A DSUR is supposed to be a comprehensive annual summary of the most important information related to the clinical trial development of a pharmaceutical product related to sites globally. The report is also expected to be high level, brief and to the point, not more than about 25 pages without appendices and listings. It is therefore important to avoid repetition wherever possible.
Examples of tasks and functions to be included in the writing of a DSUR
DSUR writing resources
Below are links to resources that can be helpful to your DSUR writing process:
Examples of the Summary of Important Risks
Health Canada has published a guidance for how narratives should be written in the successive DSURs.
This appendix depicts fictitious examples of the Summary of Important Risks, prepared in three consecutive years, from 2012 to 2014. The Summary of Important Risks can be provided in either narrative (Appendix C1) or tabular (Appendix C2) format.
Appendix C1: Narrative Format
19 Summary of Important Risks
New or updated risks are denoted with an asterisk.
Drug Z is a para-aminoglycolate that bears structural similarities to aminoglycosides, currently under development for amelioration of angina pectoris in patients with stable coronary artery disease. Other members of this class are known to be nephrotoxic, and there was evidence of nephrotoxicity in both rats and rabbits at doses of 20 and 60 mg/kg/d, respectively.
In Phase I trials in healthy volunteers, 2 of 30 subjects (6.7%) who received the highest dose of drug Z (100 mg po qd for 7 days) exhibited transient increases in serum creatinine associated with proteinuria: subject 0127 had an increase in creatinine from 0.9 mg/dL at baseline to 1.8 mg/dL at Day 7; subject 0139 had an increase from 1.0 mg/dL at baseline to 1.9 mg/dL at Day 7. Both subjects had mild proteinuria (2+ by dipstick, 24-hour urinary protein not quantified). Urinalyses of both subjects were unremarkable (minimal cells; no casts). By Day 21, serum creatinine had returned to baseline in both subjects, and proteinuria had resolved (see Sections 8.2 and 18.1 for details). None of the other 28 healthy subjects who received drug Z 100 mg qd, and none of the 119 subjects who received drug Z at lower doses (50 mg or less, including 72 subjects with coronary artery disease), experienced proteinuria or significant increases in creatinine.
The increases in creatinine in the healthy volunteers who received the highest dose of drug Z (100 mg QD) were thought likely to be drug-related, in part because of the known nephrotoxicity of the drug class. It was decided, therefore, to reduce the maximum dose of drug Z in the Phase II trials to 50 mg. In addition, subject monitoring was intensified: serum creatinine, eGFR, albumin/creatinine ratios, blood urea nitrogen, and urinalysis are now performed at baseline, Weeks 1, 2, 4, 8, 16, and 24. Twenty-four-hour urinary protein excretion will be determined for any subject who develops proteinuria by dipstick. Study drug will be discontinued in subjects with creatinine increases of 0.5 mg/dL, a 30% rise in creatinine, or a 25% decrease in eGFR (repeated 2 times over a 3-day period). The protocol, informed consent document, and Investigator’s Brochure have been revised accordingly.
In rat study KR-102, 2 of 8 rats in the highest dose group (60 mg/kg/d) developed hepatic injury, with centrilobular necrosis. None of the rats that received lower doses had evidence of hepatotoxicity, and no hepatotoxicity was evident in rabbits at doses at high as 60 mg/kg/d.
One (1) subject (102-037) with coronary artery disease in study 102 who received 50 mg po qd drug Z developed moderate elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) on Day 14 (2.7 and 2.3 x the upper limits of normal, respectively), without increases in alkaline phosphatase or bilirubin (see Sections 8.2 and 18.1 for details). Drug Z was discontinued on Day 16, and transaminases returned to normal by Day 28. The subject denied alcohol consumption, and all serology was negative. The subject had been receiving drugs X and Y concomitantly on a chronic basis for >2 years prior to enrolment. Neither drug was suspected of causing the elevation in transaminases. Both were continued during the adverse event, making it very unlikely that they were the cause of the transaminase elevations. Of note, subject 102-037 was found to have concentrations of drug Z (Cmax) approximately 8-fold higher than the mean of the 50 mg cohort, suggesting an inability to metabolize drug Z. This possibility remains under investigation. An additional 148 subjects were exposed to drug Z in the Phase I program, and none exhibited transaminase elevations.
