On 9 April 2009 the Dutch Health Inspectorate presented their findings following an investigation started in January 2008 with regard to Phase IV trials. This report is another expression of the trend to strictly monitor the commercial conduct of pharmaceutical industry and to increase legislation and regulation applicable to the pharmaceutical sector, particularly in relation to advertisement and commercial activities.

The reason for conducting this investigation was that both the Dutch Minister of Health, Welfare and Sport as well as the Inspectorate had been receiving signals that pharmaceutical companies and medical professionals were conducting Phase IV trials with an overall marketing purpose. These types of trials, generally referred to as “seeding trials” are considered to adversely affect the rational use of medication and may decrease public confidence in those issuing prescriptions. Seeding trials, or certain aspects thereof, are likely to violate legislation on pharmaceutical advertisement, industry codes on advertisement as well as legislation applicable to individual medical practitioners.

The purpose of the investigation was to gain better understanding of the extent to which Phase IV trials are used primarily as a marketing tool. The Inspectorate scrutinised a number of Phase IV trials and conducted a number of interviews. The Inspectorate concluded that seven out of twelve trials examined qualified as seeding trials.

The Inspectorate concludes that any Phase IV trial must be assessed on its own merits and identified elements suggesting, often considered in combination though, an overall marketing purpose, typically including:

  • unclear (or lack of) definition of scientific grounds;
  • large research population not justified on scientific grounds;
  • disproportionate remuneration for participating doctor;
  • simplistic design of the trial;
  • absence of monitoring and verification of the trial and results;
  • lack of compliance to trial protocol;
  • involvement of commercial departments in relation to the protocol and design of a Phase IV trial.

Further, the Inspectorate has drafted a shortlist of indications suggesting primarily marketing purpose. These criteria might serve as a starting point for the development of criteria for preliminary assessment of Phase IV trials:

  • Objective and need for trial are unclear;
  • Disproportionate remuneration;
  • Minimal scientific data is being gathered;
  • Written contract between company and doctor is absent;
  • Advertisement is integrated in the trial.

In the selection process of Phase IV trials it is assumed by the Inspectorate that the risk for seeding trials depends on the type of pharmaceutical product and the market. Therefore, selection criteria should be developed to trigger investigations and find seeding trials. The Inspectorate points to the following circumstances:

  • Chronic use;
  • Prescription by general practitioner or specialist;
  • Competitive product;
  • Relatively recent introduction;
  • “Me too” / not a first product on the market;
  • Strong increase of use not explained by the drug profile/indication/competitive products.

The Inspectorate advised the Minster to adopt legislation to subject Phase IV trials to preliminary review and approval. Also, a call is made upon professional organisations to develop protocols. Finally, a clear call is made upon the industry to implement selfregulation aimed at prior evaluation of Phase IV trials.

In response to this report, the Minister commented that although this type of Phase IV trials are already subject to preventive assessment, either by companies as part of their Standard Operating Procedures or on the basis of the Code for Pharmaceutical advertisement, the Inspection has shown that these systems do not prevent seeding trials occurring.

Also the Minister acknowledged that the current legislative framework lacks regulation of Phase IV trials. In order to address this, the Minister pointed to the proposal by the European Commission that national regulatory bodies will be competent to assess Phase IV clinical trials.

Furthermore the Minister has indicated that three out of five criteria detailed in the shortlist (remuneration of services, obligation of written contracts and rules relating to accepting presents) are subject to regulatory guidelines which are subject to enforcement by the Inspection. It is expected that the Inspectorate will watch and monitor Phase IV trials closely in the future.