Executive Summary

Question

The DG lll has asked the SCMPDM to provide it with guidelines for establishing the "similarity" of one orphan drug with respect to another in response to requests by drug manufacturers for derogation of the 10-year period of marketing exclusivity. Art. 8, paragraph 5 of the proposed legislation on orphan medicinal products (as transmitted by the lll Direction to the SCMPMD), specifies:

"For the purpose of this Article a "similar medicinal product" means one which consists of:

- the same chemical active substance or active moiety, including isomers and mixture of isomers, complexes, esters, salts or other derivatives of the substance, or

- the same biological active substance, including a different molecular structure, source material or manufacturing process of the substance, or

- the same radiopharmaceutical active substance, including a different radionuclide, ligand or coupling mechanism linking the molecule and the radionuclide".

Answer

- A medicinal product (Product B) to be used to treat a disease for which another product (Product A) has already been authorised may be considered for authorisation if it can be shown that it is not similar to Product A. To this end, Product B should be considered similar to Product A if it contains the same active substance as Product A, or an active moiety of that substance falling into one of the following categories:

1)	Complexes, salts or other non-covalent derivatives of the substance
2)	Esters, amides (including peptides) or other derivatives that can be considered pro-drugs of the substance and not significantly different from the substance in terms of pharmacokinetics
3)	A mixture of isomers that includes the same active isomer found in Product A plus other inactive isomers

All of the above characteristics must be supported by appropriate data.

- The definition of "essential similarity" applied to ethical drugs in the Notice to Applicants of June 1997 is not suitable for identifying "similarity" between orphan medical products. In the opinion of this Committee, the definition of orphan product similarity should be expanded to include biological properties of the compound cited in Article 8, paragr. 5 of the proposed legislation.

- The Committee, therefore, proposes that Article 8, paragraph. 5 of the proposed legislation be modified as follows, or, in any case, that the modifications listed below be considered in the "Guidance on similarity".

"For the purposes of this Article, a given medicinal product can be considered "similar" to another medicinal product if it is:

• the same chemical substance, or a moiety of that substance (including its isomers and mixtures of its isomers, complexes, esters, and non-covalent derivatives) that is comparable to the original chemical substance in terms of its biological activities and properties (including efficacy and safety) and acts via the same mechanism;

• another chemical substance that is comparable to the original chemical substance in terms of its activities and properties (including efficacy and safety) and acts via the same mechanis);

• the same substance or a substance that differs from the original substance in molecular structure, source material and/or manufacturing process or the same organism (living or nonliving), that it is comparable to the original substance or organism in terms of its biological actions and properties (including efficacy and safety)and acts via same mechanism;

• the same radiopharmaceutical substance, or one differing from the original in radionuclide, ligand, site of labelling or molecule-radionuclide coupling mechanism provided that it is comparable to the original radiopharmaceutical substance in terms of its biological activities and properties (including efficacy and safety) and acts via the same mechanism;

• a radiopharmaceutical substance differing in chemical structure from the original but with biological activities and properties (including efficacy and safety) and mechanism of action comparable to the original radiopharmaceutical substance.

Full opinion

Terms of reference The Scientific Committee on Medicinal Products and Medical Devices has been asked to provide guidance on the "similarity" test for use in establishing marketing rights of producers of orphan medicinal products.

Context of the question

Article 8 (Market exclusivity) of the draft Proposal for a Parliament and Council regulation on orphan medicinal products.

Assessment

The European Commission is currently completing a proposal for regulation of orphan medicinal products ( 1-8) by the Parliament and Council. It should include a procedure for designating these products and provide incentives for their research, development and marketing including a guarantee of the exclusive marketing rights of the producer for 10 years. Protective measures of the latter type might theoretically pose a conflict of interests with patients' rights or public health objectives if another producer subsequently shows that its product is clearly superior in terms of efficacy and / or safety.

For this reason, Art. 8, paragraph 5 of the proposed legislation (as transmitted by the lll Direction to the SCMPMD), specifies:

"For the purpose of this Article a "similar medicinal product" means one which consists of:

- the same chemical active substance or active moiety, including isomers and mixture of isomers, complexes, esters, salts or other derivatives of the substance, or

- the same biological active substance, including a different molecular structure, source material or manufacturing process of the substance, or

- the same radiopharmaceutical active substance, including a different radionuclide, ligand or coupling mechanism linking the molecule and the radionuclide".

