Pharm Med 2010; 24 (5): 271-279 1178-2595/10/0005-0271/$49.95/0
CURRENT OPINION
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The Development Safety Update Report A Critical Review Stewart Geary Eisai Co., Ltd, Tokyo, Japan
Abstract
This article provides a critical review of the Step 2/3 International Conference on Harmonisation (ICH) E2F guidance on the Development Safety Update Report (DSUR) and examines its contents in relation to current requirements in the US and EU. The DSUR will provide a yearly update on the safety information for compounds in clinical development in addition to providing information on total exposure in the clinical trial programme, actions taken for managing safety risks and statements on the benefit-risk balance for clinical trials undertaken in the clinical development programme. The proposed DSUR will essentially cover all requirements of the existing periodic reports required during clinical development in the US and EU. The organization of the DSUR is similar to that of the postmarketing Periodic Safety Update Report but the DSUR will require additional fields and sources of data and it makes use of several region-specific appendices. Special attention is given in this article to challenges in implementing the DSUR concept including the varieties of data required, the amount of information from the DSUR to be provided to Ethics Committees and the impact of the incomplete international harmonization proposed by the ICH E2F guidance.
1. Introduction The Council for International Organizations of Medical Sciences (CIOMS) VI Working Group was the first to suggest, ‘‘It is proposed that there be a single Development Safety Update Report (DSUR) for submission to regulators on an annual basis, with a consistent format and content which are yet to be defined.’’[1] The Working Group recognized the value of periodic evaluation and reporting of adverse events during clinical development but noting the differences in timing, format and information required by the longstanding Investigational New Drug (IND) Annual Report in the US and the more recently adopted Annual Safety Report (ASR) required under the European Clinical Trials Directive, recommended defining a single DSUR that could be submitted anywhere in the world. This proposal was taken up by the CIOMS VII Working Group, who developed the idea in a report published in 2006.[2] The proposal was endorsed by the International Conference on Harmonisation (ICH) Steering Committee on 20 September 2006, who noted that in the absence of harmonization different national regulators, even within the EU, were requiring different report formats and contents.[3] Two review articles on the DSUR in prospect have already been published.[4,5] This article aims to provide a critical review of the DSUR by reviewing the predecessor annual reporting requirements in the
US and EU, comparing the document described in the ICH E2F Step 2/3 guideline to the original proposal of the CIOMS VII Working Group and reviewing the variety of information sources for populating the DSUR. In addition, potential issues related to providing detailed exposure calculations in the DSUR, provision of the DSUR to Ethics Committees and Institutional Review Boards (IRBs) and the DSUR in relation to the Periodic Safety Update Report (PSUR), will be suggested. Finally, the question of international harmonization will be raised by showing that the ICH E2F guideline, while intending to harmonize reporting practices, actually calls attention to the need for regional variations in globally ‘standard’ reports. The Step 2/3 ICH document,[6-8] available at the time of preparation of this article, was used for all references herein to the ICH E2F guidance.
2. The US IND Annual Report and EU Annual Safety Report Pharmaceutical developers will already have extensive experience preparing the US IND Annual Report and EU ASR, although there is neither a prescribed format for these reports nor very detailed regulatory guidance on their contents. The requirement for, and contents of, the IND Annual Report are
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Summary of status of each study in progress and each study completed during the previous year: • The title of the study, its purpose, a brief statement identifying the patient population and a statement as to whether the study is completed • The total number of subjects initially planned for inclusion in the study; the number entered into the study to date, tabulated by age group, gender, and race; the number whose participation in the study was completed as planned; and the number who dropped out of the study for any reason • If the study has been completed, or if interim results are known, a brief description of any available study results Summary information: obtained during the previous year's clinical and non-clinical investigations including: • A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system • A summary of all IND safety reports submitted during the past year • A list of subjects who died during participation in the investigation, with the cause of death for each subject • A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related • A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug's actions, including, for example, information about dose response, information from controlled trials, and information about bioavailability • A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings • A summary of any significant manufacturing or microbiological changes made during the past year Description of the general investigational plan for the coming year If the Investigator's Brochure has been revised, a description of the revision and a copy of the new brochure Description of any significant phase I protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country or withdrawal or suspension from marketing in any country If desired by the sponsor, a log of any outstanding business with respect to the IND for which the sponsor requests or expects a reply, comment or meeting
Fig. 1. Published requirements for US Investigational New Drug (IND) Annual Report (text from Code of Federal Regulations, Title 21, Section 312.33).[9]
laid out in the Code of Federal Regulations[9] and summarized in figure 1. It should be clear from this list of contents that in contrast to postmarketing PSURs, the IND Annual Report is not only a summary of adverse events and other new safety information, but also a vehicle for updating the US FDA on (i) the progress of the clinical development programme; (ii) changes in the investigational plan; (iii) the latest version of the Investigator’s Brochure; and even (iv) any new changes in manufacturing or phase I protocol amendments that have not been submitted to the FDA as other filings under the IND. The European guidance[10] on the collection and reporting of adª 2010 Adis Data Information BV. All rights reserved.
