4 benefits of receiving EMA Scientific Advice; how to apply and why you should

by | Oct 13, 2023 | European Medicines Agency, Scientific Advice

If there’s one piece of advice any regulatory specialist should give you as a medicine developer, it’s to seek scientific advice from regulatory authorities.

The European Medicines Agency (EMA) offers scientific advice at all stages of development, which is especially critical to those medicines targeted for a centralized approval in Europe.

Why is scientific advice from the EMA important?

Simply put, getting scientific advice could mean the difference between successfully marketing your medicinal product or going back to the drawing board with years and millions of dollars wasted.

This may seem rather dramatic, but with the average cost of developing a new drug estimated to land between $314 million to $2.8 billion;1 failing to seek guidance from regulatory authorities may not be a risk worth taking.

Essentially, you need to know you’re on the right track with your development programme as early as possible: collecting robust data; enrolling subjects who are representative of your target population; choosing a primary endpoint that is clinically relevant, and conducting a pivotal trial that aligns with current treatment paradigms.

Failure to take advantage of scientific advice interactions could result in you being forced to make extensive changes to your product’s development; fulfil a host of post-approval measures, and even reduce the breadth of your target indication.

At the very least, scientific advice will help you to understand the prevailing regulatory science and any risks you might be taking. Taking advice sooner, rather than later, will give you as much time as possible to mitigate any risks, as well as better understanding your probability of success.

What is EMA scientific advice and protocol assistance?

Scientific advice is an opportunity to ask the EMA integral questions about your development strategy. You can receive advice from different experts on quality, non-clinical, clinical, and general methodological aspects of your product development to date.

Protocol assistance

This is the same as scientific advice, but specific to medicines for rare diseases. Therefore, advice will be tailored specifically to orphan applications and orphan maintenance strategies, as well as allowing for reductions in agency fees.

If you’re developing an orphan medicine for a rare disease, the EMA can advise you on:

  • meeting the significant benefit criteria for orphan designation if an existing medicine has been approved in the same orphan indication,2
  • how you plan to demonstrate your product’s superiority to approved orphan medicines in the same disease area, and
  • choosing appropriate study designs given the rarity of the disease you are targeting.

Why is getting protocol assistance on the criteria of significant benefit important?

According to Article 5.12 of Regulation EC No 141/2000:3 if your product is granted orphan designation, and isn’t the only one designated or approved for your target indication, and at the time you file your MA, you haven’t demonstrated significant benefit, then your orphan designation will be revoked…along with all associated benefits that come with orphan designation.

4 benefits of EMA scientific advice—supported by statistics.

The supporting statistics are derived from two review papers:

1) A 2015 review conducted by Hofer et al, evaluated 232 MAAs submitted between 2008-2012; 143 of which requested scientific advice.4

The review investigated the following outcomes:

  • Whether scientific advice led to changes in clinical trial design,
  • whether the timing of scientific advice affected the regulatory assessment and its outcome, and
  • whether compliance with scientific advice affected the regulatory assessment and its outcome.

Compliance with scientific advice at the time of MAA was analyzed based on three aspects of clinical trial design: primary efficacy endpoint, comparator treatment and, statistical methodology.

Evaluation of statistical methodology included: multiplicity control, stratification, subgroup analysis, missing values, and statistical power considerations.

2) An earlier review by Rengstrom et al., 2009 also investigated factors associated MAA success (including scientific advice). Compliance with scientific advice was evaluated using the same three clinical trial design variables at Hofer et al., 2015 and a total of 188 MAAs were evaluated between 2004-2007; 59 of which received scientific advice.5

Benefit 1: Your scientific advice letter will help you file your MAA.

You will receive scientific advice from the same expert committees within the EMA that will eventually review your MAA—the advice will help you understand the current thinking of the agency and will be beneficial when you file your MAA.

Applicants who sought and complied with scientific advice recommendations on clinical trial design at the time of MAA filing had a success rate of 84%, compared to applicants who did not (43%).4

Rengstrom et al., 2009, also reported that seeking scientific advice itself wasn’t significantly associated with MAA success, however, complying with scientific advice was.5

It’s the EMA’s responsibility to ensure the medicines it approves are supported by robust development programmes, demonstrating adequate safety and efficacy. Whatever advice you receive will be more or less relevant, depending on the strength of the pivotal data.

