Bringing a new drug to market is a complex, multi-phased process that demands rigorous planning, data generation and regulatory compliance.
For therapies targeting rare diseases, the pathway can be especially challenging due to small patient populations, limited clinical data and the urgent unmet medical need. Sponsors must also account for unique regulatory designations and streamlined approval mechanisms, leveraging orphan drug incentives and real-world evidence where appropriate.
Regulatory plays a crucial role in providing tailored pathways — such as orphan drug designation (ODD), fast track and priority review — to facilitate the clinical development and approval of these critical treatments.
In this blog, we’ll give you a brief overview of the essential components required for a successful regulatory submission, from early strategic planning and pre-clinical development to clinical trial design and post-approval commitments.
Our checklist highlights considerations specific to rare disease therapies, aligning with both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) requirements. Other regions may have differing requirements, although you can still use this checklist as a guide.
New drug approvals checklist
1. Develop a strategic planning and regulatory pathway
Define the regulatory submission strategy, including target regions (such as the FDA and EMA).
Identify eligibility for rare disease designations, including:
- Applying for ODD from the FDA and EMA.
- Requesting fast-track or breakthrough therapy designation from the FDA.
- Applying for priority medicines (PRIME) status from the EMA.
Engage early with regulatory authorities by:
- Requesting a pre-investigational new drug (IND) meeting with the FDA or seeking scientific advice from the EMA.
- Coordinating parallel scientific advice sessions, if applicable.
2. Compile pre–clinical (non-clinical) data package
Conduct pharmacology studies to evaluate primary and secondary pharmacodynamics.
Perform toxicology assessments, including single- and multiple-dose studies, genotoxicity and carcinogenicity (if required).
Execute safety pharmacology studies to assess effects on vital organ systems.
Complete reproductive and developmental toxicity studies where applicable.
3. Design and execute a clinical development plan
Design clinical trials suitable for rare diseases, including:
- Justifying small population sizes.
- Incorporating historical controls or external comparator arms.
- Using surrogate endpoints if regulatory authorities permit.
Prepare IND or clinical trial application (CTA) submissions with:
- Finalised clinical protocol.
- Investigator’s Brochure.
- Initial chemistry, manufacturing and controls (CMC) information suitable for the phase.
Register clinical studies on recognised platforms, such as ClinicalTrials.gov and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT).
4. Prepare CMC documentation
Document drug substance details, including manufacturer information, process description, specifications and stability data.
Detail drug product characteristics, including formulation, container closure system and quality control testing results.
Provide comparability data if there are manufacturing process changes during development.
Develop a paediatric formulation plan if required.
5. Assemble regulatory submission components
Compile the common technical document (CTD) according to regional requirements:
- Complete Module 1 with region-specific administrative information, including cover letter, application form and FDA Form 356h.
- Include Module 2 summaries covering clinical, non-clinical and quality aspects.
- Populate Module 3 with detailed quality (CMC) information.
- Submit Module 4, containing all non-clinical study reports.
- Submit Module 5 with clinical study reports, statistical analyses and relevant datasets.
6. Address orphan and rare disease-specific requirements
Justify the request for ODD by:
- Providing prevalence data (<200,000 patients in the US; <5 in 10,000 in the EU).
- Demonstrating medical plausibility and significant benefit over existing therapies.
Submit a paediatric investigation plan (PIP) to the EMA or a paediatric study plan to the FDA.
Include natural history study data if available.
Incorporate real-world evidence and patient-reported outcomes as supporting data.
7. Ensure compliance with electronic submission requirements
Format all documents according to electronic CTD standards.
Validate the submission through appropriate gateways, such as the FDA Electronic Submissions Gateway (ESG) or the EMA Common European Submission Platform (CESP).
Apply proper metadata tagging and ensure all portable document format requirements are met.
Track submissions using submission IDs and confirm receipt acknowledgements.
8. Execute post-submission activities
Prepare for regulatory authority review processes, including question-and-answer rounds.
Coordinate preparations for an Advisory Committee meeting, if likely.
Engage in product labelling negotiations.
Submit and manage a risk management plan (RMP) for the EMA or a risk evaluation and mitigation strategy (REMS) for the FDA.
Ensure readiness for site inspections in compliance with good clinical practice (GCP), good manufacturing practice (GMP), and good laboratory practice (GLP) standards.
9. Plan for market access
Prepare for health technology assessment (HTA) submissions.
Develop pricing and reimbursement dossiers.
Establish early access programmes, such as ‘compassionate use’ or ‘expanded access’.
10. Fulfil post-approval commitments
Implement a post-marketing surveillance or pharmacovigilance plan.
Execute plans for real-world data collection.
Conduct registry-based studies to support long-term monitoring in rare disease populations.
Accelerate your path to regulatory submission
An effective regulatory submission hinges on early engagement with health authorities, a strong evidence base across non-clinical and clinical studies and a well-documented CMC package.
By following a structured checklist and preparing for both scientific and administrative requirements, you can improve your chances of approval and expedite access to therapies for patients with limited treatment options.
At TMC, we’ll guide you, as your partner, throughout your regulatory submission — using our expertise in regulatory processes for rare diseases to help you design effective clinical trials and secure early-stage approvals.
We can also act as your marketing authorisation holder (MAH), if you don’t have a presence in Europe, to ensure compliance with all local regulations. As an established EU/EEA-based MAH with SME status, TMC can be your EU/EEA representative, simplifying your regulatory submission and helping you secure substantial discounts on EMA fees.
Find out more about TMC’s regulatory services or contact our team today at regulatory.services@tmcpharma.com to see how we can accelerate your regulatory submission and help you secure market authorisation approval — efficiently and cost-effectively.
