Practical Applications of Regulatory Requirements for Signal Detection

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TAW0010.1177/2042098620909614Therapeutic Advances in Drug SafetyMA Malikova research-article20209096142020

Therapeutic Advances in Drug Safety Review Article

Ther Adv Drug Saf Practical applications of regulatory 2020, Vol. 11: 1–15

DOI:https://doi.org/10.1177/2042098620909614 10.1177/ requirements for signal detection and 2042098620909614https://doi.org/10.1177/2042098620909614 © The Author(s), 2020. Article reuse guidelines: communications in pharmacovigilance sagepub.com/journals- permissions Marina A. Malikova

Abstract: Pharmacovigilance is a field where communication is crucial, and exchange of information is expected to be done in a timely manner. Information from individual case reports is transmitted from pharmaceutical industry and health professionals to the regulatory authorities. The safety profile of a drug is established by analyzing individual cases and aggregate reports. The cumulative information, obtained from these reports, can be used to assist pharmacovigilance professionals in the detection of potential safety signals by monitoring evolving trends. If there is a message identifying concern as potential safety signal, the transmission of individual case reports, as well as cumulative and aggregate reports will occur from pharmaceutical industry to the regulators; and based on their assessments of causality in relationship to the drug, the regulatory decisions will be made. Once regulators confirming a signal as a possible safety alert have made the decision, the decisions and the reasons must be communicated to health professionals, the pharmaceutical industry, and other parties involved (e.g. clinical trials participants, investigators, consumers and medical professionals at post-marketing stage, etc.).

Keywords: benefit–risk assessment, communications in pharmacovigilance, signal detection, signal managementbenefit–risk

Received: 22 April 2019; revised manuscript accepted: 18 January 2020.

Introduction from the pharmaceutical industry to regulators; Pharmacovigilance is a field in which communi- based on their assessments of causality in rela- cation is very crucial, and the exchange of infor- tionship to the drug, the regulatory decisions will mation is expected to be done in a timely manner be made.1–3 Once regulators confirming a signal and in accordance with applicable regulatory as a possible safety alert have made the conclu- requirements.1 Information from individual case sion, the decisions and their reasons must be reports is transmitted from pharmaceutical indus- communicated to health professionals, the phar- try and health professionals to the regulatory maceutical industry, and any other parties authorities. involved (e.g. clinical trials participants, investigators, consumers, and medical professionals at The safety profile of a drug is established by ana- the postmarketing stage, etc.). lyzing individual cases and aggregate reports. The Correspondence to: Marina A. Malikova cumulative information, obtained from these Department of Surgery, reports, can be used to assist pharmacovigilance Safety signal detection and management Boston University, Boston Medical Center, 72 East professionals in the detection of potential safety Pharmacovigilance is a field of science that Newton Street, Collamore signals by monitoring evolving trends.1–3 If there involves the collection of data on adverse events building, Boston, MA 02118, USA is a message identifying concern for a potential (AEs), which then must be analyzed and trends [email protected]; safety signal, the transmission of individual case evaluated to establish a safety profile of the drug [email protected] reports, as well as aggregate reports, will occur or biologic. Signal detection in this field involves

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looking at the patterns in AEs data that suggest a data (e.g. spontaneous reporting, individual case new, potentially causal association between a safety reports (ICSRs), aggregate data from active drug and an event or a series of related events. surveillance programs, or active interventional stud- Newly detected signals should serve as a trigger ies (clinical trials), noninterventional studies (e.g. for further in-depth investigations.1 This could be pharmacoepidemiology studies), nonclinical data an event that previously has never been suspected (e.g. acute and chronic animal toxicology studies), as associated with the drug/biologic or a known systematic review of the published literature, meta- event, which is now occurring within a patient analyses (e.g. mathematical pooling of all the clini- group for whom it has not been documented cal trial data), or events associated with other before. In addition, it can be a signal occurring products in the same therapeutic class and other with greater frequency or severity than antici- relevant sources.1–4 pated.1 The signal may be generated from qualitative analysis of spontaneous reports or Healthcare providers are encouraged to report quantitative analysis through data mining and adverse reactions via national spontaneous statistical assessment.1 reporting systems. Consumers and patients may also report adverse reactions via voluntarily The term ‘signal’ is mostly associated with bio- reporting systems as well as via a wide variety of medical products during the postmarketing media, including the internet.5,6 Relevant infor- phase, although it can be used during premarket- mation can also be made available from other ing phase in clinical trials. The definition of a sig- sources, such as poison control centers.5,6 Signals nal as provided by the Council for International arising from spontaneous reports also could be Organizations of Medical Sciences (CIOMS) detected via following sources4,5: Working Group VIII is: 1. monitoring large adverse drug reaction ‘. . . information that arises from one or multiple databases such as EudraVigilance and the sources (including observations and experiments), Food and Drug Administration (FDA) AE which suggests a new potentially causal association, reporting system; or a new aspect of a known association, between an 2. published articles; intervention and an event or set of related events, 3. postmarketing periodic safety update either adverse or beneficial, that is judged to be of reports (PSURs); sufficient likelihood to justify verificatory action’.1 4. ongoing benefit–risk monitoring.4,5