As the saying goes: forewarned is forearmed.

Benefit 2: Streamline your MAA evaluation procedure.

Obtaining scientific advice and—more importantly—complying with said advice, could streamline your MAA evaluation process. This means fewer validation issues; fewer questions to answer throughout the authorization procedure, and shorter clock stops.

Applicants who complied with scientific advice and amended their clinical trial design by the time they filed their MAA reduced MAA evaluation time by an average of 61 days. 4

Fewer major objections and an overall shorter MAA evaluation time are very appealing, particularly if you’re planning to submit a New Drug Application (NDA)/Biologics Licensing Application (BLA) in parallel to your MAA. With the average NDA evaluation taking approximately 6-10 months,6 vs the EMAs, 180/210 days (6-7 months) + 3-4 months for clock stops7—a shorter MAA evaluation because of scientific advice compliance could be significant.

Benefit 3: Know what is expected to develop a safe and efficacious medicinal product.

You’ll be made aware of what’s expected of your quality, non-clinical, clinical development strategy to demonstrate appropriate safety and efficacy. This information could be invaluable if you consider the cost of possible additional studies and how that could affect your development timelines.

Applicants who complied with scientific advice and amended clinical trial design by the time they filed their MAA received fewer overall major objections in ALL development categories.4

 Benefit 4: Reduce the risk of your MAA being rejected.

By far the greatest benefit of scientific advice/protocol assistance is the potential to dramatically reduce the risk of your product being rejected; your target indication being restricted and/or, your post-approval commitments becoming unmanageable. All these aspects invariably affect your bottom line.

What’s more, receiving scientific advice earlier in development could mean the difference between being able to implement advised changes to your development strategy before beginning pivotal clinical trials, versus conducting damage control if you already have a pivotal trial ongoing.

Applicants who received scientific advice before starting pivotal trials had an MAA success rate of 78% compared to applicants who received scientific advice with pivotal trials ongoing (64%).4

Early scientific advice is particularly pertinent if you’re an SME or developing an orphan drug. As an SME you may not have the resources to change your clinical development strategy following scientific advice if you have pivotal trials ongoing, and if you’re developing a medicine for a rare disease, it may not be a viable option to change the comparator treatment in your pivotal clinical trial given the limited number of patients available.

How does scientific advice affect the regulator’s decision on your medicine?

Scientific advice is not legally binding—you don’t have to act upon the advice given by the EMA, and you will still be expected to file your MAA in the same way and with a complete common technical document (CTD) as companies that haven’t taken advantage of scientific advice.

In essence, you pay for the advice you are given, and it is your decision to implement the recommendations…or not!

However, the findings reported by (Hofer et al., 2015) and (Regnstrom et al., 2009), highlight a striking correlation between scientific advice compliance and MAA success:

At the time of scientific advice, 67% of applicants didn’t have compliant clinical trial designs and were advised by the EMA to amend them. Of these applicants, 63% amended their clinical trial designs by the time they filed their MAAs: 4 the effect?

  • 84% MAA success rate for applicants with compliant clinical trial designs at the time of scientific advice. 4
  • 86% MAA success rate for applicants who didn’t have compliant clinical trials designs when they received scientific advice but amended this before filing their MAA. 4
  • 41% MAA success rate for applicants whose clinical trial design was considered non-compliant during scientific advice and who didn’t comply with scientific advice when they filed their MAA.4

We should emphasize that both (Regnstrom et al., 2009) and (Hofer et al., 2015) only analyzed compliance with scientific advice in relation to three aspects of clinical trial design, and didn’t include analyses on quality, non-clinical or clinical aspects that didn’t relate to clinical trial design.

But this begs the question: if scientific advice compliance correlated to fewer major objections across all categories during the MAA evaluation procedure; a shorter evaluation timeline, and higher MAA success rates, when just three clinical trial design variables were evaluated4…how does compliance or non-compliance to scientific advice affect your MAA success when all development categories (quality, non-clinical, other clinical aspects, etc.) are evaluated?

How to apply for scientific advice or protocol assistance

If it’s your first interaction with the EMA, you must register with the EMA through various portals before applying for scientific advice/protocol assistance.

