Scientific-advice briefing documents
A scientific-advice briefing document, or briefing book, is the package a sponsor sends a regulatory agency to open a formal interaction: a request for scientific advice or protocol assistance at the European Medicines Agency, or a formal meeting with the FDA. It frames the specific questions the sponsor wants answered, each with the sponsor's position and the data behind it, and its shape depends on the receiving agency's template or meeting format, on who will read it, and on how much of it they will have time to read.
Purpose of the package
A briefing book is a structured and comprehensive package a sponsor prepares to support formal interactions with a regulatory agency. It serves two main purposes: it informs the agency, usually early, about the product's development programme, and it frames specific questions to make sure the sponsor is on the right path with that programme. It is the basis of the scientific and regulatory dialogue between sponsor and agency, and it is not simply a summary or a data dump of what the programme already holds. Because it is a strategic tool for that dialogue, it requires strategic writing, with messages that are clear and concise and aligned with the goals and objectives of the development programme. It enables dialogue with the agency, informs and keeps informing the agency of the development plans, and puts questions to it for guidance.
The interactions a briefing document supports, such as meetings or written responses, may happen at different stages of development, and their intention is often to obtain scientific advice that would eventually shape product and clinical development through to marketing authorisation and beyond. They include pre-submission meetings, requests for scientific advice and protocol assistance, and because they can shape a product's clinical development they are of great importance to companies. Successful interactions rely on thorough documentation of their outcomes, which lets the sponsor make informed decisions and continuously refine its clinical development programme on the agency's feedback. Briefing documents help the sponsor make informed decisions on implementing the agency's suggestions and recommendations for future clinical development.
A well-written and well-presented briefing document may be crucial, or at the very least can smooth the path to the desired outcome. Its content significantly influences regulatory decision-making. A well-prepared briefing book reduces regulatory risk and gets the drug onto the path to approval much better than back-and-forth between agency and sponsor. Strategic writing is critical to the clarity and consistency between agency and sponsor. Scientific advice is a way to communicate with the agency and test decisions against the expectations of its assessors, so it is crucial that the briefing document be very clear and well structured.
Guidance and basic principles
Despite the importance of these packages, very little guidance or training is available on how to prepare a successful one. Examples of briefing books and documents are also lacking. Different health authorities around the world have their own guidelines on the types of interaction and on the contents of briefing documents. The FDA's guidance for regulatory meetings was updated on 17 July 2024. Regulatory procedures and requirements are subject to change, and consulting the relevant agency's website for current information is strongly advised. Medical writers must stay up to date with the requirements of the EMA and the FDA, whose guidance is available on their websites. Best practice must be applied across a briefing book for consistency, clarity and strategic alignment between sections. Everything in it needs to be clear and compliant with the relevant guidelines, and the book needs to be tailored to the authority receiving it.
Medical writers are often involved in preparing and drafting briefing documents. One writer found that EMWA's training, which covers a wide variety of document types such as clinical study reports, investigator's brochures, components of the common technical document and informed consent, had to their knowledge not covered briefing documents, and saw no references to them in a search inside books about medical writing. The neglect of briefing documents in training courses and books on medical writing may in part be related to the lack of guidance for preparing them. Clinical study reports and many other regulatory documents are subject to specific guidance that is relatively easy to teach and write about, while little guidance is available for briefing documents, though the EMA does have a template for protocol assistance and scientific advice. Another factor is perhaps that briefing documents are rather unique, needing to be tailored to the particular needs of a given situation and perhaps also to the requirements of the authority receiving them. They are also often interdisciplinary, needing input from different functions within a pharmaceutical company, rather like investigator's brochures in this respect. Perhaps the diversity of types of briefing document and the fact that they are rarely purely clinical are further reasons why more clinically oriented training programmes have not accommodated them. Some basic principles apply nonetheless.
Unlike many other regulatory documents, a briefing document is not intended to be an exhaustive presentation of its subject. In a clinical study report, for example, leaving out comprehensive data may be read as a sign that the company has something to hide. Such considerations do not really apply to a briefing document: it is for the company to decide what is interesting and important for the project and bring that to the table. Piles of data may be off-putting to hard-pressed reviewers.
Contents of the package
A briefing document provides the critical information a health authority needs to give scientific advice during a product's development. Its general content is:
- Product background information, such as the proposed indication and other relevant background, including on the targeted disease.
- Current development status and plans for chemistry, manufacturing and controls, nonclinical and clinical work.
- Regulatory status and regulatory interactions.
- Purpose of the meeting.
- The questions, with the company's rationale and positions, including the scientific data supporting each position.
- Meeting attendees, with their role and function.
In general the structure and content are similar for the FDA and the EMA, with some regional differences: the FDA gives general guidance on the topics to include, depending on the meeting type or purpose, without a strict structure, while the EMA provides templates for specific interactions.
