The Challenges pharmaceutical Small and Medium-sized Enterprises (SMEs) face

by | Mar 8, 2024 | European Medicines Agency, Regulatory Affairs

Highlights

  • The specific challenges pharmaceutical SMEs face
  • The Major Objections observed with Marketing Authorisation Applications (MAAs) submitted by SMEs
  • The link between advanced therapies and SMEs
  • The trends in scientific advice procedures for developers of advanced therapies

Small and Medium-sized enterprises (SMEs) are integral to pharmaceutical innovation but often come up against specific challenges, particularly financial challenges. The drug development process includes several regulatory milestones and missing these milestones may negatively impact the overall outcome of an SME’s MAA.

Challenges pharmaceutical SMEs face

As well as financial constraints, SMEs may have limited resource to commit to developing a detailed understanding of country-specific regulatory processes; have limited access to subject matter experts, and face competition with large and intermediate-sized enterprises.

This blog details trends in the major objections (MOs) observed in MAAs submitted to the European Medicines Agency (EMA), as well as the trends observed in scientific advice procedures between the EMA and advanced therapy developers—a significant proportion of which, were SMEs.

Major objections SMEs encountered during the MAA process

A 2018 review by Amaouche et al, investigated the most frequently observed major objections related to 64 MAAs submitted to the European Medicines Agency (EMA) by SMEs between 2011 and 2015.1

Demographics of MAAs submitted by SMEs

Of the 64 MAAs submitted to the EMA, 42 received a positive opinion from the Committee for Medicinal Products for Human use (CHMP), and 22 received a negative opinion.1

Types of MAAs submitted by SMEs1

  • Orphan medicines – 24/64 
  • Biologics – 16/64 
  • Abridged applications – 23/64 
  • Antineoplastic/immunomodulating medicines – 11/64
  • Medicines for gastrointestinal disorders – 10/64 
  • Medicines for nervous system disorders – 8/64 

Developmental aspects associated with most MOs.1

Quality – 73% of MOsClinical efficacy – 80% of MOsClinical Safety – 48% of MOsNon-clinical – 19% of MOs
Manufacturing process validation

Control and/or characterization data of drug substance/drug product

Specifications

Stability or compatibility data/shelf-life

Manufacturing process development/control strategy

Pharmaceutical development

Impurities or related substances profile
Analysis/robustness of pivotal data

Issues with study design

Marginal or no clinically relevant efficacy

Pharmacodynamics/ pharmacokinetics

Inconsistent data on clinical efficacy

Selected population

Choice of endpoint and validity of endpoint measurement
Other serious adverse events

Quantity and/or quality of long-term data
Toxicity study design

EMA Day-120 MOs: biologics vs chemical substances.1

BiologicalsChemical Substances
QualityControl and/or characterisation data of drug substance/drug product75% (12/16)27%(13/48)
Specifications69% (11/16)25% (15/48)
Impurities or related substances profile56% (9/16)17% (8/48)
Clinical efficacyInsufficient long-term follow-up efficacy data31% (5/16)4% (2/48)
Clinical safetyOther serious adverse events – unrelated to increased mortality44% (7/16)19% (9/48)
Other clinical safety concerns25% (4/16)2% (1/48)
Non-clinicalOverall objections38% (6/16)13% (6/48)

Non-approvals related to Biologics were 2.4 times higher compared with chemical substances. Non-approvals were also 0.7 times lower for orphan medicines than non-orphan medicines.1

Additional Analyses

The 2018 review included analyses to identify associations between MOs raised during the CHMP’s ‘Day-120 List of Questions’ and MA outcome. The odds of an MA being objected to were:1

  • 5.3 times higher when at least a major objection was raised in non-clinical aspects,
  • 4.7 times higher in clinical safety,
  • 3.5 times higher in clinical efficacy, and 
  • 2 times higher in quality.

What does the 2018 review tell us?

Overall, the most frequently observed MOs were regarding quality and clinical aspects of MAA dossiers submitted by SMEs. Interestingly, MOs related to non-clinical aspects were not observed frequently in any particular type of MAA, however, the odds of an MAA being rejected were 5.3 times higher if a MO was raised in the non-clinical development aspects.1

A disheartening takeaway from the 2018 review is that SMEs developing biologics were met with more MOs and were 2.4 times more likely to be rejected by the CHMP than SMEs developing chemical substances. Considering, that biologics accounted for 25% of MAAs submitted, this observation emphasises the need to highlight the support available to SMEs developing innovative medicines and advanced therapies.

SMEs and advanced therapies

As a significant proportion of advanced therapies are developed by SMEs, it’s important to address the challenges faced by developers of advanced therapies because these specific challenges may compound the existing challenges SMEs face.

