New Active Substance Status at EMA and MHRA: Assessment Criteria and Evidence Standards

New active substance status at EMA and MHRA: how claims are assessed and what evidence separates a NAS from a known therapeutic moiety

New active substance (NAS) status matters well beyond nomenclature. In the EU it determines whether a product starts a new global marketing authorisation (GMA) for data-exclusivity purposes, and it can support access to the centralised procedure. In the UK it determines the legal basis and assessment track a licensing application follows. Both regulators start from the same default: a new chemical form of an authorised substance is the same active substance unless the applicant shows a significant difference in safety and/or efficacy. This article covers the legal test, the therapeutic-moiety analysis EMA applies to chemical and biological substances, the evidence CHMP has accepted and rejected in EPARs, and how the MHRA framework compares.

The legal starting point: Article 10(2)(b) of Directive 2001/83/EC

The core rule is in the EU generic-medicines provision. Article 10(2)(b) of Directive 2001/83/EC states that "the different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy," and that in such cases the applicant must supply additional information proving the safety and/or efficacy of the various salts, esters or derivatives ²⁰⁶.

The European Commission's Notice to Applicants (Volume 2A, Chapter 1) turns this into the NAS definition. Annex I to Chapter 1 defines a NAS for human medicines as a chemical, biological or radiopharmaceutical substance not previously authorised in a human medicinal product in the EU. It also covers an isomer, mixture of isomers, complex, derivative or salt of a previously authorised chemical substance if it differs significantly in safety and/or efficacy properties ³¹. Separate criteria apply to biological substances ³² and radiopharmaceuticals. For radiopharmaceuticals, a radionuclide or ligand not previously authorised in the EU qualifies, as does a substance whose coupling mechanism between molecule and radionuclide has not been authorised before ³³.

The Notice to Applicants also sets out the evidentiary consequence. If the information supplied cannot establish the absence of a significant difference for an Article 10 application, appropriate pre-clinical tests and clinical trials may be needed under Article 10(3). If the substance qualifies as a NAS under Annex I, the applicant may consider a full Article 8(3) application instead ²²⁶.

Regulation (EC) No 726/2004 uses "new active substance" as a scope criterion for the centralised procedure. Under Annex I, point 3, a new active substance indicated for AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune dysfunctions, or viral diseases must go through the centralised procedure ²⁴⁴²⁴⁵. Article 3(2)(a) gives optional access for an active substance not authorised in the Union on 20 May 2004 ²⁴⁶. The Regulation does not itself define NAS or set criteria for deciding whether a substance is new ²³⁰²³¹²⁴⁷.

EMA's assessment framework

EMA has set out its approach in three reflection papers:

Reflection paper on considerations given to designation of a single stereo isomeric form (enantiomer), a complex, a derivative, or a different salt or ester as new active substance in relation to the relevant reference active substance (2012) ²⁸⁵
Reflection paper on the chemical structure and properties criteria to be considered for the evaluation of new active substance (NAS) status of chemical substances (2016) ²⁸¹
Reflection paper on the criteria to be considered for the evaluation of new active substance (NAS) status of biological substances (2022) ²⁸²

Parallel veterinary versions of the chemical-substance paper also exist ²⁸⁰²⁸³.

Procedural principles

The claim belongs in the MAA. The applicant must substantiate the claim with evidence in the marketing authorisation application. For situations the reflection papers do not cover, EMA invites applicants to seek scientific advice ¹⁰⁶¹⁰⁷.
Eligibility is not designation. Being accepted into the centralised procedure on the basis of a NAS claim does not establish NAS status. EMA treats eligibility as separate from the scientific assessment during the MAA, and designation is agreed only after detailed assessment. Filing under Article 8(3) or through the centralised route does not confer NAS status by itself ¹⁰⁸¹⁰⁹. A NAS assessment also has no retrospective effect on centralised-procedure eligibility that has already been granted ²⁷⁶²⁷⁸.
The determination is made once, at first authorisation. It is agreed at European level and published in the relevant public assessment report ¹¹⁰²⁷⁶²⁷⁷.
The default is "not different." NAS status is decided case by case. The burden of showing a difference sits with the applicant ⁴⁷⁹¹⁸⁴⁴⁸⁰.
The consequence is a separate GMA. If a product is designated a NAS, it is not part of the same GMA as the initial authorisation for data-exclusivity purposes ¹¹¹. A 2010 draft of the enantiomer reflection paper says that once NAS status is confirmed, the applicable 6/10-year or 8+2+1 period must run before a generic or hybrid application can use the new product as its reference ¹¹². That statement comes from draft text. Check the current final guidance before relying on it.