Signal management is activities performed to The primary objective of signal detection is to determine whether there are newly detected risks protect patient safety. It is important to empha- associated with a drug, or if known risks have size that the goal of signal management is more changed and some action is required to reassess than just identifying signals; an investigation must the drug safety profile.2,3 The signal management be done to determine whether the signal is a safety process includes the following steps: signal detec- issue and what should be done about it. Signals tion, validation, confirmation, analysis, prioritiza- can be qualitative or based on spontaneously tion, evaluation, and recommended actions, reported data and case series, or quantitative, tracking of follow-up activities, communication, which are based on data mining, epidemiologic and risk minimization (Figure 1). All actions data, or obtained from ongoing clinical trial data. taken and recommendations made must be accu- Signaling detection and management presents rately tracked and documented at every stage. many challenges. A high level of alertness and There are resulting legal obligations that must be prompt actions are needed once a new signal, fulfilled by the investigational new drug (IND) possibly related to the drug, is detected.3,5–7 sponsor/drug manufacturer in an accurate and timely manner. The main goal is to confirm or Special considerations in signal detection include: collect evidence to disprove whether there is some polypharmacy, medication errors, and drug–drug new issue with the safety of a drug, so that action and other interactions, such as cytochrome P450 might then be taken to mitigate the risk.2,3 (CYP) activation or inhibition by drug sub- stances, which is a major source of adverse drug Signals can be detected from multiple different interactions since changes in CYP enzyme activ- sources, which include the following: postmarketing ity may affect the metabolism and clearance of

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Figure 1. Signal management is a set of activities performed to determine whether there are newly detected risks with a drug or whether known risks have changed, and some action is required to re-evaluate drug safety profile. various drugs.2,3,5 Pharmacovigilance profession- The FDA’s Good Pharmacovigilance Practices als must be actively looking for signals and be pre- guidance provides information on identifying and pared to handle them when they find them. One describing safety signals using case reports, case size does not fit all with signal detection and man- series, cohort, case control, or nested case control agement. There are many factors that can influ- studies, registries, and surveys.2 In addition, it ence the approach to be taken. provides guidance on interpreting signals. Requirements for signaling are implied but not Signaling regulations and guidelines specified in the FDA Amendment Act, though Regulations and guidelines on signal identifica- they are well described in the guidance.2 tion and management are specified in the following documents. A well-documented process for signal detection and escalation is essential in order to meet 1. CIOMS VIII: Practical Aspects of Signal European regulatory requirements. EMA’s GVP Detection in Pharmacovigilance,.1 Module IX, Signal Management, specifies what 2. FDA Guidance for Industry: Good Pharma- should be done in the steps of the signal manage- covigilance Practices and Pharmacoe- ment process: signal detection, signal validation, pidemiologic Assessment./2 signal analysis, and prioritization, signal assess- 3. European Medicines Agency (EMA) ment, recommendation for action, and exchange Guideline on Good Pharmacovigilance of information with stakeholders. It also spells out Practice (GVP) Module IX: Signal Manage- the marketing authorization holders (MAHs) ment.3 responsibilities for pharmacovigilance.3

