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Directorate-General for Health and Food Safety
Question
The DG lll has asked the SCMPMD to provide it with guidelines for establishing the notion of "clinical superiority" for the purpose of applying provisions on the designation of orphan medicinal products (OMPs) and market exclusivity for their producers. Art. 3, paragraph 1 of the proposed legislation on OMPs (as transmitted by the DG III to the SCMPMD), specifies:
A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish that the medicinal product is intended for the diagnosis, prevention or treatment of a condition affecting less than five per ten thousand persons in the Community at the time that the application is made and that there exists no satisfactory method of diagnosis, prevention or treatment of considered condition that has been authorised in the Community or, if such method exists, that it can reasonably be expected that the medicinal product will be safer, more effective or otherwise clinically superior.
And Art. 8, paragraph 3:
"By derogation to paragraph 1, and without prejudice to intellectual property law or any other provision of Community law, a marketing authorisation may be granted for the same therapeutic indication to a similar medicinal product if:
a) the holder of the marketing authorisation of the original orphan medicinal product has given his consent of the second applicant, or
b) the holder of the marketing authorisation of the original orphan medicinal products is unable to supply sufficient quantities of the medicinal product or
c) the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior".
Answer
In principle, clinical superiority should be defined on the basis of greater therapeutic 1 efficacy and / or greater safety (less frequent and / or less severe adverse effects and / or a lower risk / benefit ratio, i.e., a broader therapeutic ratio or index), as demonstrated in comparative clinical trials. In the absence of such trials, which are indeed difficult to set up for an orphan indication, clinical superiority may be inferred from certain properties identified in clinical pharmacological studies, such as:
1) More favourable pharmacokinetic properties
2) Features that promote compliance
3) Fewer interactions with food and other drugs
Full opinion
Terms of reference
The Scientific Committee on Medicinal Products and Medical Devices has been asked to provide guidance on the "notion of clinical superiority" for the purpose of applying provisions on the designation of orphan medicinal products (OMP) and market exclusivity for their producers.
Context of the question
Article 3 (Criteria for designation) and Article 8-c (Market exclusivity) of the draft Proposal for a Parliament and Council regulation on OMPs.
Assessment
The European Commission is currently completing a proposal for regulation of OMPs (1-7) 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 10-year period of exclusive marketing rights. However, 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.
According to Art. 3, paragraph 1 of the legislation, a candidate drug may be granted "orphan status" for rare diseases, even when other methods of treatment are available, provided that the candidate drug will be safer, more effective or otherwise clinical superior.
On the other hand, the derogation of the exclusive rights described in art. 8, paragraph 1 is (according to paragraph 3(c) of the same Art. 8) contingent upon the demonstration of the clinical superiority of the second product.
The committee is of the opinion that criteria of clinical superiority include:
- Greater efficacy
- Less frequent and/or less severe adverse effects
- More favourable pharmacokinetic properties
- Compliance-promoting features
- Fewer interactions with food or other drugs
The drug's so-called "contribution to patient care" has been cited by the Food and Drug Administration (1998) as a possible basis for clinical superiority in unusual cases (8). This concept, which refers to those features of a drug that might be expected to facilitate treatment (e.g., intramuscular vs. intravenous administration) or patient care in general (e.g., an oral anticoagulant that does not require frequent monitoring of clotting parameters) is too broad to be considered in an Assessment of clinical superiority.
Whereas the general principles of this opinion are also applicable to medicinal products of biological origin (e.g., vaccines, plasma-derived medicinal products, rDNA biotechnology-derived molecules, other natural therapeutic biological molecules), some of the intrinsic characteristics of the biological molecules belonging to this class of products will require special consideration.
Greater efficacy
Ideally, demonstration of clinical superiority should be based on large-scale randomised clinical comparisons of drugs A e B using well defined clinical endpoints (9-12). However, because OMPs are used for treatment of rare diseases, it is often difficult, if not impossible, to enroll an adequately sized population for a clinical study these drugs (9). Hence it may be necessary to resort to comparative evaluations of single cases with careful analysis of the effects of the drugs in question using objective primary endpoints (qualitative and quantitative) or intermediate endpoints ("surrogate markers", 9, 13).