verse events from clinical trials that describes the EU ASR includes the advice that the ASR be divided in to three parts and provides a somewhat more detailed list on what specific safety issues must be considered but, again, does not recommend a specific table of contents for the report (figure 2). Japan has also added a requirement for a periodic safety report during clinical development, which unlike the EU or US reports is to be submitted every 6 months. The requirement was first proposed by an Expert Committee for Clinical Trials in September 2007. It was made a requirement under the Pharmaceutical Affairs Law[11] and good clinical practice (GCP) ordinance[12] in 2008 and went into effect on 1 April 2009. Because the reports in Japan were first submitted in late 2009, experience with the Japanese report was not a major factor in development of either the CIOMS VII report or ICH E2F guidance. Several differences in the contents of the US and EU documents point to the difficulties that would need to be reconciled by a common report. The IND report requires data (e.g. manufacturing changes, phase I protocol amendments, the updated Investigator’s Brochure, etc.) not required by the ASR, while the ASR requires explicit statements on risk-benefit assessment for individual clinical trials that are not required in the IND Annual Report. As will be shown, the general approach taken in the ICH E2F guidance was to add the two requirements together and recognize additional regional requirements for appendices or analyses in the DSUR. It should be noted that the clarity provided by a detailed table of contents in the ICH E2F description of the DSUR is a step toward more consistency in these reports and provides a more detailed roadmap on the contents and organization of the report than exists for either the current EU or US regional documents. At the same time, the more prescriptive approach of the DSUR will mean a loss in the flexibility of the current regional reports.
3. Comparison of CIOMS VII and ICH E2F Guidances The ICH E2F guidance shows an evolution of the contents and concept of the DSUR and at least in some ways is a step backward from the vision of a globally harmonized document – a single document that could be submitted to authorities in all ICH regions – as proposed by the CIOMS VII Working Group. A comparison of the tables of contents suggested in the CIOMS VII report to that of the Step 2 ICH E2F (table I) shows a general tendency to add subsections and appendices. Many of the subsections made explicit in the ICH E2F table of contents are mentioned in the text of the CIOMS report but there are Pharm Med 2010; 24 (5)
A Critical Review of the Development Safety Update Report
Part 1
Analysis of subject safety in the concerned clinical trial Analysis of new safety findings (i.e. not already in Investigator's Brochure) that could have a significant impact on the benefit-risk evaluation Analysis of the investigational medicinal product safety profile considering all available safety data including drop-outs for safety reasons and considering: • Relation with dose, duration, time course of the treatment • Reversibility • Evidence of previously unidentified toxicity in the trial subjects • Increased frequency of toxicity • Overdose and its treatment • Interactions or other associated risk factors • Any specific safety issues related to special populations, such as the elderly, children or any other at-risk groups • Positive and negative experiences during pregnancy or lactation • Abuse • Risks that might be associated with the investigation or diagnostic procedures of the clinical trial • Risks that might be associated with insufficient quality of the investigational medical product Results of non-clinical studies or other experience that are likely to affect subject safety Analysis of the implications for the clinical trial population: • Measures previously or currently proposed to minimize risks • A detailed rationale for whether or not it is necessary to amend the protocol, Investigator's Brochure, Informed Consent form, Patient Information Leaflet, etc. An update of the risk-benefit evaluation for the concerned clinical trial
Part 2
The DSUR demonstrates the added complexity and detail required for periodic reporting on the safety profile of a compound in clinical development compared with periodic safety reporting during marketing. A comparison of the DSUR, as proposed by either CIOMS VII or ICH E2F, to the ICH PSUR as described by ICH E2C (table I), shows the greatly increased number of information sources, analyses and appendices that will be required in the DSUR. The third column of this table on the PSUR should not be misinterpreted. Although the ICH E2C document on the PSUR gives a relatively simple outline of the table of contents for that document, there is detailed guidance and expectations for wide varieties of information under single categories shown here such as ‘Overall Safety Evaluation’. Volume 9A in particular is specific in instructions for populating these sections of the document. Nonetheless, the additional requirements in the DSUR should be a sobering thought for clinical trial sponsors because the PSUR can entail dozens of individual safety analyses and hundreds of pages of line listings. The more detailed analyses required under broad sections of the PSUR will also likely be necessary for similarly broad subsections of the DSUR. The DSUR will require new processes to be put in place to prepare the report and additional expertise in order to decide what information qualifies for inclusion.