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In addition, the CIOMS Working Group VIII and product safety can be assessed more mean- report, Practical Aspects of Signal Detection in ingfully.10,12 Under the previous regulations, the Pharmacovigilance, provides key definitions and IND sponsors were often reporting to the regu- describes approaches to signal detection, man- latory agencies and clinical investigators, in an agement, and interpretation of results.1 expedited manner, a substantial number of serious AEs whether or not they have had any relationship to the study drug.13,14 This caused the Premarketing clinical trial safety safety systems to be overloaded with a lot of Patient safety monitoring is a critical component potentially distracting information, which can of the clinical trial process. The objective of col- possibly lead to masking of adverse drug reac- lecting safety data from clinical trials is the early tions. Under the current regulations the IND detection of important safety signals to achieve sponsors must report to the regulatory agencies the following: and the investigators, on an expedited basis, only those events that are serious, unexpected 1. protect current research subjects and pro- (not listed previously in the Investigator’s vide information about new risks; Brochure), and are suspected to be caused by 2. assess the potential risk to future patients the drug (i.e. there is a reasonable possibility or and develop safety profile/product label of scientific evidence to suggest that the drug the drug contributing to its benefit–risk caused it).9,10,12 assessment; 3. gather information to guide drug develop- In order to ensure research subjects’ safety on an ment for a selection of populations and a active clinical study, clinical investigators must selection of doses/regimens; report to the sponsors all serious AEs on an expe- 4. explore for new indications. dited basis, regardless of whether they are considered drug-related or not,11 thus relieving them of Safety data, obtained from ongoing clinical trials, the burden of making a judgment on the causal have a direct effect on the safety and clinical care association with the drug, which they can still of research subjects enrolled in these trials. The indicate on the reports to the sponsors as treating ultimate goal of safety signal detection in clinical physician investigators who are still closest to the trials is to translate clinically significant safety subject and familiar with the details of their health information to the product label under develop- history and clinical care.11 However, individual ment and protect research subjects from experi- investigators will not have access to entire drug encing adverse drug reactions.8 Guidelines issued safety databases in order to properly evaluate new by regulatory authorities specifically for the docu- AEs and assess causality in the broader context of mentation and reporting of serious events have the whole study population. Current regulations evolved significantly to help ensure the safety of recognize that the sponsor has the broadest view clinical trial subjects.8–11 of the drug’s history and characteristics and is therefore in the best position to attribute causal- During the last decade, the regulatory landscape ity. In addition, current guidance for industry for safety monitoring of biomedical products has calls for oversight of clinical investigations by changed considerably. In September of 2010, sponsors based on the utilization of risk-based the FDA published a final rule12 amending the approach for monitoring.12,15,16 safety reporting requirements under 21 code of federal regulations (CFR) part 312 (IND stud- Events, which cannot be analyzed as single cases, ies)9 and 21 CFR part 320 (Bioavailability and need to be assessed on an aggregate basis and Bioequivalence studies).8,13 The US regulations reported if there is a difference in the reporting (effective March 2011)12 and the European rates between the drug and the control groups.17 Commission’s detailed guidance (CT 3, June Currently, the emphasis on putting expedited, 2011)10 on the collection, verification, and pres- individual reports in the context of aggregate entation of AE/reaction reports detected in clini- reviews is more pronounced in the US as com- cal trials put a strong emphasis on early reporting pared with the EU, where companies still make of serious events with a reasonable possibility of the assessments and perform expedited reporting being associated with the drug so that safety for one event at a time for the EMA, as they are analysis is not confounded by unnecessary noise not fully aligned with the FDA on this point.

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In addition, the regulations make a distinction one treatment arm has safety as well as between the AEs and mortality and morbidity effectiveness implications. endpoints, which need to be analyzed as per the 4. There is a question of ethical importance study protocol.10,12 As an additional measure to for the trial to stop early if the primary protect patient safety, the FDA also recommends question addressed has been definitively that summaries/reports of the Data Safety answered, even if secondary questions or Monitoring Boards (DSMB) meetings will be complete safety information were not fully sent to the institutional review board (IRB) for addressed.18 For further details, on how to review.12,17 determine if DSMB is needed, refer to Figure 2. Utilization of DSMBs is increasing for both industry-sponsored and investigator-initiated, Under the current European regulations (CT3, National Institutes of Health funded projects 2011/C, 172/01, June 2011) the investigator must due to the growing number of industry-spon- report all serious AEs immediately to the sponsor, sored trials with mortality and major morbidity with exception for those that the protocol or endpoints, increasing collaboration between Investigator’s Brochure define as not requiring industry and government in sponsoring major immediate reporting.10 The sponsor needs to clinical trials heightening awareness within the report on an expedited basis only the serious, scientific community of problems in clinical trial unexpected, suspected, and adverse reactions conduct.18 (SUSARs), preferably unblinded, within 7 days for fatal or life threatening events and 15 days for The DSMB/Data Monitoring Committee is an the other SUSARs (refer to Figure 3 for the time- independent group of individuals with relevant frame for AEs reporting).10 The sponsor reports expertise that review on a regular basis data col- the SUSAR directly as an ICSR to the national lected from ongoing clinical trials, which advises competent authority (CA) of the relevant mem- the sponsor regarding the safety of current and ber state, and also indirectly through the elec- future participants and on the validity and scien- tronic gateway to the EudraVigilance Clinical tific merit of the trial. Among the duties of DSMB Trial Module.10 The latter requires registration are the following:18 with the EudraVigilance. The sponsors who may not have the resources and experience for elec- 1. Review the research protocol and plans for tronic reporting may delegate indirect reporting data safety and monitoring. to a partner.10 Communication channels of 2. Evaluate the progress of the trial with safety information between different stakeholders periodic assessments of data quality involved in drug development process are illus- and timeliness, participant recruitment, trated on Figure 4. accrual and retention, participant risk versus benefit, and reports from related Annual safety reports must be generated through- studies.18 out the life cycle of the clinical trial and sent to 3. Make recommendations to the IRB and the national CA and the ethics committees/IRBs. investigators concerning continuation or These reports must contain a listing of all sus- conclusion of the trial.18 pected serious adverse reactions, which have occurred over this period, and a report of the sub- Typically, DSMB is required if any of listed below jects’ safety. Investigators at all participating sites conditions apply:18 should receive an update with a summary of newly evolving safety issues (Figure 3).10 There 1. The trial is intended to provide definitive are separate guidelines on periodic safety update information about the effectiveness and/or reports during the developmental phase, in the safety of a medical intervention. form of developmental safety update reports in 2. Prior data suggest that the intervention the EU, and annual safety reports in the US.9,12,19 being studied has a potential to induce Although the regulations are focused on serious potentially unacceptable toxicity. AEs, the sponsor is expected to monitor all AEs 3. The trial is evaluating mortality or another throughout the life cycle of the drug development major endpoint, such that inferiority of process, including nonserious events.9,19