Chemical substances: the therapeutic-moiety test

For a chemical substance structurally related to an authorised one, EMA asks a two-stage question. First: does administration expose patients to the same therapeutic moiety at the site of biological activity? If it does not, and the substance is chemically unrelated, it is considered new in itself. If it does, the second question is whether the substances differ significantly in safety and/or efficacy properties ¹⁸³. In EMA's usage, the therapeutic moiety is the entity the patient is exposed to after processes such as prodrug conversion, hydrolysis, dissolution or dissociation ³⁷¹¹⁸⁵.

How EMA applies the test to common chemical modifications:

Modification	Default treatment	What could support NAS
Different salt	Same active substance, because salts usually dissociate and separate the therapeutic moiety from the counter-ion ³⁷⁵	Evidence of significant safety and/or efficacy differences ³⁷⁵
Ester or ether hydrolysed in vivo	Not NAS, because it delivers the authorised moiety ³⁷⁴	An ester or ether that acts intact, without exposing patients to the authorised moiety, could be NAS. Evidence of intact action may be needed ³⁷⁴¹⁸⁵
Prodrug or applied metabolite	Treated as a derivative that exposes patients to the same moiety ³⁷²³⁷³	Significant safety and/or efficacy differences ³⁷²³⁷³
Cocrystal, hydrate, solvate	Weak interactions usually break on dissolution and expose the same moiety, so not NAS on that basis ³⁷⁶³⁷⁷	Demonstrated significant differences. For non-oral routes, the assessment depends on the moiety actually present at the site of action ³⁷⁶³⁷⁷
Complex	Not NAS if designed to release an already authorised substance in vivo ³⁷⁸	A complex that acts without dissociating may have a different therapeutic moiety. Evidence of non-dissociation may be needed ³⁷⁸
Single enantiomer of an authorised racemate	Same active substance, because the enantiomer already made up 50% of the racemate ³⁵⁵	Evidence of significant safety and/or efficacy differences ³⁵⁵³⁵⁶

The retrieved guidance text does not set out specific NAS rules for deuterated compounds, chelates or covalent modifications ¹⁶⁴¹⁷⁸³⁶². The deutetrabenazine EPAR below shows how CHMP has handled a deuterated substance in practice.

What the chemical dossier should contain

For chemical substances, EMA recommends that applicants:

compare structural features, including information from established databases, and discuss the therapeutic moieties of structurally related authorised substances against the claimed NAS ¹⁸⁶¹⁸⁰³⁷⁹³⁸⁰
show whether administering the proposed substance would expose the patient to the already authorised moiety, and substantiate any claimed in vivo behaviour such as intact action or non-dissociation ³⁸⁰
where the moiety is shared, provide evidence of significant differences in safety and/or efficacy. The exact documentation depends on the case, and EMA advises seeking scientific advice ¹⁸⁷³⁵⁸

What counts as a "significant difference"

This is where most contested claims succeed or fail. The 2012 reflection paper sets out a clear hierarchy of evidence:

Direct comparison is preferred. Scientifically justified indirect evidence may be accepted, but it may be less compelling ⁴⁸¹¹⁸⁸.
Clinical data carry the most weight. Clinically relevant differences in human safety or efficacy are the most compelling evidence, so head-to-head clinical studies are preferred where feasible. Compelling preclinical and/or other clinical evidence can substitute ⁴⁸¹¹⁸⁸.
Supporting data can be non-clinical. Pharmacology or pharmacodynamics, microbiology, animal disease models and toxicology can all contribute ⁴⁸¹¹⁸⁸.
NAS-specific studies are not mandatory. The studies needed for NAS status are not necessarily those needed for the MA, and applicants do not have to run extra studies just to pursue NAS status. Without the required degree of difference, however, the designation will not be granted ⁴⁸¹¹⁸⁸.

Differences EMA regards as potentially sufficient include:

a change in dosing frequency or route of administration driven by safety or efficacy
improved efficacy at clinically relevant doses
clinically relevant changes to warnings, adverse reactions or drug interactions
substantiated use in patients who could not previously be treated ⁴⁸²¹⁸⁹

Differences unlikely to be enough include pharmacokinetic differences alone, inconclusive preclinical findings, and unsupported extrapolation between separate studies ⁴⁸²⁸⁸.

Biological substances: basic structural elements

The 2022 biological reflection paper uses two routes ¹⁷⁷³⁹²³⁸².

Route 1: a different therapeutic moiety. The therapeutic moiety is made up of the substance's basic structural elements. These are its core structure, excluding added functional structures and structures arising from, for example, post-translational modification. EMA's examples are the filgrastim portion of PEG-filgrastim and the FVIII portion of an FVIII-Fc conjugate. A substance with substantially different basic structural elements is likely to be a NAS without any evidence of a safety or efficacy difference. For proteins, EMA compares amino-acid sequences:

a single conservative substitution may not be substantial
a substantially different monoclonal antibody sequence, or B-domain-deleted versus full-length FVIII, may qualify
applicants may need to support the claim with sequence alignments against authorised substances ¹⁷⁷³⁹²³⁸²

For heterogeneous substances such as heparin, a changed range of basic structures (additional structures, or changed relative proportions) can support the claim ³⁹³¹⁶⁸.

