Regulatory News - September 2019

Survey on the renovation of the ICH Good Clinical Practice Guidelines (ICH E6)

A survey on the renovation of the ICH Good Clinical Practice Guidelines (ICH E6) has been conducted independently by the Clinical Trials Transformation Initiative (CTTI). This survey will help to identify areas of the ICH GCP guidelines that are or are not in need of renovation. Findings will be provided to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) for their consideration. Professionals involved in research should take the survey and complete it on their own (not as a group) by August 30th, by following this link.

Review of cyproterone-containing medicinal products

EMA has started a review of medicines containing cyproterone, which are used for treating a range of conditions, including excessive hair growth, prostate cancer, and acne, as well as in hormone replacement therapy. The review will look into the risk of meningioma, a rare, usually non-malignant tumour of the membranes covering the brain and spinal cord. The risk of meningioma with cyproterone daily doses of  10 mg or more has been known since 2008 and information was included in the prescribing information for these medicines along with a warning that cyproterone should not be used in people who have or have had a meningioma tumour. However, there was no information at the time on the magnitude of the risk and how the risk could change with different doses. A recent study in France has now suggested that the risk of meningioma, although still very low, maybe greater in those taking high doses of cyproterone for a long period. The study also showed that after patients had stopped cyproterone treatment for at least one year, the risk of developing these tumours was much reduced but remained slightly higher than usual.

Due to their location in and around the brain and spinal cord, meningiomas can cause serious problems. The French medicines authority has therefore asked EMA to investigate this risk, taking into account all the latest data. EMA's safety committee (PRAC) will now examine the available evidence and make recommendations as to whether the marketing authorisations for cyproterone-containing medicines should be amended across the EU. PRAC recommends new measures to avoid dosing errors with methotrexate. EMA’s safety committee (PRAC) is recommending new measures to avoid dosing errors that have led to some patients incorrectly taking methotrexate-containing medicines daily instead of weekly. The new measures include restricting who can prescribe these medicines, making warnings on the packaging more prominent and providing educational materials for patients and healthcare professionals. In addition, to help patients follow the once-weekly dosing, methotrexate tablets for weekly use will be provided in blister packs and not in bottles (or tubes).

Review of methotrexate-containing medicinal products

EMA’s safety committee (PRAC) is recommending new measures to avoid dosing errors that have led to some patients incorrectly taking methotrexate-containing medicines daily instead of weekly. The new measures include restricting who can prescribe these medicines, making warnings on the packaging more prominent, and providing educational materials for patients and healthcare professionals. In addition, to help patients follow the once-weekly dosing, methotrexate tablets for weekly use will be provided in blister packs and not in bottles (or tubes). Methotrexate is used for treating both inflammatory diseases and cancers. When used for inflammatory diseases, such as arthritis and psoriasis, it is taken once a week but for some types of cancer, a much higher dosage is needed and the medicine is taken more frequently. Mistakes in prescribing or dispensing methotrexate as well as misunderstandings of the dosing schedule have led to patients taking the medicine daily instead of weekly for inflammatory diseases, with serious consequences, including fatalities. The risk of dosing errors with methotrexate-containing medicines is well known. However, despite several measures already in place, these errors continue to be reported. The PRAC examined the available evidence and recommended additional measures to reduce dosing errors so that benefits of methotrexate-containing medicines continue to outweigh their risks. The measures were agreed after consultation with patients and healthcare professionals. More information about these measures can be found here. The PRAC recommendations will now be sent to the Committee for Medicinal Products for Human Use (CHMP), which will adopt an opinion. Healthcare professionals will be informed in writing of the above changes. Patients who have any concerns about their medicine in the meantime should discuss them with their doctor or pharmacist.

Updated restrictions for Gilenya: multiple sclerosis medicine not to be used in pregnancy

EMA has recommended that the multiple sclerosis medicine Gilenya (fingolimod) must not be used in pregnant women and in women able to have children who are not using effective contraception. If a woman becomes pregnant while using Gilenya, the medicine must be stopped and the pregnancy will have to be closely monitored. This is because the active substance in Gilenya, fingolimod, can harm the unborn baby and may cause birth defects. To minimise this risk, women able to have children must have a pregnancy test before starting treatment with Gilenya to ensure they are not pregnant, and must use effective contraception during treatment and for two months after stopping the medicine.

These recommendations follow a review triggered by reports suggesting that the risk of birth defects in infants who have been exposed to Gilenya during pregnancy is twice as high as the 2 to 3% risk observed in the general population. The most frequently reported birth defects in infants exposed to Gilenya were those affecting the heart, kidneys, bones and, muscles. Doctors, patients, and carers will receive updated educational materials with information about this risk and what actions and precautions need to be taken to ensure the safe use of Gilenya. More information about the updated restrictions can be found here.

These updated recommendations follow a review of available data triggered by post-marketing reports suggesting that infants born to mothers treated with fingolimod during pregnancy have a two-fold increased risk of major congenital malformations compared with the rate observed in the general population (which is 2-3 %, according to EUROCAT - the European network of population-based registries for the epidemiological surveillance of congenital anomalies. The most frequently reported major malformations in infants exposed to fingolimod in utero are congenital heart diseases (such as atrial and ventricular septal defects, tetralogy of Fallot), renal abnormalities and musculoskeletal normalities. Updated educational materials to help counsel patients about the risk of reproductive toxicity will be made available and will include a physician’s checklist, a guide for patients, parents and caregivers and a pregnancy-specific patient reminder card.

Risk Evaluation and Mitigation Strategies: Modifications and Revisions; Guidance for Industry; Availability (Notice availability)

The Food and Drug Administration (FDA or Agency) announced the availability of a final guidance for industry entitled ''Risk Evaluation and Mitigation Strategies: Modifications and Revisions. (IDRAC 296898)'' This guidance provides information on how FDA will define and process submissions for modifications and revisions of risk evaluation and mitigation strategies (REMS), as well as information on what types of changes to approved REMS will be considered modifications or revisions of the REMS. The guidance also provides instructions to application holders related to procedures for submission of REMS modifications and revisions to FDA as well as different timeframes for FDA's review of and action on such changes. The definitions of REMS modifications and revisions apply to all types of REMS. This guidance updates the guidance of the same name (IDRAC 211062), issued April 7, 2015, including finalizing the portion that sets forth the submission procedures for REMS revisions.

Final Guidance for Industry and FDA Staff on Postmarketing Safety Reporting for Combination Products; Availability (Notice of availability)

The Food and Drug Administration (FDA) announced the availability of a final guidance for industry and FDA staff entitled ''Postmarketing Safety Reporting for Combination Products Guidance for Industry and FDA Staff. (IDRAC 297224)'' The guidance describes and explains the final rule on postmarketing safety reporting (PMSR) for combination products, issued on December 20, 2016, and provides recommendations for complying with the PMSR requirements as well as hypothetical scenarios that illustrate how to comply with certain PMSR requirements.