No Reference-Country Approval: Two Independent Expert Opinions

1. Key takeaways

Where a device is not registered in a reference country, Israel’s reliance mechanism does not apply, and the applicant must submit the results of a risk analysis, a clinical evaluation and a summary of clinical trials; in practice, opinions from two independent experts on the safety and effectiveness of the device must also be provided (practical estimate). At the same time, the four registration conditions of Article 6 of the Law must be met: the benefit of use outweighs the risk, effectiveness is demonstrated, quality is suitable for the intended use, the product is manufactured under appropriate manufacturing conditions, and its name does not mislead the public about health. This is the most expensive and slowest route to approval in Israel.

Because every element of evidence must be generated from scratch rather than borrowed from a foreign regulator, the workload on this route is qualitatively different from the reference-country routes. Applicants should not view it as a slower version of the Standard Route but as a separate evidence-building exercise with its own cost structure, its own timeline risks and its own sequencing decisions.

It is worth being precise about which products end up here. The route captures any device for which no reference-country approval exists — including devices holding only approvals from authorities outside the recognised reference-country set. The list of accepted approvals is broad (covering CE, FDA, Canada, Australia, Japan and others), so a company should exhaust every possibility of positioning an existing approval as a reference before concluding that its product must run the full evidence route in Israel.

2. Legal basis

This route rests on the same 2013 regulations and parent law as the Standard Route, with the specific evidentiary duties set out in the provisions below.

3. Expert insights

The core difficulty of this route lies not in the number of documents but in the independence of the evidence.

First, the risk analysis must be built by the applicant itself. Under the reference-country routes, the risk analysis may draw on conclusions already accepted by a notified body or the FDA; on the no-reference-country route, the applicant must submit a complete risk management file conforming to ISO 14971 and demonstrate the acceptability of the risk control measures.

Second, the clinical evaluation cannot be a literature review alone. Article 3(c) of the Regulations lists the clinical evaluation and the summary of clinical trials side by side, which means that where clinical data exist, a summary of the trials themselves must be submitted; where no clinical data of the applicant exist, the case must be argued through the equivalent-device route, and the equivalent device must itself be a product already on the market in a reference country — which is practically unworkable for a wholly novel product.

Third, the two independent experts are the most underestimated timeline variable. The expert opinions must come from clinically recognised experts, involve ethics and conflict-of-interest review, and their conclusions may themselves trigger new deficiency requests. GRZAN’s working assumption: this stage typically adds a further 3–6 months (practical estimate).

For companies holding only a China NMPA registration with no CE or FDA approval, this is the real situation. GRZAN’s judgement is that obtaining CE or FDA first, then entering Israel, is in most cases faster and cheaper overall — because a reference-country approval can be reused across markets, whereas investment in the no-reference-country route serves only the single Israeli market.

The comparison is not only about elapsed time. Evidence built for Israel alone has no second life: a risk analysis assembled to answer one reviewer, expert opinions commissioned for one dossier, and clinical summaries framed for one market cannot be redeployed the way a CE technical file or an FDA submission can. When the two routes are placed side by side in a business case, the reuse value of the reference-country evidence is usually what tips the arithmetic.

4. Practical recommendations

• Model the sequencing first: compare the two routes — “CE/FDA approval plus the Israeli Fast Track” and “the Israeli Standard Route directly” — on time and cost side by side.
• Get the risk management file right in one pass: prepare it fully to ISO 14971 so it can be reused in other markets.
• Engage the experts early: start expert selection and conflict-of-interest review three months before submission (practical estimate).
• Set stage-gate review points: at the end of the first deficiency round, evaluate whether to continue, avoiding open-ended investment.

5. Verification checklist

• □ Confirmed the product holds no reference-country approval (including CE, FDA, Canada, Australia, Japan and others)
• □ Risk analysis file fully prepared to ISO 14971 and reusable
• □ Clinical evaluation complete, and the feasibility of the equivalent-device argument assessed
• □ Summary of clinical trials prepared (where available)
• □ Selection and scheduling of the two independent expert opinions initiated (practical estimate)
• □ Sequencing comparison completed between “obtain CE/FDA first” and “file directly in Israel”

Regulatory information verified as of 29 October 2026. The names, numbers, publication dates and article numbers cited in this article were checked against official Israeli legal databases and authoritative public sources on that date; AMAR procedure documents are updated frequently, so please rely on the current version published on the Ministry of Health website before formal submission.

How GRZAN can help. GRZAN provides medical device and IVD registration, quality system, authorised representative and local testing support for the Israeli market. Our team manages MOH registration applications across risk classes, prepares reference-country dossiers, and supports post-market vigilance obligations. Business enquiries: info@grzanglobal.com