This includes:

  1. getting your customer account number to settle fees for the scientific advice you receive,
  2. registering your organization through the EMA’s organization management service (OMS),
  3. delegating appropriate user access roles to apply for scientific advice through the IRIS portal, and
  4. registering your medicinal product with a unique identifier called a Research Product Identifier (RPI).

Preparatory meeting

The EMA offers a meeting free of charge to address any regulatory-specific questions that fall outside the scope of scientific advice questions and to ask for general feedback on your proposed list of questions.

Preparatory meetings are particularly beneficial for small and medium-sized enterprises (SMEs) or companies requesting scientific advice/protocol assistance for the first time.

 Briefing document

This is a mandatory document to include in your application, detailing the disease you are targeting; your product and its mechanism of action, and the quality, non-clinical and clinical development you have conducted to date.

You should then list the questions you want to address with the regulatory experts separated by the relevant development category (quality, non-clinical, clinical, etc).

It’s critical that you don’t just list questions.

Each question you ask must be accompanied by your company’s position and you will be expected to justify your reasoning for approaching each area of your product’s development the way you have.

This is important because (as you’re now aware) compliance with any scientific advice you receive will be considered during your MAA evaluation.4 Therefore, if you have a suspicion that part of your development strategy won’t be compliant with EMA scientific advice recommendations, but it’s a hill you’re prepared to make your last stand on, the briefing document is your opportunity to thoroughly articulate your company positions aided by any supplementary data you think will support your justifications.

What types of questions can you ask the EMA?

Scientific advice doesn’t evaluate the overall benefit/ risk of the small molecule or biologic you’re developing—nor does it evaluate the results of the studies you have underway. These topics will be addressed when you file your MAA.2

Specifically, scientific advice incorporates:

Quality and chemistry, manufacturing, and controls (CMC)

  • Manufacturing of your drug product and substance,
  • characterization, comparability, and specification.

Non-clinical

  • Toxicology and pharmacology testing,
  • choice of animal model, and
  • adequacy of your non-clinical testing regimen.

Clinical

  • Primary endpoints and using biomarkers as surrogate endpoints,
  • patient-reported outcomes (PROs), patient selection and stratification,
  • study design, from first-in-human studies to pivotal study design,
  • recommended dosing regimens, and safety monitoring plans.

Methodologies

  • Statistical analysis plan (SAP), statistical considerations, and Bayesian methods,
  • extrapolation strategies, and modelling and simulation studies.

General development strategy

  • Benefit of potential conditional marketing authorization (CMA),
  • advice on your safety database, and
  • adequacy of your development strategy to support an MAA.

How does the scientific advice procedure work?

The Scientific Advice Working Party (SAWP) is a dedicated committee within the EMA made up of external experts and incorporates members of other committees within the EMA.

Two SAWP members are assigned as coordinators for your scientific advice/protocol assistance application and are responsible for compiling comments from all experts involved in your case, and for writing the reports responding to your scientific advice request. Once you’ve submitted your application and briefing package and passed all validation issues, SAWP will begin evaluating your application. This could result in you receiving your written scientific advice letter on Day 402 or being expected to attend a meeting with SAWP to discuss outstanding issues around Day 63 of the evaluation timeline.2

EMA Scientific Advice Evaluation Timeline
Flowchart adapted from EMA Guidance for Applicants seeking scientific advice and protocol assistance (2022).2

How much does EMA scientific advice cost?

As of 2023, the fees for scientific advice range from €51,800 to €103,8008 depending on the depth of advice you request on each category of your medicinal product development, e.g., quality or quality, safety and clinical development, etc.

The EMA does however offer generous fee incentives to different types of medicine developers, including:

Special instancesFee reductions
Protocol assistance for orphan medicines75% fee reduction8
Scientific advice for Small and medium-sized enterprises (SMEs)90% fee reduction8
Protocol assistance for SMEs developing orphan medicines100% fee reduction8
Somerville Development Partners is registered as an SME with the EMA. We can support your scientific advice procedure and apply for associated fee reductions if you qualify as an SME but do not have a legal entity established in the European Union.

Parallel scientific advice (PSA)

…between the EMA and HTA bodies

The EMA also offers parallel scientific advice with the European Health Technology Assessment (HTA) for all questions relating to reimbursement and market access. This will help determine how your product might work in terms of costs and outcomes in relation to approved precedents in your target indication.2

…between the EMA and the Food and Drug Administration (FDA)

If you’re planning to file a new drug application (NDA) in the US and an MAA in Europe, parallel scientific advice between the EMA and the FDA is not only possible but encouraged.

