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7th March 2024
Many oncology drugs approved by the European Medicines Agency (EMA) between 2005 and 2020 provide ‘little or no added benefit’ for patients, according to new research.
This was particularly true for medications that had ‘fast-tracked’ approval pathways, the Dutch researchers said.
Many drugs with higher benefit ratings were associated with more significant revenues for the associated pharmaceutical companies, they added.
The study, published in the BMJ, highlights the need for better alignment between regulatory and reimbursement processes, enabling the most effective drugs to be developed and utilised.
The added benefit of a medication refers to its therapeutic value compared with other treatments, and it can aid decisions about treatment priorities and inform drug-related decisions.
Oncology drugs are increasingly being approved on less robust evidence, and as global spending on these drugs is projected to rise from $167bn in 2020 to $269bn in 2025, and concerns have been raised about the misalignment of incentives in the pharmaceutical market with patient interests.
This retrospective cohort study aimed to evaluate the added benefits and revenues of oncology drugs, explore their association and investigate potential discrepancies between added benefits and revenues across different approval pathways of the EMA.
The researchers collected ratings from evaluation reports from several organisations, including HTA agencies from Europe and the United States, medical oncology societies and a drug bulletin.
To assess growth revenues, they collected information on the financial performance of pharmaceutical companies and compared the revenue figures with previously reported estimates of research and development (R&D) expenses.
The revenue figures were correlated with the added benefit ratings to analyse the performance of the pharmaceutical company against the benefits of the medications they provide.
Of the 458 added benefit ratings identified, nearly two-thirds of the medications have limited or no added benefits. Some 41% of the drugs had a negative or non-quantifiable added benefit, and 23% had a minor added benefit. The remaining drugs had a major (13%) and a substantial added benefit (23%).
Compared with drugs approved under the standard pathway (SMAs), drugs which were approved under conditional marketing authorisation (CMA) and authorisation under exceptional circumstances (AEC) were more likely to have a negative or non-quantifiable added benefit rating, at 57% and 47% respectively compared to the SMA rate of 36%.
Revenues generated from the oncology drugs were generally found to outpace minimum R&D costs quickly, with median cumulative revenues exceeding minimum R&D costs of $166m within two years, the median R&D costs of $684m within three years, and the maximum R&D costs of $2,060m within just over five years after market entry. By eight years of market entry, 91% of drugs surpassed the median R&D costs.
The researchers found a correlation between the level of added benefit a drug had and the associated revenues. Cumulative revenues three years after market entry generally increased with the level of added benefit. For medications with major and substantial added benefit, cumulative revenues three years after market entry were $502m and $506m higher respectively than drugs without benefit.
The researchers stated that the findings underscore ‘the need for better alignment between regulatory and reimbursement processes, particularly for drugs approved through expedited pathways’.
They concluded: ‘It is crucial for policy makers to assess whether the current regulatory and reimbursement incentives are properly structured to promote and facilitate the development of the most effective drugs for patients with the greatest needs.
‘These findings could inform policy initiatives in the field of drug regulation and reimbursement, contributing to equitable and sustainable patient access to innovative treatments.’
In 2020, researchers found that while increasing numbers of oncology drugs are being approved my medicines regulators, cancer patients wait longer for innovative new cancer drugs than for more conventional treatments.
17th January 2024
The UK and European medicines regulators are considering new evidence suggesting that children whose fathers took valproate during the three months before conception are at increased risk of neurodevelopmental disorders such as autism.
A new study, commissioned by the European Medicines Agency (EMA), found that around five in 100 children born to fathers treated taking valproate around conception were diagnosed with a disorder, compared with three in 100 children with fathers who took other antiseizure drugs.
The Medicines and Healthcare products Regulatory Agency (MHRA) has confirmed that these results will be ‘rigorously analysed’, but in the meantime urged caution for male patients who want to have children.
‘As a precaution, male patients on valproate who are planning a family in the next year should talk to their healthcare professional about their treatment,’ the MHRA said.
PRAC, the EMA’s safety committee, is also recommending precautionary measures, including that valproate treatment in male patients is started and supervised by a specialist in the management of epilepsy, bipolar disorder or migraine.
’Doctors should inform male patients who are taking valproate about the possible risk and discuss the need to consider effective contraception, for both the patient and their female partner,’ the PRAC said.
It also advised the regular review of valproate treatment in male patients to consider whether it remains the most suitable treatment, particularly when the patient is planning to conceive a child.
’The potential risk of neurodevelopmental disorders and the precautionary measures will be reflected in updates to the product information and educational material for valproate medicines,’ the PRAC concluded, adding that ’a direct healthcare professional communication will be sent in due course to healthcare professionals prescribing, dispensing or administering the medicine’.
Previous recommendations to avoid exposure to valproate medicines in women during pregnancy due to the risk of congenital malformations and neurodevelopmental disorders remain in place.
The PRAC reviewed data from a retrospective observational study carried out by companies that market valproate as an obligation following a previous review of valproate use during pregnancy.
The study used data from multiple registry databases in Denmark, Norway and Sweden and focused on birth outcomes in children born to men who were taking valproate or taking lamotrigine or levetiracetam around the time of conception.
A meta-analysis of data resulted in a pooled adjusted hazard ratio (HR) of 1.50 (95% CI: 1.09-2.07) for neurodevelopmental disorders in children of fathers treated with valproate in the three months prior to conception compared with lamotrigine or levetiracetam.
