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The Legal Basis for Applications

An issue of understated importance in the EU

Prof. emeritus Tamás L. Paál

• University of Szeged, Institute of Drug Regulatory Affairs • external advisor to the Hungarian human medicines agency, the National Institute of Pharmacy and Nutrition

Bioequivalency, dissolution, biosimilarity: from the Chain Bridge to other bridges of the pharmaceutical world. 25th April 2015 in Antalya

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Acronyms used •  ANDA Abbreviated New Drug

Application •  BE bioequivalence or bio-

equivalent •  CMDh Coordination Group,

human medicines •  CT Clinical Trial •  DE Data Exlusivity •  EEA European Economic

Area •  EU European Union •  EURD European Union

Reference Dates (of the first authorisations of MPs)

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•  GMA Global Marketing Authorisation

•  MA Marketing Authorisation •  MAH Marketing Authorisation

Holder •  MP Medicinal Product •  NDA New Drug Application •  NTA Notice to Applicants •  PK Pharmaco-kinetics •  PSUR Periodic Safety Update

Report •  Q/A Question and Answer •  WEU Well-Established Use

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What is „legal basis for applications”?

•  The applications for medicinal product marketing authorisation are categorised all over the World (e.g. NDA, ANDA, etc.)

•  They (more or less) determine and indicate also the content of the dossier

•  The Applicant requests and the authority endorses it –  as a rule, in the validation phase

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The aim of the present lecture To point out that the „legal bases for applications” mean in the EU • originally the source and kinds of data • but it has gradually changed • to-day they indicate regulatory categories (with prerequisites and consequences) • not necessarily revealing the kinds of data you will find in the submitted dossier • and all these created certain mess and disagreement among the Member States as well as litigations

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Consequences of the legal base (examples)

Using certain legal bases the Applicant, e.g. •  is entitled / is not entitled a 10-year Data Exclusivity

DE •  has to / has not to submit a Risk Management Plan •  has to / has not to or it is subject to the EURD list

regularly submit PSURs •  has to pay higher / lower user then annual

pharmacovigilance fee (For the last point MAHs are very keen to know the

legal base of the original MA of their „old” medicines – but this is another story!)

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The past: „legal bases” (not named as such) in the Directive 65/65/EC

•  complete para 1-2, para 3(1- 8) •  essentially similar, informed consent a(i) •  Well Established Use a(ii) •  essentially similar a(iii) – entitles 6/10-year DE •  fix combination („…not hitherto used…”) – non-clin.

and clin. data for the combination exclusively! if essentially similar but different indication or route of

administration, or doses, the necessary non-clin. and clin. data must be submitted in addition to the proof for essential similarity!

It can be seen that – except the DE – this outlines mostly the source and kinds of data, not the regolatory consequences! 6

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Present legal bases (para of Dir. 2001/83/EC)

•  Complete 8(3) •  (Mixed Annex I Part II 7) •  Bibliographic (Well Established Use) 10a •  Generic 10(1) •  Informed Consent 10c •  Hybrid 10(3) •  Fixed combination 10b •  (Line Extension Dir. 1234/2008/EC)

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Complete submissions 8(3)

•  The complete data set is to be submitted for a „new” Medicinal Product

•  Misinterpretation: all data should be new, generated by the Applicant

•  Right interpretation: some of them may be from the literature (this is why the „mixed” application is not a real legal base and can be found only in the Annex of the hard law) – they are mostly „own” data only because the product is new! 8

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Bibliographic (WEU) submissions 10a

•  Still a complete submission, but all data taken from the literature

•  Rigth interpretation: all data (like under 8(3) applications, including good CT)

•  Misinterpretation 1: not all, only „pivotal” data (e.g. human exposure vs. animal toxicology…) – not this is written in the hard law – but all data are rarely published for all

products… 9

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Further ambiguities about WEU

•  Original meaning: many similar products used already, it is known that smaller PK variations are not important

•  But the legal prerequisite: at least 10 years from the first authorisation (in the EEA) of a similar product, and

•  this is the same time-period for DE/market exclusivity for generic applications!

