Regulatory news - November 2016

EUROPE

European Medicines Agency (EMA)

EMA revises guideline on First-in-Human trials

Together with the European Commission and EU member states, the EMA recently published revisions to the first-in-human clinical guideline (EMEA/CHMP/SWP/28367/07 Rev 1) in an effort to develop the safety of participants at the transition from non-clinical to early clinical development.

These revisions follow a review of the guideline in response to events in France last January involving the death of one individual and five hospitalised during a first-in-human trial with healthy volunteers. Adverse reactions in healthy volunteers are rare with one other severe incident reported since 2005 in approximately 14700 phase I trials in Europe which include 3100 first-in-human studies.

The update is particularly focused on non-clinical aspects, including improved integration of pharmacokinetic & pharmacodynamic data and toxicology testing for the overall risk assessment as well as the role of non clinical data for therapeutic dose, maximal dose, and dose steps and intervals. Clinical guidance related to stopping criteria, dose escalations and handling of adverse events are also addressed.

Click here to view the draft guidance.

New search page for periodic safety update report single assessments (PSUSAs)

A PSUR is a pharmacovigilance report submitted regularly by a marketing-authorisation holder at defined time points following a medicine's authorisation. The EMA assesses the information in the related PSURs to determine whether the balance of benefits and risks has changed and whether any updates should be made to the marketing authorisation.

The outcomes of PSUR assessments for active substances found only in centrally authorised medicinal products are published as part of each medicine's European public assessment report (EPAR). The outcomes of PSUR single assessments (PSUSA) for active substances or combinations of active substances contained in nationally authorised medicines can now be found on a new search page on the EMA website.

Click here to view the new search page.

UNITED KINGDOM

Advanced Therapies Manufacturing Taskforce report published

On the 23rd November 2016, the Advanced Therapies Manufacturing Taskforce (ATMT) published a report with their strategic recommendations for developing the UK as a global hub of advanced medicinal therapy manufacturing. The ATMT was launched early this year by the Medicines Manufacturing Industry Partnership (MMIP) and is working to identify opportunities and actions to anchor advanced therapy manufacturing and the associated supply chain in the UK as well as identifing any gaps in the manufacturing landscape that need to be tackled.

Cell and Gene Therapy Catapult CEO, Keith Thompson, who was attending the Bioprocess event and is a member of the taskforce leading the technology workstream, welcomed the report:

The recommendations from the advanced therapies manufacturing task force could further improve the position of the UK as an anchor for the cell and gene therapy industry. On top of the fantastic potential to tackle many unmet health needs, there’s a huge prize at stake in the form of jobs and investment so I hope that the recommendations now become a reality.

Click here to view the full report.

HPRA

Ireland sets up new Innovation Office for regulatory advice

This month, Ireland’s Health Products Regulatory Authority (HPRA) announced the establishment of it’s Innovation Office, offering advice to developers of novel health products and technologies.

According to a press release published:

The HPRA’s Innovation Office will be a dedicated centre providing individuals, academics, SMEs, pharmaceutical and medical device companies, and other groups with an initial point of contact and access to regulatory information and advice. It will be of interest to those involved in the early development of innovative health products or technologies and queries can be submitted in respect of initial research and design, formulation, testing, clinical studies or manufacture.

The European Medicines Agency (EMA) and the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) are among the organisations taking a similar approach to supporting early innovation across the industry.

USA

FDA

FDA publishes new guidance on the use of non-inferiority trials to establish efficacy

In early November, the FDA finalised its guidance on the use of non-inferiority studies to provide evidence of effectiveness. This supersedes a previous guidance entitled "Antibacterial Drug Products: Use of Noninferiority Trials to Support Approval”. The new guidance provides detail on when non-inferiority studies demonstrating effectiveness of an investigational treatment can provide interpretable results, how to choose the non-inferiority margin and how to test the non-inferiority hypothesis.

