Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
Eli Lilly Threatens to Move API Production out of the EU in Broadside Against REACH
Eli Lilly has warned it may move production of certain active pharmaceutical ingredients (APIs) out of the European Union because of REACH regulations. The production of two of Lilly’s veterinary APIs is tied to the availability of cobalt salts, something it says is becoming a “significant problem” that may ultimately force it to relocate its manufacturing operation.
Lilly made the comments in feedback to a United Kingdom parliamentary inquiry into the effect of EU regulation on the life science industry. While the life science sector has generally argued in favor of the UK remaining in the EU, the feedback from Lilly shows there are sections of the industry that are unhappy with the current situation. For Lilly’s veterinary API plant in Liverpool, the problem is REACH, the EU regulation on the Registration, Evaluation, Authorisation and Restriction of Chemicals that first came into force almost nine years ago.
In its feedback, Lilly said REACH is a “significant burden” on the pharmaceutical industry and makes Europe a less attractive location for the production of drug ingredients. APIs themselves are exempt from REACH, but the regulation does affect processing solvents and other ingredients that are used in their production. To use materials on the REACH authorization list, companies need to apply to the European Chemical Agency (ECHA) for clearance, a process Lilly claims is unpredictable. Lilly also thinks the lengths of the clearances granted by ECHA can be incompatible with industry lead times.
With Lilly viewing REACH as a “substantial regulatory and financial burden” that only applies to API plants in the EU, it thinks the regulation is giving overseas companies an advantage. “[It] is having a significant detrimental impact on the competitiveness of pharmaceutical manufacturing in the UK,” Lilly wrote. For Lilly, the biggest REACH-related issue is the availability of cobalt salts. “There are no substitutes for cobalt. If we were unable to continue using cobalt salts in the production of these veterinary medicines, we would be forced to move that production outside of the EU,” it wrote.
The feedback form submitted by Lilly is one of nearly 30 documents received by the parliamentary committee since it began the consultation in late January. To date, Lilly is the only pharmaceutical company to submit its own feedback, with the views of the rest of the industry being represented in a filing by the UK BioIndustry Association (BIA). BIA is in favor of the UK staying in the EU, in part because of the loss of influence it thinks would result from Brexit, both in terms of the drug industry and its regulator.
“The UK would be in the paradoxical situation of having a world-leading regulator...that is only able to create regulation for 3% of the global market, and whose work would be informed by a European framework that it cannot influence,” BIA wrote. “Overall, from the perspective of the UK life sciences industry sector, it is vital that the UK remains engaged in the EU and takes a leading role in shaping legislative and regulatory policy developments affecting the life sciences ecosystem.”
Lilly Feedback, BIA Comments, More
CHMP Adds Safety Section to Guideline on Clinical Trials of Anticancer Medical Products
The Committee for Medicinal Products for Human Use (CHMP) has proposed adding a safety section to its guidelines on clinical trials of anticancer medical products. Whereas safety takes up one page of the current version of the guidelines, the draft text dedicates six pages to the subject, allowing CHMP to go into more detail about collecting data and using patient-reported outcomes.
Safety in oncology trials is a particularly complex topic, in part because the symptoms of the disease itself and toxicity of backbone therapies can make it difficult to tell whether an adverse event was caused by the experimental treatment. Tolerance for risk also varies significantly across the various cancer indications. Patients with inoperable tumors may be willing to tolerate significant side effects if the treatment is potentially curative. This is unlikely to be the case in cancer indications for which adequate treatments already exist.
CHMP is encouraging drug developers to consider benefit-risk assessments and other factors as they design trials of cancer drugs. “The size of the safety database should be sufficient for benefit-risk assessment in the specific target population studied,” CHMP wrote. Size is one of several aspects of study design CHMP is encouraging companies to assess when designing cancer trials. The committee also mentions the potential for longer overall survival in the experimental arm of a trial to introduce a source of bias into the safety data.
Another layer of complexity is added when the product is being tested in a pediatric population. For such trials, CHMP wants drug developers to gather adverse event data related to the maturation of organs and the long-term growth and development of patients. Recognizing that gathering such data pre-approval can be impossible, CHMP will allow companies to submit nonclinical results to support marketing authorizations. In this scenario, long-term human data would be collected post-approval. CHMP also thinks modeling and simulation data can help in some instances.
The committee has given the industry until 15 September to comment on the draft, which is the fifth revision of a guidance document first introduced in 1996.
EMA Publishes 113 Pages of Comments on Duchenne Muscular Dystrophy Guideline
The European Medicines Agency (EMA) has published the 113 pages of comments it received on its draft guideline on development of treatments for Duchenne and Becker muscular dystrophy. EMA took more than two years to review the comments and formalize a final draft.
CHMP released the draft guideline for a six-month comment period in March 2013, but it took EMA until October 2015 to finalize the text. The release of the feedback gives an indication of the issues EMA was grappling with over that period. EMA received many ages of comments from individuals and patient groups with links to Duchenne muscular dystrophy, a rare genetic disorder that has become a particularly charged field of drug development in recent years.
Faced with criticism from patient representatives that the guideline failed to reflect the severity of the disease, EMA was forced to defend its approach. “The severe and fatal character of the disease is very well known and recognized, as well as the urgent need for the development of possible treatments. This may not be obvious from the text of the guideline due to the formal style in which it is written similar to all other guidelines,” EMA wrote in its response to two pieces of feedback.
The release of the comments comes several months after CHMP adopted a final text, which is set to come into force on 1 July.
The United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) is seeking feedback on a plan to allow over-the-counter sales of an ibuprofen formulation. The formulation, Ibuprofen Seven Plus 200mg/5ml Oral Suspension, is currently only available on prescription, but could be downgraded on the grounds that it unlikely to be a danger to health. MHRA ConsultationMHRA
has published a warning about defective hearing aid batteries. There is a low risk of the batteries exploding during use. MHRA Alert