Článek
Thinking like a regulator: How to reduce risk in the first-cycle submission review
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Michael Day, Ph.D.
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Lin Li
Adopting a cross-functional approach to preparing the product submission to successfully navigate the review cycle
Note: For additional guidance on this topic, attend our webinar, “Thinking like a regulator,” to be held April 22nd and available on-demand after.
Regulatory expectations for submission readiness have evolved significantly in recent years. While sponsors may believe they have assembled a technically sound dossier, regulators are increasingly assessing whether the entire development program holds together scientifically, strategically, and operationally. As a result, submissions that appear strong on paper can still encounter major review obstacles when cross-functional alignment is missing.
Many review challenges do not stem from missing data, but from inconsistency in the dossier narrative across regulatory strategy, clinical study design, CMC readiness, evidence planning, pharmacovigilance, and commercialization considerations. For example, a company may have a strong clinical story, but the CMC package is not well rounded, or the data package is sound, but the sponsor hasn’t clearly explained the benefit-risk of their product.
In practice, these misalignments often appear in subtle ways that are easy to miss. For example, the clinical program may support a broader patient population than the eventual regulatory label allows, or risk evaluation and mitigation strategy (REMS) considerations may not be aligned with the safety narrative.
Regulatory expectations for submission readiness have evolved significantly in recent years. While sponsors may believe they have assembled a technically sound dossier, regulators are increasingly assessing whether the entire development program holds together scientifically, strategically, and operationally. As a result, submissions that appear strong on paper can still encounter major review obstacles when cross-functional alignment is missing.
Many review challenges do not stem from missing data, but from inconsistency in the dossier narrative across regulatory strategy, clinical study design, CMC readiness, evidence planning, pharmacovigilance, and commercialization considerations. For example, a company may have a strong clinical story, but the CMC package is not well rounded, or the data package is sound, but the sponsor hasn’t clearly explained the benefit-risk of their product.
In practice, these misalignments often appear in subtle ways that are easy to miss. For example, the clinical program may support a broader patient population than the eventual regulatory label allows, or risk evaluation and mitigation strategy (REMS) considerations may not be aligned with the safety narrative.
Manufacturing comparability questions may undermine confidence in later-phase data, integration-site or biodistribution risks may not be clearly addressed, and administrative or inspection-readiness gaps can trigger avoidable delays.
Because regulatory reviews – including complete response letters (CRLs) – are structured by discipline, these cross-functional issues can become hidden submission risks that can surface late in the review cycle and lead to an unanticipated authorization delay.
These issues do more than create technical delays. They can push sponsors past critical regulatory timelines, trigger major review questions, or require additional analyses or studies late in the cycle. The downstream impact can be significant: delayed patient access to innovative therapies, erosion of competitive advantage, greater costs and revenue delays, and potential detrimental impact on investor confidence.
Submission readiness in a more complex scientific and regulatory environment
Research and development (R&D) has moved away from simple molecules to complex biologicals, including monoclonal antibodies, mRNA technology, cell and gene therapies, antibody drug conjugates, and other advances.
Sponsors are seeking to take advantage of programs to expedite development and review, such as fast-track designation, breakthrough therapy designation, accelerated approval, and priority review designation by the U.S. Food and Drug Administration (FDA)1, and accelerated assessment by the European Medicines Agency.2
While the agencies are supportive of faster assessment of products that address an unmet need or are of major public health interest, they are reviewing these products holistically. As a result, regulators are uncovering gaps in sponsors’ development programs, which could have been mitigated with an early program-level assessment of the process.
Sponsors are seeking to take advantage of programs to expedite development and review, such as fast-track designation, breakthrough therapy designation, accelerated approval, and priority review designation by the U.S. Food and Drug Administration (FDA)1, and accelerated assessment by the European Medicines Agency.2
While the agencies are supportive of faster assessment of products that address an unmet need or are of major public health interest, they are reviewing these products holistically. As a result, regulators are uncovering gaps in sponsors’ development programs, which could have been mitigated with an early program-level assessment of the process.
What does submission readiness look like?
Submission readiness means having a robust and coherent scientific narrative. Typically, however, dossiers are developed in silos, with the CMC team compiling the quality section, while the toxicology team separately addresses toxicology issues that go to the safety of the drug. The full narrative doesn’t come together until the sponsor starts to prepare for submission.
When this integration happens only at the submission stage, it is often too late to address underlying gaps. Sponsors need to bring teams together earlier to apply the science behind the development to the application of the drug. What formulation will make most sense for the patient population and physicians or sites of care? Are there evidence gaps that could affect the product’s commercialization and reimbursement?
Regulators are also increasingly open to real-world evidence (RWE) to provide insight into how medications work in a specific population, for example, children, the elderly and people with comorbidities, and to support their decisions about new products.
