Trabectedin

Detailed information

General information about assessment reports

Since 2006, an Environmental Risk Assessment (ERA) for the active pharmaceutical substance shall accompany an application for a marketing authorisation in EU for a medicinal product for human use. Parts of environmental data are available in the public assessment report (PAR/EPAR for centrally approved medicines). Environmental considerations are not included in the benefit-risk assessment for human medicines. If new data emerge after approval that necessitate an update of the environmental risk assessment, a variation application (“type IB C.I.z variation”) must be submitted to the regulatory authority.

The PEC (predicted environmental concentration) values used to calculate risk in the manufacturers' assessment reports are based on the estimated use of the medicinal product to which the assessment report relates, as well as possibly other products from the same company, not all medicinal products containing the same active substance.

Assessment report Yondelis

Assessment report for a variation for Yondelis (trabectedin), London, 28 October 2009, EMEA/640507/2009.

Hazard

Persistence: No data.

Bioaccumulation: The Marketing Authorisation Holder (MAH) has estimated the partition coefficient log K_ow theoretically. Although the value is far from the action limit, this approach is not considered acceptable. The MAH shall determine log K_ow in accordance with current OECD guidelines (OECD 107 or 117, the latter only applicable for compounds with a log K_ow < 4) and submit the study report when available. … The Marketing Authorisation Holder (MAH) commits to submit the experimental value of log P according to the relevant OECD methods. No such data have been found for Yondelis in a search of the EMA website (2025‑11‑18).

Toxicity: No data.

Risk

The MAH has calculated the PEC_sw based on the maximum dose per patient adjusted for treatment duration, but this approach is not acceptable. In the Phase I assessment, PEC_sw should be calculated using the screening model in which the patient population is treated with the product and the maximum daily dose on a given day. Using epidemiological data and the refined Fpen, the PEC_sw is estimated at approximately 0.0003 microg/L for both soft tissue sarcoma and ovarian cancer, which is well below the threshold for a Phase II assessment.

Assessment report Trabectedin Accord

Assessment report for Trabectedin Accord, 27 February 2025, EMA/97108/2025.

"The Applicant submitted a justification that marketing authorization of the proposed product will not lead to any increased environmental risk since it is a generic. The justification was updated with consumption data for trabectedin in Europe. Submitted data show that consumption of the trabectedin increased through last 4 years. The Applicant was asked to perform Phase I environmental risk assessment for trabectedin in accordance with the respective EMA guideline. The Applicant refined Fpen based on published epidemiological data and the treatment regimen for each of the two indications. The total PEC_{surface water} is below the action limit for Phase II assessment. The study report confirms that the log K_ow value of trabectedin is below the action limit for further PBT assessment."

Hazard

Persistence: No data.

Bioaccumulation: Log P_ow = 2.41.

Toxicity: No data.

Risk

PEC_{surface water} = default = 0.013 microg/L and refined (prevalence) 0.00001 microg/L.

Comment on only the phase 1 environmental study

Trabectedin has only undergone a phase I study in accordance with regulatory requirements for environmental risk assessments (Guideline on the environmental risk assessment of medicinal products for human use, EMEA/CHMP/SWP/4447/00 Rev. 1- Corr.) A phase I study includes data on bioaccumulation and an estimation of the environmental concentration of trabectedin(PEC_{Surface water}). If the specified threshold values are not exceeded, the company is not required to conduct a Phase II study, which includes data on toxicity, persistence, and risk assessment based on PEC/PNEC.

Comment on generics

After the implementation of the latest European Medicines Agency (EMA) ERA guideline (1 September 2024), a generic company has the following options for Article 10 procedures under Directive 2001/83/EC:

i) to argue that a full ERA is not required because the pharmaceutical substance belongs to certain substance groups (e.g., so-called natural substances);

ii) to identify an official ERA from a previously accepted product and use it; or

iii) to develop its own ERA according to the latest EMA ERA guideline.

Arguments for not submitting an Environmental Risk Assessment (ERA) based on the claim that total environmental exposure has not increased (via total sales volumes) belong to the previous ERA guideline system (2006–2024) and are no longer applicable. Regarding option ii), it should be noted that if a reference ERA exists, the generic company must demonstrate that its conclusions remain technically relevant (since the latest ERA guideline introduced several new technical requirements absent in the previous ERA guideline) and in terms of exposure (showing that the estimated exposure used in the reference ERA remains reasonable). Regulatory authorities (national and EMA) recommend that generic companies attempt to obtain reference ERA documentation from other companies via a so-called Letter of Access (LoA). However, if this is not possible, it remains feasible to argue that the conclusions of an existing reference ERA are still relevant based on information gathered from public assessment reports (summarized descriptions of environmental risk assessments) and product information (to confirm that dosages, indications, etc., have not changed). It should be noted that in some cases, reference ERAs approved between 2006 and 2024 may need to be modified (e.g., with additional experimental studies). If no previous reference ERA can be identified or used, the generic company must commit to developing its own ERA.

Fass environmental information

Fass environmental information for Yondelis from Immedica Pharma AB (retrieved on 2025-11-18).

Hazard

Persistence: No data.

Bioaccumulation: Log P = 2.5.

Toxicity: No data.

Risk

PEC/PNEC is based on sales data in Sweden in year 2023.

PEC = 0.0000001 microg/L.

Risk of environmental impact of trabectedin cannot be excluded, since no ecotoxicity data are available.