A line listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the concerned trial, also including serious adverse reactions from third countries Trial-specific line listing of all suspected serious adverse reactions from all sites within the period covered by the report
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An aggregate summary tabulation of suspected serious adverse reactions that occurred in the concerned trial Summary tabulations of all serious adverse reactions that occurred during the trial specifying the number of reports for each: • Body system • Adverse reaction term • Treatment arm, if applicable
Fig. 2. Published requirements for EU Annual Safety Report. SUSARs = suspected unexpected serious adverse reactions.
some substantial differences. For instance, information on clinical trial drop-outs is not necessarily in the safety database used for ongoing regulatory reporting (because drop-outs may be due to a non-serious adverse event or no event) and can be difficult to collect in ‘real time’ while a clinical trial is ongoing. The CIOMS VII report states, ‘‘routine lists or tabulations of dropouts are not recommended for the DSUR.’’[13] The ICH E2F document, doubtless tasked with maintaining the existing requirement under 21 CFR 312.33 for the IND Annual Report, includes drop-outs due to adverse events both in the table of contents and as an appendix ‘‘if required by regional authorities.’’ ª 2010 Adis Data Information BV. All rights reserved.
4. Information Sources for the DSUR The preparation of pre- or postmarketing periodic or aggregate safety reports usually falls to the pharmacovigilance or drug safety organization in a company. Much of the data required for the DSUR, including information based on individual serious adverse event reports and published literature with new safety findings, should be readily available to the drug safety organization because it resides in the company’s safety database used for regulatory reporting. Those reports will also have already been reviewed and analysed when they were first received in order to maintain compliance with expedited safety reporting requirements. However, there are several examples of information required for the DSUR that are likely to require increased coordination within the company to assure that accurate and timely information is provided in the DSUR including: drop-outs due to non-serious adverse events; interim clinical trial analyses; significant manufacturing changes (including determining which changes were ‘significant’); new non-clinical data (especially if it did not result in expedited reporting); phase I protocol modifications; Pharm Med 2010; 24 (5)
ª 2010 Adis Data Information BV. All rights reserved.
Update on actions taken for safety reasons
Changes to reference safety information
Inventory and status of ongoing and completed interventional clinical trials
Estimated patient exposure in clinical trials
Presentation of safety data from clinical studies
Significant findings from interventional clinical trials
Observational and epidemiological studies
3
4
5
6
7
8
9
Other information
Worldwide authorization status
2
10
Introduction
1
Other information
Safety findings from marketing experience
11 12
Relevant findings from other sources
New safety data related to combination therapies
10
Other therapeutic use of investigational drug
8.4
Relevant findings from non-interventional studies
Ongoing clinical trials
8.3 9
Completed trials and any interim analysis
Subjects who dropped out in association with any adverse event in the reporting period
7.5
8.2
Deaths in the reporting period
7.4
8.1
Cumulative summary tabulations
7.3
Significant findings from clinical trials during the reporting period
Interval line listings of SARs
7.2
8
General considerations
7.1
Patient exposure from marketed setting
6.2 Presentation of safety data from clinical studies
Cumulative subject exposure in clinical trials (phase I–IV)
6.1
7
Estimated exposure
Status of clinical trials ongoing and completed during the reporting period
Changes to reference safety information
Update on actions taken for safety reasons
Worldwide authorization status
Introduction
6
5
4
3
2
1
Executive summary
heading
section
heading
section
Executive summary
ICH E2F (Step 2)
CIOMS VII
Continued next page
Other information: efficacy-related information; late-breaking information
Studies: newly analysed company-sponsored studies; targeted new safety studies; published studies with important safety findings; other studies with information on pregnancy
Presentation of individual case histories: cases presented as line listings; cases presented as summary tabulations; MAH analysis of individual case histories
Patient exposure: clinical trial exposure; postmarket exposure
Changes to reference product information
Update of regulatory authority or MAH actions taken for safety reasons
Worldwide market authorization status
