MARS Global: The GCC Evidence-to-Market (E2M) Framework
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Evidence-to-Market Framework  ·  11-Step Protocol

The GCC Evidence-to-Market
E2M Framework

A Protocol for Rare Disease RWE & Consensus

The E2M framework is a specialised 11-step methodology designed for Medical Affairs and CRO partners to bridge the evidence gap in the Middle East. Developed by Nouran Hamza, this protocol optimises Real-World Evidence generation, evidence gap identification, and Consensus Statement development, particularly for Rare Diseases. By shifting focus from simple research questions to strategic evidence generation, the E2M framework ensures that clinical data translates into market access and peer-reviewed publications.

01

Identifying the Gap

What You Think Is an Evidence Gap

A research question is not always an evidence gap. An evidence gap is a void in knowledge that, if filled, would inform a key decision for a stakeholder: a regulator, payer, or clinician. We will explore this distinction during the workshop.

A) Your Initial Idea

Start by capturing your initial thoughts. Don't worry about perfection. This is about getting the raw idea down.

Component Your Entry
Disease Areae.g., PNH, gMG, HPP
Product Namee.g., Soliris, Ultomiris, Strensiq
Lifecycle Stage
General Idea or Hypothesis "Patients in our region initiate therapy later than in EU registries." "No local data on pediatric gMG outcomes, even globally it's scarce."
Source of the IdeaOptional
Key Message to Support or Explore "This idea could help strengthen the case for earlier treatment."
B) Categorise Your Idea

Tick one or more categories your idea falls into. Items that naturally touch more than one bucket are noted as cross-cutting.

1: Public Health / Epidemiological
2: Treatment Patterns
3: Clinical Outcomes
4: Safety
5: Economic (Value, Access, System Impact)
Other
02

Evidence Review

Literature Search Process

You are likely familiar with PubMed, and your internal teams can support the search process. However, be aware of publication bias; you might not always find the whole story in published literature. We will also explore Google Scholar, Embase, and ClinicalTrials.gov.

Use the table below to document your findings. The goal is to extract key findings for each database and then list 2 potential evidence gaps based on what you found, or didn't find.

2A: Search Table: One Row per Source
Database Search Method Exact Search String Date Results Relevance Key Notes / Observations
PubMed
Embasevia EMTREE
Google Scholar
ClinicalTrials.gov
Cochrane Library
Other:

Potential Evidence Gaps Identified

Based on your literature search, list two potential evidence gaps.

03

Landscape Mapping

Evidence Gap Mapping

Use this Gap Matrix to organise the studies you found during your literature review. Each row represents a study. The goal is to visualise the landscape of existing evidence. Empty cells across countries, endpoints, or populations represent evidence gaps.

Evidence Mapping Table (Gap Matrix)
Study Type Study Subcategory Country / Region Patient Population Endpoint Studied Citation(s) / Source
Example subcategories: Single-center, multi-site, cross-sectional, interviewer-led, claims-based, chart abstraction, KAP survey, exploratory analysis, payer-focused, etc.
04

Research Question

Formulate PICO with Clinical Precision

"PICO isn't just an acronym. It's the GPS for your research. Every component must be defined with surgical precision, especially in rare diseases."

Transform the general idea and identified gap into a clinically precise research question using the PICO format. This creates alignment between research intent, study design, and outcomes.

You don't need all four components to proceed. Fill as much as you can and leave a field blank if it's not applicable. There is also a P-E-O format (Population, Exposure, Outcome) useful for non-comparative questions, which we will discuss during the workshop.
PICO Table
Component Description Prompting Question Your Entry
P Patient / Population / Problem How would I describe a group of patients similar to mine?
I Intervention / Prognostic Factor / Exposure Which main intervention, prognostic factor, or exposure am I considering?
COptional Comparison What is the main alternative to compare with the intervention?
O Outcome What do I hope to measure, accomplish, or affect?
05

Reality Check

Apply the FINER Criteria

You have a PICO. But is it a question worth asking? The FINER criteria are your reality check. Score each criterion from 1 (very low) to 5 (very high).