In our experience, sponsors can struggle to connect all the elements – regulatory, clinical, CMC, and safety – and develop a clear regulatory narrative. They may not have the regulatory insight to understand what the health authorities are expecting from a benefit-risk perspective or what they will allow on the regulatory label, such as comparator claims, mechanism of action differentiation, and dosing and administration.
Early cross-functional reviews can identify and remediate potential issues sooner. Having a third party provide a cross-functional lens and translate the technical data into regulatory positioning can help sponsors to bridge the submission readiness gap.
When this integration happens only at the submission stage, it is often too late to address underlying gaps. Sponsors need to bring teams together earlier to apply the science behind the development to the application of the drug. What formulation will make most sense for the patient population and physicians or sites of care? Are there evidence gaps that could affect the product’s commercialization and reimbursement?
Regulators are also increasingly open to real-world evidence (RWE) to provide insight into how medications work in a specific population, for example, children, the elderly and people with comorbidities, and to support their decisions about new products.
In our experience, sponsors can struggle to connect all the elements – regulatory, clinical, CMC, and safety – and develop a clear regulatory narrative. They may not have the regulatory insight to understand what the health authorities are expecting from a benefit-risk perspective or what they will allow on the regulatory label, such as comparator claims, mechanism of action differentiation, and dosing and administration.
Early cross-functional reviews can identify and remediate potential issues sooner. Having a third party provide a cross-functional lens and translate the technical data into regulatory positioning can help sponsors to bridge the submission readiness gap.
A framework for integrated submission assessment
True submission readiness is not assessed by a single function, rather it is the integration of all the parts that make up the submission. While the scientific perspective is integral to the submission, often what is missing is the strategic perspective: How has the overall narrative been told and will it meet the expectations of the health authorities?
To do that, sponsors need to understand how the FDA and/or EMA will review their entire program and to adopt a common strategic positioning before submitting to the regulators. The framework for an integrated assessment of the submission must cover all elements of the program: strategic regulatory alignment; CMC and quality execution; and clinical evidence generation. Later, this framework will also apply to market access and commercialization evaluations. The key question for sponsors is not whether each component of the submission is complete, but whether the pieces reinforce one another.
To do that, sponsors need to understand how the FDA and/or EMA will review their entire program and to adopt a common strategic positioning before submitting to the regulators. The framework for an integrated assessment of the submission must cover all elements of the program: strategic regulatory alignment; CMC and quality execution; and clinical evidence generation. Later, this framework will also apply to market access and commercialization evaluations. The key question for sponsors is not whether each component of the submission is complete, but whether the pieces reinforce one another.
Strategic regulatory alignment
When reviewing a submission, regulators are looking for a cohesive narrative from non-clinical data, for example toxicology data, to how that translated into how the sponsor designed the dose for human studies. That, in turn, must loop back to the quality of the material used in the non-clinical study from a CMC perspective. For example, when using different batches of the drug in later studies, can the sponsor demonstrate that it met the same purity as the batch used for the first cohort?
Sponsors must ensure they are not adopting a retrospective approach to their studies and that they have identified all the potential risks and potential scientific and strategic gaps well before filing.
By engaging proactively with the health authorities, sponsors can get alignment around their program before going too far down the development path. In addition to formal meetings open to sponsors – in the U.S., for example, Type A, Type B, Type C, Type D3, and Initial Targeted Engagement for Regulatory Advice on CDER and CBER ProducTs (INTERACT) meetings – there are also options to have more impromptu discussions with the regulators.
Sponsors must ensure they are not adopting a retrospective approach to their studies and that they have identified all the potential risks and potential scientific and strategic gaps well before filing.
By engaging proactively with the health authorities, sponsors can get alignment around their program before going too far down the development path. In addition to formal meetings open to sponsors – in the U.S., for example, Type A, Type B, Type C, Type D3, and Initial Targeted Engagement for Regulatory Advice on CDER and CBER ProducTs (INTERACT) meetings – there are also options to have more impromptu discussions with the regulators.
CMC and Quality Execution
With the release in 2025 of more than 200 Complete Response Letters (CRLs) from the FDA, sponsors can gain insight into how the agency is thinking and see the kinds of issues that are occurring, including process control gaps, inadequate stability data, unvalidated analytical methods, and ongoing issues following Good Manufacturing Practice (GMP) inspections.
Manufacturing readiness is a common issue for sponsors. For example, we often see lack of preparedness for ramp-up from clinical studies to market adoption or sponsors with a single manufacturing site discovering barriers when trying to import their product into another market.