To demonstrate the efficacy of immunological products aimed at preventing infectious diseases (e.g., monoclonal and polyclonal antisera and vaccines), large study populations are even more important than they are in the assessment of chemical medicinal products. The number of subjects needed to demonstrate differences in efficacy in these cases will depend on regional and local differences in infection epidemiology (e.g., prevalence of the disease, degree of exposure, virulence and cross-reactivity of circulating strains(s), demographic characteristics of the target population (e.g., population density, level of hygiene, social status, race, sex, ...), inherent variability of the qualitative protection (+/- protection) criterion. In many cases, therefore, it may be necessary to use surrogate markers of protection ( e.g., systemic/local, functional/non-functional antibodies, cellular responses), if available. In short, demonstration of clinical superiority based on efficacy will generally be quite complicated for the above products.
Safety and Adverse effects
In any assessment of clinical superiority the role of adverse drug reactions (ADR) must be considered within the context of the ratio of risk to expected or anticipated benefits (14a). There is no doubt that the severity of a given ADR must be weighed in light of the severity of the disease being treated, the course of the disease with treatment weighed against its untreated course, and the incidence of the ADR examined in relation to the improvement produced by the product (15). The elimination of an ingredient or contaminant that has been responsible for relatively frequent and / or important adverse effects may result in a new (though similar) product that does indeed display greater safety than the original OMP.
In particular for immunological products aimed at preventing infectious diseases (e.g., monoclonal and polyclonal antisera and vaccines), the risk/benefit ratio is a delicate balance since these products will be administered to healthy subjects. Local and systemic adverse effects, particularly those that can be considered severe, are generally rare for this class of products. As a result, a very large study population will usually be required to demonstrate clinical superiority in terms of a lower frequency of adverse reactions. The special nature of possible impurities such as proteins, lipids, toxins, or cytokines originating from the production substrate or structural forms deviating from the native molecule will require specific attention. In addition to the conventional concept of safety and adverse effects mentioned above, the notion of microbiological safety has to be applied to biological medicinal products. The biological nature of the product itself, of the production substrate, and of some of the products used during production make biological medicinal products particularly susceptible to extraneous infection. Furthermore, for biological medicinal products consisting of live micro-organisms, transmissibility, the risk of reversion to pathogenicity, possible generation of pathogenic recombinants, and associated environmental safety issues all have to be taken into account in assessing comparative safety.
More favourable pharmacokinetic properties (9, 14b,16a, 17, 18)
A more favourable pharmacokinetic profile may be one of the most important differences between a new candidate for orphan medicinal product status (drug B) and a similar drug that has already received authorisation (drug A). Features which could lead to consider a new product superior include :
The above differences can be achieved by various means, e.g., molecular manipulation, use of special delivery systems or devices.
Whereas the concept of pharmacokinetic profile is fully applicable to therapeutic biological medicinal products and to prophylactic antisera, it is generally not applicable to vaccines. For these products, the kinetics of induction of protective immunity (pharmacodynamics?) are important. In case of a vaccine, bioavailability can be translated as availability to the relevant parts of the immune system which may be linked to the presentation of the antigen as mediated by factors such as the route of administration and the effect of antigen delivery system (adjuvants). Excretion of vaccine antigens (after oral or respiratory administration) must be evaluated both in terms of immunogenicity as in terms of safety (see above).
Compliance-promoting features
Two active substances used for the same disease may differ only in dosage schedules (e.g., once-daily administration vs. two or more administrations/day) or route of administration. Both features may be grounds for clinical superiority, particularly when the drug is used for long-term treatment.
This concept can also generally be applied when comparing biologicals, including vaccines. It is particularly important in the case of products intended for prophylactic use in healthy individuals.
Fewer interactions with food and other drugs (14c, 16b,19-28 )
All other properties being equal, a drug that displays fewer and/or less significant interactions with food and other drugs can be considered safer and more effective ("clinically superior") since such interactions are a major potential source of response variability and adverse reactions.
Generally speaking, this concept can also be applied when comparing biologicals (e.g., oral vaccines, inhibition of live micro-organisms by drugs being used concomitantly).
