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Draft FDA Guidance on Acceptance of Foreign Medical Device Clinical Data

The US Food and Drug Administration (FDA) issued a draft guidance for industry this month entitled ‘Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States’. The draft guidance expresses the FDA’s policy of accepting scientifically valid clinical data from foreign clinical studies in support of premarket submissions for devices. The guidance describes special considerations that apply when relying on clinical data from foreign studies. These include:

  • Differences in clinical conditions – countries outside of the US may have different standards of care which may affect the analysis of the benefits and risks of the studied device relative to standard practice. Differences in clinical facilities and levels of clinical skill can also affect study data from outside the US to the extent that such data may not be generalised to US clinical practice and the differences could impact the data’s usefulness in supporting the safety and/or effectiveness of the device.
  • Differences in study populations – differences in the race, ethnicity, age and gender of a foreign population can affect the applicability of the study to the intended US population. The foreign studied population and the intended US patient populations may also differ in the prevalence of confounding clinical factors that can affect risks of an intervention as well as clinical response. For example, populations vary widely in the prevalence of smoking, diabetes and obesity, and rare or regionalised co-morbidities occur in certain populations that can confound study results.
  • Differences in regulatory requirements – when studies conducted outside the US are initiated to satisfy the requirements of foreign countries, rather than, or in addition to FDA the studies may not be designed to address the questions necessary to satisfy FDA requirements.

Valid scientific evidence is only one factor in determining whether FDA can use the data to support a decision on premarket submission but does not generally address ethical considerations. In 2013, FDA proposed a rule – ‘Human Subject Protection: Acceptance of Data from Clinical Studies for Medical Devices’ – which requires that clinical studies conducted outside the US in support for premarket submissions be conducted in accordance with good clinical practice. The proposed rule, when finalised, is intended to help ensure the protection of human subjects and the quality and integrity of the data obtained from these studies.


MHRA releases Pharmacovigilance Inspection Metrics Report

The Medicines and Healthcare products Regulatory Agency (MHRA) has released the pharmacovigilance inspection metrics report covering the period from April 2013 to March 2014. During this period the MHRA conducted 56 inspections of Marketing Authorisation Holders (MAH). The largest proportion of these were performed as routine re-inspections, while 12 were triggered due to critical findings from previous inspections or in response to a specific issue, 19 were performed to fulfil the EMEA programme of inspections relating to centrally authorised products, and two were requested by the European Committee for Medicinal Products for Human Use (CHMP). Out of the 56 inspections, 19 critical, 192 major and 172 other findings were identified during this period. The 19 critical findings were from 16 different inspections and can be broken up into the following categories:

  • Maintenance of reference safety information (42%) – failures and significant delays to submit safety variations to update the safety sections of Summary of Product Characteristics (SmPC) and Patient Information Leafletes (PILs).
  • Non-interventional programmes (21%)
  • Signal management (11%)
  • Complete system failure (6%)
  • Individual Case Safety Report (ICSR) Data management (5%)
  • Pharmacovigilance quality management system (5%)
  • EU-QPPV (5%)
  • Periodic Safety Update Report (PSUR) production (5%)

Major findings were identified across 18 categories, with the largest proportion of major findings identified in relation to spontaneous case processing, representing 16% of all major findings. The four most common categories in which major findings were identified were spontaneous case processing, signal management, quality systems and reference safety information, representing 50% of all major findings identified.

The impact of the revised pharmacovigilance legislation was more apparent in this reporting period. In areas where legislation and guidance has been strengthened, an increased number of inspection findings have been reported. Examples include: an increased number of findings across the Quality Management System, incorporating pharmacovigilance auditing, training and procedures, representing a 66% increase in the average number of QMS findings identified; an increased number of inspection findings following the introduction of the Pharmacovigilance Master File; and an increase in the number of findings reported in association with deficiencies in the collection of data from non-interventional studies which has increased due to the changes in the data collection requirements introduced in the revised legislation.


MHRA Grants First Scientific Opinion

The MHRA has issued the first positive Early Access to Medicines Scheme (EAMS) scientific opinion this month following the assessment of quality, safety and efficacy data for a medicine used to treat advanced melanoma (a form of skin cancer). The EAMS is a UK-specific scheme which supports the early access of unlicensed medicines in patients with seriously debilitating or life-threatening conditions where there is an unmet need. The scientific opinion describes the risks and benefits of the medicine and its context for its use, supporting the prescriber and patient to make a decision on whether to use the medicine before its licence is approved.


MHRA Issues Data on its Assessment of Clinical Trial Applications

The MHRA has issued data this month on the time taken to assess clinical trial applications and substantial amendments. The data summarises the number of applications assessed by the MHRA, split by phase and by commercial versus non-commercial sponsors and provides data on the number of applications approved after first review versus grounds for non-acceptance after first review.


MHRA Updates GMP Data Integrity Guidance

In January 2015 the MHRA released a guidance document on Good Manufacturing Practice (GMP) data integrity. An update to this guidance was released this month to include additional clarifications following questions from industry. The guidance sets out expectations for data integrity in GMP and complements existing EU GMP relating to active substance and dosage forms, and should be read in conjunction with national medicines legislation and the GMP standards published in Eudralex volume 4 . Data integrity requirements apply equally to paper and electronic data. The guidance provides definitions of terms such as ‘raw data’, ‘metadata’, data lifecycle’, ‘audit trail’ and the expectations/guidance associated with each. It gives examples of the varying complexity of systems which may generate data and the inherent risks to data integrity posed by these systems. Although this guidance has been released in relation to GMP, it is worthy of note across the different GxPs.