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Figure 2. Determination chart for Data Safety Monitoring Board (DSMB) requirement. Clinical research conducted as a multicenter, phase III study which is intended to provide definitive information about the effectiveness or safety of a medical intervention will require institutional review board (IRB) approval, Data Safety Monitoring Plan (DSMP) and DSMB. Also, DSMB will be required for phase I and II studies (if these are blinded), utilizing high risk interventions (i.e. intervention being studied has a potential to induce unacceptable toxicity or there is an uncertainty about toxicity in humans at early phases of drug development), involving vulnerable populations or trial evaluating mortality as a major endpoint. All other clinical research projects will need an IRB approval and possibly DSMP.

The Investigator Brochure needs to be updated In addition, the FDA recognized guidance, the by the IND sponsor promptly, according to International Conference on Harmonization changing safety profile as AEs evolved on the clin- (ICH) guidance E6: Good Clinical Practice,16 ical trial. provides additional recommendations relating to the IB (as indicated in section 7). This guidance European CAs (e.g. the EMA) specifically require recommends that the investigator’s brochure be their approval of IB updates.6,7 Whereas, FDA’s reviewed at least annually and revised as neces- regulations do not specifically require that the sary, and that more frequent revisions may be Investigator’s Brochure be updated or submitted appropriate depending on the stage of develop- to FDA as the trial advances from phase to phase. ment and the generation of relevant new informa- However, the regulations require that investigation (as indicated in section 7.1).16 tors be informed of new observations discovered by or reported to the sponsor on the drug under All participating institutions, investigators, and Title 21 CFR 312.55(b).9 This information may IRBs will need to be informed and an updated IB be distributed to investigators by means of peri- provided with tracked changes. Safety informa- odically revised Investigator’s Brochures. A copy tion from the IB needs to be translated into of the revised IB is to be submitted to the FDA in changes in risk/benefits ratio in the informed con- the annual report for the IND along with a sent form, with an updated list of AEs provided in description of the revisions according to Title 21 order to fully appraise research subjects on chang- CFR 812.33(d).9 ing the safety profile of the study drug. Study

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Figure 3. Adverse event (AE) reporting algorithm. Timeframe for adverse event reporting to national competent authority (i.e. Food and Drug Administration (FDA) in the United States and European Medicines Agency in European Economic Area) can vary, depending upon the seriousness, expectedness, and causality determined by the investigational new drug sponsor. Adverse events related or possibly related to the drug need to be reported in an expedited manner to regulatory authorities. Safety updates will need to be send out by the sponsor to all participating investigators at individual clinical research sites and institutional review boards (IRBs).

participants then can make a decision whether or require subjects to be followed as long as they not to accept these new risks and continue with remain on the study, including the follow-up the study or withdraw from it. It has to be an period after the active treatment phase is com- informed decision based on the most up-to-date pleted, and for all unanticipated events to be information provided on study procedures, if reported (related or not to the study drug). The there are any changes, and an updated safety difference in interpretation and requirements profile. needs to be discussed upfront between the IND sponsors and participating institutions before the The physician investigator at the clinical site level trial commences at each participating clinical site is responsible for the review of all internal and in order to avoid any communication issues and external AEs and to ensure research subjects’ standardize the safety reporting process. well-being and protection.11 IRB can put a clinical trial on hold for enrollment at participating The FDA can put a clinical trial on hold if an institutions if they deem that there is a serious AE annual report is not provided or safety informa- (internal or external) related or possibly related to tion is incomplete, inaccurate, or safety claims are the study drug; pending further clarification and not supported by the data provided. additional information from the sponsor of the trial, the hold can be lifted if safety the concern is Based on the drug safety profile established dur- resolved. Often, institutional policies for local ing the clinical trials and information provided in IRBs vary and require even more extensive AE premarket new drug application (NDA), the FDA reporting than the sponsor is looking for on a spe- can request formal postmarketing phase IV clini- cific clinical trial. Based on the half-life of the cal trials to further monitor and evaluate the drug drug, the IND sponsor may require AEs to be safety profile. In clinical trials, data are collected collected for shorter periods of time (only for on a limited number of patients in a strictly con- treatment phase) than the local IRB, which may trolled environment (e.g. subjects must meet

