Row flares over authorization process for new drug

When COVID-19 broke out across the globe in 2020, Spain was hit especially hard, with an average of over 800 deaths a day at one point.

Naturally, it fell to pharmaceutical companies to develop solutions which can cure the disease or alleviate its effects on patients. Many of these companies looked into drugs previously developed for other diseases and conditions to examine their efficiency on this coronavirus.

That is what PharmaMar, a well-known global oncology company, sought to achieve with Aplidin, a drug developed for relapsed/refractory Multiple Myeloma (MM), which was under analysis for treatment of adults with COVID-19 requiring hospitalization. 

The company’s confidence was based on several successful in-vitro studies conducted around the world. According to PharmaMar data, the potency of Aplidin against the coronavirus was more than 1,000 times that of other drugs.

The drug faced and overcame a series of challenges when put through the authorization process at the Spanish Agency of Medicines and Medicinal Products (AEMPS) and was ultimately granted approval to proceed to clinical trials for the drug.

However, the European Medicines Agency (EMA), considered to be the EU’s equivalent to the FDA in the U.S and the body responsible for the approval of new drugs, refused authorisation. It is not the first time that Aplidin and other promising drugs, with proven efficacy were subject to obstacles.

A closer look at the market authorization process leads to the company’s suspicion that, allegedly, “politics” might have played a role in creating “obstacles” to the decision-making process - an allegation that has been strongly refuted by the EMA.

The Myeloma Patients Europe, an NGO network of over 40 patient associations across Europe, has now sent a letter to the chair of the Committee for Medicinal Products for Human Use (CHMP), the EMA committee responsible for human medicines, expressing “severe concern” that this promising drug might never get approved.

When Aplidin was put forward for market authorisation in 2016, hopes were high that it would be approved. Instead, the drug has since faced several rejections from the EMA leading PharmaMed to question why? It has asked: How was the rejection of Aplidin justified? Could there be “powerful political forces” at play favouring certain drugs and companies over others?  To what extent, it also asks, is the market authorization process aligned with the needs of patients - both client and victim in this scenario - eager to gain access to life-saving drugs?

The company says there is “compelling evidence” to support the approval of the drug and, it claims, that the EMA simply seems “determined” to delay its authorization.

In the wake of the EMA’s rejection of Aplidin, the case was taken to the EU General Court and PharmaMar requested clarification of the procedural examination criteria applied during a marketing authorization procedure before EMA.

The company action centred around specific alleged flaws in the market authorisation process at the EMA, alleged bias in their treatment by the CHMP and further alleged discrimination from various EMA organs. All of these allegations were flatly and robustly denied by the EMA but the EMA’s rejection of PharmaMar’s Aplidin drug has been questioned, not least as it has been approved for the treatment of myeloma in Australia.

In October 2022, the European Count found in favour of PharmaMar, opening the doors to an acceptance of Aplidin as a commercial medicine. The company says the EMA attitude towards Aplidin is “political” and a “result of pressure by other competing governments and companies”.

More generally, according to PharmaMar, the case raises some pointed questions: Do governments or private companies “influence” EMA’s decision-making process? Are the existing processes efficient enough to avoid conflict of interest? Why are some drugs with comparatively limited efficacy allegedly receiving approval, while others are rejected? Why are regulatory agencies allegedly willing to support certain companies more than others?

Another hurdle to the entry of new medicines to the market appears when considering that the same EU Member States which are required to reimburse medical institutions for any drugs issued are also, it is alleged, the ones performing the EMA’s oversight.

In 2020, the General Court of the European Union granted the application, in full, annulling the European Commission's decision.  In its examination of the case, the General Court looked at alleged potential bias in the procedure that led of the adoption of the contested decision by the Commission. Specifically, it looked at the allegation, which is disputed, that some of the experts appointed by EMA were employed by a university hospital and performed activities aimed at developing rival medicinal products to Aplidin.

The decision reads: “the procedure that led to the adoption of the contested decision did not provide sufficient guarantees to exclude any legitimate doubt as to possible bias.”

PharmaMar insists that the EU and European Ombudsman should investigate all formal and informal communications between officials of the EMA and the Member States that participate in appeals, as well as the pharmaceutical industry of these countries. The company believes that many cancer and Covid-19 patients could have benefited from Aplidin - indeed, they still hope it will be approved “in the end”. Meanwhile, it has demanded an investigation into any “pressure” that may have been brought to bear in this case.

An EMA spokesman issued a strongly worded statement which reads, “We cannot comment on the ongoing legal proceedings regarding Aplidin.

“But these are unfounded allegations and we consider that it is important to set the record straight.

“First of all, we would like to point out that our human medicines committee (CHMP) operates solely on the grounds of rigorous scientific principles and independent expertise. It includes members from all EU member states as well as EEA-EFTA States.

“CHMP assessments are based on a thorough evaluation of the available evidence on the quality, efficacy and safety of a medicine and are subject to peer review and collegial decision-making. For each application for a new medicine, two committee members − known as rapporteur and co-rapporteur − from different countries are appointed to lead the assessment and conduct the scientific evaluation of the medicine independently from each other. The CHMP also appoints one or more peer reviewers from amongst the CHMP members. Their role is to look at the way the two assessments are performed and ensure that the scientific argumentation is sound, clear and robust. A final recommendation, representing the totality of the committee’s analysis and opinion on the data, is then developed.

“For many years now, EMA has been at the forefront of transparency with respect to the evaluation of medicines. The Agency considers that transparency is key to reinforcing trust in regulatory decisions.

“Transparency towards the public is ensured by publication of the CHMP assessment reports on our corporate website. We welcome external views and feedback on our scientific opinions, and in responding to comments or queries aim to provide consolidated, clear explanations on our positions as well as being fully transparent on our engagement with stakeholders.

“In the case of Aplidin, at the time of the original evaluation, we published a detailed assessment report which clearly described the CHMP’s considerations on the evidence regarding the benefits of this medicine in the treatment of multiple myeloma and the possible safety risks. A majority of the CHMP was of the opinion that the benefits of Aplidin did not outweigh its risks and recommended that it be refused a marketing authorisation.

When a new CHMP opinion on Aplidin will be ready, it will be published exactly as the previous one.

“That said, we firmly reject any allegation of wrongdoing and of political pressures on the CHMP assessments leading to a recommendation to the European Commission, not only in the Aplidin case but for any other product. We are concerned that instead there may be deliberate attempts to interfere with an on-going regular administrative action, which is being performed fully in compliance with relevant legal provisions.”

It goes on: “Two EU member states have appealed against the General Court ruling in the Aplidin case, and that a third member state has intervened in their favour, besides EMA. In the opinion of the appellants, the first instance ruling is legally flawed and should be set aside or corrected. This information is in the public domain.”

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