Criteria Question to Ask Score (1–5) Justification / Notes
F: Feasible Can we actually do this? Do the data sources exist? Are the endpoints captured in routine practice? Can we enrol enough patients?
I: Interesting Is it interesting to anyone other than us? Will it change clinical practice? Will a payer or regulator care?
N: Novel Does it genuinely fill an evidence gap, or are we replicating a study from Europe?
E: Ethical Is it appropriate to conduct this study? For observational studies, this primarily relates to patient privacy and data protection.
R: Relevant Will the answer impact decisions? Will it support a market access submission, change a guideline, or inform patient care?
06

Objective Setting

Define the SMART Research Objective

You've clarified your evidence gap and framed it with PICO. Now articulate a SMART research objective, a clear, fundable, and measurable statement that will drive the entire project forward.

Section A: RWE Project Concept Summary
Component Guidance Your Entry
Project TitleConcise and descriptiveNot "gMG study" but "Hospitalization trends in gMG patients treated with SC therapy in KSA"
Target Country / RegionSpecific MENA market
Primary StakeholderWho needs this evidence?
Evidence GapBrief summary of the gap this study will address
SMART Research ObjectiveTo be developed in Section B
Proposed Study DesignRetrospective cohort, registry analysis, payer survey, etc.
Potential Data SourcesLikely sources (hospital EHR, insurance claims, national registries)
Initial Feasibility CheckShort note on practicality (based on FINER test, availability of sites/data)
Section B: SMART Research Objective Builder

Use the SMART acronym to refine your study objective into one that is clear and actionable.

SMART Component Prompting Question Your Entry
S: SpecificDoes the objective clearly define the patient group, intervention/exposure, and setting?
M: MeasurableCan outcomes be measured from the data source? What are the specific metrics?
A: ActionableWill the findings influence decision-making or fill a known gap?
R: RealisticIs it feasible within MENA constraints (data, access, sample size)?
T: Time-boundIs the timeframe clearly defined (data from which years, follow-up period)?

Final SMART Objective

Write a one-sentence objective. This is a statement, not a question, avoid "Does…?" or "Is…?". This will guide protocol development.

Example: To assess the 12-month hospitalisation rates among AQP4+ NMOSD patients in Saudi Arabia treated with eculizumab, using EHR data from two tertiary hospitals collected between 2020 and 2024.
07

Study Architecture

Match Your Objective to the Right Study Design

Anchoring Your SMART Objective to Feasible RWE Design

You now have a SMART research objective. Step 7 ensures you select the most appropriate study design, aligned with your aim, data availability, and regional expectations, especially in MENA, where local data is emphasised.

Section A: Research Aim → Study Design Decision Matrix
Research Aim Common RWE Designs Typical Data Source Key Data Captured Alexion Example
Treatment PatternsRetrospective Cohort StudyEHR, claims dataPrescription fills, administration records, therapy datesgMG treatment sequence in UAE
Effectiveness / ComparativeRetrospective or Prospective Cohort; Historical ControlsEHR, registries, trial armsRelapse rates, clinical scores, imaging, survivalNMOSD relapse comparison on Eculizumab vs. SOC
Safety / Signal DetectionCase-Control Study, Signal MiningPV databases, claimsAE codes, lab alerts, co-medicationsRare AE detection in long-term users
QoL / Economic BurdenCross-Sectional Survey, PRO + Claims LinkagePRO tools (EQ-5D, FACIT), payer dataQoL scores, resource use, indirect costsHPP caregiver burden survey
Epidemiology / Burden of IllnessDescriptive Registry, Cross-sectional studyNational registries, hospital discharge logsICD-10 codes, demographics, prevalencePNH prevalence in KSA via registry
Clinical Pragmatism / AccessPragmatic Clinical Trial, Registry-nested TrialHospital records + minimal trial dataRoutine practice outcomes, limited exclusion criteriaSC vs IV formulation in real-life gMG patients
Comparative Realism in MENAHistorical Control Study
MENA requires local dataset		Past trial arm data + local EHR populationEfficacy from prior studies + regional confirmationNew therapy vs. historical SOC using hybrid local + global
Note: While FDA may accept pragmatic trials and historical control designs, MENA agencies (SFDA, DOH, MOH Egypt) often expect local, recent, and population-specific data.
Section B: Guided Decision Questions
Decision Question Your Notes
What is the main research aim (treatment pattern vs. effectiveness)?
Is this Launch or Pipeline? Refer to Step 1.
What data source(s) are available locally? (hospital, payer, registry)
Is it ethical or feasible to randomise in this disease area?
Can historical data be used as a comparator? (Justify)
Would regulators or payers accept this study in our region?