The medical writer's part
Strategic writing of a briefing document involves technical expertise, strategic planning and a very deep understanding of the clinical development process, and medical writers work very closely with the sponsor's regulatory and other multidisciplinary teams. They support the teams in making sure the questions are not vague, and offer strategic guidance on how to present the data and arguments effectively.
Because clear communication is key to obtaining appropriate and useful advice, medical writers have an important part in preparing the briefing document, working with regulatory affairs and with the subject matter experts who supply input to the questions and the applicant's positions. Medical writers can support the phrasing of clear, concise questions and the drafting of convincing and consistent scientific argument for the applicant's positions. They can also help make sure the content is appropriate: enough background, focused on the most relevant aspects, with the product's development clearly described, especially for a novel therapy.
Medical writers are normally not responsible for drafting the questions, although their input on language may be welcome, and the questions are often drafted first and the rest of the document constructed around them.
Preparing the package
It is important for the writer to get to know the programme and its history before the kick-off. That brings the writer up to speed and sheds light on the problem the project team currently faces, and so on the reason for the interaction. Important information to request includes documents on the product, such as the investigator's brochure and the protocol or study design, and on prior interactions, such as previous briefing documents and meeting minutes. These show the development history and what the authority currently understands about the programme, so the writer can help the team be mindful of gaps between the last interaction and the current one when developing the background and framing the questions and positions.
The questions with the company's rationale, positions and supporting data are the core of the document. The other sections are relatively straightforward and could be drafted well before the kick-off if the relevant background information can be provided ahead of time. The sponsor's questions and the preliminary company position are the last and most important content to ask for. Granular detail on them is often unobtainable and the most time goes into them during development, but it is good to touch base with the team on a general direction so the writer can prepare a starting position. Logistics and timing differ with the type of interaction, and the agency's feedback has to fit into the sponsor's clinical development programme. An overview of the logistics and timing of each type of interaction is useful in setting the document's development timelines. It is good to obtain the background information from the project team before the kick-off, so that the team can agree on the proposed timelines and the preliminary content. If time permits, these preparations can be done ahead of the kick-off and a preliminary draft or skeleton developed for the kick-off meeting.
The kick-off covers:
- The background and rationale for the briefing document, usually led by the team.
- The logistics: how the document's development will work, the timing of each step, who else will contribute content directly, and who the reviewers and approvers are. This is best led by the medical writer.
- The structure of the document, such as the important sections to keep and the amount of detail, also best led by the medical writer.
- Background: ideally in good shape by this point, provided the background materials were available ahead of the meeting, though further background may be needed to support the company position, and this will need to be discussed and highlighted.
- Questions: a good amount of time should be spent on the list of questions. A clinical programme often has overlapping topics, and it is important to develop the logic and rationale for whether a question stands alone or sits as a subset of another, such as Question 1 by itself or Questions 1a and 1b.
- Company position: each question carries a company position with the sponsor's proposal for tackling it, and a good amount of time should be allocated to obtaining the team's thoughts and overall position.
Depending on the stage of development, the complexities of the product's development programme and the dynamics of the project team, briefing documents can range vastly in complexity. Depending on that complexity, a briefing document's development can be smooth or quite turbulent. Where the briefing document is a very standard procedure and all the functions are prepared with their questions and positions, it can go quite smoothly. Where the strategy keeps changing and new information arises, it is important to be flexible and mindful of working with a lot of ambiguity. Effective collaboration and flexibility during development make a positive outcome more likely.
The questions
The questions have to be phrased precisely and clearly, with the main differences between the agencies in mind. It is recommended to frame a question in a positive light and in a way that draws a clear answer, for example "Does the Agency agree that…?" rather than "What do you think about…?", and it is important to back the company position behind it with good scientific justification. In one simple example, a sponsor asks whether the FDA agrees that a four-month safety update is not required and can be waived for a supplemental new drug application, and its position is that the update is not warranted, because a pharmacokinetic study, a long-term safety study and a pivotal efficacy and safety study are all provided with the application and no further clinical studies are ongoing.
Some questions are out of scope. A question should not ask whether the proposed active substance and finished product specifications are acceptable, but whether the plan for deriving them is. It should not ask whether the phase 3 results are adequate to support a marketing authorisation, because that is a question for the application itself. A better question asks whether the agency agrees with the proposed approach, such as the dose and schedule to be evaluated, and supplies the rationale for it.
The common errors of less experienced teams are vague questions, too many questions, data overload, time pressure and cross-functional misalignment. Vague or open-ended questions will not get a good response from the assessors. Questions that are too vague will likely get answers that are equally vague and unhelpful. To avoid too many questions, a briefing document should aim for no more than ten in total. Sending all the available data will just confuse the reviewers. Time pressure from parallel submissions and projects overburdens the team and does not lead to a good-quality document. Cross-functional misalignment is miscommunication among team members about what the overall aim is.
