Talking to the authority during development
A sponsor exchanges information with the health authority from before its first application to test a medicine in people, through each stage of development and the review of its dossier, and on after approval. The exchanges begin early, each asks the authority something different, and together they shape the route a medicine takes to approval. Once the medicine is on the market, safety remains their subject.
Early contact with the authority
Early contact with the regulatory authorities helps to expedite development, and regular communication between the authorities and drug developers is instrumental in streamlining the review of new products. Health authorities therefore encourage regular exchange with drug developers and are usually prepared to give guidance at an early stage. Professionals in the pharmaceutical industry should make use of that opportunity, so that issues with the manufacture, formulation or testing of a new drug candidate can be addressed early, preventing unexpected delays.
Many factors influence the speed and efficiency of a development programme, but the value of effective communication during development and approval is unquestioned, especially for novel medications for which regulatory guidelines have not yet been established. Early consultation with the authorities is indispensable, and other bodies relevant to the target indication may also have to be addressed, but such consultations should be undertaken only once the pertinent medical and drug information data are available.
Ideally, the first contact with the authorities should take place even before an investigational new drug (IND) application is made. The FDA compared the development times of new drugs approved with the benefit of pre-IND meetings with those of drugs approved without them. Average clinical development time was substantially shorter where a pre-IND meeting between the developer and the FDA had been held, and for all new drugs approved between 2010 and 2012 it was more than 3 years shorter.
The exchanges at each stage of development
Key interactions with a regulatory authority fall essentially at two stages of development. The first comes before the registration dossier is submitted, in formal and informal exchanges such as meetings the sponsor requests or its responses to the agency's inquiries. The second comes after submission, when the authority poses questions that need written responses. With the FDA, the exchange before submission generally seeks the agency's further insight on the sufficiency of the available data and on the planned clinical programme. The agency provides recommendations on technical changes, the clinical development plan, the IND application documentation or a special protocol assessment, or guidance on ways to resolve critical issues that might affect the approval process. These formal communications are set out in FDA guidance.
Regulatory authorities keep an eye on every product as it moves from discovery through development and onto the market. Between drug discovery and preclinical work, a company requests a meeting with the FDA to introduce the drug and the preclinical studies it proposes, which tells the agency that the company is working on the product. Between preclinical work and phase 1, at the pre-IND (PIND) stage, the company must obtain the agency's agreement that the preclinical safety data are sufficient to proceed to human testing, and that no strong safety signal makes giving the drug to a human inadvisable. On moving into phase 1, the company has to talk very intensely with the regulatory authorities about how it will move the drug into the clinic.
At the end-of-phase-2 meeting, the company submits a briefing package summarising all its data and asks the agency whether anything is missing before phase 3 begins. The meeting is not obligatory but strongly advisable. The agency may not give feedback and may call a point a review issue to come back to when it sees the data, but it is worth asking so that the agency is not surprised by phase 3 data and a submission package it did not expect.
The months before an investigational new drug application
The request for a meeting with the agency marks month zero. The request typically carries preliminary questions, and regulatory affairs typically drives it. Roughly a month later the meeting is granted or denied. If it is granted, regulatory affairs typically prepares the final list of questions with the subject-matter experts and all the stakeholders involved. The FDA meeting, its written comments and the IND submission follow, and approval comes roughly four months after month zero.
A good deal of pre-IND activity happens before month zero, and there nonclinical medical writers can have a very large impact on teams: they prepare the questions, drive the subject-matter experts and summarise the nonclinical datasets in tables and a variety of other content. From the IND kickoff to the submission takes roughly six months under optimal conditions, though it can take more or less. Over those six months, nonclinical medical writers are much involved in finalising the questions. They typically support teams with briefing documents and with other nonclinical documents as needed. Eventually some level of feedback comes from the agency.
Meeting rehearsals
A medical writer sometimes attends meetings with the health authorities. Whether or not the writer attends, taking part in the team's meeting rehearsals is often beneficial. Important discussions about potential questions, and about gaps in the submitted information that may be challenged, could arise there. Those discussions are important for understanding the rationale and the proposed responses, and through them for understanding the project further.
The outcome of a meeting
After the interaction the health authority often gives the sponsor the outcome of the meeting as minutes, and these agreements are stored as part of the history of the clinical development programme. The sponsor is often recommended to implement the suggestions, but depending on the suggestion, the overall programme and the company's plans, it may not implement all of them. A medical writer who continues on the project will be able to work with the team and implement the required changes in the relevant documents seamlessly. Briefing documents are crucial tools for facilitating interactions between companies and health authorities, and they help the sponsor make informed decisions on implementing the suggestions and recommendations for future clinical development.
The FDA and the EMA as counterparts
The FDA, as a centralised agency, has the direct authority to approve or reject products for the entire US market. The EMA provides scientific advice and guidance but is not the body with the authority to approve medicines: the final marketing decision is made by the European Commission.
Both agencies offer scientific consultations throughout drug development and before the dossier is filed, and both give non-binding opinions. Because the FDA has the power to approve or reject, its opinion carries more weight and is slightly more binding than the EMA's. The FDA emphasises meeting types, while the EMA focuses on scientific advice.
The FDA is generally considered to give the faster feedback. The main reason is that it operates as a single agency with full-time in-house reviewers, while the EMA works through a network of national regulatory experts from the 27 EU member states, a larger machinery to pass through before a decision or feedback comes. Approval pathways, review timelines and regulatory culture are the key differences between the two, and knowing them is important for a sponsor's planning: when to request feedback, and how the agencies differ if it submits to both.
Safety and the balance of benefit and risk
Regulatory authorities such as the FDA and the EMA prioritise safety above efficacy. The threshold of benefit against risk varies with the severity of the disease. Diabetes and obesity progress slowly, and authorities have very low tolerance for severe adverse events in treating them. In a disease such as cancer, which can kill acutely, they may accept certain non-ideal safety signals and may approve the drug for marketing if its benefit outweighs the risk of treating the patient.
Once the drug is marketed, the company writes post-marketing safety reports, and it can use briefing packages to inform the agency of emerging safety signals. In one experienced regulatory writer's view, it is better for the company to inform the agency of something it thinks could be going on than to let the agency find it in its own surveillance. An agency that finds something it thinks the company is not aware of will shut the product down, while a company that raises it can talk with the agency as it works out what is going on.