Case in point, a 2017 survey investigated the challenges faced by developers of ATMPs—of which 65% of respondents were SMEs. The greatest challenges the 68 respondents reported facing were in the domains relating to regulatory (34%), technical (30%), and scientific (10%). Further classification into themes showed that the top three challenges developers reported were country-specific requirements (16%), manufacturing (15%), and trial design (8%).2

How can SMEs mitigate unnecessary MOs and MAA rejections?

Somerville Development Partners typically advises SME clients to seek Scientific Advice from regulatory authorities such as the EMA as early in development as possible. This may seem obvious, but it’s one of the best ways to pre-empt agency concerns and mitigate some of the MOs observed in the 2018 review by Amaouche et al.1

A review conducted by Tavridou et al in 2020, investigated 56 scientific advice requests made to the EMA in 2018 for Advanced Therapeutic Medicinal Products (ATMPs). In total, 28 SA requests came from SMEs and public bodies.3

Tavridou et al traced the origins of 21 scientific advice requests to a public body. Of those 21 requests, 15 requests pertained to products being developed by SMEs/public bodies. The developmental aspects most commonly raised during scientific advice interactions related to:3

  • Clinical – 17 requests, 
  • Quality – 15 requests and finally, 
  • Nonclinical –10 requests. 

The order of developmental topics raised reflects the trends of MOs reported by Amaouche et al., 2018. 

Interestingly, Tavridou et al., 2020 observed that scientific advice concerning quality and nonclinical developmental aspects was requested more frequently by large pharmaceutical companies (100% quality, 83% nonclinical) compared to SMEs/public bodies (60% quality, 33% nonclinical).3 Again, when comparing the observations of Amaouche et al, 73% of MOs were reported in quality aspects of MAAs submitted by SMEs, and although non-clinical MOs observed less frequently (19%), the odds of an MAA being rejected were 5.3 times higher if an MO was raised in the non-clinical documentation.1

The findings of Tavridou et al could support the assumption that large pharmaceutical companies have the regulatory expertise to pre-empt which aspects of their development could be the target of MOs during the MAA procedure.

The most frequently raised topics during EMA scientific advice3

Quality =15 requestsNon-clinical =10 requestsClinical =17 requests
10/15 comparability before and after manufacturing process changes,5/10 toxicity studies13/17 endpoints
8/15 control strategies4/10 need for and results of bridging and comparability studies as development progressed12/17 population and indication
8/15 definition of active substance/finished product, orphan similarity and batch release exemption3/10 acceptability of the nonclinical development data package for a specific development milestone12/17 pivotal/confirmatory trials
8/15 potency testing3/10 biodistribution/shedding studies<50% of requests included questions on comparator, dose/dosing regimen, sample size/statistical analysis, study duration.
3/10 pharmacodynamics*SMEs sought advice on pivotal trials whilst at exploratory stages of development
3/10 proof of principle

Conclusion

SMEs face specific challenges which may limit their opportunity to take scientific advice. This, in turn, could foreshadow unnecessary MOs at the time of MAA filing and result in an MAA being rejected. Not taking advantage of important interactions like scientific advice at the exploratory stages of development could be extremely detrimental to SMEs during the MAA procedure. The EMA offers several tools to help SMEs throughout development, including dedicated meetings with the SME office and financial incentives for regulatory procedures.  

Somerville Development Partners has over 20 years of experience preparing and submitting regulatory documents for all pre-authorisation regulatory deliverables; from initiating scientific advice with European regulatory authorities to the marketing authorisation application.

How Somerville Development Partners can help

We are a registered SME in Europe.

This means we can access SME benefits and fee incentives on your behalf if your organisation is not established in the European Union (EU)/ European Economic Area (EEA).

We have decades of experience navigating regulatory agency interactions and regulatory submissions in Europe and can confidently guide you through your regulatory milestones, including; 

Get in touch

We welcome the opportunity to discuss scientific advice and regulatory strategy with you!

Nicole

Author

Nicole Brooks, Regulatory Consultant / Copywriter
Nicole@somerville-partners.com

References

1. Amaouche N, Casaert Salomé H, Collignon O, Santos MR, Ziogas C. (2018). Marketing authorisation applications submitted to the European Medicines Agency by small and medium-sized enterprises: an analysis of major objections and their impact on outcomes. Drug Discovery Today. 23(10):1801–5. Available from: https://www.sciencedirect.com/science/article/pii/S1359644618300503

2. Ten Ham RMT, Hoekman J, Hövels AM, Broekmans AW, Leufkens HGM, Klungel OH (2018). Challenges in Advanced Therapy Medicinal Product Development: A Survey among Companies in Europe.Molecular Therapy Methods & Clinical Development. 11: 121-130. Available from: https://doi.org/10.1016/j.omtm.2018.10.003

3. a., et al (2022). Towards a better use of scientific advice for developers of advanced therapies. British Pharmaceutical Society. 87(6): 2459-2464. Available from: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.14672