One of the most pressing issues facing CMC is comparability planning, since changes over the course of clinical development or in manufacturing processes can significantly impact product characteristics and performance. To de-risk the review process, sponsors need to provide a clear link between the data from non-clinical and early clinical trials and later phases to establish a comparability narrative throughout development.
Embedding a holistic approach into the organization from concept through development and product submission can help to mitigate the CMC issues highlighted in the CRLs. Many CMC issues cited in CRLs reflect uncertainty about whether the sponsor’s development narrative is internally consistent.
Manufacturing readiness is a common issue for sponsors. For example, we often see lack of preparedness for ramp-up from clinical studies to market adoption or sponsors with a single manufacturing site discovering barriers when trying to import their product into another market.
One of the most pressing issues facing CMC is comparability planning, since changes over the course of clinical development or in manufacturing processes can significantly impact product characteristics and performance. To de-risk the review process, sponsors need to provide a clear link between the data from non-clinical and early clinical trials and later phases to establish a comparability narrative throughout development.
Embedding a holistic approach into the organization from concept through development and product submission can help to mitigate the CMC issues highlighted in the CRLs. Many CMC issues cited in CRLs reflect uncertainty about whether the sponsor’s development narrative is internally consistent.
Clinical and Evidence Strategy
Regulators are looking for alignment and coherence across the clinical trial design and evidence generation.
Endpoint robustness means designing endpoints that are scientifically valid, clinically meaningful, and acceptable to the regulators. Don’t assume the regulators will accept an endpoint that has not been vetted. When using a surrogate endpoint, such as a new biomarker or intermediate clinical outcome, sponsors need to demonstrate to the regulators why it is valid, from both a scientific and regulatory perspective.4
As important in the overall strategy is a sustainable trial design that considers recruitment in the context of patient population size (e.g. rare and ultra-rare indications), whether the disease state is more prevalent in one region than another, and whether there are competitors that might impact patient recruitment.
Labeling is another crucial element in the overall clinical strategy, both from a regulatory and commercial perspective. Overly restrictive inclusion/exclusion criteria could negatively impact the regulatory label and potentially limit how and by whom it can be used, for example population breadth (e.g., “moderate-to-severe” vs. “severe”) and line of therapy (e.g. “after failure of ≥1 prior therapy”)
Endpoint robustness means designing endpoints that are scientifically valid, clinically meaningful, and acceptable to the regulators. Don’t assume the regulators will accept an endpoint that has not been vetted. When using a surrogate endpoint, such as a new biomarker or intermediate clinical outcome, sponsors need to demonstrate to the regulators why it is valid, from both a scientific and regulatory perspective.4
As important in the overall strategy is a sustainable trial design that considers recruitment in the context of patient population size (e.g. rare and ultra-rare indications), whether the disease state is more prevalent in one region than another, and whether there are competitors that might impact patient recruitment.
Labeling is another crucial element in the overall clinical strategy, both from a regulatory and commercial perspective. Overly restrictive inclusion/exclusion criteria could negatively impact the regulatory label and potentially limit how and by whom it can be used, for example population breadth (e.g., “moderate-to-severe” vs. “severe”) and line of therapy (e.g. “after failure of ≥1 prior therapy”)
Market Access and Evidence Value
Submission readiness does not end at approval; it extends to whether the evidence supports real-world adoption. Beyond regulatory submission and approval, sponsors should look to implement an evidence package that supports real-world adoption and optimizes patient access. Consider the data that may be needed to support specific market requirements, addressable patient population, and reimbursement channels.
In parallel with the clinical trial evidence package, consider broader evidence generation activities, including systematic literature reviews, indirect treatment comparisons, budget impact assessments, and real-world evidence (RWE) studies. Determine the comparators payer and health technology assessment (HTA) bodies will require as part of their evaluation and determine how best to provide this evidence.
Consider how RWE might help to differentiate a product from its competitors, for example, demonstrating the product has superior outcomes for specific subpopulations.
In parallel with the clinical trial evidence package, consider broader evidence generation activities, including systematic literature reviews, indirect treatment comparisons, budget impact assessments, and real-world evidence (RWE) studies. Determine the comparators payer and health technology assessment (HTA) bodies will require as part of their evaluation and determine how best to provide this evidence.
Consider how RWE might help to differentiate a product from its competitors, for example, demonstrating the product has superior outcomes for specific subpopulations.
The role of statistics, data science and AI in submission readiness
The data generated during clinical trials needs to produce credible results, explicit uncertainty, and a conclusion that is robust against reasonable alternative explanations. This is what statistics and quantitative approaches do through defensible inference, and is key to de-risking the regulatory submission.
Statistics and quantitative approaches are increasingly leveraged to turn “data” into “evidence”, characterizing net benefits after accounting for risk and risk mitigation measures, and substantiating quality consistency.