Introduction
heading
ICH E2C (R1)
(CIOMS) VII Working Group or the International Conference on Harmonisation (ICH) E2F guideline, with the ICH Periodic Safety Update Report as described by ICH E2C guideline
Table I. Comparison of tables of contents of the Development Safety Update Report (DSUR), as proposed by either the Council for International Organizations of Medical Sciences
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Chemistry, manufacturing, and formulation issues
Non-clinical findings
Literature
Information from marketing experience
Late-breaking information
Overall safety evaluation
Summary of important risks
New actions recommended
Conclusions
10.2
10.3
10.4
11
12
13
14
15
16
DCSI available at beginning of report period
Line listings
Cumulative summary tabulation
Cumulative summary tabulations by indication
Cumulative summary tabulation by formulation
B
C
D
E
F
Phase I protocol modifications
12.7
Benefit-risk considerations Conclusions
14.2 14.3
Summary tabulations of SARs
Deaths
Drop-outs in association with adverse events
Regional appendices
Scientific abstracts (if relevant)
Cumulative summary of tabulations of SAEs
Line listings of SARs
Cumulative summary of tabulations of demographic data
Status of ongoing and completed clinical trials
Cumulative table of important regulatory advice
Investigator’s Brochure (if required)
Summary of important risks
Evaluation of the risks
14.1
15
Overall safety assessment
14
Late-breaking information
Lack of efficacy
12.6
13
Other DSURs Significant manufacturing changes
12.4
Literature
Long-term follow-up
12.5
12.3
12.2
Non-clinical data
(Line listings)a
Company core data sheet
Conclusion
Overall safety evaluation
heading
ICH E2C (R1)
DCSI = Development Core Safety Information; MAH = market authorization holder; R1 = first revision; SAEs = serious adverse events; SARs = serious adverse reactions.
a The line listings do not appear in the ICH E2C table of contents but in fact they are included in the submitted document as appendices.
Inventory of ongoing and completed interventional clinical trials
A
Appendices
Lack of efficacy
10.1
12.1
section
heading
section
heading
ICH E2F (Step 2)
CIOMS VII
Table I. Contd
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cumulative exposure estimates; status of ongoing and completed clinical trials. Each of these categories are already required in one or more regions for periodic reporting during clinical development (typically for the US IND Annual Report), but to the extent that responsibility for the DSUR is assigned to an organization without experience in meeting that regional need, it will be important to ensure this information is provided to those who create the document. It is also important to note that judgement must be applied when deciding which manufacturing changes are ‘significant’, and this level of expertise in the manufacturing process will typically not be found in the safety department. This coordination of a variety of information sources to populate the DSUR will be even more difficult when there is co-development of a product with two or more companies involved, as the expectation is that a single DSUR will be produced for a single development compound.
5. Exposure Calculations Data on cumulative clinical trial exposure, especially to the extent this information is broken down by age group, sex and ethnic group, are likely to present a particular challenge for the organization. Although detailed analyses of exposure by sex and age group are recognized as an important part of any New Drug Application, having information close to this detail at the time of a yearly periodic report will be difficult. In some form, exposure data are already required in the current US and EU periodic reports submitted during development, but the level of detail on exposure (or even its meaning, given that during a large blinded trial with variable drop-out rates by treatment group, no one knows how much ‘exposure’ to the study drug has occurred before unblinding) that is provided in these reports varies. This is not to suggest that exposure data are not useful. Knowing whether the ‘denominator’ of patient exposure is ten patients or 1000 patients may make a significant difference to the evaluation of even small numbers of serious adverse event reports. However, perhaps it should be recognized that total patient-days of exposure by treatment group are not known prior to unblinding, so even carefully obtained and reported data will not give exposure to active treatment. Regarding the level of detail to be provided in exposure estimates, the ICH E2F guidance states that either the number of trial subjects or patient-time is appropriate for cumulative exposure figures during clinical trials and that in any case the method used to calculate exposure should be clearly explained. ª 2010 Adis Data Information BV. All rights reserved.
