Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
EMA Posts Draft Guideline on Clinical Trials of Acute Coronary Syndrome Treatments
The European Medicines Agency (EMA) has released a draft guideline about the clinical development of treatments for acute coronary syndrome (ACS). EMA drafted the text to update a pair of existing guidance documents, which have been rendered outdated by advances in the diagnosis, treatment and management of ACS.
European regulators last addressed the topic in 2003 through the publication of a guideline about the development of fibrinolytic products to treat ST-segment elevation myocardial infarction. That text was preceded by another on clinical trials of treatments for ACS without persistent ST-segment elevation by three years. In the intervening 13-year period, the European Society of Cardiology (ESC) has introduced clinical practice guidelines that established new definitions and practices related to ACS.
The latest EMA guideline is intended to bring its advice in line with these advances. Several of the notable changes are evident in the title of the document — “Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome” — which reflects the new definitions and their impact on the scope of the text. By using the umbrella term ACS, which was absent from the titles of either of the earlier documents, EMA has been able to combine its advice on ST-segment elevation and non-ST-segment elevation myocardial infarction into a single text.
EMA sees the consolidation of the documents as a response to the evolution of the term ACS, which is today used operationally to refer to a range of clinical symptoms that are reconcilable with acute myocardial infarction. The sections of the guideline that discuss the choice of endpoints and ways to assess efficacy are applicable to all the subcategories of ACS. EMA makes no reference to ST-segment elevation and non-ST-segment elevation in these sections. All-cause mortality and cardiovascular mortality are EMA’s primary endpoints of choice regardless of the target population.
The regulator is proposing to leave it up to sponsors to decide whether their clinical trials will limit enrollment to patients in one of the subcategories of ACS, or make the study open to all people who are covered by the umbrella term. Whatever inclusion criteria the sponsor selects, EMA expects to see a justification of the decision “based on the mechanism of action of the investigated product and the proposed time of intervention.” The exception to this policy is unstable angina, a condition that EMA thinks should be studied separately because of its distinct risk category and prognosis.
In drafting the guideline, EMA’s Cardiovascular Working Party has also addressed the use of scoring systems to stratify patients by risk and clinical trials of medical products designed for people who have moved past the acute phase of the condition. EMA has given people until the end of October to comment on these and other topics discussed in the guideline.
CHMP Proposes Strengthening Warnings on Drugs Containing Fructose and Sorbitol Excipients
The Committee for Human Medicinal Products (CHMP) has proposed strengthening the warnings on the packaging of drugs that use fructose or sorbitol as excipients. Officials think the action is needed to correct the lack of information on the current warning regarding the specific risks the excipients pose to some people when administered intravenously.
EMA included fructose and sorbitol, which is converted into fructose in the body, in a 2003 document listing the excipient-related safety warnings manufacturers must include on labels and leaflets. The warnings were specifically aimed at patients with hereditary fructose intolerance (HFI), a rare genetic disorder. When undiagnosed in children, HFI has been associated with death, a complication that can arise from the inability to break down fructose.
The existing warnings only cover oral dosage forms, which HFI patients are somewhat protected from anyway because of their tendency to vomit anything they ingest that contains fructose or sorbitol. CHMP became aware of the limitations of this warning when reviewing a filing for approval of Grifols’ intravenous immunoglobulin Flebogamma DIF. The treatment, which contains high levels of sorbitol, is designed for intravenous formulation in children.
As this route of administration bypasses the vomit defense and children may be unaware of their HFI status, CHMP thinks it is necessary to add a section to the excipient-related warning labels. The new warning asks healthcare professionals to review parents and infants’ histories of HFI-like symptoms before administering an intravenous formulation containing fructose or sorbitol to a child aged two years or younger.
CHMP has proposed the change as part of a clutch of planned amendments to the warning labels of certain excipients. The committee is also planning to change the labels of drug products that contain aspartame and fragrances that are designated as allergens. Each of the documents is open for comment until 3 August.
Fructose-Sorbitol Draft, Aspartame Draft, Allergens Draft
General Practitioners Create Expert Group to Contribute to EMA Activities
General practitioners have formed an expert group to liaise with EMA. The creation of the 20-person group follows an EMA-organized workshop with general practitioners and family doctors, at which attendees discussed how to involve such healthcare professionals in regulatory decisions.
Having discussed these matters with EMA, 20 of the general practitioners who attended the workshop set up the expert group. The expectation is that members of the group will facilitate cooperation and communication between their peers and EMA, leading to general practitioners having a greater say in regulatory decisions that affect their activities and the patients they serve.
Specifically, EMA foresees the expert group contributing to the scientific advice it provides to drug developers, to understanding of the impact of risk minimization measures on patients and to the review of product information. The expert group is also expected to help spread information of the outcomes of these and other initiatives among their peers and patients.
By working with general practitioners in this way, EMA is hoping to gain a better understanding of the real-world use of medicines and the implications of its actions, an ambition that overlaps with its attempts to incorporate the perspectives of patients into its decisions. This feedback loop is expected to grow stronger as more general practitioners become aware of the option to contribute.
CVMP Broadens Scope of Anthelmintic Resistance Paper Following Industry Feedback
The Committee for Medicinal Products for Veterinary Use (CVMP) has revised and reissued a draft reflection paper on anthelmintic resistance following feedback from industry. Commenters criticized the scope of the original draft, which some felt was too narrow to address the problem.
CVMP accepted many of the criticisms leveled at the first draft by the Federation of Veterinarians of Europe (FVE) and other commenters. The committee has responded by replacing its 2014 draft with a new reflection paper intended to better address the full scope of anthelmintic resistance, which arises when worms and other parasites develop the ability to withstand drugs designed to stun or kill them.
In the revised draft, CVMP has expanded a section on management strategies capable of delaying the development of resistance and added a list of recommendations. CVMP wants veterinarians to report instances when an anthelmintic is less effective than anticipated and only use such medical interventions when an infection has been confirmed using fecal egg counts or other diagnostic tools.
Draft Paper, Comments