Who a clinical study report is written for
A clinical study report is written for more readers than the regulator who receives it, and for more purposes than a marketing application. Health technology assessors, guideline authors, researchers, patients and prescribers rely on what it reports long after approval, and its findings feed a chain of later documents.
The purposes a report serves
Clinical studies drive both internal decisions on how to proceed with a development programme and external decisions on regulatory approval and labelling. Internally, the study reports determine whether a programme proceeds or stops, and a successful programme provides the evidence of safety and efficacy required for regulatory approval.
A clinical study report is a key component of a regulatory submission for demonstrating the clinical safety or efficacy, or both, of a new drug or a new indication. It is the basic building block of the marketing authorisation application, so whatever the reason for writing it and whatever the breadth of its audience, a well-structured and well-written report supports the development programme, the submission process and ultimately the labelling.
Not every report is intended to contribute to a marketing authorisation application. A report of a proof-of-concept study may be used to secure development funding or to pass information on to an acquirer of the drug, and such a study may later be redesigned and repeated with greater regulatory rigour if it is repurposed for an application.
A report is also the formal documentation that a trial was conducted in accordance with the principles of good clinical practice.
Readers of the submitted report
The target audience of a report is most often the regulatory reviewer. The sponsor prepares the report to give the study's outcomes to regulatory authorities, such as the FDA in the US or the EMA in the EU, and these authorities use its information to evaluate the safety, efficacy and quality of the medicinal product and to determine whether it should be approved for marketing. Regulatory bodies around the world refer to reports to assess a drug's safety, efficacy and risk–benefit profile, which makes the reports the backbone of submissions for marketing authorisation. Regulatory agencies such as the EMA and the FDA, to which most reports are targeted, use them as a basis for their decisions.
Lay members of an ethics committee, for example, should be able to understand protocols and study reports, so particular effort should go into their summary sections. Many protocols and study reports are excessively long, complex, difficult to read and repetitive, probably from fear of litigation. Crucial information lost in a long, complicated document that is difficult to read has the same impact as a document that is too brief and leaves out essential information.
Readers after approval
Clinical study reports served as documents for drug approval, but not as a data source for further research and post-regulatory decision-making. Their content was classified as commercially confidential information, so access to them was mainly limited to regulatory bodies, which published only parts of the data in their own reports, such as the EMA's European Public Assessment Reports. One may therefore be tempted to assume that reports are written for the archives of pharmaceutical companies and drug authorities and are only sometimes resurrected as a data source for selected publications in scientific journals or conference proceedings. But the need for clinical study data does not end with the approval of a new drug.
The times when writing these reports was called purely regulatory medical writing are over. Reports will remain the core documents for drug approval, but their use is extending beyond regulatory activities and beyond serving as a data source for heavily condensed publications that report selected data. They will be available as information sources for independent researchers and post-approval decision-makers. So reports have gained in importance and will continue to do so, the audience of those who write them is constantly growing, and their work may be relevant and sought after for years to come.
Post-approval decision-making involves far-reaching questions, one of which is whether a new drug has an added benefit over the existing standard of care. A country's health technology assessment agency usually answers it, and the answer is required first to support decisions on reimbursement and pricing, and second to ensure the development of high-quality clinical guidelines and patient information. If complete information on treatment options is available, individual patients, together with their physicians, can decide whether they wish to use a drug in their specific situation. This ensures patient autonomy, which is itself a criterion resulting in better treatment and ultimately in high-quality health care.
Regulatory agencies and post-approval decision-makers have different aims, tasks and concerns. Health technology assessment agencies and health policy decision-makers usually place greater emphasis than regulatory bodies do on a new drug's relative effectiveness, that is, on its added benefit against its harm and on its cost-effectiveness. Local settings, such as availability and reimbursement policies, also differ between countries, so local health technology assessment agencies and health policy decision-makers often require a different set of data. The same applies to the authors of clinical guidelines, which are largely developed within the conditions of a specific health care system. In spite of these differences, the evidence divide between regulatory bodies and policy-makers must be overcome. As mediators in attaining high-quality health care, health technology assessment agencies and the authors of clinical guidelines and patient information should not have to rely on the selective and limited information available in journal publications, but should have access to complete information, the methods and results of all relevant studies.
Reports are an important source of information for regulatory authorities, healthcare professionals and the public. Researchers and other stakeholders, patients and the public among them, use the information in a report to evaluate the safety and efficacy of the treatment tested and to make decisions about its potential use in clinical practice. Prescribers depend on the content of reports, together with clinical experience, through the drug label.
What post-approval readers need from a report
Data from all relevant studies are required to inform health technology assessment agencies and the authors of clinical guidelines and patient information adequately, and these data must be available in a high-quality publication format. A valid interpretation of study results is possible only if these requirements are met:
- All study methods as specified in the protocol must be reported, including patient selection, the mode of randomisation and blinding, the study treatments and comparators, the definition of outcomes, data collection and the statistical analysis.
- Changes to the study protocol must be documented clearly and with sufficient justification.
- Study results must be presented in an adequately aggregated form as specified in the protocol, and, for specific research questions, as individual patient data.
- Both study methods and results must be presented at a level of detail that allows critical appraisal of the study.
These requirements are far from being met, as reporting bias is still a common problem. Sound post-regulatory decisions also require data other than those available in publications, because of the reporting bias found in the literature. Clinical study reports are the only documents comprehensive enough to solve this problem.
A report meets all the requirements for valid decisions, at the policy-making level as well as at the regulatory level. It also offers high-quality reporting, as its structure follows the standard requirements of ICH E3. Reports should be disclosed to allow scrutiny, so that readers can see the omission of pre-specified data, data dredging, arbitrary changes to data collection and other sources of bias. Developments by the EMA and journal editors towards data transparency may make reports the core documents of the future.
Where the report and its findings go
Sponsors in the EU are required to submit all reports intended to be used for marketing authorisations. As part of a marketing authorisation application, reports are compiled in Module 5 of the common technical document, a standardised format for submitting regulatory information to health authorities globally.
The findings reported in clinical study reports are disseminated in several ways:
- European Public Assessment Reports, prepared by the EMA and published on its website, which give information on the medicinal product, including the evaluation process and the decision to approve or reject the application
- clinical trial registries: the EMA's EudraCT and CTIS databases, the WHO's International Clinical Trials Registry Platform and the ClinicalTrials.gov registry in the US
- other public disclosure platforms: the EMA clinical data website under EMA Policy 0070 and Health Canada's Public Release of Clinical Information
- lay language summaries, published in the CTIS or on company websites
- publications: manuscripts in peer-reviewed journals, conference posters and presentations, abstracts, preprints and plain-language summaries
- product information: the summary of product characteristics or prescribing information, prepared for healthcare professionals, and the package leaflet, aimed at the patient
Several checklists exist to ensure that findings from a report are reported accurately and transparently in peer-reviewed medical journals, among them CONSORT for randomised controlled trials and STROBE for observational studies.
Reports form a continuum in the transition of an investigational drug into a product label and post-marketing safety surveillance.