is considered an unanticipated problem, which\nneeds to be reported to the IRB, only if it is<\/p>\n\n\n\n
- unexpected,<\/li>
- serious, and<\/li>
- would have implications for the conduct of the study.<\/li><\/ul>\n\n\n\n
The guidance document uses\nthe example of a research subject who is having liver issues such as hepatic\nnecrosis. The subject never had the underlying disease before, and the protocol\nand investigators brochure do not mention liver issues. This AE is unexpected\nand serious, thus, it must be reported to the IRB.<\/p>\n\n\n\n
The FDA guidance documents\nhave examples of corrective actions for unanticipated problems. The unanticipated\nproblem might require a significant and usually safety-related change in the\nprotocol such as revising the inclusion\/exclusion criteria. Other corrective\nactions for unanticipated problems include new monitoring requirements, revisions\nto the informed consent form, or revisions to the investigators brochure. In\nsome cases, the study might be suspended.<\/p>\n\n\n\n
The OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving\nRisks to Subjects or Others and Adverse Events<\/em> (January 2007) is very\nsimilar to the FDA regulations. Reporting is required for any incident,\nexperience, or outcome that meets all of the following criteria:<\/p>\n\n\n\n
- Unexpected (in terms of nature, severity, or frequency) given the\n procedures and characteristics of the subject<\/li>
- Related or possibly related to participation in the research<\/li>
- Places subjects or others at a greater risk of harm (including\n physical, psychological, economic, or social harm) than was previously\n known or recognized.<\/li><\/ul>\n\n\n\n
In November 2016, the ICH\nreleased the Integrated Addendum to ICH\nE6 (R1): Guideline for Good Clinical Practice E6 R2<\/em>. The revision was\nnecessary due to the increasing complexity of research studies because the\noriginal guideline was published in 1996. The revisions do not affect IRBs or safety\nreporting. They focus on quality management, clinical monitoring, and so forth.\n<\/p>\n\n\n\n
ICHE6 GCP states that the sponsor is responsible for the ongoing\nsafety evaluation of the investigational product(s). The sponsor must promptly\nnotify investigators, institutions, and the regulatory authority(ies) about\nfindings that could adversely affect the safety of subjects, impact the conduct\nof the trial, or alter the IRB\u2019s approval\/favorable opinion to continue the\ntrial. The sponsor must expedite the reporting of all serious and unexpected\nadverse drug reactions to all concerned investigator(s)\/institutions(s), to the\nIRB(s)\/institutional ethics committee(s) where required, and to the regulatory\nauthority(ies). <\/p>\n\n\n\n
The investigator must report\nall SAEs immediately to the sponsor except for those SAEs that the protocol or\nother document (for example, the investigators brochure) identifies as not\nneeding immediate reporting. The investigator should also report unexpected\nserious adverse drug reactions to the regulatory authority(ies), the IRB, and\nthe institutional ethics committee. ICHE6\nGCP does not mention safety reporting to IRBs.<\/p>\n\n\n\n
The Burden of Over-reporting<\/strong><\/h2>\n\n\n\n
Over-reporting of IND safety\nissues is a burden on more than clinical research site personnel time. There\nare costs associated with over-reporting, and it is also a burden on IRB time.\nIn 2015, the Clinical Trials Transformation Initiative (CTTI) conducted a study\ncomprised of an online survey of in-depth interviews with 47 principal\ninvestigators and 154 study staff. CTTI develops and drives adoption of\npractices that will increase the quality and efficiency of clinical trials. It comprises\nmore than 80 organizations from across the clinical trial enterprise, including\nrepresentatives of government agencies, industry representatives, patient\nadvocacy groups, professional societies, investigator groups, academic\ninstitutions, and other interested parties.<\/p>\n\n\n\n
The participating principal\ninvestigators and study staff had an average of 10 years of clinical trial\nexperience. Many were working on 30 studies concurrently.1<\/sup> <\/p>\n\n\n\n
The survey assessed the FDA\u2019s\nFinal Rule: Investigational New Drug\nSafety Reporting Requirements for Human Drug and Biological Products and Safety\nReporting Requirements for Bioavailability and Bioequivalence Studies in Humans<\/em>\n(March 2011) to determine whether IND safety reporting by clinical research\nsites had decreased. Table 3 highlights survey results, including the estimated\nnumber of IND safety reports received per month. Over 90% of the clinical\nresearch sites received 10 or more safety reports per month. More principal\ninvestigators than study staff (coordinators) estimated that it took more than\n20 hours per month to manage IND safety reports. Overall, more than 50% of both\nprincipal investigators and study staff estimated that more than 10 hours per\nmonth were spent managing IND safety reports. There is a cost associated with\nthis time.<\/p>\n\n\n\n