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WEU ambiguities 2

•  Theoretically, 8 years after the first authorisation another Firm may file a generic application (and start marketing +2 years later = 10 years) – Generic product, interchangebility proven

•  But after 10 years this Firm may choose to file a WEU application instead, collecting all data from the literature – WEU product, interchangebility not known

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WEU ambiguities 3 •  Hard law: „The active

substance…” (logically, in similar dosage-forms and strenghts) „…has a well-established use…” (min. 10 years)

•  Experiences in the EU: – Vitamin D oral dosage forms are marketed in

200, 400 and 600 IU strengths – A new Applicant stated that Vitamin D 450 IU

capsules have well-established use in the EU – Question: may this completely new strength

be authorised on the basis of WEU? 12

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Fixed combinations 10b

•  Hard law: „…combination of active substances not hitherto used in MPs…” – moreover, this legal base entitles for DE

•  Misinterpretation: this legal base may be used by different Firms for similar combinations (more then once) if no reference to another dossier (exlcuded by the DE)

•  Our interpretation: the 10b legal base may be used only for the first MP authorisation! The second 10b is excluded not by the DE bot the „not hitherto used…” condition in the hard law! 13

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Fixed combinations 10b 2 •  The DE exludes only the reference to the

dossier of the already authorised product but the „…not hitherto used” condition excludes the second „same fix combination”!

•  The latter may be submitted – still without any reference to the authorised dossier – e.g. as a full 8(3) application, but not as a 10b!

•  Maybe, this was not the intention of the law-maker but it is in the hard law! 14

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The issue of Combination packs I.e. two monocomponent preparations (frequently prescribed together) are packed in the same blister • At present, they are „new medicinal products” in the EU • What is it (as a legal base)? • Former Notice to Applicants (NTA, Vol. 2A): „By analogy, the Fixed combination 10b legal base should be applicable” • New NTA (2013): „The Fixed combination 10b legal base cannot be considered” 15

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Combination packs

•  In my personal opinion they are not new medicinal products but new (pack) presentations

•  However, this is very difficult to accept because this would mean that the combipack belongs, at the same time, to two Global Marketing Authorisations (of the two monocomponents)

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The Global Marketing Authorisation (GMA) concept

Global Marketing Authorisation: (Directive 2011/83/EC Art. 6.):

•  When a medicinal product has been authorised…as a stand-alone one (complete 8(3) , WEU 10a or Fixed combination 10b)

•  …any additional –  strength, –  dosage-form, –  route of administration, –  presentation, –  modification, –  extension

•  shall belong to he same Global Marketing Authori-sation GMA

•  (i.e. no new DE starts!) 17

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What is important concerning the GMA

•  „The” medicinal product = the product of the same Marketing Authorisation Holder (MAH) as well as to MAHs not independent from the first (e.g. licencee, filiale…)

•  If a completely independent other MAH receives MA of a „similar” product with a stand-alone application (but not as Fixed combination 10b!), a new DE period starts! –  as interpreted also by the EU Commission providing

DE for two MAHs for orphan MP cholic acid in two different indications

•  For DE does not hinder the MA, only the submission with reference to an existing dossier!

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Generic applications Before starting: a small remark

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Art. 10(1) is the generic legal base! •  BE instead of non-clinical and clinical part, if DE

is over •  Concept of Eurogenerics

10(2)a is the definition of the reference product •  Authorisedon the basis of Art. 8 (complete!)

10(2)b definition of the generic medicine! •  Active substance(s) quali-quanti the same •  Dosage-form same (but all immediate-release

oral ones!) •  Various salts, esters… •  BE with the reference productl

Many wrong applications as 10(2)!

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Generic applications 10(1)

•  What is not a legal base issue: „generics are interchangeable with the reference medicine” – even the BE guideline says it is not the issue –  Interesting: misconceptions often taught at

University level: •  Generic = the patent expired. •  Generic = interchangeability. This may be true,

but it is not the consequence of the legal base!

