Grey Literature in Evidence Synthesis: Overlooked but Critical

In today’s evidence-driven healthcare environment, how complete your evidence package is can be just as important as the findings themselves. Health Technology Assessment (HTA) bodies, regulators, and payers aren’t just asking what your data shows — they’re asking what might be missing.

One often-overlooked element in literature reviews is grey literature. Far from being optional, grey literature is increasingly viewed as essential for comprehensive, unbiased, and regulator-ready evidence synthesis.

In this article, we’ll explore:

• What grey literature is and why it matters

• The risks of ignoring it

• How to systematically integrate it into evidence synthesis

• A real-world case study showing how grey literature strengthened an HTA submission

• Best practices for teams looking to future-proof their evidence strategy

🔹 What Is Grey Literature?

Grey literature refers to evidence that sits outside traditional peer-reviewed journals but can still be highly relevant. Examples include:

• Clinical trial registries (ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP)

• Conference abstracts and proceedings (e.g., ASCO, ISPOR, EULAR)

• HTA reports and regulatory submissions from other markets

• Government and NGO reports on epidemiology, costs, and burden of illness

• Unpublished dissertations, theses, and technical reports

This evidence is often more timely, comprehensive, and practical than published studies — making it a critical component of robust evidence synthesis.

🔹 Why Grey Literature Matters

1. Completeness and Avoiding Bias

Peer-reviewed journals are not a neutral sample of all research. Studies with positive outcomes are more likely to be published, while negative or inconclusive findings may remain buried in registries or internal reports. Excluding grey literature risks publication bias, skewing your conclusions.

2. Relevance to Regulators and Payers

HTA agencies such as NICE, CADTH, and PBAC explicitly ask whether grey literature has been considered. Many rely on international HTA reports, registry data, and unpublished RWE to validate findings. Leaving this out weakens credibility.

3. Timeliness of Data

In therapeutic areas like oncology, immunology, or rare diseases, the latest survival or HRQoL data often first appears in conference abstracts or trial registries. If you only rely on journals, your evidence base may already be out of date at submission.

4. Transparency and Trust

Documenting grey literature searches shows regulators that you’ve left no stone unturned. Proactive inclusion signals rigor, foresight, and methodological integrity.

🔹 Risks of Ignoring Grey Literature

If grey literature is not systematically included, the consequences can be serious:

• HTA pushback: Agencies may challenge completeness, request additional searches, or reject submissions.

• Weaker models: Missing comparator, utility, or cost data can undermine cost-effectiveness analyses.

• Delays: Re-running reviews after feedback can set back submissions by months.

• Loss of trust: Payers may question whether omissions were intentional.

In short: ignoring grey literature isn’t just an oversight — it’s a methodological flaw.

🔹 Case Study: How Grey Literature Strengthened an HTA Submission

The Challenge

A specialty pharma company was preparing an HTA submission for a rare disease therapy. Their initial literature review focused exclusively on peer-reviewed journals (PubMed, Embase).

When the internal HEOR team assessed it, they discovered key omissions:

• Unpublished trial results in ClinicalTrials.gov showing early termination data

• Conference abstracts with updated survival outcomes not yet published in journals

• HTA reports from other jurisdictions (HAS in France, ICER in the US) containing comparator insights and utility values

⚠️ Without this, the review risked appearing incomplete and biased, leaving the submission vulnerable to rejection or delay.

Our Approach: Systematic Integration of Grey Literature

We rebuilt the review around a structured grey literature framework:

1️⃣ Expanded Search Sources

• Added ClinicalTrials.gov, EU CTR, WHO ICTRP for unpublished and ongoing trials

• Screened major conferences (ASCO, ISPOR, EULAR) for abstracts with survival and HRQoL data

• Extracted comparator and cost inputs from international HTA reports

2️⃣ Transparent Documentation

• Included grey searches in the PRISMA flow diagram

• Created appendices linking directly to registry entries and HTA reports

• Clearly flagged grey sources in evidence tables

3️⃣ Critical Appraisal

• Assessed methodological quality of abstracts and registry data

• Classified strength of evidence while acknowledging limitations

4️⃣ Integration into Submission

• Updated survival curves with abstract data to calibrate models

• Supplemented cost-effectiveness inputs with values from HTA reports

• Added a “Limitations & Grey Literature” section to demonstrate transparency

The Results

✔️ HTA Acceptance – The submission passed with no methodology-related objections 

✔️ Stronger Models – Survival and utility inputs from grey literature improved credibility 

✔️ Time Saved – Avoided 3–6 months of rework delays 

✔️ Future-Proofed Process – The company formalized grey literature searches as an SOP for all reviews

The Insight

This case reinforced a key truth: grey literature isn’t optional — it’s critical. Registries, abstracts, and HTA reports often contain the “missing pieces” regulators are already looking for. Including them proactively transforms potential weaknesses into evidence of rigor and foresight.

🔹 Best Practices for Grey Literature in Evidence Synthesis

For teams preparing systematic reviews, CERs, or HTA submissions, here are five practical tips:

✅ Define Scope Clearly – Identify relevant grey sources upfront (registries, HTAs, conferences). 

✅ Document Searches – Apply the same transparency as for journal searches, including PRISMA diagrams. 

✅ Appraise Quality – Not all grey evidence is equal; weigh accordingly but don’t omit. 

✅ Integrate, Don’t Isolate – Use grey evidence in analyses and narratives, not just as appendices. 

✅ Stay Current – Re-run grey searches near submission deadlines to capture the most recent findings.

🔚 Final Thoughts

In evidence synthesis, what you leave out can be just as damaging as what you include.

Grey literature fills the gaps left by peer-reviewed journals, ensuring reviews are comprehensive, unbiased, and regulator-ready. By systematically integrating trial registries, abstracts, HTA reports, and other non-journal sources, organizations can:

• Avoid publication bias

• Strengthen credibility with HTAs and payers

• Build stronger models and dossiers

• Save months by avoiding costly rework

Grey literature may be overlooked by some, but in today’s evidence environment, it is nothing short of critical.

📌 Looking to strengthen your next HTA submission, CER, or global dossier with structured grey literature integration? 

Our HEOR and medical writing experts conduct systematic, PRISMA-compliant reviews that fully incorporate grey literature — ensuring your evidence packages are comprehensive, transparent, and regulator-ready.

👉 [Contact us] to explore how we can support your evidence strategy.