Statistics have long been required for study design and proper pre-specification that minimizes bias, quantifies uncertainty, and determines if results are conclusive in supporting hypotheses. In clinical trials, estimand thinking with sensitivity analyses helps to ensure trial goals are precise and transparent by clearly defining the trial objectives . This was addressed by an addendum (R1) to the original guidance ICH E9 (Statistical Principles for Clinical Trials).6
With advanced tools, there are opportunities to de-risk the regulatory submission review cycle by leveraging artificial intelligence to build on statistical modeling by identifying key features and quantifying potential outcomes (what that outcome could be, how likely it is, and what is the uncertainty). For example, when looking at the submission materials statistical modeling combined with AI could help highlight inconsistencies between modules, detect weak comparability links, or flag areas likely to generate major review questions based on patterns observed in prior regulatory feedback.
Statistics and quantitative science can be viewed as the connective tissue in drug development to support regulatory success by connecting clinical, non-clinical, clinical pharmacology, regulatory affairs, pharmacovigilance, market access, and beyond.
Statistics and quantitative approaches are increasingly leveraged to turn “data” into “evidence”, characterizing net benefits after accounting for risk and risk mitigation measures, and substantiating quality consistency.
Statistics have long been required for study design and proper pre-specification that minimizes bias, quantifies uncertainty, and determines if results are conclusive in supporting hypotheses. In clinical trials, estimand thinking with sensitivity analyses helps to ensure trial goals are precise and transparent by clearly defining the trial objectives . This was addressed by an addendum (R1) to the original guidance ICH E9 (Statistical Principles for Clinical Trials).6
With advanced tools, there are opportunities to de-risk the regulatory submission review cycle by leveraging artificial intelligence to build on statistical modeling by identifying key features and quantifying potential outcomes (what that outcome could be, how likely it is, and what is the uncertainty). For example, when looking at the submission materials statistical modeling combined with AI could help highlight inconsistencies between modules, detect weak comparability links, or flag areas likely to generate major review questions based on patterns observed in prior regulatory feedback.
Statistics and quantitative science can be viewed as the connective tissue in drug development to support regulatory success by connecting clinical, non-clinical, clinical pharmacology, regulatory affairs, pharmacovigilance, market access, and beyond.
The benefits of an independent second opinion
It is very easy for sponsors to become immersed in a project and miss the regulatory issues and questions that are likely to arise. Bringing in an independent third party to review the regulatory dossier before submission and conduct a gap analysis, perhaps leveraging data science and AI to support the review, can help to de-risk the submission process and improve the odds of first cycle approval. It can give sponsors visibility into any misalignment between functions that could flag a problem with the overall submission.
The goal is to submit a regulatory dossier with confidence that potential issues have been addressed and faster remediation if questions do arise. Beyond regulatory approval, the objective is to have a strategy that supports commercialization – including reimbursement and physician and patient adoption.
The goal is to submit a regulatory dossier with confidence that potential issues have been addressed and faster remediation if questions do arise. Beyond regulatory approval, the objective is to have a strategy that supports commercialization – including reimbursement and physician and patient adoption.
Mirroring the regulators with an integrated approach
With regulators increasingly focused on the end-to-end robustness of a product submission, it is important that sponsors adopt a similar cross-functional approach to their programs. To successfully navigate the review cycle, sponsors should integrate the regulatory strategy with clinical development, safety analysis, CMC execution, adoption of data science and analytics, and market access insight. Sponsors that mirror this integrated approach internally are far more likely to navigate the first review cycle successfully – not because they avoided challenges, but because they addressed them before submission.
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About the authors:
Michael Day, Ph.D., is Senior Director of Regulatory Strategy and CMC at Cencora. Mike brings more than 25 years of regulatory, CMC, and quality experience, including direct interactions with FDA on CRLs and BLA submissions in cell and gene therapies.
Lin Li, Ph.D., is Head of Clinical Statistics and Predictive AI at Cencora. He provides data-driven and tailored solutions that integrate biostatistics, bioinformatics, computer science, and biology to tackle challenges in discovery and clinical development.
Lin Li, Ph.D., is Head of Clinical Statistics and Predictive AI at Cencora. He provides data-driven and tailored solutions that integrate biostatistics, bioinformatics, computer science, and biology to tackle challenges in discovery and clinical development.
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Sources
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2. Accelerated assessment, EMA. Accessed 10 March 2026. https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/accelerated-assessment. Accessed 10 March 2026.
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4. O. Ciani, A.M. Manyara, P. Davies, et al. A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials, eClinicalMedicine, November 2023. Accessed 10 March 2026. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00460-1/fulltext
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6. Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials, E9 (R1), ICH, November 2019. Accessed 10 March 2026. https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf
