Getting a drug approved takes longer than most people outside the industry expect. Not because agencies are slow, or because companies are inefficient, but because the process is genuinely complex: multiple submissions, multiple agencies, multiple rounds of questions and answers, across a development programme that spans years.
This article walks through the main regulatory processes in pharmaceutical development, from the groundwork laid before the first clinical trial to the marketing authorisation and the obligations that follow it. It is the most process-focused article in this series. For the organisational context, see regulatory affairs in the pharmaceutical industry: how it works inside a company. For an overview of the roles involved, see pharmaceutical regulatory affairs: roles, responsibilities and career paths.
Before the first human dose: regulatory groundwork in preclinical development
Defining the regulatory pathway early
Before any regulatory submission is filed, a strategic decision has to be made: which pathway will this product follow, in which markets, and in what sequence? The answer depends on the product type, the therapeutic area, the target indication and the competitive landscape.
For some products, expedited pathways are available. In Europe, these include PRIME (PRIority MEdicines), which offers early and enhanced support from the EMA for medicines that target an unmet medical need. In the US, the FDA offers Fast Track, Breakthrough Therapy designation, Accelerated Approval and Priority Review, each with different criteria and implications for development timelines.
Choosing whether and when to apply for these designations is a regulatory strategy decision with real consequences. The criteria are specific, the applications require preparation, and not every product that seems like a candidate actually qualifies.
Pre-submission meetings with health authorities
One of the most valuable things a regulatory affairs team can do early in development is talk to the agencies before submitting anything formal. Pre-submission meetings allow companies to present their development plans, ask specific questions and get agency feedback before committing to a particular approach.
Type A, B and C meetings with the FDA
The FDA classifies its pre-submission meetings into three types. Type A meetings address urgent matters that are blocking development, such as a clinical hold. Type B meetings are the most common and include pre-IND meetings, end-of-phase meetings and pre-NDA or pre-BLA meetings. Type C meetings cover any other topic not addressed in the other two categories.
Each type has different timelines for scheduling and different formats. Preparing well for these meetings, with clear questions and a focused briefing document, is a skill in itself. Agencies respond better to precise, well-framed questions than to broad requests for general guidance.
Scientific advice at the EMA
In Europe, the EMA offers scientific advice to companies at any stage of development. Companies can request advice on the design of preclinical or clinical studies, on the acceptability of proposed endpoints, or on the regulatory strategy for a particular indication.
Scientific advice is not binding on the agency, but it provides a documented record of what was discussed and agreed. Companies that follow scientific advice recommendations and then deviate from them in their actual submissions tend to have more difficult review processes.
The Investigational New Drug application and the Clinical Trial Application
IND: structure, content and FDA review process
To start a clinical trial in the United States, a company must file an Investigational New Drug application with the FDA. The IND contains three main components: animal pharmacology and toxicology data to establish that it is reasonably safe to begin human testing; manufacturing information on the composition, stability and controls of the drug; and clinical protocols describing the planned trials, along with information on the investigators who will run them.
The FDA has 30 days to review an IND and place a clinical hold if it identifies safety concerns. If no hold is placed within that period, the trial can proceed. The IND remains active throughout the clinical development programme, and it must be updated as new studies are added and new safety information becomes available.
CTA: the European equivalent and how it differs
In Europe, each clinical trial requires a Clinical Trial Application submitted to the competent authority of each member state where the trial will be conducted, as well as to the relevant ethics committees. The process has been significantly reformed under the EU Clinical Trials Regulation (EU No 536/2014), which introduced a centralised submission portal and a coordinated review process across member states.
Unlike the IND, which has a 30-day default approval period, European CTA timelines vary by country and procedure. The EU portal has simplified multi-country submissions considerably, but national requirements and timelines still differ in practice.
The content requirements are broadly similar to the IND: preclinical safety data, manufacturing information and clinical protocols. The format follows the structure of the Investigator’s Brochure and the clinical trial protocol, both of which are subject to specific ICH guidelines.
Responding to agency questions and holds
Agencies rarely accept initial submissions without questions. How a company responds to those questions can determine whether a trial starts on time or gets delayed by months.
Clinical holds in the US
A clinical hold is an order from the FDA to delay or suspend a clinical investigation. Holds can be placed on an IND before a trial starts or during an ongoing trial. The reasons range from safety concerns identified in preclinical data to deficiencies in the clinical protocol or the investigator information.
Responding to a clinical hold requires a complete response addressing every issue the FDA has raised. The agency then has 30 days to lift the hold or identify any remaining deficiencies. Speed matters, but so does completeness: a partial response that fails to address all points restarts the clock.
Requests for supplementary information in Europe
European competent authorities and ethics committees can issue requests for supplementary information during CTA review. These are not equivalent to a clinical hold but they pause the review clock until the company responds. Managing these requests efficiently, with clear and complete responses, is essential for keeping trial start-up timelines on track.
Regulatory oversight during clinical development
Protocol amendments and their regulatory implications
Clinical trial protocols change during development. New safety data, evolving scientific understanding or practical difficulties in recruitment can all lead to amendments. Some amendments are minor and can be implemented by notification. Others are substantial, meaning they could affect the safety of participants or the scientific validity of the trial, and require prior approval from the competent authority before implementation.
Classifying amendments correctly and managing the submission process for each one is a continuous regulatory task throughout a clinical development programme.
Investigator’s Brochure updates
The Investigator’s Brochure is the document that summarises the clinical and non-clinical data on an investigational product relevant to its study in humans. It is provided to trial investigators and must be kept current. When new information emerges that is clinically relevant, the IB must be updated and the new version distributed to investigators and submitted to regulatory authorities.
Managing IB updates across a programme with multiple ongoing trials in multiple countries is more logistically complex than it sounds.
Safety reporting obligations: ICSRs and DSURs
Two main safety reporting obligations run throughout clinical development. Individual Case Safety Reports (ICSRs) must be filed for suspected unexpected serious adverse reactions (SUSARs): adverse events that are both serious and unexpected based on the current IB. These must be reported to agencies within defined timelines, typically 7 days for fatal or life-threatening events and 15 days for others.
Development Safety Update Reports (DSURs) provide a periodic comprehensive review of safety information accumulated during the development programme. They are submitted annually on the international birth date of the IND and follow the ICH E2F guideline format.
End-of-phase meetings and alignment with agencies
Before moving from Phase 2 to Phase 3, companies typically seek alignment with health authorities on their Phase 3 programme. In the US, an End-of-Phase 2 meeting with the FDA provides an opportunity to agree on the study design, the primary endpoints, the patient population and the statistical approach for the pivotal trials. Agreement at this stage significantly reduces the risk of disputes later, during the NDA review.
In Europe, scientific advice at the end of Phase 2 serves a similar purpose. Companies present their proposed Phase 3 programme and ask the EMA to confirm whether the design is acceptable to support a marketing authorisation application.
Building the dossier: from CTD structure to MAA submission
The Common Technical Document: what goes where
The Common Technical Document (CTD) is the internationally agreed format for marketing authorisation applications. Developed under the ICH M4 guideline, it organises the entire dossier into five modules used by the EMA, the FDA and other major agencies worldwide, though with some regional variations in Module 1.
Module 1: regional administrative information
Module 1 contains administrative and regional information specific to each market: the application form, labelling, product information and any regional-specific documents required by the competent authority. It differs by region and is not part of the internationally harmonised CTD content.
Module 2: summaries and overviews
Module 2 contains the CTD table of contents, the introduction, and a series of summaries and overviews of the quality, nonclinical and clinical data. These documents are critical: reviewers often read Module 2 before the detailed reports in Modules 3, 4 and 5. Quality of writing and clarity of argument in Module 2 directly influences how an application is received.
Modules 3, 4 and 5: quality, nonclinical and clinical data
Module 3 covers the quality information: drug substance, drug product, manufacturing processes, specifications and stability data. Module 4 contains the nonclinical study reports: pharmacology, pharmacokinetics and toxicology. Module 5 contains the clinical study reports, including all Phase 1, 2 and 3 trial data, and any post-marketing data if relevant.
The volume of data in Modules 3 to 5 can run to hundreds of thousands of pages for a complex product. Organising, compiling and reviewing this material is a substantial undertaking that typically involves dedicated regulatory operations teams alongside the scientists who generated the data.
eCTD publishing and submission management
All major agencies now require electronic submissions in eCTD format. eCTD is not just a file format but a structured XML backbone that defines how documents are organised, sequenced and submitted across the product lifecycle. Every subsequent submission after the initial application, whether a variation, a renewal or a response to agency questions, is filed as a new sequence within the same eCTD lifecycle.
Managing the eCTD lifecycle requires specialised publishing tools and the expertise to use them correctly. Errors in eCTD structure can lead to validation failures that delay acceptance of a submission.
Submission strategies: centralised, decentralised and mutual recognition procedures in Europe
In Europe, companies have three main procedural options for marketing authorisation. The centralised procedure, managed by the EMA, results in a single approval valid across all EU member states. It is mandatory for certain product categories, including biotechnology-derived medicines and products for HIV, cancer, diabetes and neurodegenerative diseases, and optional for others.
The decentralised procedure allows simultaneous submission in multiple member states, with one acting as the reference member state that leads the assessment. The mutual recognition procedure is used to extend an existing national authorisation to additional member states. The choice between these procedures depends on the product, the target markets and the company’s commercial priorities.
NDA and BLA in the US: key differences from the MAA
In the United States, small molecule drugs are approved through a New Drug Application and biologics through a Biologics License Application. Both follow the CTD structure for their technical content but have specific FDA requirements for Module 1 and differ from the MAA in their administrative and labelling requirements.