The adjusted cumulative risk of neurodevelopmental disorders was estimated to be around 5% in the valproate group versus around 3% in the lamotrigine and levetiracetam group. No difference in the risk of congenital malformations was seen between the two groups.
The study did not evaluate the risk of neurodevelopmental disorders in children born to fathers who stopped using valproate more than three months before conception.
The study data on male patients had limitations, including differences between the groups in the conditions for which the medicines were used and in follow-up times.
The PRAC could therefore not establish whether the increased occurrence of these disorders suggested by the study was due to valproate use.
In addition, the study was not large enough to identify which types of neurodevelopmental disorders children could be at increased risk of developing.
Nonetheless, the PRAC considered precautionary measures were warranted to inform patients and healthcare professionals of the potential risks.
In December, the MHRA urged healthcare organisations to prepare for new tightened rules on prescribing valproate which are due to come in later this month.
Under these rules, the epilepsy drug must not be started in new patients – male or female – under the age of 55 unless two specialists have agreed and documented that there are no other effective or tolerated treatments.
In August, when the study on paternal risk was first submitted, the brand leader for valproate informed the MHRA of errors in the study which forced the researchers to conduct a full re-analysis.
After re-submission, the MHRA confirmed it will review the results as part of its ‘ongoing monitoring of the safety of valproate’.
But this will not have ‘implications’ for the new strengthened safety rules coming in this month, according to the MHRA.
Any further guidance resulting from the study’s findings, based on the MHRA’s review and independent advice from the Commission on Human Medicines, will be communicated to healthcare professionals ‘as soon as possible’.
In June last year, NHS England launched a new tool to help with decisions on whether sodium valproate should be prescribed for epilepsy or bipolar disorder by weighing up the benefits and potential harms.
31st August 2023
Mitazalimab has received orphan drug designation status by the European Medicines Agency (EMA) for the treatment of patients with pancreatic cancer, its manufacturer Alligator Bioscience has announced.
A human CD40 agonistic antibody targeting CD40, mitazalimab kickstarts the cancer-immunity cycle by priming and activating tumour-specific T cells. Targeting CD40 with mitazalimab has the potential to augment responses to chemotherapy.
Pancreatic ductal adenocarcinoma (PDAC) is known to be the fourth-leading cause of cancer related mortality in the world and has a poor prognosis, with a five-year survival rate of below 5%.
To qualify for the EMA’s orphan designation, a medicine must be intended for the treatment, prevention or diagnosis of rare, life-threatening or chronically debilitating diseases that affect fewer than five in 10,000 persons in the EU. Medicines that meet these criteria are eligible for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval.
The EMA orphan drug designation follows a similar approval by the FDA in May 2023.
Commenting on the EMA approval for orphan drug designation status, Søren Bregenholt, CEO of Alligator Bioscience, said: ‘We are very pleased that the European Medicines Agency has granted orphan designation to our lead asset mitazalimab in the treatment of pancreatic cancer.
‘It is our second orphan designation this year following the FDA‘s decision to grant us [orphan drug designation] in May, meaning mitazalimab now has stronger commercial protection through market exclusivity in these two key markets. This latest designation adds to the momentum we are building in our efforts to bring this promising drug candidate to market.‘
Mitazalimab is currently being evaluated in the phase 1b/2 OPTIMIZE-1 trial in combination with mFOLFIRINOX chemotherapy for adult patients with previously untreated metastatic PDAC.
In the trial, participants receive mitazalimab and mFOLFIRINOX via intravenous infusions following a 14-day cycle schedule. Mitazalimab is administered two days after mFOLFIRINOX, except for the first cycle of 21 days, where the drug is administered on days one and 10 with infusion of mFOLFIRINOX starting on day eight.
Interim results from OPTIMIZE-1 released in June 2023, showed a deepening of tumour response and an increase in the objective response rate (ORR) from 52% to 57% in a cohort of 23 patients.
In the full study cohort of 57 patients, there was an interim ORR of 44%, and this is expected to further improve with longer follow-up. A median duration of response of 8.7 months was also reported.
27th February 2023
The Medicines and Healthcare Products Regulatory Agency said it had initiated a review after regulators in France alerted the European Medicines Agency (EMA) about a small number of cases.
EMA officials first announced they were looking into the issue on 10 February 2023 following concerns about posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) related to use of the decongestant medicines.
Both conditions can lead to reduced blood supply to the brain and may cause major and life-threatening complications, including seizures, the EMA said.
There had been a small number of reported cases of PRES and RCVS associated with pseudoephedrine-containing medicines and a committee would look at the evidence to decide whether the marketing authorisation in the EU should be maintained, varied, suspended or withdrawn.
The MHRA stressed that the side effects that had been reported with use of the medicines were extremely rare.
The products, which include Sudafed, Actifed and Neurofen Cold and Flu, already include warnings about the rare side effects as well as more common ones such as headache and dizziness.
Officials said they had received two Yellow Card reports on this issue including one case of PRES where the person recovered and one for RCVS where the outcome was reported as unknown.
A spokesman said: ‘We keep the safety of all medicines under close review to ensure that the benefits outweigh any risks – the safety of the public is our top priority.
‘We are reviewing the available evidence regarding the use of medicines containing pseudoephedrine and the risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), which have been very rarely reported with these medicines. We will provide any further advice as appropriate.
‘We would also like to remind patients and parents/carers to report any suspected side effects to our Yellow Card scheme.
‘If you have any concerns about your medicine, please seek advice from a healthcare professional.’
This article first appeared in our sister publication Pulse
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