Specific questions can also be dangerous. They can elicit specific responses that tie the company to commitments it did not want, and although the outcomes of many of these meetings are non-binding, they will be taken into account in later submissions.
The EMA briefing book
Sources differ on how binding the EMA's template is. A webinar on briefing books calls it mandatory and says it must be followed with no deviations, including its style and format conventions. A review of EU scientific-advice procedures describes the use of the templates on the EMA website for the letter of intent and the briefing document as highly encouraged.
The briefing book has three parts: background on the disease and the product, with the regulatory rationale for seeking advice; an overview of the product's development, covering quality, nonclinical and any clinical data the agency needs; and, most important, the questions on which advice is sought. It is a standalone document, but it may cross-reference annexes, and material such as protocols can be submitted with it. Questions typically begin "Does the CHMP…", addressing the Committee for Medicinal Products for Human Use. Each question is followed by the applicant's position, with a justification of the approach chosen.
Most briefing documents begin with a short executive summary, followed by the questions with the company's positions, then a background information section where a reviewer can find more detail, and then any annexes or appendices. The EMA template for CHMP protocol assistance and scientific advice includes guidance text for each of its main sections: the summary, the questions and company's positions, and the background information. Its summary should be limited to three pages, with subheadings for background on the disease to be treated, background on the product, clinical development, regulatory status and the rationale for seeking advice, and optional subheadings for quality and non-clinical development where appropriate. The summary should be well crafted and to the point, and ideally it gives the reviewer a good idea of why the company is seeking advice. Each company position should function as a stand-alone argument, although it can cross-reference the background information to substantiate it further, should be objective and critical, and should ideally not exceed three pages. The background information section supplies additional information to allow further assessment of the development programme, while essential information should be presented in the corresponding company position. It is not intended as an exhaustive overview: tables and graphs should be considered to make it quickly understandable, and if necessary protocols, study reports and investigator's brochures can be provided as annexes. This structure, with selected and summarised information first and the opportunity to drill down to greater detail, is similar to that of many other regulatory documents. A logical, well-organised structure helps reviewers quickly find the information they want at the level of detail they want, and so puts them in a better position to give useful feedback.
The briefing document is the core of the advice request and consists of three main parts: the summary, the questions with the applicant's positions, and the background information on the product. The summary, typically no longer than three pages, gives background on the disease to be treated, a brief description of the product including its quality, nonclinical and clinical development, its regulatory status and the rationale for seeking advice. The questions are grouped by area of expertise and numbered sequentially. Each is phrased carefully, clearly and unambiguously to obtain a clear and precise answer, with a scope neither too broad nor too narrow to obtain meaningful advice, typically starting "Does the CHMP agree that" or "agree with" followed by the applicant's proposal. The applicant's position after each question gives a comprehensive justification of the chosen approach, including its context and the alternative options considered, with a critical discussion of their relative advantages and disadvantages. With a recommended length of one to three pages, each applicant's position should contain enough detail to serve as a stand-alone argument, cross-referring to relevant parts of the briefing document or its annexes as needed. The background information gives a comprehensive overview of the development programme, with detailed information on quality, nonclinical and clinical aspects, though its content and level of detail should be weighed to keep the overall size of the briefing document reasonable. Tabulated summaries in the background section are particularly helpful to keep the information comprehensive yet concise. The final package typically includes relevant annexes, such as the investigator's brochure, clinical study protocols, reports or synopses, advice previously received from the EMA or other regulatory agencies, regulatory documents such as orphan designations or agreed paediatric investigation plans, and literature references. If the procedure includes a discussion meeting, the applicant also prepares written responses to the issues to be addressed before the meeting, and slides for presenting and discussing the issues at the face-to-face meeting.
A briefing book can be submitted to the EMA at any stage of a drug's development. Protocol assistance follows a similar template and design but gives advice specifically on orphan-designated medicines for rare diseases. Its briefing document is usually submitted before the pivotal trials the sponsor plans, to get the agency's feedback early. Protocol assistance can be requested before the marketing authorisation application by applicants whose product has an orphan designation, and follows the same procedure as regular scientific advice. Beyond the usual scope of advice, it can also cover topics specific to orphan drugs: the clinical development strategy for generating the appropriate data to demonstrate significant benefit in the designated orphan indication or in relation to orphan similarity.