Opinion
In principle, clinical superiority should be defined on the basis of greater efficacy and/or greater safety (less frequent and / or less severe adverse effects), as demonstrated in comparative clinical trials. In the absence of such trials, which are indeed difficult to set up in these cases due to the rarity of study cases, clinical superiority might be inferred from certain features identified in clinical pharmacology studies, such as:
- More favourable pharmacokinetic properties
- Features that promote compliance
- Fewer interactions with food and drugs
Greater clinical efficacy should ideally be assessed by means of large randomised clinical trials (RCTs), meta-analysis of smaller RCTs, direct comparative clinical trials and other types of trials, and appropriate consideration should be given to any inter-trial discordance among the results. It must be recognised, however, that, while such instruments are indispensable for the evaluation of new pharmaceutical products, it may be difficult or even impossible to apply them to the comparative evaluation of orphan products for the treatment of rare diseases. When randomised clinical trials or direct comparative studies cannot be performed because of the paucity of cases available for treatment, a valid alternative might be the comparative analysis of individual cases published in the literature, in which treatment efficacy has been evaluated in terms of reliable and clinically relevant objective parameters specific for the disease (e.g., selected blood chemistry values in metabolic defects). Historical controls may be used if the disease to be treated is constantly lethal. Surrogate end-points are acceptable if they present plausible correlation with the true end points from a pathophysiological point of view.
The safety of a product must be based on various types of clinical data (RCTs, other types of trials, spontaneous reports of adverse events). It is important to remember that the safety profiles of newer drugs may be less complete than those of older drugs, which have been in use longer.
Factors indicative of clinical superiority are more favourable pharmacokinetic characteristics, features that facilitate compliance, and a relatively low rate of interaction with food and or other drugs.
The drug's contribution to patient care, as a possible basis for affirming its clinical superiority over another, has not been dealt with in the present opinion due to the numerous and ill-defined implications of this concept.
Compared to chemical compounds that are, structurally speaking, better defined, medicinal products of biological origin will require special consideration in the assessment of efficacy, safety and adverse effects, and pharmacokinetic properties.
References
The DG lll has asked the SCMPMD to provide it with guidelines for establishing the notion of "clinical superiority" for the purpose of applying provisions on the designation of orphan medicinal products (OMPs) and market exclusivity for their producers. Art. 3, paragraph 1 of the proposed legislation on OMPs (as transmitted by the DG III to the SCMPMD), specifies:
A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish that the medicinal product is intended for the diagnosis, prevention or treatment of a condition affecting less than five per ten thousand persons in the Community at the time that the application is made and that there exists no satisfactory method of diagnosis, prevention or treatment of considered condition that has been authorised in the Community or, if such method exists, that it can reasonably be expected that the medicinal product will be safer, more effective or otherwise clinically superior.
And Art. 8, paragraph 3:
"By derogation to paragraph 1, and without prejudice to intellectual property law or any other provision of Community law, a marketing authorisation may be granted for the same therapeutic indication to a similar medicinal product if:
a) the holder of the marketing authorisation of the original orphan medicinal product has given his consent of the second applicant, or
b) the holder of the marketing authorisation of the original orphan medicinal products is unable to supply sufficient quantities of the medicinal product or
c) the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior".
Answer
In principle, clinical superiority should be defined on the basis of greater therapeutic 1 efficacy and / or greater safety (less frequent and / or less severe adverse effects and / or a lower risk / benefit ratio, i.e., a broader therapeutic ratio or index), as demonstrated in comparative clinical trials. In the absence of such trials, which are indeed difficult to set up for an orphan indication, clinical superiority may be inferred from certain properties identified in clinical pharmacological studies, such as:
1) More favourable pharmacokinetic properties
2) Features that promote compliance
3) Fewer interactions with food and other drugs
Full opinion
Terms of reference
The Scientific Committee on Medicinal Products and Medical Devices has been asked to provide guidance on the "notion of clinical superiority" for the purpose of applying provisions on the designation of orphan medicinal products (OMP) and market exclusivity for their producers.
Context of the question
Article 3 (Criteria for designation) and Article 8-c (Market exclusivity) of the draft Proposal for a Parliament and Council regulation on OMPs.
