European Regulatory Roundup: EMA Overrode Pharma Concerns in Adopting First-in-Human Guideline (28 September 2017)

Welcome to our EU Regulatory Roundup, our weekly overview of the top regulatory news in Europe.

EMA Overrode Big Pharma Concerns in Adopting First-in-Human Trial Guideline

An overview of comments on first-in-human trial guidance has revealed industry concerns with the draft. Merck and trade group EFPIA called out the draft for going beyond the scope of current ICH guidelines and being too prescriptive, only for the European Medicines Agency (EMA) to dismiss their worries.

EMA adopted the guideline earlier this year and it is due to come into force in February. The final version differs in significant ways from the draft, but the release of feedback from the consultation period has now shown the adopted text is unlikely to satisfy everyone. Overarching criticisms of the draft included the accusations that it is too prescriptive and goes beyond the scope of today's ICH — International Conference on Harmonisation — guidelines.

EFPIA thinks these perceived shortcomings will have significant negative effects.

"The guidance is overly prescriptive in the scientific principles required in a regulatory submission, which may lead to the unnecessary use of animals and slow clinical development and, importantly, access of beneficial medications to patients," the trade group wrote in its feedback to EMA.

Merck, a member of EFPIA, made a similar point in its submission but neither comment caused the EMA to change its position. Instead, the agency responded by stating the "revision is intended to further assist stakeholders in the transition from nonclinical to early clinical development and in identifying factors influencing risk for new [investigational medicinal products]."

The currently unanswerable question is whether the prescriptive approach will have the desired effect. EMA revised the text to prevent a situation like the Bial trial, in which one patient died, from happening again. Yet, without raw data from that study, it is impossible to predict whether the new guideline would have prevented that tragedy.

Other industry comments on the draft focused on the relationship between the guidance and ICH documents. EFPIA said the EMA draft deviated "from the existing ICH guidance (especially for the non-clinical part) and add expectations that exceed current ICH guidance." EMA disagreed. The agency said it considered consistency with ICH "in detail" and that its guideline is supposed to be read in conjunction with those of the harmonization organization.

The upshot of these different interpretations is some of the biggest issues the largest organizations have with the draft have gone unaddressed. Similar cases have occurred recently. Last year, EFPIA told EMA its draft guideline on the collection, management and submission of individual case safety report was "unnecessarily specific," only for the agency to adopt a final version that still dictated how companies should handle certain tasks.

Like that time, EMA was more receptive to some of the other comments it received on the clinical trial guideline. Changes made by EMA in response to the feedback include the broadening of the intended audience of the guideline to include investigators, members of ethics committees, Phase I units, CROs and clinical investigators.

Industry Feedback, Adopted Guideline

Delay in Publishing Clinical Data Prompts EMA to Update Advice on Redaction Packages

EMA has revised its position on when companies should file their redaction proposal document packages. The agency is currently processing applications adopted in the third quarter of 2016, and given this delay has dropped the timeline for package submission set out in its guidance.

Under the terms of EMA's policy on the publication of clinical data, sponsors must prepare and file redaction proposals after the Committee for Medicinal Products for Human Use (CHMP) gives its opinion on their dossiers. The document package is the sponsor's clinical report plus proposed redactions of commercial confidential information and personal data.

This timeline is not currently in place. Instead, EMA is sending invitation letters to companies when it wants them to submit their proposals. The agency is advising companies not to send proposals until it has contacted them.

EMA has adopted this alternative way of working because of delays in the publication of clinical data submitted in 2015 and 2016. The agency is processing data submissions in the order in which it received them and is up to applications CHMP ruled on in the third quarter of last year.

Officials attributed the slower-than-anticipated progress to the "extensive pilot phases for first publications" under the policy.

EMA Q&A

Tens of People Speak at First EMA Public Hearing

EMA has held its first public hearing. The event saw tens of patients, healthcare professionals and other people talk about their experiences with valproate to inform the agency's review of its risks and benefits.

Over the course of the roughly five-hour event, representatives of EMA and its Pharmacovigilance Risk Assessment Committee (PRAC) listened to and, to some extent, questioned speakers who had come from six European countries to express their views.

The speakers included representatives of groups such as the Fetal Anti-Convulsant Support Association, the European Academy of Neurology and Sanofi.

EMA now has strong evidence there is public interest in contributing to reviews of the safety and benefits of medicines. More immediately, PRAC has another batch of information to consider as it assesses whether further risk minimization measures are needed to mitigate the danger of valproate causing harm to babies who are exposed to the drug in the womb.

Hearing Video

NICE Proposes Clamping Down on use of Antibiotics to Treat Infections in Children

The United Kingdom is planning to curb the use of antibiotics in the treatment of certain childhood infections through new guidelines. If both guidelines come into force, doctors will stop prescribing antibiotics to treat some cases of otitis media, and only do so after performing tests on suspected urinary tract infection (UTI) patients.

Work on the UTI guideline is more advanced. The National Institute for Health and Care Excellence (NICE) adopted the updated version this week, marking the start of a new, more stringent era of antibiotic use. NICE is recommending doctors perform a dipstick urine test when a patient aged between three months and three years presents with a suspected UTI.

If the test is negative for both leukocyte esterase and nitrite, NICE recommends against starting the patient on antibiotics or sending a urine sample for microscopy and culture. The opposite is true if the test is positive for one or both of leukocyte esterase and nitrite.

NICE made the change after concluding dipstick tests are a reliable proxy for urine culture results.

"Evidence showed that a positive urine dipstick test for leukocyte esterase or nitrite in children 3 months or older but younger than 3 years greatly increases the likelihood of finding a positive urine culture. Sending only positive samples for culture offered a better balance of benefits and costs for these children than prescribing antibiotics and urine culture for all children," NICE wrote in its explanation for the change.

The second proposal is at the draft stage. If adopted in its current form, the proposal will limit the use of antibiotics in patients with otitis media, an ear infection that mainly affects children. The condition can be caused by either viruses or bacteria, or both, and in many cases clears up without the use of antibiotics. As such, NICE's draft recommends doctors only offer paracetamol or ibuprofen for pain, unless the patient has certain symptoms that justify the use of antibiotics.

Otitis Media Draft, UTI Guideline