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Figure 4. Communications in pharmacovigilance scheme. A Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises the investigational new drug sponsor and the study investigators. The members of the DSMB serve in an individual capacity and provide their expertise and recommendations. The DSMB advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial. Institutional review boards (IRBs) can be local to the participating sites or centralized, chosen by the sponsor. IRBs provide oversight for ethical conduct of the study to ensure well-being and safety of clinical research subjects. The sponsor must update the Investigator’s Brochure and inform investigators at participating sites about adverse events, so investigators can appraise research subjects and local IRBs on any safety profile changes. The sponsor can outsource part of their duties, including safety monitoring, to the contract research organizations (CROs), Site management organizations (SMO) or third-party vendors. If critical value is detected by the vendors (i.e. central laboratories, imaging facilities, data management vendors, etc.), it has to be promptly communicated to the site investigators for assessment of clinical significance and relationship to the investigational product. It is important to establish upfront clear channels of communications, define roles and responsivities, and escalation processes for all parties involved in signal detection and drug safety management. CRA- clinical research associate; CRC, clinical research coordinator.

eligibility criteria and adhere to study protocol divergence in regulations for safety reporting in and procedures, in which drug regimens are con- ongoing clinical trials and reharmonize pharma- stantly monitored), and only for certain periods of covigilance regulations globally, TransCelerate time. In the real world, patients do not always championed a collaborative effort of 19 pharma- adhere to prescribed drug regimens and larger ceutical companies, including most of the largest number of subjects gets exposed for longer peri- ones, which identified a concerning trend of ods of time, especially if a drug is taken for chronic diverging regulations with regard to the handling indications. of pharmacovigilance findings from ongoing clinical trials.20 Over the last few decades, the clinical trials landscape has changed significantly, including the Singh and colleagues pointed out that examples expansion of research conducted on a global include the processes for determining whether AEs scale; divergence in regulatory requirements for reported by investigators are related to investiga- safety reporting based on geographic location; tional drugs and are expected (i.e. consistent with diverse populations, often with significant under- the known safety profile of the product or events lying comorbidities, are being evaluated; and anticipated in the population).20 Unexpected and development of new technologies. The pharma- related serious AEs may be subject to expedited ceutical industry has to modernize according to reporting to inform investigators and regulators of advances in technology, complexity of clinical tri- potential risks. Recent European guidelines require als, and globalization. In an attempt to address comprehensive expedited reporting of serious

8 journals.sagepub.com/home/taw MA Malikova events,10 while FDA guidance restricts reporting to information. In the EU, all valid, serious reports, key (sponsor adjudicated) related events.11,12 regardless of' ‘expectedness’, must be submitted While taking into consideration separately, the to the EMA within 15 calendar days.19,22 rationale for each of the above guidelines is com- mendable. However, the divergence of these According to EMA and FDA guidelines, requirements is complicating the consistent com- ‘Unexpected adverse drug reaction is an adverse munication of safety profile updates to stakehold- reaction, the nature or severity of which is not ers. Communication of safety data by sponsors on consistent with the applicable product informa- ongoing clinical trials to other stakeholders has tion (e.g. Investigator’s Brochure for an unap- become especially important. If regulatory require- proved investigational medicinal product or ments will be harmonized on a global scale for package insert for marketed product)’.19,21,22 pharmacovigilance, investigators and regulators across all geographic regions will have comparable Postmarketing expedited reporting requirements insights into the evolving safety profile of new are similar to those for premarketing, except that products. To meet these goals, TransCelerate took 7-day reporting does not exist in postmarketing, an initiative to implore representatives for regula- and there is no assessment of causality since it is tory authorities to work with industry sponsors, in assumed.19,21,22 collaboration with the ICH, to identify potential ways to reharmonize global pharmacovigilance Spontaneous reporting presents challenges to processes and requirements.20 obtaining an accurate safety profile for a drug, including the Weber effect,23 the secular effect,24 and under-reporting of AEs. Postmarketing safety management and communications process In many recent publications, the Weber effect is implied to operate in various global AE data- Spontaneous reporting bases.23 It is often too simply summarized as ‘after Because premarketing clinical trial safety infor- regulatory approval of a drug, AE reporting mation about a drug is limited, ongoing monitor- increases over the first 2 years, peaks near the end ing of the drug is critical after it is introduced to of year 2, and then reliably, and rapidly, dimin- the market in order to obtain an accurate safety ishes with further time on the market’.23 The sec- profile for the drug and ensure the safety of ular effect refers to the changes over a long period consumers. of time, generally years or decades in a drug safety profile.24 In the postmarketing environment, spontaneous reporting is an unsolicited, voluntary reporting of Other challenges with the spontaneous report- AEs by health care professionals, patients, and ing system include the sheer number of AEs, other individuals. Spontaneous reporting is the complexities in determining true safety issues primary way that sponsors monitor drugs for from many signals and reports, long time peri- safety in the postmarketing phase. ods to identify new issues (during which morbidity and mortality occur), conflicting data, Different regulatory authorities require different AEs from manufacturing problems, misuse, forms for reporting spontaneous reports. Many counterfeiting, and other reasons, and the fact maintain an online reporting site that patients and that there is no single repository for AEs around health care professionals can use, such as the the world. There are also organizational issues FDA’s MedWatch Online Voluntary Reporting due to individual process variabilities, internal Form and the The Medicines and Healthcare communication issues within the company, as products Regulatory Agency’s (MHRA) Yellow well as health agency issues with spontaneous Card Scheme.21,22 reporting.