Areas of therapeutic and developmental interest between the EMA and FDA include oncology, paediatric medicines, orphan medicines, vaccines, nanotechnologies, blood products, and advanced therapy medicinal products (ATMPs)/biologics.9

You will receive separate advice letters from each agency to review. This is an important feature of PSA because separate scientific advice comments could provide invaluable guidance to increase your chances of gaining approval for your MAA and NDA.

However, as we’ve already established, compliance with scientific advice has historically been associated with MAA outcome4-5 but, what isn’t clear, is the scope of changes you may be advised to make—particularly to your pivotal clinical trial designs…now encompassing comments from both the FDA and EMA in parallel.

Summary

Scientific advice is a valuable tool to ensure you’re developing a safe and efficacious medicinal product with the most robust development strategy. The EMA provides extra support for SMEs and orphan medicines as well as medicine developers initiating regulatory discussions for the first time.

Although not formally binding, research has shown that complying with the scientific advice you receive—particularly in relation to your clinical trial design—could significantly impact your MAA’s success or failure.

Finally, the earlier you request scientific advice, the more you can benefit from the guidance the EMA provides and the more time you have available to mitigate any potential issues raised.

How Somerville Development Partners can help

We will:

  • Provide expert advice on European regulatory requirements,
  • guide you through the EMA registration process,
  • arrange and attend scientific advice meetings with the EMA and FDA,
  • draft your scientific advice briefing document,
  • work with you to solidify justifications for questions you pose to regulators,
  • manage the operational aspects of the submission,
  • respond to validation/review comments, and
  • make sure you benefit from fee reductions.

To ensure we support you effectively, we will build a foundational understanding of your product and data, so that we are able to act as a strategic partner and proactively look out for your best interests.

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. Wouters, Olivier J et al. “Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018.” JAMA vol. 323,9 (2020): 844-853. doi:10.1001/jama.2020.1166. Available at: https://jamanetwork.com/journals/jama/fullarticle/2762311

2. European Medicines Agency (2022). European Medicines Agency Guidance for Applicants seeking scientific advice and protocol assistance. EMA/4260/2001 Rev.14. Scientific Evidence Generation Department. Available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/european-medicines-agency-guidance-applicants-seeking-scientific-advice-protocol-assistance_en-0.pdf

3. Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products. 2000 No. 141. Article 3(b), Article 5.12. Available at: https://www.legislation.gov.uk/eur/2000/141

4. Hofer MP, Jakobsson C, Zafiropoulos N, Vamvakas S, Vetter T, Regnstrom J, et al. Impact of scientific advice from the European Medicines Agency. Nat Rev Drug Discov [Internet]. 2015 May [cited 2023 Oct 6];14(5):302–3. Available at: https://www.nature.com/articles/nrd4621

5. Regnstrom J, Koenig F, Aronsson B, Reimer T, Svendsen K, Tsigkos S, et al. Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency. Eur J Clin Pharmacol [Internet]. 2010 Jan 1 [cited 2023 Oct 6];66(1):39–48. Available at: https://doi.org/10.1007/s00228-009-0756-y

6. Food and Drug Administration (2018). The Drug Development Process. Step 4: FDA Drug Review. Available at: https://www.fda.gov/patients/drug-development-process/step-4-fda-drug-review#:~:text=Directions%20for%20use-,FDA%20Review,whether%20to%20approve%20the%20drug.

7. European Medicines Agency (2023). The Evaluation of Medicines, step-by-step. Available at: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/evaluation-medicines-step-step#:~:text=The%20assessment%20of%20a%20marketing,of%20a%20marketing%20authorisation%20application.

8. European Medicines Agency (2022). Explanatory note on fees payable to the European Medicines Agency. EMA/646632/2022. Pg 12-13, 42-44. Available at: https://www.ema.europa.eu/en/documents/other/explanatory-note-general-fees-payable-european-medicines-agency-1-april-2023_en.pdf

9. European Medicines Agency (2021). General Principles EMA-FDA Parallel Scientific Advice (Human Medicinal Products). Available at: https://www.ema.europa.eu/en/documents/other/general-principles-european-medicines-agency-food-drug-administration-parallel-scientific-advice_en.pdf