The DG lll has asked the SCMPDM to provide it with guidelines for establishing the "similarity" of one orphan drug with respect to another in response to requests by drug manufacturers for derogation of the 10-year period of marketing exclusivity as described above.

The concept of "similarity" expressed in Art. 8, paragraph 5 of the proposed regulation appears to be based on the chemical characteristics of the compounds under examination, whereas, in paragraph 3 of this article, the derogation of the exclusive rights described in paragraph 1 seems to be linked to the demonstration of the clinical superiority (mainly in terms of greater safety and / or efficacy) of the second product.

Art.8, paragraph 3.

"...unless the second applicant can establish in theapplication that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior".

In the opinion of this Committee, the definition of "product similarity" should, therefore, be expanded to include the biological properties of the compounds cited in Art. 8 paragraph 5 of (i.e., synthetic and biologically derived compounds and radiopharmaceuticals).

Discussion was thus opened on the "Guidance on similarity", including the definition and analysis of the chemical and biological properties, as well as of efficacy and safety. In fact, the latter parameters were also considered to be fundamental in distinguishing the concept of "similarity" with reference to orphan medicinal products from those of "similarity" and "essential similarity" between ethical drugs, which were defined by the Council and the Commission in the Notice to Applicants (NTA) of July 1997 paragraph 5 ("Abridged applications for a marketing authorisation"), as follows:

5.2 Product, essentially similar to a product authorised for 6 or 10 years

"the same qualitative and quantitative composition in terms of active principles, and the pharmaceutical form is the same; and, where necessary, appropriate bioavailability studies have been carried out; by extension, the concept of essentially similar applies to different oral form (e.g. tablets and capsules) with the same substance for immediate release".

Within the scope of Article 8 of the proposal for a Council Regulation on orphan medicinal products, a "similar medicinal product" is one consisting in:

The same chemical active substance, or an active moiety of the substance including:

• Isomers
• Mixtures of isomers
• Complexes
• Esters
• Salts
• Other derivatives of the substance.

The marketing exclusivity enjoyed by the holder of marketing authorisation for an orphan medicinal product may be challenged if a second applicant develops a new medicinal product containing the same active substance or a chemical derivative of the latter, or an organism of biological origin that can deliver in vivo the moiety responsible for the biological activity of the original product. If the rights of the original marketing authorisation holder are to be protected, an unequivocal definition must be found for the concept "same chemical active substance" that covers the possibility mentioned above.

Certain chemical modifications of a molecular structure do not affect the biological activity attributed to the original molecule, salt formation being the simplest. If the original substance is an acid (e.g., carboxylic, phenolic) or a base (e.g., an amine), the biological activity of its active moiety will be the same if a different metal or acidic ion of the substance is used.

The covalent bond is the strongest (i.e., the most thermodynamically stable) type of link between atoms or groups of atoms in a molecule. If the basic structure of a molecule is associated with a specific biological action, the addition, deletion or modification of a group within this basic structure will not necessarily affect the biological action unless such a change involves a covalent bond, in which case the resulting structure is usually considered to be a new active substance (NAS) (cf. NTA, July 1997, page 60).

Salts and complexes

New active substances can also be produced by modifications involving other weaker types of bonds, namely ionic or co-ordinating bonds, to produce new salts and complexes. When such NASs are delivered to a biological system, the moiety responsible for the biological actions is the same as that of the original substance. Therefore, a new medicinal product (Product B) based on a new salt or complex of the active substance contained in a previously authorised product (Product A) should be considered similar to Product A since this type of chemical bonding does not alter the pharmacokinetics or the pharmacodynamics of the active substance in Product A.

Esters

The formation of esters or amides (peptides) represents a particular type of covalent bonding that can alter the pharmacokinetics of an active substance to various degrees. These substances may be highly unstable under physiological conditions, and they are especially susceptible to the effects of enzymes normally present in the intestinal tract, the circulating blood and the hepatic parenchyma, all or some of which have to be crossed before the drug reaches its site of action. Ester formation does modify the pharmacokinetics of a substance but generally not its pharmacodynamics. Some esters are claimed to offer an advantage in that they represent pro-drugs of the original molecule. For the purposes of the orphan medicinal products legislation, a new medicinal product (Product B) should be considered similar to a previously authorised product (Product A) when Product B contains a pro-drug of the active substance of Product A, representing an ester, amide (peptide) or other chemical function of the original substance. If the appropriately documented advantages of such a pro-drug are reflected in clinical superiority, Product B can be considered for orphan medicinal product status.