Assessment
The European Commission is currently completing a proposal for regulation of OMPs (1-7) 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 10-year period of exclusive marketing rights. However, 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.
According to Art. 3, paragraph 1 of the legislation, a candidate drug may be granted "orphan status" for rare diseases, even when other methods of treatment are available, provided that the candidate drug will be safer, more effective or otherwise clinical superior.
On the other hand, the derogation of the exclusive rights described in art. 8, paragraph 1 is (according to paragraph 3(c) of the same Art. 8) contingent upon the demonstration of the clinical superiority of the second product.
The committee is of the opinion that criteria of clinical superiority include:
- Greater efficacy
- Less frequent and/or less severe adverse effects
- More favourable pharmacokinetic properties
- Compliance-promoting features
- Fewer interactions with food or other drugs
The drug's so-called "contribution to patient care" has been cited by the Food and Drug Administration (1998) as a possible basis for clinical superiority in unusual cases (8). This concept, which refers to those features of a drug that might be expected to facilitate treatment (e.g., intramuscular vs. intravenous administration) or patient care in general (e.g., an oral anticoagulant that does not require frequent monitoring of clotting parameters) is too broad to be considered in an Assessment of clinical superiority.
Whereas the general principles of this opinion are also applicable to medicinal products of biological origin (e.g., vaccines, plasma-derived medicinal products, rDNA biotechnology-derived molecules, other natural therapeutic biological molecules), some of the intrinsic characteristics of the biological molecules belonging to this class of products will require special consideration.
Greater efficacy
Ideally, demonstration of clinical superiority should be based on large-scale randomised clinical comparisons of drugs A e B using well defined clinical endpoints (9-12). However, because OMPs are used for treatment of rare diseases, it is often difficult, if not impossible, to enroll an adequately sized population for a clinical study these drugs (9). Hence it may be necessary to resort to comparative evaluations of single cases with careful analysis of the effects of the drugs in question using objective primary endpoints (qualitative and quantitative) or intermediate endpoints ("surrogate markers", 9, 13).
To demonstrate the efficacy of immunological products aimed at preventing infectious diseases (e.g., monoclonal and polyclonal antisera and vaccines), large study populations are even more important than they are in the assessment of chemical medicinal products. The number of subjects needed to demonstrate differences in efficacy in these cases will depend on regional and local differences in infection epidemiology (e.g., prevalence of the disease, degree of exposure, virulence and cross-reactivity of circulating strains(s), demographic characteristics of the target population (e.g., population density, level of hygiene, social status, race, sex, ...), inherent variability of the qualitative protection (+/- protection) criterion. In many cases, therefore, it may be necessary to use surrogate markers of protection ( e.g., systemic/local, functional/non-functional antibodies, cellular responses), if available. In short, demonstration of clinical superiority based on efficacy will generally be quite complicated for the above products.
Safety and Adverse effects
In any assessment of clinical superiority the role of adverse drug reactions (ADR) must be considered within the context of the ratio of risk to expected or anticipated benefits (14a). There is no doubt that the severity of a given ADR must be weighed in light of the severity of the disease being treated, the course of the disease with treatment weighed against its untreated course, and the incidence of the ADR examined in relation to the improvement produced by the product (15). The elimination of an ingredient or contaminant that has been responsible for relatively frequent and / or important adverse effects may result in a new (though similar) product that does indeed display greater safety than the original OMP.
In particular for immunological products aimed at preventing infectious diseases (e.g., monoclonal and polyclonal antisera and vaccines), the risk/benefit ratio is a delicate balance since these products will be administered to healthy subjects. Local and systemic adverse effects, particularly those that can be considered severe, are generally rare for this class of products. As a result, a very large study population will usually be required to demonstrate clinical superiority in terms of a lower frequency of adverse reactions. The special nature of possible impurities such as proteins, lipids, toxins, or cytokines originating from the production substrate or structural forms deviating from the native molecule will require specific attention. In addition to the conventional concept of safety and adverse effects mentioned above, the notion of microbiological safety has to be applied to biological medicinal products. The biological nature of the product itself, of the production substrate, and of some of the products used during production make biological medicinal products particularly susceptible to extraneous infection. Furthermore, for biological medicinal products consisting of live micro-organisms, transmissibility, the risk of reversion to pathogenicity, possible generation of pathogenic recombinants, and associated environmental safety issues all have to be taken into account in assessing comparative safety.
