EU Regulatory Roundup: Rising Complexity Drives Sharp Fall in MHRA Pharmacovigilance Inspections

Regulatory NewsRegulatory News | 06 December 2018 |  By 

Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
EMA Advises Novartis on use of eSource Direct Data Capture in Clinical Trials
The European Medicines Agency (EMA) has outlined its views on eSource direct capture of clinical trial data in response to questions from Novartis. EMA sees no theoretical obstacles to the use of the technology in a way that complies with good clinical practices (GCPs), but thinks sponsors must look closely at the disadvantages before moving to eSource data capture.
Today, study site staff typically record clinical data on paper or in electronic medical records. The data are then transcribed into electronic case report forms (eCRF) for later analysis by the sponsor. In contrast, eSource direct data capture (DDC) enables site staff to capture data at the point of care in a format this is validated for use in clinical trials. As such, eSource DDC stands to eliminate data transcription and the errors and delays it can cause.
Novartis is among the companies interested in the potential of the technology but, having piloted the approach in several clinical trials, it has found that opinions on its acceptability vary globally. In light of that finding, Novartis wrote to EMA to get its take on the potential for eSource DDC to improve data quality and what sponsors should consider before adopting the technology.
EMA agreed that direct transcription into an eCRF “seems likely to improve data quality” and stated the technology can be made compliant with GCPs. However, EMA also highlighted that the benefits to sponsors must not come at the expense of physicians. That means physicians must continue to be able to record clinical information in patient medical records without any constraints. In the long term, EMA wants to see systems that automatically pull data into eCRFs from medical records.
Whatever the system, sponsors will need to comply with certain existing rules. That means eSource DDC must meet International Conference on Harmonisation source data requirements and national rules, and that sponsors are responsible for ensuring the system works as intended.
While EMA’s responses show there are some barriers to widespread use of eSource DDC, Novartis’ experience suggests sponsors that overcome them will be rewarded. Novartis’ pilot projects linked eSource DDC to a 45% reduction in manual queries compared to conventional electronic data capture trials. Other benefits include an estimated 38% decline in source data verification monitoring time and data becoming available for cleaning 14 days sooner.
EMA’s draft opinion is open for comment until 14 March.
Draft Opinion
Rising Complexity Drives Sharp Fall in MHRA Pharmacovigilance Inspections
The number of pharmacovigilance inspections conducted by regulators in the United Kingdom fell again last year. The sharp drop means the number of inspections has fallen by around 60% over the past five years.
In the 2013 to 2014 fiscal year, the Medicines and Healthcare products Regulatory Agency (MHRA) performed 56 pharmacovigilance inspections of marketing authorization holders (MAHs). The figure trended downward over the following years, falling to 36 in the 2016-2017 reporting period. MHRA published the figures in annual reports that made no attempt to explain or justify the decline.
That changed with the publication of the 2017-2018 report, which showed MHRA performed just 22 pharmacovigilance inspections last year. MHRA attributed the decline to the “increasing complexity of the higher risk pharmacovigilance systems” it inspects.
Specifically, MHRA argued that complexity has increased as a result of products “that have unique and detailed requirements,” such as risk minimization measures. The other drivers of complexity relate to the organizations MHRA inspects. MHRA noted that large organizations and those that have undergone mergers or bought many drug licenses take longer to assess, without explaining why there were more MAHs with these characteristics on last year’s list of inspection targets.
MHRA did cite data to support its claim that inspections are getting more complex, though. The data, which were absent from previous annual reports, show how many days MHRA staff spent on each inspection, on average. Last year, the median inspection took 12 days, more than double the average duration in the 2016-2017 reporting period.
In MHRA’s explanation, rising complexity caused inspection durations to increase, which in turn led the agency to conduct fewer assessments. The sequence of events also appears to have affected the number of observations made by inspectors. While the number of critical observations only declined slightly year on year, the number of major findings fell by more than 40%.
A subset of the major observations made last year affected MHRA’s ability to complete inspections. Fourteen of the 89 major findings from last year related to the provision of complete and accurate information. Most of these cases stemmed from deficiencies with the pharmacovigilance system master file (PSMF), such as missing or inaccurate information. As PSMFs contribute “to the planning and conduct of inspections,” MHRA argues the deficiencies impede its activities.
MHRA Report
UK Research Institute Calls for Regulatory Changes to Increase Pediatric Cancer Trials
The Institute of Cancer Research (ICR) has published a report criticizing the European regulatory “loophole” that makes it “too easy” for companies to avoid testing their cancer drugs in children. ICR wants regulators to update the rules to force companies to run more pediatric oncology trials.
European regulations require all marketing authorization applications to include data from studies set out in a pediatric investigation plan, unless a deferral or waiver means the drug is exempt from the rule. Deferrals are permitted when a sponsor needs more time to show the safety and efficacy of a drug in adults. Waivers apply to drugs that are not needed by children.
As ICR sees it, the regulations are enabling sponsors to skip pediatric trials of their candidates “even
where there is evidence that a drug could benefit [children].” To improve the situation, ICR wants to see stronger incentives for pediatric drug development and updated regulations.
The proposals, which are part of a broader report into access to cancer drugs, come at a time when the success, or otherwise, of the 2006 pediatric regulation is in the spotlight. In 2016, the European Commission published a report on the effect of the regulation and followed up late last year with the initiation of a two-year investigation into the development of drugs to treat rare diseases in children.
ICR Report
EMA Draft Guidance Opens Door to new Sources of Water of Injectable Quality
EMA has published a draft guideline on the quality of water for pharmaceutical use. The document is part of EMA’s efforts to align its guidance with the European Pharmacopoeia’s revised, more liberal position on the methods companies can use to produce water of injectable quality.
Prior to 2017, distillation was the only method of pharmaceutical water production permitted under European rules. That changed with the adoption of a monograph that allowed the use of reverse osmosis and other non-distillation techniques. EMA published a concept paper in response to the monograph and has now followed up with a draft guideline.
Under the guidelines set out in the draft, manufacturers can produce water for injections using the processes detailed in the revised monograph. The only caveat EMA adds is that companies should inform their good manufacturing practice supervisory authority when they plan to introduce reverse osmosis at a production plant.  
The guideline is open for feedback until 15 May.
Draft Guidance


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