Isomers

The various isomers of a given substance usually differ in their pharmacokinetic, pharmacodynamic and pharmacotoxicological characteristics. Different enantiomers, for example, can elicit completely different biological responses. Therefore, for the purposes of orphan medicinal product legislation, a new medicinal product (Product B) cannot be considered similar to previously authorised product (Product A) solely because the two products contain different isomers (Isomers B and A, respectively) of the same active substance. If, however, Isomer A is the only one of the substance's isomers to display pharmacodynamic and pharmacotoxicological activity, then a new medicinal product (Product C) based on a mixture of Isomers A, B, C and D might be considered similar if it can be shown that Isomer A and Isomer mixture A,B,C,D differ from one another only in quantitative terms, i.e. that there exists an equivalent dose for the two.

Biological properties

Biological properties are general characteristics of the drugs that will be considered in the evaluation of possible similarity . Efficacy and safety are related to biological properties.

The biological properties of an active substance may indeed be defined as the effects resulting from the interaction of said chemical (or biologic product) with living systems and processes (9, 10). Equivalent therapeutic outcomes can be obtained with compounds that interact with different target sites and/or possess different mechanisms of action leading to different physiological and biochemical changes. Examples of drugs that produce very similar therapeutic effects by different mechanisms can be found within many drug classes. In these cases, the toxicological profiles of the potentially similar medicinal products assume the utmost importance.

In an ideal in vitro system, "efficacy" is expressed in terms of the effects produced by agonists or partial agonists that act on the same receptor. In therapeutics, the term "efficacy" denotes the magnitude or degree of an effect that can be achieved in the intact human patient (11,12). Therefore, it is certainly related to the drug-target interaction, but it also depends on a number of other factors including pharmacokinetic features.

Opinion

1. Producers seeking authorisation for a medicinal product (Product B) intended for treatment of a disease for which another product (Product A) has already been authorised must demonstrate that Product B is not similar to Product A, or, if it is similar, that it is also clinically superior to Product A. To this end, Product B should be considered similar to Product A if it contains the same active substance or the same organism (living or nonliving) as Product A, or an active moiety of the active substance of Product A, which falls into one of the following categories:

1)	Complexes, salts or other non-covalent derivatives of the substance
2)	Esters, amides (including peptides) or other derivatives that can be considered pro-drugs of the substance and not significantly different from the substance in terms of pharmacokinetics
3)	A mixture of isomers that includes the same active isomer found in Product A plus other inactive isomers

All of the above characteristics must be supported by appropriate data.

2. The definition of "essential similarity" applied to ethical drugs in the Notice to Applicants of July 1997 is not suitable for identifying "similarity" between orphan medical products, which must be expanded to consider biological properties, therapeutic efficacy, safety to which and are related.

The Committee, therefore, proposes that Article 8, paragraph. 5 of the proposed legislation be modified as follows, or, in any case, that the modifications listed below be considered in the "Guidance on similarity".

"For the purposes of this Article, a given medicinal product can be considered "similar" to another medicinal product (Not to be confused with "essentially similar products" as defined by European legislation) if it is:

• the same chemical substance, or a moiety of that substance (including its isomers and mixture of its isomers, complexes, esters, and non-covalent derivatives) that is comparable to the original chemical substance in terms of its biological activities and properties (including efficacy and safety)and acts via the same mechanism;

• another chemical substance that is comparable to the original chemical substance in terms of its biological activities and properties (including efficacy and safety) and acts via the same mechanism;

• the same substance or a substance that differs from the original in molecular structure, source material and/or manufacturing process, or the same organism (living or nonliving) that is comparable to the original substance or organism in terms of its biological actions and properties (including efficacy and safety) and acts via the same mechanism;

• the same radiopharmaceutical substance, or one differing from the original in radionuclide, ligand, site of labelling or molecule-radionuclide coupling mechanism that is comparable to the original radiopharmaceutical substance in terms of its biological activities and properties (including efficacy and safety) and acts via the same mechanism;

• a radiopharmaceutical substance differing in chemical structure from the original but with biological activities and properties (including efficacy and safety) and mechanism of action that are comparable to those of the original radiopharmaceutical substance.

References

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13	OPRR 1993 NIH, PHS, HHS Protecting human research subjects title 45, Code of Federal Regulations part. 46 chapter 3, A Risk benefit analysis 3-1 - 3-2