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.
In this article, we discuss the challenges that are specific to small and medium-sized enterprises developing medicines, based on review papers investigating the major objections posed to SME's by regulatory authorities and the scientific advice requests made to the EMA for Advanced Therapeutic Medicinal Products (ATMPs).
What challenges do 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.
What major objections have SMEs encountered during the medicine approval 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 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
The types of MAAs submitted by SMEs included:1
- 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 major objections.1
| Quality – 73% of MOs | Clinical efficacy – 80% of MOs | Clinical Safety – 48% of MOs | Non-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 major objections: biologics vs chemical substances.1
| Biologicals | Chemical Substances | ||
|---|---|---|---|
| Quality | Control and/or characterisation data of drug substance/drug product | 75% (12/16) | 27%(13/48) |
| Specifications | 69% (11/16) | 25% (15/48) | |
| Impurities or related substances profile | 56% (9/16) | 17% (8/48) | |
| Clinical efficacy | Insufficient long-term follow-up efficacy data | 31% (5/16) | 4% (2/48) |
| Clinical safety | Other serious adverse events - unrelated to increased mortality | 44% (7/16) | 19% (9/48) |
| Other clinical safety concerns | 25% (4/16) | 2% (1/48) | |
| Non-clinical | Overall objections | 38% (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
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.
SMEs struggled most with quality and clinical development objections
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.
What about SMEs developing 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 major objections 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
Scientific advice is a regulatory deliverable whereby a sponsor approaches a regulatory body—be it a national body or the EMA—to obtain advice on the quality, non-clinical and clinical development of a medicine.
Worth noting is that the sponsor isn’t legally obligated to take the scientific advice given. Development decisions are at the sponsor’s risk, and justification will be needed as to why the scientific advice—or certain aspects of the scientific advice given—were not followed when filing the marketing authorisation application (MAA).
There are several benefits of taking scientific advice, but foremost are:
- Prospectively understanding the potential risks to mitigate earlier in development,
- streamlining the MAA evaluation procedure, and
- reducing the risk of a negative outcome from the MAA.
Trends observed in EMA scientific advice for advanced therapy developers
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 requests | Non-clinical =10 requests | Clinical =17 requests |
|---|---|---|
| 10/15 comparability before and after manufacturing process changes, | 5/10 toxicity studies | 13/17 endpoints |
| 8/15 control strategies | 4/10 need for and results of bridging and comparability studies as development progressed | 12/17 population and indication |
| 8/15 definition of active substance/finished product, orphan similarity and batch release exemption | 3/10 acceptability of the nonclinical development data package for a specific development milestone | 12/17 pivotal/confirmatory trials |
| 8/15 potency testing | 3/10 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;
- scientific advice interactions,
- paediatric development
- orphan designation and maintenance, and
- the marketing authorization application itself.