In light of the rat findings and the transaminase elevations in subject 102-037, more frequent monitoring has been implemented for the Phase II study. Assessments at Weeks 4 and 16 have been added, so that subjects now undergo assessment of ALT, AST, bilirubin, and alkaline phosphatase at baseline, Weeks 1, 2, 4, 8, 16, and 24. The protocol, informed consent document, and Investigator’s Brochure have been revised accordingly.
19 Summary of Important Risks
New or updated risks are denoted with an asterisk.
Drug Z is a para-aminoglycolate, one of a class of drugs bearing structural similarities to aminoglycosides, and known to be nephrotoxic. Two of 30 healthy volunteers (6.7%) in the Phase I program who had received drug Z 100 mg PO qd developed transient increases in serum creatinine associated with mild proteinuria (by dipstick), and the 100 mg dose was dropped from further development. In the completed Phase II trial of drug Z in patients with coronary artery disease and stable angina pectoris (Study 201), increases in creatinine >1.25 but ≤1.5 times baseline were observed in 5 of 60 subjects (8.3%) in the 50 mg group, 5 of 62 subjects (8.1%) in the 25 mg group, and 3 of 59 subjects (5.1%) in the 10 mg group, versus 6 of 61 subjects (10%) in the placebo group. For all of these subjects, the study drug was continued (per protocol), and serum creatinine returned to baseline within 2 weeks. Increases in creatinine >1.5 times baseline were observed in 1 of 60 subjects (1.7%) in the 50 mg group, 0 of 62 subjects in the 25 mg group, and 1 of 59 subjects (1.7%) in the 10 mg group, versus 2 of 61 subjects (3.3%) in the placebo group. The study drug was discontinued in all of these subjects (per protocol), and serum creatinine returned to baseline within 2 weeks. As explained in Sections 8.2 and 18.1, the “recovery” of creatinine to normal (i.e., the slope of the creatinine vs. time relationship) was the same in subjects who continued and discontinued the study drug, suggesting that this was not a specific drug effect. Of note, 3 of the 4 drug Z-treated subjects who developed creatinine elevations were taking concomitant diuretics. In ongoing studies 202 and 204, serum creatinine, eGFR, blood urea nitrogen, and urinalysis continue to be monitored at baseline, Weeks 1, 2, 4, 12, 24, and 48. Twenty-four-hour urinary protein excretion is determined in any subject who develops proteinuria by dipstick.
Drug Z caused centrilobular necrosis at the highest dose tested (60 mg/kg/d) in rats (although there was no evidence of liver damage at this dose in rabbits). One (1) of 149 subjects (0.7%) in the Phase I program developed unexplained elevations of ALT and AST approximately 2.5 x the upper limit of normal on Day 14; which resolved on discontinuation of the drug. Two drug Z-treated subjects in the completed Phase II study #201 (2/181, 1.1%) had transaminase elevations (see Section 8.2), but these were mild and transient, and one subject in the placebo group (1/61, 1.6%) had more severe elevations. Based on this information, the present monitoring plan seems appropriate, and no changes have been made to the protocol, Investigator’s Brochure, or informed consent document. Of note, one subject with elevated transaminases (102-037) had been thought to have had an unusually high Cmax; however, this was subsequently determined to be a laboratory error.
Drug Z is thought to be a mild nitric oxide (NO)-dependent vasodilator, which could be partly responsible for its anti-anginal effect. During this period there were 2 reports of syncope (2/81, 1.1%) from study #201 that were considered by investigators to be causally-related to drug Z (subjects 201-119 and 201-212). The subjects had been receiving 10 and 25 mg of drug Z, respectively. Although both subjects were predisposed to syncope (one was apparently very dehydrated; the other had a long history of syncope), there is mechanistic plausibility and we will continue to focus on syncope as a possible drug-related side effect. No specific changes have been were made to the monitoring plan as a result of these adverse events.
19 Summary of Important Risks
New or updated risks are denoted with an asterisk.