Another question asked about\nreasons for not reporting safety issues. The most common reason was that the\nissue did not meet the IRB\u2019s reporting requirements. Other answers were that\nthe issue did not comply with the FDA rules and workload.<\/p>\n\n\n\n
Since the rule became\neffective, the number of reports has not decreased. CTTI reviewed the findings\nand concluded that IND safety reporting still posed a substantial burden on clinical\nresearch sites without enhancing the safety of research subjects. Respondents\nfavored a centralized overall platform-independent system for dissemination of\naggregate safety data, with email alerts to investigators. This would reduce the\nreporting burden on clinical research sites by facilitating only necessary\nreporting.<\/p>\n\n\n\n
In 2015, Jonathon Jarrod and\nSean Khozin at the FDA reviewed a random sampling of 160 expedited safety\nreports. They concluded that 86% of the reports were uninformative or did not\nmeet the criteria for submission. Jarrod and Khozin wrote:<\/p>\n\n\n\n
\u201cMore than half (54%) were expedited reports of\nexpected adverse events, listed in the product labeling of the investigator’s\nbrochure \u2026 of the 38 expedited safety reports that met all three criteria, 16\n(42%) were anticipated.\u201d1<\/sup><\/p>\n\n\n\n
The\nFDA\u2019s efforts not only failed to improve the quality of the reports, but it also\nfailed to reduce the sheer number of expedited reports submitted each year. The\nmain barriers to improving the quality of expedited reports are a \u201clack of\ninternational harmonization for reporting rules, liability risks, and a lack of\nclarity of threshold rules for aggregate reporting.\u201d The FDA is looking into\nways to modernize expedited safety reporting, and has called on sponsors to work\nto identify and address the underlying issues that result in over-reporting.1<\/sup><\/p>\n\n\n\n
The Cost of Over-reporting<\/strong><\/h2>\n\n\n\n
As\nmentioned, over-reporting to the IRB is costly for clinical research sites.\nSay, for example, that a study coordinator spends five minutes submitting the\nIND safety report to the IRB and another five minutes obtaining the principal\ninvestigator\u2019s signature and putting the report in the site file. That is 10\nminutes per IND safety report. If there are 10 IND safety reports per month, each\nstudy coordinator is spending 100 minutes, or 1.5 hours, per month on IND safety\nreports, most of which are not relevant to the study being conducted at the\nclinical research site. If a study is using a central private IRB that charges\n$25 (or more) per IND safety report and these reports are not unanticipated\nproblems and thus, are not required to be submitted to the IRB, then you see\nhow this affects a project\u2019s budget. If there are 100 clinical research sites\nparticipating in a study and each submits two reports each month, the cost of\nreporting could be $5,000 per month. <\/p>\n\n\n\n
Instead of handling unnecessary IND safety reports,\nstudy coordinators could be working on many other important tasks such as study\nvisits, recruitment, data entry, and answering queries. Monitors could be spending their time\nreviewing studies for non-compliance instead of reviewing IND safety reports. IRBs\nmust review every IND safety report that they receive. This requires resources,\nincluding a scientific reviewer and the time and cost for follow-up if\nnecessary. Often, IRBs do not receive all of the information or the context for\nthe safety reports.<\/p>\n\n\n\n
Identifying Solutions <\/strong><\/h2>\n\n\n\n
It will take time to identify solutions (Table 4).\nClinical research professionals should discuss IND safety reporting for each\nprotocol with the IRB. For example, if the sponsor\u2019s standard operating\nprocedure requires reporting of any event to the IRB, it may be possible to submit\nthese reports to the IRB on a monthly basis or in batches. Another possible\nsolution is to report only risks that were previously unknown or unexpected in\ntype, severity, or frequency of occurrence.<\/p>\n\n\n\n
The IRB\u2019s role is to protect the safety, welfare, and rights of subjects; however, over-reporting does not enhance these goals. Educating sponsors, contract research organizations, and clinical research sites about appropriate IND safety reporting is crucial. Reporting only unanticipated problems to the IRB does protect the safety, welfare, and rights of subjects, and it does not compromise the integrity of the study. Appropriate IND safety reporting improves efficiencies. Following the regulatory requirements will decrease study budgets, reduce IRB processing and reviews, save time for study coordinators and principal investigators, and save money for clinical research sites.<\/p>\n\n\n\n
\n\n\n\nTABLE 1<\/strong><\/h2>\n\n\n\n
OHRP\nDefinition of Unanticipated Problem2<\/sup><\/strong><\/p>\n\n\n\n
The\nphrase \u201cunanticipated problems involving risks to subjects or others\u201d is found\nbut not defined in the HHS regulations at 45 CFR part 46. OHRP considers an unanticipated\nproblem<\/em>, in general, to include any incident, experience, or outcome that meets\nall<\/strong> of the following criteria.<\/p>\n\n\n\n
