How often are medicines approved without data from all clinical trials?

A drug to treat attention deficit hyperactivity disorder (ADHD) was approved by several regulatory agencies without all relevant clinical trials having been reviewed, a study published in November 2021 suggests.

The omitted trials accounted for a median of 45% of all data from participants in relevant studies, raising concerns that regulators may not be looking at all relevant trials when assessing the safety and efficacy of new treatments.

Six regulators did not consistently list all relevant trials in public approval documents:

• BfArM (Germany)

• FDA (United States)

• Health Canada

• MHRA (United Kingdom)

• PMDA (Japan)

• TGA (Australia)

With the exception of Health Canada, regulators did not explain why certain trials were omitted. The study authors concede that it is possible that regulators excluded some trials from public documents after determining that they were not relevant or reliable data sources, but also note that past researchers have identified instances in which regulators have simply failed to take relevant trials into consideration:

“One could argue it is reasonable to include only those trials supporting the authorised indications in public documents. However, it obscures transparency when excluded trials are not listed, and it can give a distorted impression of the submitted evidence and of the drug’s benefits and harms.”

“Despite our lengthy investigation, we are still not certain on what basis most drugs were approved.”

“Drug regulators need to ensure that their decisions are based on all data from all relevant trials and not just a selection of them.”

In an accompanying editorial, the former chair of the Dutch medicines regulator welcomed the study:

"They report about an odyssean, almost forensic, journey across clinical trial registers, scientific literature, regulatory dossiers, freedom of information procedures, public assessment reports, extensive correspondence with regulatory authorizes, and not to forget translated texts of regulatory websites."

"The study of Boesen and colleagues shows examples of non-transparent and unwarranted exclusion of trials."

"For the moment the study remains important in adding to the awareness and need for continuous learning and improvement. Regulatory science is too important to leave it to the regulators."

The researchers identified 18 relevant trials and 13 drug applications filed with 7 different regulators by four pharma companies: Janssen, Medice, Novartis, and Purdue. They found that in just over half of regulatory documents, relevant clinical trials were not mentioned.

The 18 relevant trials used as the basis for the the assessment included 16 industry-sponsored trials and 2 publicly funded trials with ‘industry involvement’, but no publicly funded trials. They tested six different extended-release methylphenidate formulations for adult ADHD.

The authors recommend that regulatory agencies should systematically search for trials themselves, rather than relying on drug companies to identify all relevant studies, and that pharma companies should be held accountable if they fail to inform regulatory agencies about all available evidence.

The full study and extended recommendations are available open access here. The accompying editorial is here.