Biopharma Consulting

ERA

EU Environmental Risk Assessment (non-GMO products)

Guidance

Main guideline: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500003978.pdf

Q&A: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/06/WC500207858.pdf

Concept paper for revision of main guideline: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/05/WC500205987.pdf

 

Simplified Scheme for ERA of New Chemical Entities

Generic Products or New Products Containing Existing Drug Substances

The main guidance on generics is contained in the Q&A document:

Please note that according to Directive 2001/83/EC, applicants are required to submit an ERA also for applications under Art 10-generic medicinal products, Art 10(3)-hybrid, Art 10a-well established use/bibliographical, Art 10b fixed combinations, Art 10c informed consent and Art 10(4) similar bio-logical applications.

However, the ERA dossier may consist of an adequate justification for the absence of specific study data. The justification of the absence of significant increase of the environmental exposure, demonstrated by suitable information, can be accepted as a justification for the absence of a complete ERA. In certain cases, consumption data of the active ingredient in kg/year over time, preferably for at least the last 4 years in several involved Member States, might be helpful in this respect. In case of a generic application, however, the applicant can also provide other convincing arguments that the introduction of their product to the market will not lead to an increase of an environmental exposure.

On the basis of the above, generics are not exempted from providing an ERA and cross reference to the ERA dossier of the originator is not possible without consent from the originator. Even though a generic does not generally lead to an increase of the treated population, there could be situations that could lead to an increase of the environmental exposure. An example of such a situation could be the introduction of a new generic medicinal product in a member state where the reference product is not marketed.

ERAs for generics are assessed by the competent authority in individual member states (or by the rapporteur/co-rapporteur) for centralised applications. Some Member States appear to have a default position that a generic product will merely substitute for existing originator/generic products intended for the same or closely similar indication and containing the same drug substance. For example:

http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con355527.pdf.

Conversely, other Member States regularly refuse to accept the generic substitution concept and ask for consumption data over 4 years in the principal Member States involved in the particular application procedure (normally a Decentralised Application Procedure, DCP). A typical deficiency question is shown in Figure 1 below.

The validity of an evaluation based on marketing data over the last four years in appropriate concerned Member States can be challenged based on the following reasons:

 
  1. No validation information has been provided by EMA to demonstrate that consumption/marketing data are correlated with environmental impact, measured for example by the concentration of the API in the aquatic compartment;
  2. No data interpretation criteria are pre-specified – a critical requirement in any scientific evaluation;

3.       Data are requested for individual member states while the ERA guidance assumes even distribution through the geographical area and since several of the concerned member states are contiguous or in close proximity, it is considered more logical to evaluate the total overall consumption, assuming that points 1 and 2 can be addressed.

4. If the drug substance under consideration is significantly metabolised before excretion and/or is readily biodegradable in the aquatic environment, determining inputs via marketing data in considered to be a largely futile exercise.

 

Figure 1: Typical Deficiency Question on Generic Product

According to Article 8 (3) of Directive 2001/83/EC for generic and hybrid medicinal products (as defined by Article 10(2)b) and Article 10(3) of Directive 2001/83/EC, respectively) an environmental risk assessment is basically required; an exemption in accordance with Article 10(1) is not applicable.

However, the environmental risk assessment might be waived if it can be shown that an increase in environmental exposure of the active substance is not to be expected. The respective justification should be based on suitable information, e. g. data on consumption in kg/year for at least the last 4 years for the 4 concerned member states with the highest prevalence. If acceptable data cannot be provided, the applicant is asked to submit an environmental risk assessment according to the EMA guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2*, June 2006).

Rationale

The justification provided by the applicant is considered not acceptable as no reliable data were submitted to show that an increase in the environmental concentration of the active substances is not to be expected. (Point for clarification)

The respective prerequisite is a constant or decreasing consumption of the active substance in the last 4 years in several concerned member states. If an increase of consumption is observed in one or more members states, an ERA is required since more products on the market will lead to increasing consumption.