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Generic applications

•  (We shall return to the generic-or-hybrid issue…)

•  In my opinion: what can be authorised on the basis of the BE guideline, that is a generic, since the waivers are also covered by this guideline: –  Dosage forms, that are BE without testing –  In which cases the in vitro comparison will do –  The criteria of the extension of the BE to other

strengths (a) to e))

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Informed Consent 10c •  The MAH may allow use to be made of the

pharmaceutical, non-clinical and clinical documentation contained in the (authorised) file on the medicinal product, with a view to examining subsequent applications relating to other medicinal products (of the same active ingredient content and the same dosage-form)

•  Complicated text meaning that the MAH may, e.g. sell the dossier waiving the purchaser from the 10-year Data exclusivity period

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Ambiguities around the „informed consent” 10c

•  Frequently the MAH gives the informed consent to „himself”

•  And imagine: this possibility is permitted in the Vol. 2A of the Notice to Applicants: „informed consent giver and acceptor may be the same MAH”

•  But this is completely meaningless! What the Informed consent ment originally? The original MAH waives the Data Exclusivity period giving another Applicant the right to refer to its data in the application (e.g. licence purchase)

•  Would NTA mean that the MAH waives the DA to himself? But the original MAH is not entitled to DE any more because of the GMA!

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Line extension Dir. 1234/2008/EC

•  Adding new strength, dosage-form, etc. to the authorised ones

•  Naturally, it will belong to the same global marketing authorisation

•  New phenomenon: after completing a marketing authorisation, to add a new strength the applicant starts a new 8(3) procedure, not a line extension

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Ambiguities around the Line extension

•  In the hard law it is not the MAH’s decision that the legal basis to add a new strength is a LE or a full application!

•  Essence of the LE is that the new strength belongs to the same Global Marketing Authorisation, thus, no new DE period may start

•  Is this application a „new legal basis, a full application without a DE”?

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Hybrid 10(3) •  If the new and the reference products

are not pharmaceutically equivalent… – E.g. eye-drops application refers to the data

of an injection •  …or the BE can not be demonstrated… •  …or changes in the active substance,

indications, strength, pharmaceutical form, route of administration

•  Results of appropriate (non-)clinical studies shall be provided

Ambiguities around the hybrid legal basis 10(3) 1/2

The strengths • BE guideline: if BE established for one strength, criteria for BE waiver for another strengths • Hybrid legal base 10(3): „in case of changes in the …strength It is obvious that in the first case the same application concerns different strengths while in the second is a new application for a new strength 27

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Ambiguities around the hybrid legal basis 10(3)

Itt happened: •  „The whole application is hybrid for biowaiver was

claimed for one of the strengths” •  „BE study was done but failed. The application

appeared as hybrid for ’the BE could not be demonstrated’ (with some arguments BE is not important in this case)”

•  Two aqueous eye-drops of the same active ingredient? It is a hybrid application for BE can not be demonstrated for locally active products”

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Generic or hybrid? Which is the first question?

•  Is it that the „BE study is not necessary” to establish bioequivalence (independently from that were possible or not)

•  or •  the „BE can not be demonstrated” by pharmacokinetic way

(independently from that is necessary or not)? •  In my opinion the first question: is it necessary to establish BE

or not? (If it is not, e.g. the BE guideline says two aqueous solutions are BE without further proof, who cares that pharmakokinetic BE study is not possible with eye-drops?)

•  Thus, the issue may be settled via the generic legal basis. •  However, according to an existing CMDh Q/A document:

–  „We have agreed by majority vote that this is hybrid” –  „Although the hard law requires results of appropriate non-clinical

or clinical tests, but „it is not necessary for the compositions are the same”

Majority vote vs. inherent logics/common sense?

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Is the „hybrid” a logical legal base or is it the wastepaper

basket of the EU applications?

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Conclusion

•  The meaning of the legal bases for applications has been changed in the EU – Originally: „this is a way for compiling

data for MA” – To-day: the same plus many benefits or

commitments •  The practice of their use does not

always follow their inherent logics at present…

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