More favourable pharmacokinetic properties (9, 14b,16a, 17, 18)
A more favourable pharmacokinetic profile may be one of the most important differences between a new candidate for orphan medicinal product status (drug B) and a similar drug that has already received authorisation (drug A). Features which could lead to consider a new product superior include :
The above differences can be achieved by various means, e.g., molecular manipulation, use of special delivery systems or devices.
Whereas the concept of pharmacokinetic profile is fully applicable to therapeutic biological medicinal products and to prophylactic antisera, it is generally not applicable to vaccines. For these products, the kinetics of induction of protective immunity (pharmacodynamics?) are important. In case of a vaccine, bioavailability can be translated as availability to the relevant parts of the immune system which may be linked to the presentation of the antigen as mediated by factors such as the route of administration and the effect of antigen delivery system (adjuvants). Excretion of vaccine antigens (after oral or respiratory administration) must be evaluated both in terms of immunogenicity as in terms of safety (see above).
Compliance-promoting features
Two active substances used for the same disease may differ only in dosage schedules (e.g., once-daily administration vs. two or more administrations/day) or route of administration. Both features may be grounds for clinical superiority, particularly when the drug is used for long-term treatment.
This concept can also generally be applied when comparing biologicals, including vaccines. It is particularly important in the case of products intended for prophylactic use in healthy individuals.
Fewer interactions with food and other drugs (14c, 16b,19-28 )
All other properties being equal, a drug that displays fewer and/or less significant interactions with food and other drugs can be considered safer and more effective ("clinically superior") since such interactions are a major potential source of response variability and adverse reactions.
Generally speaking, this concept can also be applied when comparing biologicals (e.g., oral vaccines, inhibition of live micro-organisms by drugs being used concomitantly).
Opinion
In principle, clinical superiority should be defined on the basis of greater efficacy and/or greater safety (less frequent and / or less severe adverse effects), as demonstrated in comparative clinical trials. In the absence of such trials, which are indeed difficult to set up in these cases due to the rarity of study cases, clinical superiority might be inferred from certain features identified in clinical pharmacology studies, such as:
- More favourable pharmacokinetic properties
- Features that promote compliance
- Fewer interactions with food and drugs
Greater clinical efficacy should ideally be assessed by means of large randomised clinical trials (RCTs), meta-analysis of smaller RCTs, direct comparative clinical trials and other types of trials, and appropriate consideration should be given to any inter-trial discordance among the results. It must be recognised, however, that, while such instruments are indispensable for the evaluation of new pharmaceutical products, it may be difficult or even impossible to apply them to the comparative evaluation of orphan products for the treatment of rare diseases. When randomised clinical trials or direct comparative studies cannot be performed because of the paucity of cases available for treatment, a valid alternative might be the comparative analysis of individual cases published in the literature, in which treatment efficacy has been evaluated in terms of reliable and clinically relevant objective parameters specific for the disease (e.g., selected blood chemistry values in metabolic defects). Historical controls may be used if the disease to be treated is constantly lethal. Surrogate end-points are acceptable if they present plausible correlation with the true end points from a pathophysiological point of view.
The safety of a product must be based on various types of clinical data (RCTs, other types of trials, spontaneous reports of adverse events). It is important to remember that the safety profiles of newer drugs may be less complete than those of older drugs, which have been in use longer.
Factors indicative of clinical superiority are more favourable pharmacokinetic characteristics, features that facilitate compliance, and a relatively low rate of interaction with food and or other drugs.
The drug's contribution to patient care, as a possible basis for affirming its clinical superiority over another, has not been dealt with in the present opinion due to the numerous and ill-defined implications of this concept.
Compared to chemical compounds that are, structurally speaking, better defined, medicinal products of biological origin will require special consideration in the assessment of efficacy, safety and adverse effects, and pharmacokinetic properties.
References
