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Posted 18 February 2016 | By Nick Paul Taylor
Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of Tysabri, the Biogen multiple sclerosis drug associated with increased risk of developing progressive multifocal leukoencephalopathy (PML). To mitigate this danger, PRAC is recommending doctors perform more frequent MRI scans of patients who have certain risk factors associated with the adverse event.
As PRAC sees it, patients who have antibodies against the John Cunningham virus that causes PML, have been treated with Tysabri for more than two years and have used immunosuppressant drugs before starting on Biogen’s medicine are at the highest risk of contracting the brain infection. Data analyzed by PRAC also suggest patients who have a high antibody index, defined as 1.5 and above, and have been taking Tysabri for at least two years are at risk, regardless of their recent history of immunosuppressant use.
When physicians are caring for such a high-risk patient, PRAC wants them to weigh the benefits and risks of prescribing Tysabri. If treatment with the drug continues, patients are to undergo an MRI scan every three to six months. The more intense brain scanning regimen is designed to detect PML while it is still asymptomatic. At these early stages of the disease, PRAC thinks it is possible to limit the brain damage and disability experienced by people with PML. Once PML is detected, treatment with Tysabri must stop immediately.
The PRAC review, which was initiated in May at the request of the European Commission, also covers how to manage long-term users of Tysabri who are otherwise free from risk factors. Once a patient has been taking Tysabri for two years, PRAC is advising they have their antibody index tested every six months. Patients whose results are negative for John Cunningham virus should continue on the six-month antibody testing regimen, while those who generate a positive result may need to be reclassified as high risk.
PRAC made the recommendations, which have now passed to the Committee for Medicinal Products for Human Use (CHMP) for final adoption, at a meeting that also featured other notable rulings. A team looking into SGLT2 inhibitors, a class of diabetes medicines linked to dangerously high levels of blood acids, advised patients and doctors to be vigilant for signs of ketoacidosis. Typically, the condition is associated with high blood glucose levels, but this is not necessarily the case in patients taking SGLT2 inhibitors such as Boehringer Ingelheim and Eli Lilly’s Jardiance.
PRAC Statement, Tysabri Recommendation, SGLT2 Ruling
The European Medicines Agency (EMA) has released draft guidelines about the Summary of Product Characteristics (SmPC) for intravenously administered forms of human anti-D immunoglobulin. EMA has updated the text to bring it in line with the current Quality Review of Documents (QRD) template and add details of risks now associated with the class of products.
Members of EMA’s Blood Products Working Party (BPWP) last revised the document in 2007, seven years after the original version came into force. Since the last revision, EMA has updated its QRD template, necessitating changes to the core SmPC for human anti-D immunoglobulin for intravenous use. The QRD template and accompanying explanatory notes, which BPWP is encouraging people to read alongside its SmPC guidelines, sets out general guidance on the format and text to use. BPWP’s revised guidelines also point readers to the general SmPC guidance, which was updated in 2009.
As well as harmonizing the guidelines with regulatory changes that have occurred since 2007, BPWP has updated the text in response to the advance of best practices and understanding of risks linked to human anti-D immunoglobulin. In terms of best practices, the guideline is designed to provide clearer advice on intravenous administration of products that feature dosage recommendations for intramuscular use. The advice is particularly pertinent for the care of obese patients, a population in which intramuscular injections can be ineffective.
Intravenous-intramuscular dosing considerations are the topic of one of several special warnings BPWP has added to the revised guideline. The working party has also drafted sections on the risk of thromboembolism and importance of monitoring for hemolytic reactions in patients who are taking high doses of anti-D immunoglobulin. Having updated the text with these warnings, BPWP has given the industry until the end of April to provide feedback. Previous versions of the guidelines were finalized after one round of feedback.
Another BPWP document, the guideline on clinical trials of recombinant and human plasma-derived factor VIII products, was adopted by CHMP recently. The final guideline will come into force on May 1.
Draft Guideline, Final Guideline
CHMP has confirmed its acceptance of the use of an ingestible sensor to monitor drug adherence in clinical trials. The committee’s core conclusion, which it reached last year, was unchanged following a period of public consultation.
In finalizing the qualification opinion, CHMP has cleared the way for the technology from Proteus Digital Health to be used in clinical research. The technology, a CE-marked Class IIa medical device, can be coformulated with a drug. Then, when the drug-device combination is taken, it sends a timestamp to a wearable patch that, in turn, passes the data on to a centralized repository.
The process is intended to show adherence to the treatment regimen. In clinical trials, particularly of medicines to treat mental health disorders, poor adherence is known to be a problem and can skew the data. Following the CHMP opinion, companies concerned about such considerations can use the Proteus sensor.
Last year, the sensor became the first digital medicine to be filed for approval with the United States Food and Drug Administration. In that filing, the Proteus’ sensor was formulated with Abilify, a mental illness drug sold by Otsuka.
The United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) has moved to clarify the status of transitional qualified persons (QP) under the Clinical Trials Regulation. Such QPs will need to show they meet requirements stipulated by the incoming law.
Under the Clinical Trials Regulation adopted in 2014, manufacturers and importers of investigational medicines need to have a QP with certain qualifications, the details of which were set out in an older document. Some QPs who trained prior to the released of the older document lack the necessary qualifications, but have been allowed to continue working on the strength of their experience.
Having looked into how such people, classed as transitional QPs, are affected by the Clinical Trials Regulation, MHRA has concluded the original qualification eligibility assessments are still valid. As such, QPs who can back up their qualifications with two years or more experience of working in a licensed manufacturing facility will remain eligible.
MHRA is preparing an application form and reassessment process to enable QPs to show they meet the incoming requirements. With the application form scheduled for release in April, MHRA thinks it can ensure the status of all QPs is resolved well before the Clinical Trials Regulation comes into force in 2018. MHRA does not intend to charge for the application.
Tags: EMA, PRAC, SmPC, Tysabri, MHRA, ingestible sensor
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