Exposure by ethnicity presents another problem. Intrinsic genetic factors common to a population (or racial group) and extrinsic factors common to a self-identified social group (or ethnic group) that affect drug safety and efficacy, are an important issue for clinical development but the categories for ‘ethnic origin’ in the ICH E2F report are broad, regionally different in interpretation, closer to racial than ethnic categories and never defined. The current document gives ‘Caucasian, Black, Oriental, Other’ as categories, but this leaves to the classificatory biases of the DSUR writer how to assign Indians or Malays (to give just two examples of populations increasingly involved in clinical trials who could fall under ‘Oriental’ or ‘Other’ depending on who is doing the classifying). This is an intractable problem but it is worth remembering that there is a degree of arbitrariness both to the self-identification of these categories and their combination and ultimate classification.
6. Running Summary of Current and Historical Important Risks The final section of the DSUR, the ‘Summary of Important Risks’, is intended to feed directly into the Safety Specification of the Risk Management Plan (RMP) but according to the CIOMS VII report[14] and the ICH E2F guidance the section should include not only current potential or identified risks but also ‘safety concerns that have been fully addressed or resolved’. This will mean that unlike any other safety reporting document the DSUR contains a historical summary of risks that have been resolved (i.e. been determined not to apply to the compound) and therefore potentially includes items that are no longer appropriate for the RMP. This may be a source for confusion when reconciling the DSUR content with the RMP.
7. Provision of the DSUR Executive Summary to Ethics Committees, Institutional Review Boards and Investigators Both the CIOMS VII report and the Step 2/3 ICH E2F guidance anticipate the possible need to update Ethics Committees, IRBs or investigators using the Executive Summary of the DSUR. It is common under current practices (under FDA and Japanese regulations) for these groups to receive reports of individual serious adverse reactions (usually those that are ‘unexpected’ in comparison to safety information in the Investigator’s Brochure), but the difficulties in interpreting sometimes large numbers of individual reports has led to calls for periodic reporting. The Executive Summary is proposed for this Pharm Med 2010; 24 (5)
A Critical Review of the Development Safety Update Report
purpose supplemented with line listings of serious adverse reactions where required. Nonetheless, there is no indication that the advent of the DSUR will mean that individual adverse reactions no longer need to be provided to investigators and because the current requirement in the EU is for providing line listings every 6 months, it is unclear whether the annual DSUR Executive Summary will replace or come in addition to current reporting requirements in that region. Likewise, there is no evidence this will lead to any change in the current FDA guidance on reporting ‘unanticipated problems’ to the IRB.[15] ICH E2F guidance notes that the Executive Summary should be a stand alone document to serve its purpose of updating trial stakeholders and recommends the following content: introduction: report version and reporting period; investigational drug: mode of action, class, indications, dose, route of administration; estimated cumulative clinical trial exposure; marketing authorization(s)? (yes/no): if yes, number of countries; summary of overall safety assessment; summary of important risks; actions taken for safety reasons including significant changes to the Investigators Brochure; conclusion. Because of the important role of this document in updating key trial stakeholders, it will be important that close attention is given to creating a clear and complete summary of the key ongoing safety issues for the development programme. In some cases, company safety personnel are selectively unblinded to treatment assignment for certain serious adverse reactions for purposes of regulatory reporting, while others involved in the clinical trial remain blinded. Careful attention will be required to make sure that, if unblinded information on treatment assignment appears in the DSUR or its Executive Summary, these documents do not reach groups (including groups within the sponsoring company) who are intended to remain blinded. There are already regional differences in practices that may make this a challenge. In Europe some Ethics Committees receive unblinded information on treatment assignment in the course of expedited reporting of an adverse reaction while IRBs in the US and investigators in both the EU and US may receive the same adverse reaction report without information on treatment assignment.
8. DSUR to PSUR While not addressed in the ICH E2F guidance, the CIOMS VII Working Group ‘‘considered ways to align the DSUR with ª 2010 Adis Data Information BV. All rights reserved.
