The documents a development programme produces
Every stage of a medicine's development leaves documents behind, from the record of the first nonclinical findings through the documents each trial needs to the dossier that asks for approval and the safety reports that follow it. Each is written for its own reader, each has its own job in the chain of evidence, and together their content and timing decide whether and how quickly the medicine is approved.
The stages of development
The development of a medicine runs from chemistry, where many molecules are invented to decide which is best, through pharmaceutical formulation, where it is decided whether the medicine is better presented as a syrup, an injection or a tablet, and preclinical research and toxicology in animals, to clinical research in humans across four phases. Medical writers do not usually write much about chemistry and are not expected to know much about it, and whatever they do have to write about it is copied and pasted. Medical writers probably write a little about formulation in some documents, but it is not their main area of expertise: other people provide the text, which is probably just copied and pasted. Some medical writers specialise in pharmaceutical formulation and chemistry, although that work usually falls outside medical writing, in the realm referred to as CMC. Medical writers write a bit more about preclinical research in some documents, although at that point the work is not really called medical writing but scientific writing, with which medical writing overlaps to some extent; some medical writers write about preclinical research, though not all, and some specialise in it. Most of a medical writer's work involves the four phases of clinical research. In one experienced writer's view, all medical writers write about clinical research.
A standard path to marketing authorisation starts with nonclinical studies and moves to a first-in-human study and, with luck, to phase 2, with a couple of studies in parallel and some additional phase 1 studies, then to phase 3 with at least two studies, then, usually once all the data are in, to the marketing authorisation submission and, with luck and a convincing application, to phase 4. Medical writers can also write the nonclinical reports along this path.
Documents before the first trial
The first documents notify the authorities of the intention to develop the drug in a market. In the United States this is the investigational new drug application, and in Europe the investigational medicinal product dossier, the request to be allowed to perform a clinical trial in a particular country, which is submitted every time a company would like to perform a trial. The investigator's brochure is needed before the first clinical trial and is updated at specific time points during development.
Documents for each trial
Medical writers develop most of the documents needed for trial start-up, conduct, close-out and reporting, while working away from the front line. From study start-up and first patient first visit to last patient last visit and study close, these documents include the investigator's brochure, the statistical analysis plan, protocol amendments and the annual investigator's brochure update, the clinical study report, the statistical outputs (tables, figures and listings) and the lay summary, and on some of them the medical writer works as a reviewer or contributor.
Clinical trials start with the study protocol. Before and during a clinical trial, medical writers write the clinical study protocol, the patient informed consent form, the investigator's brochure, patient narratives describing serious adverse events, the investigational medicinal product dossier and sometimes the paediatric investigation plan. Each trial needs at least one protocol and at least one informed consent form, but in practice both are usually amended and updated, and there are different types of consent form, so there are many documents to write. The protocol and the informed consent form are sent to the ethics committee, which decides whether it considers the study ethical.
After a trial, the first and most important document is the clinical study report, a separate report for each study that describes its methodology and results and gives a clinical interpretation of them. With the protocol, it is probably the most common document regulatory medical writers write. Once the data exist, each study needs at least one clinical study report.
The results of a clinical study are the basis for deciding whether to continue developing the drug or to look at new subgroups or, for instance, at paediatric patients, and in that case the cycle continues and the documents are adapted to the new study or completely rewritten.
Documents exchanged with health authorities
At specific time points in a development programme the sponsor needs to reach out to the health authorities to align on the programme, and the questions it needs to raise, or that come up while the drug is developed, are contained in a briefing document, also called a briefing book or a meeting request. The authorities can also come back to the sponsor with questions, for instance about a submitted protocol, or ask for changes, in a request for information that the sponsor must reply to. A sponsor that is lucky has a medical writer to help draft that response.
The marketing application
At some point enough data have been collected and, if they look positive, the sponsor decides to submit for marketing authorisation. Once many trials have been performed on a drug, perhaps 20 or 30, the Common Technical Document summarises all of its research and development. It is not one document but quite a few, running to thousands of pages, that summarise all the efficacy, safety and preclinical data so that the health authorities can quickly understand what the company is claiming for the drug and consider it for approval. Its electronic form, the electronic common technical document, is the submission package sent to the health authorities to ask for approval. Medical writers are most commonly involved in the clinical modules, module 2.5 the clinical overview and module 2.7 the clinical summaries, and some also write the preclinical modules 2.4 and 2.6, although, in one writer's view, fewer have experience of those.