If the company receives information about an AE, if the event is valid, serious, and unexpected, the Solicited reports company must submit a 15-day alert report, or an Solicited reports are reports derived from organ- expedited report, to the appropriate regulatory ized data collection systems, which include the fol- authority within 15 calendar days of receipt of the lowing sources: clinical trials, postapproval named

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patient use programs, other patient support and decisions in support of the recognized importance disease management programs, surveys of patients of training in ensuring a globally consistent or healthcare providers, or information gathering approach to ICH guideline implementation.26 on efficacy or patients’ adherence to prescribed dose regimen and compliance with instructions for use. AE reports obtained from any of these sources Safety information communication to patients should not be considered spontaneous. For the through the patient package inserts purposes of safety reporting, solicited reports The healthcare providers play a critical role in should be handled as if they were study reports drug safety in a postmarketing phase by adhering and, therefore, should have an appropriate causal- to the instructions for use listed on drug labels, ity assessment. also referred to as a package insert in the US, which is a technical document oriented towards In the postmarketing environment there are some medical professionals as prescribers of FDA challenges around solicited reports, as these approved medications.27 Package inserts for pre- turned out to be the main source of lower-quality scription drugs often include a separate docu- safety reports (e.g. issues with classification, cau- ment called a ‘patient package insert’ with sality assessment, completeness, and validity of information written in plain language and reports, etc.) that is now subject to revision by the intended for the end-user such as the person who ICH. will take the drug or give the drug to a minor.27

Inserts for over-the-counter medications are also Aggregate reporting written in plain language.27,28 These instructions The ICH first harmonized aggregate reporting to promote the correct, and hence safe, use of medi- regulatory authorities in a common format in cines. In the US, the FDA determines the require- 1996, with the ICH Guideline E2C, Clinical ments for patient package inserts, and it will Safety Data Management: Periodic Safety Update occasionally issue revisions to previously approved Reports for Marketed Drugs (the PSUR). The package inserts.27 primary objective of the PSUR was to provide a comprehensive picture of the safety of approved In the EU, the EMA has jurisdiction and the rel- drugs.14 evant technical documents are called the ‘summary of product characteristics’ (SPC or SmPC) In 2012 the ICH issued the revised ICH E2C and the document for end-users is called the (R2), Periodic Benefit–risk Evaluation Report ‘patient information leaflet’ or ‘package leaflet’.29 (PBRER). The PBRER includes a formal evalua- The SPC is not intended to give general advice tion of benefit–risk. The European Economic about treatment of a condition but does state how Area requires the PBRER, which is still referred the product is to be used for a specific treatment. to as the PSUR or the ‘new PSUR’.25 It forms the basis of information for health professionals to know how to use the specific product In the US, the current periodic report is the safely and effectively. The package leaflet sup- Periodic Adverse Drug Event Report (PADER). plied with the product is aimed at end users.29 Companies may choose to use the PBRER/new PSUR and FDA offers waivers for companies that Patients play an important role in drug safety. wish to do this.25 On a global scale, countries out- They are the people who experience the adverse side of the EU and US typically use the PSUR. effects, and without their input, we cannot develop systems that would enable us to identify Significant advancements in global harmonization side effects that have not emerged from clinical efforts in pharmacovigilance have been made in trials. Individual patients, by monitoring the ben- the recent ICH’s largest biannual meeting.26 It is eficial as well as adverse effects of their treatment, emphasized in the press release from this meeting can take timely treatment decisions if required. that the assembly reviewed the excellent progress New technologies are becoming available that will made by ICH working groups both at and prior to allow patients to monitor their conditions in the the meeting, approved new areas for harmoniza- comfort of their own homes, thus further enhanc- tion, discussed ICH revision of the postapproval ing the opportunities for more actively empow- safety reporting requirements E2D,2 and took ered health-care consumers. Yet, in order to