 

EMA Response to FoI Request (ASK-24077) on ERAs for Generics (December 2016)

Original request: Environmental Risk Assessment of generic medicinal products The recently confirmed Q&A document on ERA contains the following statements on generic medicinal products: Please note that according to Directive 2001/83/EC, applicants are required to submit an ERA also for applications under Art 10-generic medicinal products, Art 10(3)-hybrid, Art 10a-well established use/bibliographical, Art 10b fixed combinations, Art 10c informed consent and Art 10(4) similar bio-logical applications. However, the ERA dossier may consist of an adequate justification for the absence of specific study data. The justification of the absence of significant increase of the environmental exposure, demonstrated by suitable information, can be accepted as a justification for the absence of a complete ERA. In certain cases, consumption data of the active ingredient in kg/year over time, preferably for at least the last 4 years in several involved Member States, might be helpful in this respect. In case of a generic application, however, the applicant can also provide other convincing arguments that the introduction of their product to the market will not lead to an increase of an environmental exposure. On the basis of the above, generics are not exempted from providing an ERA and cross reference to the ERA dossier of the originator is not possible without consent from the originator. Even though a generic does not generally lead to an increase of the treated population, there could be situations that could lead to an increase of the environmental exposure. An example of such a situation could be the introduction of a new generic medicinal product in a member state where the reference product is not marketed. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/06/WC500207858.pdf I have three questions for EMA 1. Has this guidance been validated to demonstrate that consumption/marketing data for a wide range of generic products are correlated with environmental impact, measured for example by the concentration of the API in the aquatic compartment? 2. If the drug substance under consideration is significantly metabolised before excretion and/or is readily biodegradable in the sewage treatment works or aquatic environment, surely determining inputs via marketing data as a surrogate for environmental impact will be highly misleading? 3. Can EMA provide examples (as many as possible) of where the kind of marketing information requested has accurately predicted an increase in environmental exposure?

EMA Response:

Thank you for your question on the use of consumption data in the environmental risk assessment of generic medicines. The responses to questions 1 and 3 are addressed under response 1. 1 The EMA does not hold data on or track the correlation of environmental impact with consumption/marketing data for generic products. The impact of the introduction of a new generic on environmental levels may differ depending on whether it is the first generic introduction or if the market for the product is already well genericised. The guidance therefore speaks in general terms and allows applicants to put forward their reasoning on the impact of the product on environmental exposure. 2. Although, the EMEA guidance follows a ‘total residue approach’, in which environmental fate and toxicity of metabolites and degradation products are assumed to be covered by that of the parent compound in Phase II, there is an option for further refinement of the ERA based on risk quotients for separate metabolite fractions when, based on the total residue approach, a risk is still identified. The release of pharmaceuticals that are degradable in the environment does not always eliminate environmental residues as levels being detected represent the equilibrium between a constant input from wastewater treatment plants and the environmental degradation rate. The biodegradation of the drug substance can be used in the refinement of the risk assessment in Phase II. The guidance mainly relates to the use of medicinal products, however, Directive 2001/83/EC, as amended, is also concerned about those risks to the environment arising from the storage and disposal of medicinal products. It is possible that some active substances which are excreted mainly as metabolites could be released into the environment (including groundwater via landfill) unchanged due to improper disposal of unused or expired product and this needs to be taken into consideration in the risk assessment. The use of consumption data with regards to its use in the tiered approach strategy currently under review for the revision of guideline as outlined in the concept paper (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/05/WC500205987.pdf). It is anticipated that the draft revised guideline will be available 18 months after CHMP adoption of the concept paper.

Conclusions on ERAs for Generics

  • ·    Use the generic substitution argument citing appropriate precedents (from Public Assessment Reports) preferably applying to the same drug substance;

    ·    Search for published environmental toxicity and fate data;

    ·    Consult the Swedish Environmental Classification of Pharmaceuticals: http://www.janusinfo.se/Global/Miljo_och_lakemedel/Miljobroschyr_2014_engelsk_webb.pdf

    ·    In general avoid submission of marketing data since the technique is unvalidated, no evaluation criteria are available and the whole concept is under review.