Route 2: the same basic structural elements, but a significant difference in safety and/or efficacy. Differences in molecular structure, source material or manufacturing process, alone or together, can support NAS status, but only if they cause a significant difference. The applicant must define the substance and its differences unequivocally, then demonstrate their consequences ¹⁶⁹³⁸². A different manufacturer or process on its own is not enough ¹⁷⁷¹⁹⁰¹⁹¹. For example:

PEGylating an existing protein is not NAS in itself, though it can qualify if it produces a significant difference
switching from plasma-derived to recombinant coagulation factor does not qualify automatically
potential differences in viral safety do not count, because they are not properties of the active substance ¹⁶⁹³⁸²
product-related and process-related impurities and extraneous agents cannot establish NAS ¹⁷⁷

Claimed differences in quality attributes must be shown with sensitive analytical methods to be consistently present, not just batch-to-batch variability ¹⁶³. One sufficient justification, such as a demonstrably different amino-acid sequence, makes further arguments unnecessary ¹⁷⁷.

For ATMPs, where basic structural features can be hard to identify, EMA may instead assess substantial differences in biological characteristics or activity. Its examples include:

mesenchymal versus haematopoietic stem cells
certain differences in cell source or controlled cell composition
differences in viral vectors
different engineering technologies, such as zinc-finger nucleases versus Cas9 ³⁹⁴¹⁸²³⁹⁵

Clinical data are not required for a Route 1 ATMP claim. For a Route 2 claim, new clinical data do not have to be generated in advance ¹⁷².

How CHMP has ruled: EPAR case examples

The EPARs show that a structural difference alone rarely settles a claim. The deciding factor is either a genuinely different therapeutic moiety or demonstrated clinical consequences.

Substance (comparator)	Evidence and reasoning	CHMP outcome
Dimethyl fumarate, Tecfidera (Fumaderm: dimethyl fumarate plus monoethyl fumarate salts)	Chemical, physical, pharmacological and metabolic comparisons, including evidence that the compounds do not interconvert ¹⁴⁵	NAS accepted. Different therapeutic moieties, so no significant safety or efficacy difference had to be shown ¹⁴⁶. The conclusion was later contested in EU court proceedings brought by a generic applicant
Tenofovir alafenamide, Genvoya (tenofovir disoproxil)	Non-clinical and clinical properties of the two tenofovir prodrugs ¹⁴⁷	NAS accepted. A derivative, but one that differed significantly in safety and efficacy ¹⁴⁷
Icosapent ethyl, Vazkepa (omega-3-acid ethyl esters 90)	Review of the available data ¹²¹	NAS accepted. Significantly different efficacy properties ¹⁵⁶
Deutetrabenazine, Austedo (tetrabenazine)	Applicant argued that replacing six hydrogens with deuterium produced different active metabolites and moieties ¹⁵²¹⁵³	Not NAS. A derivative exposing patients to the same moiety, with insufficient evidence of a significant difference ¹⁵⁴¹⁵³
Levacetylleucine, Aqneursa (racemic N-acetyl-DL-leucine)	Enantiomer claim. No comparative clinical efficacy or safety data, and the comparative non-clinical pharmacology and toxicology were not compelling ⁴⁶¹⁴⁶²	Not NAS ⁴⁶³¹⁵⁵
Eszopiclone, Lunivia (racemic zopiclone)	Comparative PK, PD and tolerability data and claimed sleep-latency benefits, without a prospective comparison ⁴⁶⁵⁴⁶⁶	Not NAS. The claimed advantages were theoretical. The NAS decision was later subject to re-examination ⁴⁶⁷⁴⁶⁸
Teriflunomide, Aubagio (leflunomide)	An in vivo derivative of leflunomide. CHMP's initial opinion found the differences of questionable clinical relevance ⁴⁷¹	NAS accepted on re-examination (majority decision). It differed significantly in safety from leflunomide ⁴⁶⁹
Follitropin delta, Rekovelle (follitropin alfa and beta)	Different glycosylation and phase 3 findings. However, the amino-acid sequence was identical to existing products and the glycosylation did not affect relative potency ¹⁴⁸	Not NAS ¹⁴⁹
Botulinum toxin type A, Nuceiva (Botox/Vistabel, Dysport/Azzalure, Xeomin/Bocouture)	Claimed greater purity from a different manufacturing process. The applicant later withdrew the claim ¹⁵⁰¹²⁰	Not NAS. Process differences alone were not enough ¹⁵¹

Three patterns stand out. First, successful claims rest either on a different moiety (Tecfidera) or on demonstrated safety or efficacy differences (Genvoya, Vazkepa, and Aubagio on re-examination). Second, enantiomer and deuterated-analogue claims backed mainly by mechanistic or pharmacokinetic arguments have failed. Third, for biologicals, differences in glycosylation or process that do not change potency or clinical performance have not been accepted.

