Decreasing the data deficit: improving post-market surveillance in pharmaceutical regulation.

• Author: Lemmens, Trudo
• Position: Technological Innovation and Civil Responsibility

The drug regulatory system is currently largely based on market-entry review of safety and efficacy data and involves only very limited post-market review. Failures in the industry-controlled production of pre-market data and the lack of solid post-market surveillance contribute significantly to highly problematic drug prescription and consumption practices, which have become a very serious public health concern. In this paper, we first discuss how historically grown drug regulations have contributed to the development of industry control over clinical trials, which is one of the key factors behind the limits of pre-market evidence. We then explore some problematic aspects related to the fixation of the drug approval system on pre-market activities, including the lack of good "real-world" evidence on drug safety; the lack of comparative evidence on patient benefit between different drugs; the lack of evidence of the safety and efficacy of off-label prescribed drugs; and the inadequate reporting of adverse drug reactions (ADRs). We argue that a more rigorous and intense post-market surveillance system could counterbalance, at least in part, the distorted situation created by the regulatory reliance on premarket, industry-produced clinical trials data. In particular, we advocate for improvements to the current ADR reporting system, more explicit requirements for both comparative effectiveness studies and post-market clinical research in real-world settings, the promotion of transparency of pharmaceutical data, and insulating clinical research from industry control.

Le systeme reglementaire des medicaments se base actuellement en grande partie sur l'etude des donnees de securite et d'efficacite au point d'entree sur le marche, mais ne comporte qu'une etude tres restreinte apres l'entree sur le marche. Des defauts dans la production de donnees avant l'entree sur le marche, entreprise par l'industrie meme, et l'absence de surveillance appreciable apres l'entree sur le marche contribuent de facon importante a des pratiques tres problematiques de prescription et de consommation des medicaments. Ces pratiques sont devenues un probleme de sante publique tres grave. Dans cet article, nous etudions d'abord comment la reglementation des medicaments developpee a partir d'antecedents historiques a contribue au developpement du controle par l'industrie pharmaceutique des essais cliniques. Ced est l'un des facteurs essentiels qui explique les limites des donnees prelevees avant l'entree sur le marche. Nous abordons ensuite les aspects problematiques de la fixation du systeme d'autorisation des medicaments sur les activites avant l'entree sur le marche, y compris : l'absence de donnees reelles sur la securite des medicaments; l'absence de donnees comparatives par rapport aux avantages de differents medicaments pour les patients; l'absence de donnees sur la securite et l'efficacite des medicaments prescrits pour des usages non autorises; et le rapport inadequat des effets indesirables des medicaments (EIM). Nous soutenons qu'un systeme de surveillance apres l'entree sur le marche plus rigoureux et intense pourrait compenser, du moins en partie, la situation deformee qu'a engendree la dependance reglementaire sur les donnees basees sur des essais cliniques conduits par l'industrie avant l'entree sur le marche. En particulier, nous pronons l'amelioration du systeme actuel de rapport des EIM, des exigences plus explicites pour les etudes sur l'efficacite comparative et pour la recherche clinique apres l'entree sur le marche dans un contexte reel, la promotion de la transparence dans les donnees de recherche, et le cloisonnement de la recherche clinique du controle par l'industrie.

Introduction I. Challenges in Pre-Market Evidence Development A. Historical Developments in Requirements for Maiket Entry B. Issues in the Production of Clinical Trials Data C. Understanding the Interests of industry D. The Limitations of Pre-Market Clinical Trials Evidence II. Specific Challenges in Post-Market Surveillance A. Adverse Drug Reaction Reporting B. Issues Around Off-Label Prescribing C. Improving Information Sharing with Patients and Consumers III. Tackling the Data Deficit A. The Need for Independent Research B. Promoting Transparency and Data Access 1. The Raison d'Etre of Transparency 2. The International Move Toward Data Access 3. Canada's Hesitant Steps Toward Transparency 4. The Saga of Pharmaceutical Data Transparency in Europe Conclusion Introduction