Final Output for Step 7

Based on the matrix and reflection above, what study design are you selecting?

Proposed RWE Study Design
Rationale (one-line summary)
08

Analytical Rigour

Ensure Statistical Rigour Through the Right Complexity Level

All RWE must meet statistical rigour, but not all studies require the same level of complexity. In this step, align your analysis methods to the decision being supported, the study design, and the feasibility of your data.

Reminder: "Complexity ≠ Quality." It's about matching the method to the decision.
Section A: Define the Decision Context

What is the primary purpose of this evidence? Tick one, this will guide the expected complexity of the analysis.

Decision Type Description Select
Regulatory Decision Label expansion, new indication, or safety profile change. Requires highest complexity.
Clinical Guideline Decision Influence expert consensus or published pathways. Moderate-to-high complexity needed.
Internal Strategy Decision For descriptive insight or local burden mapping. Lower complexity acceptable.
Section B: Match Study to Statistical Complexity Level
High Complexity

Comparative effectiveness, causal inference, confounding adjustment

Propensity Score Matching, IPTW, Instrumental Variables, sensitivity testing

Moderate Complexity

Association studies or time-to-event outcomes

Logistic regression, Cox models, Linear regression, GEE, mixed-effects

Low Complexity

Descriptive or exploratory studies

Frequencies, means, medians, proportions, visual trends

Note: Low complexity does not mean low quality, it means the objective doesn't require causal or comparative modelling.
Section C: Key Statistical Considerations
Don't ignore missing data! It's not just about the percentage missing, it's about the trend or pattern of what's missing. A pre-specified plan is mandatory.
Element Guidance Notes
Time-to-Event AnalysisUse Kaplan-Meier curves, report medians and CI. Consider log-rank or Cox models.
Longitudinal DataUse mixed-effects models to manage repeated measures across multiple clinic visits.
Missing DataPre-specify approach (e.g., multiple imputation); run sensitivity analyses.
Small Sample SizesUse exact tests (e.g., Fisher), or Bayesian inference. Justify the power limitations.

Final Output for Step 8

09

Regulatory Alignment

Understand MENA Regulatory Frameworks

A perfect study design means nothing if regulators don't buy into it. MENA is not uniform, you must understand and align with local expectations before you start.

"In MENA, regulatory success = scientific merit × localisation."
Section A: Country-Level Requirements Snapshot
Country / Region RWE Acceptance Local Nuance Submission Tip
Saudi Arabia (SFDA)High & FormalisingLocal data preferred. PASS designs common.Use scientific advice. Position study as post-marketing.
UAE (MOH / DOH Abu Dhabi)Moderate to HighGCC data accepted; UAE-specific better. Strong HTA interest.Follow formal advice; cite DOH RWE guidance.
Egypt (EDA)EmergingLocal PI required. Cost-effectiveness focus.Go through CROs or academia. Submit to special study board.
Other GCC (Qatar, Kuwait)Moderate & FollowingGCC-level data acceptable. Emphasis on value to the system.Submit as HTA evidence. Emphasise local relevance.
Section B: The ADAPT Strategy

In the absence of unified MENA regulation, follow this 3-step playbook:

  1. Adopt Global Standards: Build on FDA, EMA, and ISPOR guidance to gain baseline credibility.
  2. Adapt to Local Context: Address specific local needs such as:
    • Arabic-language PROs
    • Saudi PDPL & other regional privacy laws
    • Local IRB/ethics expectations and timelines
  3. Engage Early & Often: Never present a completed study as a surprise. Align with regulators and key stakeholders via pre-submission meetings and scientific advice.