FDA review timelines differ from EMA timelines. Standard review is twelve months from acceptance; priority review is six months. The FDA’s review process involves a different structure of questions and interactions than the EMA’s centralised procedure, and companies with experience in one system need to adapt their approach for the other.
The agency review process
Validation and acceptance
After a submission is filed, the agency first validates it: checking that the dossier is technically complete and in the correct format. Validation is not a scientific assessment. It is an administrative check that the submission contains all required components and can be accepted for review.
Validation failures at this stage are more common than they should be and almost always reflect avoidable errors in preparation. A submission that fails validation loses weeks before the scientific review even begins.
Day 120 and Day 180 in the EMA centralised procedure
The EMA centralised procedure runs to a standard 210-day timeline, with clock stops built in for the company to respond to questions. At Day 120, the CHMP sends the company its list of questions: points where the data is considered insufficient or unclear. The clock stops while the company prepares its responses.
At Day 180, after the company’s responses have been assessed, the CHMP issues either a list of outstanding issues, if significant questions remain, or moves toward an opinion. The Day 120 and Day 180 responses are among the most demanding regulatory writing tasks in the entire development process: the arguments made here directly determine whether the application succeeds or fails.
List of outstanding issues and the company’s response
If the CHMP issues a list of outstanding issues at Day 180, the company must address each point in a final response before the committee can issue its opinion. These are typically the most critical unresolved scientific questions about the product. The response needs to be both scientifically robust and clearly communicated, since the committee’s final assessment of the benefit-risk balance depends on how well these issues are resolved.
CHMP opinion and European Commission decision
Once the CHMP issues a positive opinion, the formal marketing authorisation is granted by the European Commission, typically within 67 days. The Commission decision is legally binding across all EU member states and includes the approved Summary of Product Characteristics, labelling and package leaflet.
From approval to market: the post-authorisation phase
Approval conditions and post-authorisation measures
Most marketing authorisations come with conditions attached. Post-authorisation efficacy studies, post-authorisation safety studies, risk management plans: these are commitments the company makes as part of the approval, often because the clinical data package at the time of submission, while sufficient for approval, left certain questions open.
Managing these commitments is a post-approval regulatory obligation. Failing to deliver on them, or delivering late, can result in regulatory action up to and including suspension or withdrawal of the authorisation.
Labelling finalisation and package leaflet
The approved Summary of Product Characteristics and the patient-facing package leaflet are not finalised until the very end of the review process. Negotiating label language with agencies, particularly around indication wording, contraindications and safety warnings, is a detailed and sometimes protracted exercise.
The label matters commercially as well as scientifically. What is and is not in the approved indication directly affects how the product can be promoted and used. Getting the label right is one of the last but most important regulatory tasks before a product reaches the market.
First variations and the start of lifecycle management
Within months of approval, most products require their first variations. A manufacturing change, an update to the stability data, a revision to the package leaflet: the post-approval regulatory workload begins almost immediately.
This is not a failure of planning. It reflects the reality that products and their manufacturing processes continue to evolve after approval, and that the regulatory framework requires those changes to be reflected in the approved dossier. From this point on, regulatory affairs manages a continuous cycle of submissions across the product’s commercial life.
Professionals who want to develop a thorough understanding of these processes, from IND and CTA preparation through to post-approval lifecycle management, can explore the regulatory affairs training programmes offered by LS Academy, designed for pharmaceutical and medical device professionals at all career stages.
FAQ
Both are regulatory submissions required before starting a clinical trial, but they are filed in different jurisdictions. An IND is filed with the FDA in the United States. A CTA is filed with the competent authorities of European member states where the trial will be conducted. The content requirements are broadly similar, but the formats, procedures and timelines differ. Companies running multinational trials typically file both.
The standard timeline is 210 active days, but clock stops for company responses mean the total elapsed time is typically longer, often between twelve and eighteen months from submission to Commission decision. Products granted accelerated assessment have a reduced active review time of 150 days, though this is subject to the dossier being sufficiently complete.
The Common Technical Document is the internationally harmonised format for organising and presenting the data in a marketing authorisation application. It is used by the EMA, the FDA and most other major regulatory agencies worldwide. Its importance lies in the fact that it allows companies to prepare a single core dossier and adapt it for submission in multiple markets, rather than preparing entirely different documents for each agency.
A clinical hold from the FDA requires the company to stop or not start a clinical trial. The company must address all the issues raised in the hold order and submit a complete response. The FDA then has 30 days to lift the hold or identify remaining deficiencies. The process can delay a programme by months if the underlying issues are complex or if the initial response does not fully address the agency’s concerns.
Post-authorisation measures are commitments made by a company as a condition of receiving marketing authorisation. They typically arise when the data package at approval time is considered sufficient to establish the benefit-risk balance but leaves specific questions unanswered, such as long-term safety data or efficacy in a particular subgroup. The company agrees to conduct additional studies or take specific actions after approval, and the results are reviewed by the agency.