Drug Z is a para-aminoglycolate, one of a class of drugs bearing structural similarities to aminoglycosides, and known to be nephrotoxic. A 100 mg dose, studied in Phase I, was dropped from further development because of increases in creatinine and proteinuria in normal volunteers. In the Phase II program, increases in creatinine >1.25 but <1.5 times baseline were observed in 7.8%, 6.8%, and 5.8% of subjects in the 50, 25, and 10 mg treatment groups, respectively, versus 6.3% in the placebo group. Increases in creatinine >1.5 times baseline were observed in 1.5%, 0.5%, and 1.9% of subjects in the 50, 25, and 10 mg treatment groups, respectively, versus 2.7% in the placebo group. As noted in Sections 8.2 and 18.1, increases in creatinine seem to be associated with dehydration and diuretic use. In addition, a number of the subjects with increases in creatinine of more than 50% from baseline have had unusually low baseline values (i.e., ≤0.6 mg/dL). The clinical meaning of this is unclear.
In the ongoing Phase III trial (301), serum creatinine, eGFR, blood urea nitrogen, and urinalysis are monitored at baseline, Weeks 1, 4, 12, and 48. Twenty-four-hour urinary protein excretion is determined in any subject who develops 3+ or greater proteinuria by dipstick.
Drug Z caused centrilobular necrosis at the highest dose tested in rats. There was frequent monitoring of ALT, AST, alkaline phosphatase, and bilirubin in the Phase I and II trials, and no consistent pattern of laboratory abnormalities has emerged suggestive of liver injury.
In the ongoing Phase III study (301), the above laboratory tests of liver injury are monitored at baseline, Weeks 1, 4, 12, and 48.
Drug Z is thought to be a nitric oxide (NO)-dependent vasodilator, which could be partly responsible for its anti-anginal effect. There have been 21 reports of syncope in drug Z-treated subjects thus far in the development program (21/632, 3.3%), versus 3 (1.4%) in placebo. Most of the cases were orthostatic, and/or associated with coadministration of nitrates or vasodilators. In the Phase III program, subjects are advised against concurrent administration of vasodilators (e.g., nitrates, dihydropyridine calcium channel blockers), and given general precautions regarding orthostatic dizziness. The protocol, informed consent document, and Investigator’s Brochure have been revised to include this risk.
Three case reports of pancreatitis have been reported from subjects in the completed Phase II and ongoing Phase III trials (see Sections 8.1 and 8.2, respectively). Although there were plausible alternative explanations for each case, evidence of pancreatitis will be carefully sought thorough laboratory monitoring: all subjects enrolled in the Phase III trial (301) undergo screening evaluations of lipase and amylase, with repeat evaluations at Weeks 1 and 4.
Appendix C2: Tabular Format
19 Summary of Important Risks
This section summarises the important identified or potential risks that have been recognised during the conduct of the Drug Z clinical development programme. At present, all are considered as potential risks, with none characterised as identified risks associated with the administration of drug Z.
The following have been recognised as important potential risks during the reporting period:
Additional details are provided in Table X, below:
The international standard for periodic safety update reports is now the ICH standardized “periodic benefit risk evaluation report” (PBRER) most places in the world. It was first implemented in the European Union where it is included in the pharmacovigilance legislation that was implemented in 2012.
However many other countries like Australia, USA, Egypt, Israel etc also adhere to the PBRER format for mandatory benefit risk reporting. In the USA there is a legal requirement for a different type of report called the PADER report which is an old and more simple type of report that eventually probably will be replaced by the PBRER report. Companies that want to produce only one report are allowed to submit the PBRER report also in the US, but they need to apply for a waiver.
The PBRER is a periodic assessment of the risk-benefit balance of the product. The report must be submitted in countries where there is an approved product or and active application. So you need to submit periodic safety update report as soon as a marketing application has been submitted.
Note that the PSUR/PBRER report does not substitute notification of agencies of significant new information relating to the safety and efficacy of your product. Such information have to be submitted immediately independent of individual case reporting and aggregate reporting (PSUR/PBRER)
Follow the good pharmacovigilance practices for guidance on how to report such urgent safety information.
Main components of the PBRER report
Only one PBRER must be submitted for each medicinal products with the same active substance (even if the product has different names and approval paths) and it should include the following:
You should also include the results of any new studies carried out on the safety of your product related to off-label use, with a summary of their impact.