The FDA briefing package
Formal meetings give sponsors and applicants guidance on developing new drugs or on the review of marketing applications, and the goal is an efficient, well-managed and productive meeting that provides the information the sponsor seeks. A well-written meeting request and briefing book are the first steps toward it. The FDA's guidelines require the written meeting request to include the general nature of the critical questions to be asked, where the meeting fits in the overall product development plans, a list of the specific objectives or outcomes expected from the meeting, and a proposed agenda. The request states clearly the type of meeting requested. If the FDA grants the meeting, the sponsor supplies the information package, the briefing book, within the predetermined time frame.
The FDA has no mandatory template. It asks only that the briefing package be sequentially paginated, with a table of contents, appropriate indices, appendices and cross-references.
A typical FDA briefing package gives background on the product and the indication in its first five sections and, because the package supports an actual meeting held in person or by video, gives information on the sponsor attendees. It also carries the history of the development programme and the status of the product's development, much as the EMA book does. Sections seven and eight state the purpose of the meeting and the agenda. Section nine puts the questions to be discussed with the agency, and section ten holds the data supporting them. The attendee information has no counterpart in the EMA template. Nor do the purpose and the agenda, because no meeting is expected at the EMA.
The contents of the briefing book should support the objectives of the meeting and will vary with the product, the indication, the phase of development and the issues to be discussed. The book should provide current and accurate summary information about the product, plus whatever further information is needed to elicit responses to the issues raised by the sponsor, the applicant or the FDA. Carefully worded, focused questions are needed to obtain answers that will advance the development programme. The book should be well organised by topic and should not be voluminous. Summarising data in bulleted lists or tables should be considered, figures can illustrate data, and relevant background such as journal articles can go in appendices. The information should be presented in clear, concise, objective language that is non-confrontational.
Pre-NDA and pre-BLA meetings are usually held 6 to 12 months before the planned submission, to allow a comprehensive review of the summary of relevant data generated during development, so their meeting package should include details of any critical issues that may affect approval of the application.
How the EMA and FDA packages differ
The two packages answer different requests. An EMA briefing book supports scientific advice or protocol assistance; an FDA briefing package supports a meeting of type A, B or C. The EMA's template includes the applicant's position and rationale, while the FDA has no strict template, although what it expects in content overlaps quite a bit with the EMA briefing package. EMA advice has no fixed milestones and can be requested at any time; FDA meetings sit at defined time points.
The two agencies fulfil different roles. The FDA focuses on face-to-face interaction and decision-making, because it operates with full authority to approve or reject products. The EMA prioritises written scientific advice as a continuous support tool rather than a series of discrete meeting events. EMA scientific advice and protocol assistance are usually a written response only, with a meeting only when discussion is required.
Other authorities accept briefing documents too, and at a high level each follows one of the two patterns: Health Canada, India's CDSCO and Australia's TGA follow more or less the FDA style, while the UK's MHRA and Japan's PMDA follow more the EMA's scientific advice.
Who reads the package
At the EMA the question is addressed to the CHMP, which issues the advice on the recommendation of the Scientific Advice Working Party. The package goes to that working party, a multidisciplinary group of a chairperson and up to 36 members that also includes external experts, so it reaches a large audience of assessors. Its members are selected for complementary scientific expertise, and between them they cover a broad range of therapeutic areas and of aspects of drug development, including manufacturing, preclinical pharmacology and toxicology, clinical pharmacology and pharmacokinetics, gene and cell therapies, clinical trials and statistics. The working party has access to a network of European experts and regularly interacts with the FDA, health technology assessment bodies, the WHO and patient organisations. It gives its advice on the basis of the applicant's position on the questions asked and of current scientific knowledge. Patients are sometimes involved, especially for rare diseases. In 2018, one in five scientific-advice procedures involved patients.
At the FDA the audience is the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research: medical officers, pharmacology and toxicology experts, and statisticians, who assess the questions between them.
An advisory committee is occasionally added where the data interpretation is uncertain, where the issues are complex or novel, or where there are safety or efficacy concerns. The FDA then prepares its own briefing package and submits it to the committee together with the sponsor's. The committee consists of independent experts the FDA recruits and can include consumer, patient or industry representatives. Its recommendations are non-binding, and the FDA makes the final decision. The committee's input nevertheless carries quite significant weight.
Reviewers may read little of the package. In a survey of how FDA advisory committee members prepare for a public advisory committee meeting, 20% of members spent less than four hours preparing for the meeting. That time also covered the sponsor's slides and the FDA's own briefing pack, so the time spent actually reading the sponsor's material can be minimal. Because the outcomes of most of these meetings are not binding, a reviewer will perhaps also be less inclined to focus on the detail and look more at the big picture. Many of the members surveyed generally preferred less text and more tables, and the vast majority wanted the document to run to less than 100 pages excluding appendices. Public advisory committee meetings are a special case and may not represent other kinds of meeting with other agencies, but reviewers elsewhere are likely also hard-pressed for time, so considerations of brevity will also apply to them.