10 journals.sagepub.com/home/taw MA Malikova ensure that a qualified person is at the controls in order to construct it; hence the necessity of infor- drug therapy, adequate, timely, and unequivocal mation on likelihood, characteristics, and information should reach the patient. expected time of occurrence of side effects, as well as on measures that will prevent, relieve, or The growing number of different sources of infor- eliminate them. Such information enhances a mation to which a patient is exposed causes some patients’ confidence that they can cope when concerns among those involved in drug safety, confronted with an adverse effect and, as a conse- not least when there is a drug scare. In the mod- quence, increases the likelihood that they will ern world, the landscape of information is very continue the treatment as prescribed.30 diverse. Not only are there patient package inserts and the medical professionals available as sources Amery30 pointed out that individuals exposed to of information, but also the specialized health most medicines are spread out geographically. magazines, health or self-care sections in popular The benefit–risk balance of a medicine is thus pri- magazines, and numerous health advertisements marily a personal issue, however it has public- on radio and television programs, not to mention health ramifications. Moreover, in the area of the flood of health information on the internet. health care, benefit–risk analyses and the associ- However, patient package inserts are the most ated trade-offs are predefined as personal matters direct source with verifiable content, which is as people’s values and beliefs play a crucial role.30 issued via regulated channel and delivers information from the scientifically evaluated drug The communicator of safety information must be safety database directly to the patient. The latter aware of specific patient’s needs in order to feature is a significant asset because each human address their specific concerns and have detailed link in a communication chain can change a mes- knowledge of efficacy and safety information sage due to inaccuracies in receiving, interpreting, listed in a specific patient package insert. evaluating, or recoding before the message is passed on to the next recipient. The treating physician’s skill in translating general benefit–risk information into common terms/ Significant distortions, however, may be less language that is meaningful to their patient likely to occur when a medically trained profes- remains a very important one. The doctor should sional serves as the single communication link. tell the patient if they are choosing from a number This is why the doctor should remain the main of treatment options, if there are common side living information channel on prescription drugs effects and what the patient might expect, how to and why pharmacists and nurses should keep act to avoid problems, and what to do if a prob- their very important complementary supportive lem occurs. In addition, doctors and pharmacists roles in the therapeutic process.30 need to be educated and trained on how to deal effectively with safety information when they Amery30 in his review emphasized that the differ- speak with patients and how to pay proper atten- ent messages a patient receives should be mutu- tion to the emotional component of the patients’ ally consistent otherwise the patient may be struggle with their illness.30 Patient package bewildered and fail to comply with the instruc- inserts are a channel for conveying benefit–risk tions for use. In addition, since the public is not information to patients, and they supplement the homogeneous in any respect, patients may differ physician’s, nurse’s, and pharmacist’s more direct in their receptivity to different communication roles. These medical professionals play a crucial modes, although they are all entitled to receive role in patient education about prescription medi- the same message.30 It is important to improve cations. In addition, the patient package insert the patients’ knowledge of their medicines, and a may be particularly helpful in dealing with the well written patient package insert should help overwhelming emotional state that patients may patients to deal with a risk situation such as a side experience at home after their visit to the doctor effects or dose omission. However, the availability while trying to deal with their health condition or of information doesn’t ensure compliance with changing health status and digest all information treatment regimens. they have received. It will help them to make more informed decisions about their treatment Patients can develop a strategy on how to manage options, and understand the risks and benefits AEs if they receive the information they need in associated with the proposed drug therapy.

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Benefit–risk assessment applicant’s weighing of benefits and risks and Recent changes to drug safety and pharmacovig- communicate a critical and succinct presentation ilance regulations around the world emphasize of the benefit–risk assessment.34 benefit–risk evaluation rather than only an evaluation of the safety of a product.10,12,25 Benefit– Effective, clear, and timely risk information is risk assessments are complex and difficult to key to protecting public health. The FDA has make since different people have different established the Risk Communication Advisory risk tolerance levels. Efforts are underway inter- Committee and maintains an informational web- nationally to develop a standardized methodol- page on potential signals of serious risks and new ogy for quantitative or qualitative benefit–risk safety information. assessment. The EU covers safety communications in GVP A rudimentary quantitative benefit/risk ratio Module XV, Safety Communication.6 can be calculated by dividing the number needed to benefit by the number needed to harm.31 The FDA has developed a qualitative Risk management plans grid to identify key issues for benefit–risk evalu- In the European Economic Area, an EU risk ation for biomedical products. The Medical management plan (RMP) is a required part of the Device Innovation Consortium works closely marketing application for all new products.7 This with Center for Devices and Radiological Health requirement is in addition to the product labeling (CDRH) on the Patient Centered Benefit–Risk (SPC). If additional measures are needed, a risk Project.31 The project was created to support minimization plan will be required. In addition, the benefit–risk assessment component of 2012 legislation requires an electronic benefit/risk CDRH approvals of medical devices,31 the management plan.7 PrOACT-URL framework, which lists eight steps in determining the benefit–risk balance of Not all products require an EU RMP. An EU a product.32 RMP may need to be submitted at any time of a product’s life cycle. Certain situations require an The Centre for Innovation in Regulatory Science RMP, such as a new marketing authorization (CIRS) has two initiatives underway. The unified application, an application for a pediatric use, or methodologies for benefit–risk assessment was an application involving a significant change in developed to provide a platform for the coordi- marketing authorization.7 nated development of benefit–risk methodologies that can be used internationally.33 The goals are The EU risk management system is specified in to increase transparency, predictability, and GVP Module V, Risk Management System.7 consistency. Details on risk minimization and measurement of its effectiveness are included in Module XVI.35 The CIRS-BRAT tool allows users to generate tabular and graphical displays to assist in the The RMP must include sections for product interpretation of benefit and risk findings.33 The overview, safety specification, pharmacovigilance purpose of the tool is to enable users to generate plan, plan for postauthorization efficacy studies, value trees, key benefit–risk summary tables, and risk minimization measures, summary of the forest plots.33 RMP, and annexes.35

