Recursos contra el acuerdo de adjudicación

For abridged applications under Article 4(8)(a)(iii) of Directive 65/65/EEC as amended, the question of demonstrating the essential similarity of their second (or subsequent) applicant product to an originator product arises.

6.6.1

The Smith Kline and French judicial review

On 2 October 1987, Smith Kline and French Laboratories (SKF) instituted judicial review proceedings against the UK Licensing Authority, seeking to restrain it in its use of their (the originator’s) confidential data for cimetidine tablets (Tagamet) in the assessment of any second applicant’s abridged application. On 23 February 1988, Mr Justice Henry declared that reference to such confidential data could not be made ‘except with the express consent of the appellants’.

On 29 June 1988, the UK Court of Appeal set aside the Henry judgement. On 9 February 1989, the final appeal court in the UK (the House of Lords) dismissed SKF’s appeal.

The House of Lords confirmed the right of the Licensing Authority in the UK to refer to the originator’s confidential data, stating: ‘It is for the Licensing Authority, comparing the information received from the second applicant and taking into account all other information available to the Licensing Authority, from whatever source and whether confidential or not confidential, to decide in the case of a particular application whether it shall be declined or granted’.

6.6.2

Essential similarity and the active ingredient

One of the arguments raised by SKF in their case was that the UK Licensing Authority had to require the generic product manufacturers (the second applicants) to provide data to show that their cimetidine drug substance was essentially similar to that of the originator (SKF).

It is this consideration of essential similarity of the active ingredient which has given rise to considerable difficulties for the second applicants (the generic product manufacturers). Different sources of an active ingredient may be made by different synthetic routes or variants of the same route. Such differences will inevitably give rise to differences in the impurity profile of the active ingredient. The words ‘essential similarity’ in the Directive do not mean absolute identicality of impurity profile, but what do they mean? The House of Lords did not specifically address this issue to give a legal definition, although it was mentioned in argument. One widely accepted view is that a second applicant’s source of active ingredient can be regarded as ‘essentially similar’ if the physical form of the active ingredient and its attendant impurities make it similar in its biological properties to the patient. Thus, a new pattern of impurities in the second applicant’s source of active ingredient should not then cause any difference to the safety or efficacy of the product in which it is used. The presence of (say) a new impurity which was known to be immunogenic in the second applicant’s source of active ingredient might cause allergic reactions in some patients taking the product, and the product could not then be regarded as essentially similar.

The above highlights the need to have detailed information on the impurity profiles of the active ingredient used by the second applicant. The major impurities should be identified and their levels known in typical production batches. The levels of other minor impurities should also be known, approximately. The Pharmaceutical Expert Report should consider the impurities and cross refer to a detailed consideration of what is known about their toxicology in the Pharmacotoxicological Expert Report. The impurity limits need to be justified in relation to the toxicology of the impurity, the pharmacology and toxicology of the active ingredient itself, the route of administration, the daily dose, the duration of therapy, and the proposed indications for the product.

The essential steps in considering essential similarity are as follows:

• First, for the applicant to identify the impurity profile of his source of active ingredient and to comment on the potential toxicology problems as part of the justification for the proposed impurity limits in the active ingredient specification.

• Second, for the pharmaceutical assessor in the national authority to compare the impurity profile of the new source of active ingredient with that of the 80 ABRIDGED APPLICATIONS [CH. 6

originator’s active ingredient and to identify any major differences between them.

• Third, for the toxicological and clinical assessors in the national authority to consider the potential hazard to patients exposed to the different impurities or different levels of impurities and to decide whether they feel that they are satisfactory or not. If they do not accept the proposed levels or feel that insufficient information had been presented to make an informed judgement, they would probably need to refer the application to the national committee (see Chapters 17 and 18) for advice and or possible refusal.

As detailed in Chapter 7 (Drug Master Files), the information on impurities could come from either the active ingredient manufacturer himself, or from the product marketing authorisation applicant. In this latter case, the active ingredient manufacturer must impart the relevant information on the impurities and their potential toxicology to the applicant for the marketing authorisation for the dosage form—since it is he who will be responsible (and legally liable) if there are adverse reactions to the product which he should have foreseen.

6.6.3

Essential similarity and the finished product

Article 4(8)(a)(iii) requires the product to be essentially similar. The ‘Notice to Applicants…’ quotes the definition agreed in the Expert Working Group of the Council of Health Ministers:

‘For the purposes of this provision, a proprietary medicinal product will be regarded as essentially similar to another product if it has the same qualitative and quantitative composition in terms of active principles, and the pharmaceutical form is the same and where necessary, bioequivalence with the first product has been demonstrated by appropriate bioavailability studies….’

There are clearly many questions which arise from the above, and the CPMP will in due course revise and extend its guidance on the definition of essential similarity.

6.6.4

Essential similarity and the clinical indications

The second applicant has to demonstrate that an originator’s product has been marketed for at least ten years, with the precise indications which are now being sought in one Member State, and is also currently marketed in the Member State in which the application is made. If the originator product added new indications or a new dose regimen within the ten year period, the second applicant can either

cite published clinical and other data to provide the evidence, or provide evidence from new toxicology tests (where needed) and clinical trials to show that the new indications or dose are justified.

6.7

SECOND APPLICANT PRODUCTS BY DETAILED