The development safety update report
While a medicine is in clinical development, its safety is reported to regulators each year in the development safety update report (DSUR). The report covers whatever in the trials bears on the safety of their subjects, falls due from the first human exposure to the substance and runs for as long as trials continue, and it is the first document to define the medicine's important risks. It can overlap with post-marketing reporting, has a counterpart in the US, and asks more of its writer than drafting.
What the report covers
The DSUR is a periodic report submitted every year in the pre-authorisation phase, while clinical trials are conducted. Its aim is to monitor the safety of patients in clinical trials and to reassure the stakeholders — ethics committees, investigators, health authorities and sponsors — about it. Each year it reports anything that could bear on the safety of patients in the trials: any relevant adverse event, new adverse drug reactions, relevant discontinuations of patients, fatal cases, any regulatory action taken for safety reasons such as a hold placed on a trial, and safety-related protocol amendments.
Why the report exists
Reviewers assess a drug's safety exhaustively once the marketing authorisation application is submitted, but safety issues detected then are found too late to prevent patients' exposure to the risk, so health authorities monitor the safety of drugs continually during development. Regulators use DSURs to assess periodically the ongoing safety profile of an investigational drug and whether its current benefit-risk ratio warrants continuing to expose subjects to it.
When the report is required
The first DSUR is written as the first patient is exposed to the substance at the start of the very first approved clinical trial. A DSUR has to be written for any interventional clinical trial, first-in-human studies in healthy volunteers included: it falls due as soon as any human takes the substance, whether a patient or a healthy volunteer. Some countries, perhaps including New Zealand, do not require a DSUR, so a single trial run only in such a country would not need one, but that is an exception.
The requirement lasts as long as clinical trials of the product are conducted. It does not end when the marketing authorisation is granted, even though the DSUR focuses on the development of a new medicinal product. A drug that has already been approved still needs a DSUR while its clinical development continues, for a different indication for example. Once the clinical development programme has ended, DSUR writing can be discontinued.
Overlap with post-marketing reporting
Although it is used mainly during clinical development, a DSUR can overlap with post-marketing safety reporting, particularly for a product in long-term follow-up studies or in further trials after marketing authorisation, and hybrid formats may then be produced to integrate data from ongoing development and post-marketing sources.
The important risks it defines
The DSUR is the first of a medicine's pharmacovigilance documents to define its important risks, and defining them is a complex task. The definition can be interpreted differently under the ICH guidelines and under the EU good pharmacovigilance practice guidelines, so it helps a writer preparing a DSUR to understand post-marketing pharmacovigilance requirements and documents too, and it is important to stay aware of both worlds, pre- and post-authorisation, when defining the risks.
Important identified and important potential risks may already be introduced in a DSUR, before the substance has been approved anywhere in the world, whether the sponsor defines or finds them or a health authority imposes them. Missing information, the third kind of safety concern, is not yet known at this stage and is introduced later, when the substance is approved. A first-in-human trial very likely has no important risks, unless something is already known about the product, there is a comparator, or the risks are known from the substance's class; a new entity likely has none. Phase 1 does not usually have many safety concerns.
A team can still list potential concerns it suspects and solicit information about them, since signals are hard to track unless they are looked for in a particular direction. But a risk introduced in the DSUR has to be kept until submission and then taken over into the RMP, so risks have to be selected carefully against the definitions if a programme is not to end up with twenty or more safety concerns. Non-clinical studies may give rise to potential risks for a first-in-human trial, but whether each could be considered important should be weighed carefully, since at that stage there may not yet be enough data to know whether a risk affects the benefit-risk balance or public health. There may be a number of potential risks, and the investigator's brochure serves to manage them. The DSUR is about significant safety issues, not just any safety information, and only important risks should be included in it. Importance is a defined term, so a relevant non-clinical result is not by that alone a safety concern.
The writer's role
It is crucial that a DSUR accurately characterise the important clinical and preclinical safety events, safety actions, class-related toxicities and new and significant literature reported during the review period, and that it place those data in the context of the entire programme. Regulatory medical writers can play a pivotal role in creating a DSUR beyond providing technical expertise, working with clinicians on it. One systematic process for creating DSURs, built on the DSUR guidance and on best practices learned from experience, has the writer author the content, evaluate literature, assess pertinent safety actions, review cases, reconcile comments, drive consensus between functional areas, synchronise the DSUR with other safety documents and aggregate reports, and assess the utility and proper placement of tables, figures and listings. Writers can apply that process successfully only under the necessary conditions, particularly the team structure and the resources available.
The US investigational new drug annual report
In the US the clinical development phase is associated with annual submissions of the Investigational New Drug (IND) Annual Report, though submitting a DSUR is also acceptable there. The Code of Federal Regulations sets out the IND Annual Report's requirements and contents. Unlike a post-marketing periodic safety update report, it is not only a summary of adverse events and other new safety information but also a vehicle for updating the FDA on the progress of the clinical development programme, changes in the investigational plan, the latest version of the investigator's brochure, and even any new manufacturing changes or phase 1 protocol amendments not submitted to the FDA as other filings under the IND.