Non-inferiority with an active control, is used to demonstrate that a new therapy provides at least the same benefit to patients compared to a treatment already available (as opposed to superiority, against a placebo or no-treatment control). Non-inferiority studies are therefore usually selected for ethical reasons, allowing patients to have access to an alternative treatment that could provide a benefit for the same condition.

The FDA goes on to say:

There may be other reasons to include an active control […] Caregivers, third party payers, and some regulatory authorities have increasingly placed an emphasis on the comparative effectiveness of treatments, leading to more studies that compare two treatments. Such studies can provide information about the clinical basis for comparative effectiveness claims, which may be helpful in assessing cost effectiveness of treatments.

The 56 page guidance document is split into four areas:

• A general discussion of regulatory, study design, scientific and statistical issues associated with the use of non-inferiority studies to establish the effectiveness of a drug or biologic
• Some issues related to these studies, including the statistical approaches used to determine the non-inferiority margin and to test for non-inferiority
• Commonly asked questions about non-inferiority trials
• Four examples of successful and unsuccessful efforts to define non-inferiority margins and test for non-inferiority

Click here to view the guidance.

FDA withdraws proposed rule on public disclosure of information on unapproved gene therapies

In a Federal Register notice from the FDA on the 10th November, the agency announced withdrawing a proposed rule from 2001 that would have required the public disclosure of summaries of safety and effectiveness data, in addition to other information, from pre-market clinical trials of gene therapies and transplanted non-human tissues to humans (xenotransplantation).

The agency said:

FDA has reconsidered our position on this issue and deemed our concerns from 2001 outdated. We will continue to assess whether rulemaking in this area is necessary, and if so, we will proceed with a new proposed rule.

The public disclosure would have included various information relating to the product, clinical protocol, sponsor and other data

Click here to view the notice.

Revised Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products Who Have Received Human-Derived Clotting Factor Concentrates

The FDA no longer considers the receipt of human derived clotting factor concentrates (HDCFCs), or sex with a person who has received clotting factor concentrates, to be a risk factor for HIV, HBV, or HCV.

As such, donors of human cells, tissues, and cellular and tissue-based products should not be considered ineligible (under regulation 21 CFR 1271.45) due to the following conditions, and screening for the conditions below is no longer necessary:

1. Persons with hemophilia or other related clotting disorders who have received HDCFCs at any time;

2. Persons who received clotting factors once to treat an acute bleeding event at any time; or

3. Persons who have had sex at any time with either of the persons described above.

Click here to view the revised guidance.

INTERNATIONAL

ICH

Public consultation on ICH update to pediatric clinical trial guidance

The FDA, EMA and other global agencies have recently announced a public consultation period into a new addendum supplementing the International Council for Harmonisation’s (ICH) guidance on pediatric clinical trials. The initial guidance (ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population) was published in 2000. This addendum expands on issues pertinent to pediatric studies in light of scientific and regulatory advances in the field.

It includes sections on ethical considerations, age classification and pediatric formulations, as well as discussions on multiregional pediatric trials, extrapolation and modelling. Regarding multiregional trials, the addendum lays out a series of questions for developers to consider.

These include:

• Based on the existing knowledge, including developmental physiology, disease pathophysiology, nonclinical data, data in adult or pediatric populations or subgroups, or data from related compounds, what are the knowledge gaps?
• What clinical studies and/or methodological approaches could be considered?
• Are there different formulations/dosage forms that will be needed for specific pediatric subgroups, both to facilitate an optimal dose-finding strategy, and for treatment of pediatric patients in different subgroups?

The addendum goes on to state that "a common scientific approach, not common regional requirements, is at the cornerstone of efficient pediatric drug development and timely delivery of safe and effective medicines for children"

Click here to view addendum (R1) to ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population

Open Consultations

EUROPEAN COMMISSION (EC)

EUROPEAN MEDICINES AGENCY (EMA)

ICH

AUSTRALIA TGA