- The problem must be unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document, and (b) the characteristics of the subject population being studied.<\/li>
- The problem must be related or possibly related to participation in the research (in this guidance document, possibly related<\/em> means that there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research).<\/li>
- The problem suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.<\/li><\/ul>\n\n\n\n
TABLE 2<\/strong><\/h2>\n\n\n\n
Requirements\nof 21 CFR and 45 CFR<\/strong><\/p>\n\n\n\n
- Sponsor requirements:
- General responsibilities of sponsors:
- Ensuring that the FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug<\/li><\/ul><\/li>
- IND safety reporting:
- Promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations<\/li><\/ul><\/li>
- Sponsors are specifically required to notify all participating investigators (and the FDA) in a written IND safety report of \u201cany adverse experience associated with the use of the drug that is both serious and unexpected\u201d and \u201cany finding from tests in laboratory animals that suggests a significant risk for human subjects. There is no federal regulation that states that the sponsor should report IND safety reports to an IRB.<\/li><\/ul><\/li>
- Investigator requirements:
- An investigator must immediately report to the sponsor any serious adverse event:
- Whether or not considered drug related, including those listed in the protocol or investigator brochure<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
- Must include an assessment of whether there is a reasonable possibility that the drug caused the event<\/li>
- The investigator shall also ensure that they promptly report to the IRB:
- All changes in the research activity<\/li>
- All unanticipated problems involving risk to human subjects or others<\/li><\/ul><\/li>
- There is no federal regulation that states that the investigator should report IND safety reports to an IRB.<\/li>
- IRB requirements:<\/li>
- Follow written procedures to ensure prompt reporting to: the FDA, Sponsor, and appropriate institutional officials of:
- Any unanticipated problems involving risks to human subjects or others<\/li>
- Any instance of serious or continuing non-compliance<\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 3<\/strong><\/h2>\n\n\n\n
CTTI Survey\nResults1<\/sup><\/strong><\/p>\n\n\n\n
- Estimated number of IND safety reports received per month for studies at the site:
- More than 20:
- 81.15%<\/li><\/ul><\/li>
- 11-20:
- 10.99%<\/li><\/ul><\/li>
- 1-10:
- 7.85%<\/li><\/ul><\/li><\/ul><\/li>
- Estimated number of staff hours per month required to manage IND safety reports:
- More than 20:
- Staff: 38%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li>
- 11-20:
- Staff: 23%<\/li>
- Principal investigators: 19%<\/li><\/ul><\/li>
- 5-10:
- Staff: 17%<\/li>
- Principal investigators: 24%<\/li><\/ul><\/li>
- Less than 5:
- Staff: 22%<\/li>
- Principal investigators: 14%<\/li><\/ul><\/li><\/ul><\/li>
- Reasons for not reporting safety issues:
- Does not comply with FDA rule
- Staff: 54%<\/li>
- Principal investigators: 33%<\/li><\/ul><\/li>
- Does not meet IRB requirements:
- Staff: 68%<\/li>
- Principal investigators: 78%<\/li><\/ul><\/li>
- Workload:
- Staff: 44%<\/li>
- Principal investigators: 43%<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
TABLE 4<\/strong><\/h2>\n\n\n\n
Solutions\nto Over-reporting<\/strong><\/p>\n\n\n\n
- Educate sponsors, contract research organizations, and clinical research sites on the regulatory requirements<\/li>
- Report only risks that were previously unknown or unexpected in type, severity or frequency<\/li>
- Change protocol wording on what to report to IRBs<\/li>
- Revise standard operating procedures<\/li>
- Submit reports to the IRB monthly or in batches<\/li><\/ul>\n\n\n\n
Table 5<\/h2>\n\n\n\n
References<\/strong><\/p>\n\n\n\n
- Raymond Perez, MD; on behalf of the \u2018Investigator\u2019 Subgroup: CTTI\n IND Safety Advancement Project Investigator Survey and Interview Data\n [July 21, 2015]<\/li><\/ol>\n\n\n\n
https:\/\/www.ctti-clinicaltrials.org\/files\/ind-expmtg-july2015.pdf<\/a><\/p>\n\n\n\n
- OHRP: Unanticipated Problems Involving Risks and adverse events\n guidance [January 15, 2007]<\/li><\/ol>\n\n\n\n
- Raymond Perez, MD; on behalf of the \u2018Investigator\u2019 Subgroup: CTTI\n IND Safety Advancement Project Investigator Survey and Interview Data\n [July 21, 2015]<\/li><\/ol>\n\n\n\n
- Does not comply with FDA rule
- More than 20:
- More than 20:
- Estimated number of IND safety reports received per month for studies at the site:
- Whether or not considered drug related, including those listed in the protocol or investigator brochure<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
- An investigator must immediately report to the sponsor any serious adverse event:
- General responsibilities of sponsors:
- The problem suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.<\/li><\/ul>\n\n\n\n