Regulatory Readiness Checklist

Have you considered these key local requirements for your protocol?

Done? Requirement Example
Local data / registry sourceSFDA or DOH evidence expectation
Local stakeholder alignmentPI, ethics board, HTA reviewer
Arabic PROs if neededEspecially for QoL endpoints
Privacy & consent alignedPDPL (KSA), Data Protection Law (UAE)
Early scientific advice plannedSubmitted inquiry to regulator before final protocol
10

Risk Management

Conduct a Feasibility & Risk Assessment

Feasibility = Field Reality × Risk Readiness. Feasibility is not about avoiding risk, it's about identifying it early, scoring its impact, and having a realistic mitigation plan.
Part A: Site & Operational Feasibility Checklist
A comprehensive Feasibility Questionnaire Template is available for detailed site assessments, covering site capacity, population estimates, regulatory timelines, staffing, and IRB/contracting logistics. If completing this independently, use the brief checklist below with your best estimates.
Core Feasibility Item Your Initial Assessment / Notes
Estimated number of eligible patients per site / per year
Ethics committee (IRB/EC) setup and estimated timeline
Site staff availability and experience (PI, coordinators)
Data capture methods (EHR, paper, PRO tools, labs)
Part B: Risk Matrix

List and score potential risks before initiating the project. The goal is to quantify, not eliminate. What can you proactively do to prevent or reduce the impact of each risk?

Risk Category Specific Risk Description Impact (1–9) Likelihood (1–9) Risk Score (I × L) Mitigation Plan
e.g., Recruitment Patient pool smaller than estimated 6 7 42 Adjust inclusion criteria. Engage referring centres.
e.g., Contracting Long negotiation with academic hospital 5 8 40 Pre-engage with legal early. Have template ready.
e.g., Data Capture Site has no eCRF experience 4 5 20 Provide on-site training and support staff.

Output Summary

11

Final Synthesis

Finalise the RWE Synopsis

Summarise everything in one structured, strategic page. This synopsis is your internal go-to document, the bridge between concept, feasibility, and study activation.

RWE Study Synopsis Template
Item Guiding Prompt Your Entry
Study TitleDescriptive but clear
Research ObjectiveSMART objective from Step 6
PhasePipeline or Launch
Primary EndpointWhat are you measuring?
Target Country / Regione.g., KSA, UAE, Egypt
Target StakeholderSFDA, DOH, payer, internal strategy, etc.
Study DesignFrom Step 7
Data Source(s)EHR, registry, PRO tools, etc.
Sample Size EstimateApproximate based on feasibility data
Site(s)Key partners or types of hospitals
Complexity LevelLow / Moderate / High (from Step 8)
Regulatory FitBased on Step 9, aligned with country guidance?
Top 3 Risks + MitigationsShort summary from Step 10
Next Actione.g., feasibility call, protocol draft, stakeholder alignment
Sometimes We Won't Run a Study… Instead of collecting new data, you might frame insights through expert alignment or narrative synthesis. Consider a White Paper or Consensus Statement when:
  • → There's no available data, but strong expert alignment can still guide practice.
  • → You need to educate or shift clinical behaviour faster than a study timeline allows.
  • → There's a need to define local positioning or value messaging for a payer or formulary discussion.
  • → You want to re-purpose global evidence for a MENA audience with local interpretation.
  • → The topic is ethically or logistically difficult to study prospectively in the region.
  • → You're early in the lifecycle and want to shape the ecosystem or stakeholder dialogue.

Final Recommendation

"RWE isn't always about collecting data. Sometimes, it's about clarifying the conversation."

Ready to Build Your Evidence Strategy?

MARS Global provides end-to-end RWE support, from evidence gap identification through to Q1-journal publication.

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