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the PSUR as closely as possible’’[16] and their report includes a chapter on integrating pre-approval with post-approval safety reporting. As the ICH E2F guidance on the DSUR and E2C guidance on the PSUR currently stands, there will be considerable overlap in information reported within these two documents. Given the extensive lifecycle development programmes for recently approved medications and the international lags in approval times for new indications, in many cases both of these documents will be generated for a single compound. An alternative approach would be to have a single, integrated, periodic safety reporting document with a table of contents covering the needs of both the DSUR and PSUR. Over the lifecycle of the product, some of the fields in that table would be blank (no marketing exposure before the first approval, no ongoing clinical studies once a product is no longer in active clinical development, etc.) but in any case a single report would be generated and provided to relevant parties. Given the differences in report frequency and the extensive regionalization of the DSUR document, more work in harmonization would be necessary before this could be made a reality. However, the ideal of a seamless reporting system to match what should be uninterrupted drug safety oversight during the lifecycle of a product is an attractive goal and worth working toward.
9. Missed Opportunities to Reconsider the Content of Periodic Reports During Development? It is difficult to find anything in the current ASR or IND Annual Report that will not be required in the DSUR. While that means the DSUR, with appropriate regional appendices, will meet current requirements in the ICH regions, there does not seem to have been much questioning of whether all current national requirements were really appropriate or provide useful information. For instance, why the requirement for phase I protocol amendments? If clinical trial protocol amendments were useful in a periodic report (long after their implementation) then why limit the requirement to phase I and not request those for the phase II and III trials where larger numbers of subjects are put at risk? As another example, both the current ASR and the DSUR require frequent statements at the level of the overall clinical development programme or of individual trials on the balance of benefit and risk. But will there ever be a situation where a sponsor would write that this balance was unfavourable, yet they were continuing clinical development? Identifying steps taken to minimize risks is meaningful but the sponsor shows their belief that benefit-risk is favourable when Pharm Med 2010; 24 (5)
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they continue the investment in a clinical trial, not by a stock phrase in a periodic report. Ideally, the ICH process should allow regulators and industry to work toward changing current regulatory requirements so that they are more internationally consistent and rational, rather than summing the requirements of all regions when new guidances are created.
10. A Different DSUR in Each Region? Perhaps the most pressing question for sponsors is whether the DSUR will truly become a global document accepted in a single format by all regulatory authorities. Unusual for ICH guidances, the ICH E2F guidance explicitly notes a number of sections and appendices that may be required by individual authorities. The requirement is usually introduced in the document by the statement, ‘‘if required by regional authorities,’’ which appears six times in the ICH E2F document to refer to the version number for reference safety information, lists of fatalities, drop-outs associated with adverse events, manufacturing changes, phase I protocol modifications and regional appendices. With the exception of a few references to local requirements in the ICH E2D guidance on Post-Approval Safety Data Management, there is no similar wording in existing ICH guidances governing pharmacovigilance or clinical development including the ICH E2A document on Definitions, E2C on the PSUR, E2E on Pharmacovigilance Planning or even E6 on GCP. There are already extensive regional differences in requirements and even interpretation of ICH guidance documents, but it is hard to escape the sense that this much reference to different regional contents (not defined in detail in the ICH E2F guidance) and appendices for a ‘harmonized’ guideline is a step back from the ideal of global harmonization of technical requirements for drug development. This incomplete harmonization is unfortunate because for companies performing clinical development in only a single country, it is likely that the report required by their current national regulations for periodic reporting during clinical development is easier to prepare than a DSUR. Other issues faced with harmonized documents such as the PSUR are that countries require the document at different frequencies (e.g. initially at 6-month intervals in Europe and 3-month intervals by the FDA when a waiver has been granted for submission of the PSUR) or with appendices that vary by region despite a harmonized ICH guidance (consumer reports having different standings in EU reporting than FDA reporting). Japan already requires their equivalent of the DSUR predecessor document to be submitted every 6 months; will Japan ª 2010 Adis Data Information BV. All rights reserved.
harmonize to the international DSUR frequency? Finally, nonICH regions, including large countries in the rapidly developing world, which have growing importance both for clinical development and as pharmaceutical markets, have sometimes failed to agree to timing submissions of PSURs to international birthdates that vary from the initial date of approval in that country. Issues like these will likely emerge after adoption of the DSUR so that even the level of harmonization proposed in ICH E2F is not truly achieved.
11. Conclusions The Step 2/3 ICH E2F guidance on the DSUR largely combines the current EU and US requirements for the content of a periodic safety report during clinical development but provides a more detailed table of contents and instructions for organization of the report than is available for either of those two regional reports. The DSUR will require information from a variety of sources besides the clinical trial sponsor’s database of serious adverse events and, therefore, coordination between different departments in the company will be essential for preparing an accurate report. Unlike most previous ICH guidances on safety reporting, the ICH E2F guidance calls for several region-specific items within its table of contents and appendices.
