Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
EMA Gathers Experts to Discuss Pivotal Single-Arm Cancer Clinical Trials
The European Medicines Agency (EMA) is gathering oncology experts to discuss the use of data from single-arm clinical trials to support filings for regulatory approvals of cancer drugs. EMA wants to use the session to gauge whether it needs to provide additional guidance on single-arm clinical trials, which it thinks could become the standard cornerstone of cancer drug filings in the future.
Regulators on both sides of the Atlantic have shown a willingness to approve oncology drugs on the basis of data from single-arm clinical trials. These studies lack a comparator arm and, as such, have no data to show how the experimental drug performed in comparison to an alternative intervention or placebo that was given under the same conditions. The inability to make this straightforward like-for-like comparison has, to date, limited approvals based on single-arm cancer trials to what EMA describes as cases of “dramatic activity in well-defined populations with high unmet medical need.”
This statement raises questions that, in the eyes of EMA, existing regulatory guidance fails to address adequately. Specifically, EMA thinks the terms “dramatic benefit” and “high unmet need” lack clear, widely accepted definitions, creating uncertainty that regulators have, to date, failed to adequately help the industry to navigate. “There is no regulatory guidance on cancer drug development in these situations and how to manage the remaining uncertainties optimally,” EMA wrote in a statement to explain why it is holding a workshop on single-arm clinical trials.
For the workshop, which will take place at the regulator’s headquarters in London at the end of June, EMA has worked with the European Society for Medical Oncology to put together a program that includes speakers from the US Food and Drug Administration (FDA), the Medical Research Council and other organizations. The sessions will touch on the topics raised by EMA in its outline for the event, such as dealing with risk-benefit uncertainty from the perspective of regulators, patients and clinicians.
EMA is keen to gather the thoughts of speakers and attendees at the invite-only event. The feedback could lead to the creation of new regulatory guidance documents if EMA deems current texts to be lacking. EMA wants to put these documents in place to support an anticipated increase in the use of single-arm clinical trials. “[Single-arm trials] augmented with statistical approaches may become the standard basis of evidence of efficacy for new applications,” EMA wrote.
Workshop Notice, Draft Agenda
EMA Plans Guidance to Support Collection of Standardized Data on Antimicrobial use
EMA is planning to introduce revised guidance to support the collection of standardized data on the use of antimicrobials in animals across Europe. The commitment to the updating of guidance follows the completion of a trial program focused on antimicrobial use in pigs, during which EMA encountered issues relating to harmonization that could limit the effectiveness of a full-scale project.
In the trial program, EMA and 10 volunteer member states worked to gather data on antimicrobial use at farms that raise pigs from birth until they are ready for market. The program, the initiation of which followed a request from the European Commission, set out to assess the extent to which the system needed to report and analyze harmonized and standardized data already in place. While the member states in the pilot project only looked at five farms each over a one-year period, they and EMA nonetheless encountered some difficulties.
“Collecting data on the population of pigs on the farm proved to be challenging and highlighted the need for further discussion in order to agree on a harmonized denominator,” EMA wrote. In the test program, EMA allowed two denominators, namely the number of pigs produced and number of pigs present on the farm. Without a standardized, European Union-wide denominator, it will be hard to make comparisons of antimicrobial use across the region, but EMA thinks both of the approaches used in the trial have their weaknesses.
As such, EMA currently feels it needs more experience and “in-depth reflection” before it is able to decide on a harmonized denominator. Some of this work will be carried out by the expert advisory group to the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC), which intends to review the findings of the trial and assess how best to proceed. This review is expected to lead to the publication of a data collection template and protocol designed to move EMA closer to the end goal of the antimicrobial program.
“The ultimate objective is that the data will be collated by ESVAC for subsequent analyses and reporting of trends in use of antimicrobials per species over time, with the aim that the data eventually allow for an integrated analysis with data on use of antimicrobials in humans, and on resistance in animals, humans and food,” EMA wrote in its report.
Manufacturing Failure Sparks Shortage of Sanofi Cancer Drug
EMA has warned a manufacturing failure could lead to a shortage of cancer drug Taxotere. The error, which resulted in Taxotere vials containing a higher concentration of the active ingredient, led to a recall by Sanofi, which in turn could cause disruption to supplies in a handful of European countries.
Given that the over-concentrated Taxotere vials could cause healthcare professionals to administer higher doses of the drug than intended, Sanofi is recalling 15 batches thought to have been affected by the processing failure. EMA has told healthcare professionals who administered vials from the 15 batches to carefully monitor patients who received the potentially over-concentrated products for signs of toxicity. The affected batches include both 1ml and 4ml vials.
EMA expects normal supply to resume on 19 August, but in the meantime, France, Germany, Ireland, Italy and Spain could face shortages of Taxotere. The Sanofi chemotherapy drug, which is used to treat cancers found in the breast, prostate, lung and other tissues, went off patent in 2010, meaning healthcare professionals should have the option to switch to alternative products that use the same active ingredient, namely docetaxel. In 2009, Sanofi reported total sales of Taxotere of €2.2 billion ($2.4 billion). Last year, sales totaled €222 million, just €6 million of which was from Western Europe
EMA Posts Guide to What Information it Publishes and When
EMA has posted a guide to what information it publishes on the medicines it is evaluating and when. The guide is intended to inform people of the steps in the regulatory process at which EMA shares updates.
In the guide, EMA addresses the typical publication process for information related to applications for centralized marketing authorizations. The processes for changes to and withdrawals of centralized marketing authorizations are also covered by the text, as are the handling of assorted other regulatory processes such as orphan designations, pediatric investigation plans and compassionate use cases.
EMA walks through each scenario in the guide. With regard to applications for centralized marketing authorizations, for example, EMA explains that it publishes a list of new medicines that are being evaluated each month. Similarly, positive or negative opinions are typically released on the Friday following Committee for Medicinal Products for Human Use meetings.
The guide, while extensive, is not exhaustive, meaning that some EMA publications take place outside the framework laid out in the text.