Efficacy, effectiveness and safety information of the product
To help demonstrate this in your risk-benefit evaluation you need to include sources. These may include:
Writing the PSUR/PBRER
The writing process require a structured approach and many companies have detailed internal instructions on how to write the document as well as timelines. It is also important to ensure that all sources of information is available an up to date when the writing start. Also make sure that there is a dedicated quality control function that can check the document and the sources as errors are bound to happen with such a big and complex document. Errors can have long reaching consequences – so make sure everything is correct.
First you have to gather all existing information available including previous reports. These can include previous PSURs or US PADER reports as well as DSURs from the clinical development program both before and after market authorization.
All promises and commitments made to the health agencies (HAs)in any form should be noted so you can take this into account when writing the report. Sometimes these promises are included in previous reports but most often they are established in other communication with the agencies in the form of emails, letters or reports. Take care to find all of this documentation as it sometimes are forgotten or hidden in other corporate functions like medical affairs, clinical development or regulatory affairs.
If something has been missed and cant be included due to time constraints make sure that you inform the agency with a plan for correction. Dont do this too often though as you will draw the attention of the agency compliance group and it may trigger an inspection which is a lot of additional work.
Also necessary it the appropriate reference documents like Core Safety Information, local label information as well as reference information used in clinical trials like the IB if relevant.
In the time of the internet it is also important that any other concerns emerging from social media, press or internet in general are considered. For example class effects and postings from patient groups.
In addition you will need to get exposure information from all sources. Here you should note that the agencies normally require as detailed exposure information as possible so sales to wholesalers should only be a last resort. Exposure information related to filled scripts or like is to be preferred.
If there have been any actions taken for safety reasons by the company or another health agency including label changes, patient guides or prescriber guides etc you have to mention this in the PSUR.
Adverse Event review process
All Adverse Events and Serious Adverse Events in the database will need to be reviewed in detail separated in sources:
Make sure that you verify that there is no miscategorization of Serious Adverse Events as Non-Serious as they then won’t be presented right in the report otherwise.
Safety analysis of postmarket data
Based on the data available you now have to analyze the safety of the product in detail. Here you will have to review any trends and importnat details in the data listings:
Make sure you look for any trends in labeled AEs, warnings and precautions as well as looking for new signals and this has to be done within both serious and non-serious AEs.
This is a very important source for new information about the product where you normally have a much more thorough description and review of the individual events. Most literature cases will have an implied or stated causality due to the drug. These cases must be carefully scrutinized and analyzed for signals and should occur with consideration of a signal workup or even label changes.
Review if there are there any new signals or new safety information in the completed and ongoing clinical trials that may impact current labelling. This is also necessary for the IB update.
Newly identified safety concerns and signals
This is where the company review impact on indications, special populations etc and suggest any changes to the product use of labelling. It is very important that this is a clear analysis that take into account how the health agencies will react to the presented issues. Is it timely for instance. You cant sit on important safety information that will change the label in between PSUR releases. Such information have to be communicated to the agencies immediately. Where less urgent information may be appropiate to suggest in connection with the PSUR review. If the company proposes new actions like warnings or precautions or suggest other risk mitigations make sure that you consider if the agency will see this as sufficient and prepare for a possible scenario B and C so you have the right argumentation ready. It is seen before that the agencies may require more than what is actually needed or even feasible and such mistakes can be very costly. Also try to look at other information that the agency may have available like information about other drugs in the class and even information about your own drug as it is represented in the FDA database or in the Eudravigilance system for instance. There are several good sources for such information.
If it can look like some information was delayed or misrepresented make sure that you deal with this as well. Especially pay attention to commitments made in the previous PSUR like follow-up on a case etc. it does not look good if you “forget” such items.
Current global commitments
Are there any risk mitigation activities anywhere in the world like REMS or EU style Risk Management Plans and are there any deadlines or reporting requirements. All of this need to be included in the PSUR from any global activities.
Benefit/Risk assessment and profile
Finally the benefit-risk should be reviewed in detail taking all the presented information into account so an appropriate conclusion can be made.
It does take quite some time to produce a PBRER report and you need to use a fixed cut off for listings etc to complete the report so things may happen during the writing and analysis process. Dont try to change the listings, but instead include any late information in a late breaking section where any issues that have come up since datalock is presented.