The ICH guideline M4E entitled “Common Risk minimization activities may require restricted technical document for the registration of phar- access, education programs, control of a prescrip- maceuticals for human use - Efficacy” was revised tion, named patient registries, or continuing in order to standardize the content and presenta- follow-up. tion of benefit-risk information in regulatory submissions. The Revised ICH M4E(R2) guideline MAHs must conduct direct, periodic measure- specifies a structure for the Common Technical ments of the effectiveness of risk minimization activ- Document (CTD) in Section 2.5.6, Benefits and ities, and submit periodic updates to the EMA or Risk Conclusions. This section of the CTD national CAs, and include a summary in the PSUR. should represent the thought process behind the The MAH and the applicant should evaluate the

12 journals.sagepub.com/home/taw MA Malikova need for additional risk minimization activities development is meaningful and sponsors need to beyond the standard (including information in the have a systematic approach for the safety assess- label), based on the safety specification.35,36 ment of their investigational products. Managing clinical trial safety data is a collaborative process. Investigators, sponsors/CROs, ethics committees, Risk evaluation and mitigation strategies in data safety monitoring boards, and regulators all the US share the responsibility for protecting clinical trial In the US, risk minimization and management subjects by scrutinizing and evaluating safety data plans are called risk evaluation and mitigation proactively and on an ongoing basis. According to strategies (REMS). A REMS is an operational current regulatory guidelines, in the post market- manual, which includes strategies on how to han- ing environment new safety signals also should be dle risks associated with a product. It allows evaluated promptly by the marketing authorization patients to use the product but under certain con- holders and communicated to regulatory authori- ditions and surveillance.37,38 ties, healthcare professionals and consumers in a timely fashion to ensure safety of drug products. The FDA gained the authority to require a REMS under the Food and Drug Administration Funding Amendments Act legislation enacted in 2007. The author(s) received no financial support for the research, authorship, and/or publication of A REMS may include a medication guide, a com- this article. munication to HCPs, or elements to assure safe use (ETASU) such as special training for HCPs Conflict of interest statement who prescribe, dispense only in certain settings, The author declares that there is no conflict of or monitor and register patients.37,38 A REMS interest. must always include a timetable and metrics for assessment of its effectiveness, at a minimum at ORCID iD 1.5 years, 3 years, and in 7 years.37,38 There is a Marina A. Malikova https://orcid.org/0000- formal submission and approval process by the 0003-1370-187X FDA. The vast majority of products do not require a REMS. The FDA can require a REMS References at the time of an initial NDA submission, at the 1. CIOMS. Practical aspects of signal detection in time of submission for a line extension, or when pharmacovigilance. Report of CIOMS Working new safety information is received for an approved Group VIII, https://cioms.ch/working_groups/ product. ‘Class’ REMS are evolving, such as working-group-viii/ (2008). those that have been developed for extended- release and long-acting opioid medications.37 2. US Food & Drug Administration. Guidance for industry good pharmacovigilance practices and pharmacoepidemiologic assessment, A REMS must follow a specified format that https://www.fda.gov/downloads/drugs/ includes goals, a medication guide or patient guidancecomplianceregulatoryinformation/ package insert, a communication plan, ETASUs, guidances/ucm071696.pdf (2005). an implementation system, a timetable for submission of assessments, and an appendix.37–39 3. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module IX – Signal management (Rev 1), https://www.ema. The majority of initial REMS were medication europa.eu/en/documents/scientific-guideline/ guide-only REMS, which put too much burden on guideline-good-pharmacovigilance-practices- the healthcare system. A new guidance released in gvp-module-ix-signal-management-rev-1_en.pdf 2011 reversed the policy, not requiring a medica- (2017). tion guide to be a part of a REMS.38 In total about 4. European Medicines Agency. Guideline on good 200 REMS have been approved since 2008.39 pharmacovigilance practices (GVP) Module IX Addendum I – Methodological aspects of Conclusion signal detection from spontaneous reports of In conclusion, regulations are aimed to ensure suspected adverse reactions, https://www.ema. that the assessment of safety during clinical europa.eu/en/documents/scientific-guideline/

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