A paediatric plan must be presented whenever approval of a drug in adults is requested, and depending on the authority it is addressed to it is called a paediatric investigation plan or a paediatric study plan. In the risk management plan the company describes the risks to the patient of taking the product and the efforts it plans to make so that the risk is minimised and constantly followed up and safety issues are reported rapidly and efficiently.
The contents of a new drug application
Many documents go into the package sent to the agency for a new drug application.
- A protocol describes how the trial will be conducted, what drug is used, the dosing and the timing.
- A clinical study report is required by guidance for every clinical trial, whether or not the trial was considered successful.
- Protocol amendments change the protocol during a study.
- Lay summaries are for trial participants, who are not expected to understand the regulatory documents.
- The investigator's brochure is a compendium of all the information known about the drug in the target disease, given to the physicians running the trial.
- Annual reports update the agency every year during an ongoing trial, and whether one is due depends on how long the trial runs.
- Safety reports are ongoing and voluminous.
- Nonclinical study reports cover the animal model data.
- The submission package, an NDA or BLA, organises all the documents, from nonclinical and clinical reports to chemistry and manufacturing data, into the Common Technical Document triangle, and is filed electronically.
The documentation submitted with an application once came on paper, enough to fill the back of a truck. Most submissions are now prepared and delivered electronically. By 2011, electronic delivery had not changed the volume of documentation required.
Documents after approval
Pharmacovigilance follows up the safety of a product once it is on the market, and two documents in particular report its findings, the development safety update report and the periodic safety update report. The pharmacovigilance documents written after the medicine is approved and marketed also include a benefit-risk evaluation report. Pharmacovigilance continues throughout the drug's life cycle, and the periodic safety update report, which may contain real-life evidence from medical practice and spontaneous reports of any kind of adverse event, goes to the authorities at regular intervals. The risk management plan also has to be updated based on the drug's experience once it is on the market, in an ongoing process. Protocols for post-marketing phase 4 studies then start the cycle again, with an investigator's brochure, an informed consent form and the other documents a trial needs, a new study report and an updated Common Technical Document.
More and more regulatory documents are required each year, because regulatory authorities are becoming stricter about the information they want to receive before allowing a product to be marketed and in order to follow the safety and efficacy of marketed products.
The reader each document is written for
Written communication in drug development works on several levels: recording new findings from nonclinical studies; preparing the documents the development process needs, such as the investigational new drug application, the investigational medicinal product dossier, the investigator's brochure, clinical study protocols and reports and the Common Technical Document; communicating with regulatory authorities, ethics committees and other important groups; and drafting publication manuscripts about the drug in development. The data communicated at these levels differ in nature, terminology and complexity, and the audience the documents must reach changes over the course of development, which calls for considerable sensitivity from the writer. Scientific and medical information should be presented so that the targeted audience can understand and interpret it, so a good writer must be able to anticipate the intended readers' level of understanding. There is no point in overloading the nonclinical scientist with unnecessary marketing information, nor would the clinical investigator benefit from excessive technical detail on the synthesis of the drug under study. Good writing therefore also entails careful planning of the level of detail the intended audience requires.
Recording findings
Without a written account of an experiment or study, no one would know of its findings, it would be almost impossible to prove that the research had been carried out, and painstaking work may be lost. Nonclinical findings form the basis of future studies in humans. Written communication in drug development is therefore of critical importance, and its main concern should be to document new findings efficiently, effectively and truthfully. In drug development, failure to document findings inevitably delays marketing authorisation of a new drug, which costs the sponsor substantial sums of money.
The documents and approval
Regulatory documents are the basis for drug approval, and their content determines the success of a drug's clinical development. The data must be convincing on efficacy and safety, but the content must also be clear, focused and targeted. The timing of the submission determines the speed of approval: the longer a protocol takes to write, the later the trial starts, which delays the submission.
High-quality documents are critical for the health authorities to consider and judge the risks and benefits of a drug or medical device coming onto the market, which has implications for the speed and cost at which marketing authorisations are reviewed and approved, so, time being money, good clear documents save time. A director at the US Food and Drug Administration has said that the agency provides healthcare professionals and patients with the information they need to use medication safely and avoid medical errors, and that all of these efforts require excellent medical writing. An official at the European Medicines Agency has said that enthusiasm over good writing and sharing ideas across the whole pharmaceutical spectrum benefits patients, the health community and society at large.
When the marketing application goes to the US Food and Drug Administration at the end of development, every document counts. Flaws in logic or inconsistencies in data or methods will at the very least put the application on hold while the sponsor responds to questions, and in the worst case, where the submission does not reflect industry standards or lacks appropriate information, the agency may issue a refusal to file, and all the work will have been for nothing.