MHRA: the UK approach

Since leaving the EU framework, the MHRA defines a NAS as an active substance not previously authorised in a medicinal product in the UK, and treats NAS applications as innovative medicines ²⁶⁸²⁷¹. NAS applications are generally expected to be made under Regulation 50 of the Human Medicines Regulations 2012. This requires full pharmaceutical, non-clinical and clinical data under Schedule 8, which may be wholly original or a permitted mix of original and published data ⁴²⁴⁴²⁵. Products authorised on that basis can be used as reference products after eight years of data exclusivity, followed by a further market-exclusivity period ²⁷¹.

The UK test for modified substances mirrors the EU one. MHRA's application-types guidance treats a different salt, ester, ether, isomer, mixture of isomers, complex or derivative as the same active substance unless it differs significantly in properties relevant to safety or efficacy. Where a significant difference is claimed, the applicant must supply additional information proving safety or efficacy ⁷⁴. The UK comparative-studies guidance asks whether a change to a salt, ester, complex or derivative with the same therapeutic moiety alters the moiety's pharmacokinetics, pharmacodynamics or toxicity enough to change its safety and efficacy profile significantly ⁷⁵.

MHRA's guidance also reproduces the ICH Q6A definition of a "new drug substance": a designated therapeutic moiety not previously registered in a region or member state, which may be a complex, simple ester or salt of a previously approved substance ⁷³. That is a specifications definition for quality testing. It is not the legal test for NAS status.

Three points about the UK framework are worth knowing:

GMA. Where an initial UK MA is granted under Regulation 49(1)(a) in accordance with Regulation 50, later strengths, forms, routes, presentations, variations and extensions belong to the same GMA. For generic, hybrid and biosimilar applications, a product within that GMA is treated as authorised on the date of the initial authorisation ⁴²⁸. MHRA classifies changes to an active substance, including salt, ester or isomer modifications, as line extensions ⁴²⁷.
What the published guidance does not cover. The MHRA guidance retrieved does not set out a dedicated procedure for submitting and deciding an individual NAS-status claim, or say whether a claim can be made retrospectively ⁶⁴⁴²⁷⁵⁰. A statement that the claim must be made in the initial application comes from European Commission guidance hosted by MHRA, not from an MHRA-authored instrument ²⁷². Applicants with borderline modified substances should raise the question with MHRA early.
Assessment track. Under national assessment, MHRA can reach a positive decision within 150 clock-on days if one round of questions resolves all issues. If issues remain at Day 150, it aims for a final decision within 210 clock-on days. Clock-stops are excluded ²⁶⁸. The Commission on Human Medicines advises but does not decide. If major objections remain at Day 150, the applicant may receive a CHM letter and can make written or oral representations before MHRA makes its decision ⁴⁸⁸⁴⁹⁰⁴⁹¹⁴⁹². After a NAS is authorised, MHRA publishes a press release within one week and a UK PAR within 30 days ⁴⁹³. The Access Consortium New Active Substance Work Sharing Initiative is an optional joint-review route with its own timetable. Each agency still makes its own decision ⁸⁰⁸¹⁴⁹⁴.

Practical implications for NAS strategy

Start with the moiety, not the molecule. Map what the patient is actually exposed to at the site of action: after hydrolysis, dissociation or dissolution for small molecules, or the basic structural elements for biologicals. A different moiety is the strongest route to NAS and, in the EU, needs no proof of a clinical difference ¹⁸³¹⁷⁷¹⁴⁶.
If the moiety is shared, plan for clinical evidence. EMA gives most weight to head-to-head human data showing clinically relevant differences. Pharmacokinetic differences or mechanistic arguments alone have repeatedly failed ⁴⁸¹⁴⁸²⁴⁶¹⁴⁶⁵.
Make the claim in the initial MAA and treat eligibility as provisional. In the EU, the designation is decided once, at first authorisation, and published in the EPAR. Centralised-procedure eligibility does not guarantee it ¹⁰⁶¹⁰⁸¹¹⁰.
Remember the jurisdictional baseline. The EU test looks at prior authorisation in the EU ³¹. The UK test looks at prior authorisation in the UK ²⁶⁸. The same molecule can therefore raise different questions in each jurisdiction, even though the salt, ester and isomer rule is the same in both ²⁰⁶⁷⁴.