Acknowledgements The opinions expressed in this article are those of the author alone. The author is an employee of Eisai Co., Ltd, and was a member of the CIOMS VII Working Group. The author thanks Dr Valerie Simmons, Dr Ilona Surick and Dr Maria Vass for helpful comments provided during the preparation of this article. The author would like to acknowledge the hard work and deliberations of the CIOMS VII Working Group and participants in the ICH E2F topic in developing and refining the concept of the DSUR. No sources of funding were used to assist in the preparation of this article.
References 1. The Council for International Organizations of Medical Sciences (CIOMS). Management of safety information from clinical trials. Geneva: CIOMS, 2005: 212 2. The Council for International Organizations of Medical Sciences (CIOMS). The Development Safety Update Report (DSUR): harmonizing the format and content for periodic safety reporting during clinical trials. Report of CIOMS Working Group VII. Geneva: CIOMS, 2006 3. ICH. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA3302.pdf [Accessed 2010 May 6] Pharm Med 2010; 24 (5)
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4. Davis B. The development safety update report: what can we expect? Pharmaceut Med 2009; 23 (1): 19-24 5. Urushihara M, Kawakami K. Development safety update reports and proposals for effective and efficient risk communication. Drug Saf 2010; 33 (5): 341-52 6. ICH. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA4727.pdf [Accessed 2010 Jul 14] 7. EMEA/CHMP/ICH/309348/2008 [online]. Available from URL: http://www. ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ WC500002827.pdf [Accessed 2010 Sep 17] 8. Federal Register 2008 Aug 5; 73 (151): 45462-3 [online]. Available from URL: http://www.access.gpo.gov/su_docs/fedreg/a080805c.html [Accessed 2010 Sep 10] 9. FDA. Code of Federal Regulations, title 21, section 312.33 [online]. Available from URL: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?fr=312.33 [Accessed 2010 Sep 10] 10. European Commission. Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use. April 2006 [online]. Available from URL: http://ec.europa.eu/health/files/eudralex/vol-10/21_susar_rev2_2006_04_11_ en.pdf [Accessed 2010 Sep 10] 11. PFSB notification no. 0229011, 2008 Feb 29. Implementation of the ordinance on the partial revision of the Pharmaceutical Affairs Law Enforcement Regulations in relation to notifications of plans of clinical trials of drug substances and reporting of adverse drug reactions and infections related
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to clinical trials (revision of article 273 of PAL Enforcement 2008 Feb 29) [in Japanese, online]. Available from URL: http://wwwhourei.mhlw.go.jp/ hourei/doc/tsuchi/200306-b00.pdf [Accessed 2010 Sep 17] 12. PFSB notification no. 0229007, 2008 Feb 29. Enforcement of the ordinance on the partial revision of the Ordinance on the Standards for the Conduct of Clinical Trials of Medicinal Products (revision of article 20 of GCP ordinance 2008 Feb 29) [in Japanese, online]. Available from URL: http://wwwhourei. mhlw.go.jp/hourei/doc/tsuchi/200306-a00.pdf [Accessed 2010 Sep 17] 13. CIOMS VII Working Group Report. Development Safety Update Report (DSUR): harmonizing the format and content for periodic safety reporting during clinical trials. Geneva: CIOMS, 2006: 46 14. CIOMS VII Working Group Report. Development Safety Update Report (DSUR): harmonizing the format and content for periodic safety reporting during clinical trials. Geneva: CIOMS, 2006: 70 15. FDA. Guidance for Clinical Investigators, Sponsors, and IRBs: adverse event reporting to IRBs – improving human subject protection [online]. Available from URL: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ UCM126572.pdf [Accessed 2010 Jul 15] 16. CIOMS VII Working Group Report. Development Safety Update Report (DSUR): harmonizing the format and content for periodic safety reporting during clinical trials. Geneva: CIOMS, 2006: 85
Correspondence: Dr Stewart Geary, Eisai Co., Ltd, Koishikawa 4-6-10, Bunkyo-ku, Tokyo 112-8088, Japan. E-mail:
[email protected]
Pharm Med 2010; 24 (5)