The drug approval system in industrialized countries is generally divided into two distinct phases: a pre-market phase and a post-market authorization phase. The pre-market phase is characterized by substantial investments in clinical trials aimed at providing data demonstrating the safety and efficacy of a product. Subsequently, in the post-market phase, drugs are generally perceived by both the medical community and the public at large to be safe and effective. In this phase, drug companies rarely undertake additional studies to assess the safety and efficacy of the products in the real-life context in which these drugs are then consumed. (1)

To date, the focus of drug regulation, certainly in Canada, has primarily been on pre-market activities and on ensuring that products entering the market fulfill certain basic requirements with respect to safety and efficacy. Unfortunately, lay people--but also to a large degree those involved in the regulation, prescription, use, and funding of pharmaceutical products (including health care professionals)--ignore the limitations of the data produced in pre-market clinical trials. These trials are conducted under the control of an industry that has a vested and significant financial interest in showing that the products tested in these trials work. Yet the approval of drug products by regulatory agencies such as Health Canada is easily taken as a firm confirmation of their safety and value.

As we explain below, the drug regulatory system that has developed throughout the twentieth century, while obviously intended to improve the safety and efficacy of pharmaceutical products, has also had perverse side effects. This system has strengthened the dominant position of industry over the creation of clinical trials data; it has created a false assurance of safety and efficacy by the very fact of approving the marketing of these drugs on the basis of the submitted data; and finally, it has enabled industry, which is largely in control of the production and publication of the results of clinical trials, to use this false assurance as a marketing tool. At the same time, the pharmaceutical industry has at this point little inherent interest in critically evaluating or questioning whether the data produced in pre-market testing for the purpose of drug approval is sufficient or provides the most meaningful information. In fact, as we will argue, the opposite is often true.

We will not discuss in detail in this article the various components of industry control over pharmaceutical research, product development, and distribution of information. Instead, we want to explore, with an emphasis on Canadian developments, how a shift toward better post-marketing surveillance could counterbalance, at least in part, the distorted situation created by our reliance on pre-market clinical trials data produced under the control of industry.

The importance of correcting the knowledge deficit resulting from industry control over data and from the lack of post-market data cannot be overestimated. Bad information leads to bad health care practices, often resulting in serious injuries and death. The wide-ranging health risks associated with industry manipulation and misrepresentation of data, combined with aggressive marketing practices, have been highlighted, particularly in the last decade, in a panoply of media reports and publications. (2) As these publications and reports highlight, a remarkably high number of serious injuries or deaths are linked to these practices, which makes it increasingly hard to understand the so far very timid response by regulators and governmental decision makers. The extent of the control of industry over scientific data also has another important consequence that negatively affects potential legal responses (for example, tort law) to this problem: by avoiding the collection of evidence about adverse effects of pharmaceutical products that are currently on the market, or by directly manipulating the presentation of data in the scientific literature, industry can shield itself more easily from potential liability for deficiencies associated with its products. The powerful influence, if not control, of industry over the production of scientific evidence thus also impacts on legal tools that could otherwise be used to deter or provide compensation for injury resulting from defective products. (3) The legal community should therefore also start to take much more seriously the consequences of the gaps in the scientific data production processes, as they compromise the integrity of the legal system itself.

This paper provides recommendations to improve, within the contours of the current Canadian drug regulatory system, the ways in which data is being produced and distributed. We begin by describing the historical development of industry control over clinical trials, followed by a brief overview of the limitations of pre-market clinical trials. Subsequently, we argue that the inadequacy of the safety and efficacy data created at the pre-market stage only increases the importance of enhanced surveillance activities during the post-market phase. Expanded post-market surveillance is necessary in order to combat a host of problems, including the lack of good evidence on long-term safety and comparative effectiveness; the need for improved adverse event reporting; and the phenomenon of off-label prescribing. We will briefly highlight these...