The precautionary principle in the pharmaceutical domain: a philosophical enquiry into probabilistic reasoning and risk aversion

Abstract

Pharmaceutical decisions are affected by several forms of uncertainty, which are sharpened both by the high stakes at play and by the complexity of the epistemological procedures needed to provide the necessary information to make these decisions. The precautionary principle as applied to pharmaceutical decisions through the notion of ‘well-founded suspicion’ takes into account one special sort of these uncertainties: the uncertainty concerning the causal connection between observed adverse reactions and the drug suspected of causing these effects. Commentators have criticised the precautionary principle for its inhibitory action on innovation and research, for its unjustified imbalance towards the risk produced by human agency versus natural risks; and from a formal point of view, for its vagueness and unsystematic application. Their criticisms have generally been grounded in the supposed risk-aversive nature of the precautionary principle. The purpose of this article is to address these criticisms. In this article, Iengage in a discussion of the current methodological debate about epistemic asymmetries concerning standards of evidence for pharmaceutical harm and benefits to examine the rationale underpinning the logic of the precautionary principle. I show that the precautionary principle has been developed as a means of acknowledging uncertainty, and therefore, the basis of its implementation should be based on inductive rather than deductive approaches to scientific enquiry.

Keywords:

• risk
• risk analysis
• risk management
• uncertainty
• scientific evidence
• precautionary principle

Acknowledgments

I thank Bob Heyman and Andy Alaszewski and two anonymous reviewers for precious suggestions and comments.

Notes

1. Environmental law denotes the entirety of all legal instruments aimed at protecting the environment. The Vorsorgeprinzip or Vorsorgegrundsatz inters in the legal terminology through the Atomgesetz (‘Law for the non-military use of nuclear energy and the protection from its dangers’: Gesetz über die friedliche Verwendung der Kernenergie und den Schutz gegen ihre Gefahren) promlugagted on 23 December 1959. In the paragraph devoted to the licencing authorisation (§ 7, paragraph 2, n. 3), it is stated that: ‘Licencing authorisation can only be granted under the condition that the requisite precaution against damage is guaranteed at a state-of-the-art science and technology level both through plant design and operation’. This paragraph has been erased in the last amendment to the law, promlugated on 31 July 2011, which followed the decision to eliminate nuclear energy plants altogether after the Fukushima disaster. However, the key norm of the German precautionary approach to environmental policy is considered to be the Federal Law against air and acoustic pollution (‘Gesetz zum Schutz vor schädlichen Umwelteinwirkungen durch Luftverunreinigungen, Geräusche, Erschütterungen und ähnliche Vorgänge’: Bundes-Immissionsschutzgesetz – BimSchG: 15.03.1974), which insists on precaution and prevention (‘Vorbeugung’) of environmental damage through harmful pollutants, both in § 1, that declares the law's purpose and in the commas devoted to licencing and building requirements (§ 5, paragraph 1, n. 2, and § 50). Other relevant norms are the Federal Building Code (Baugesetzbuch: 23.06.1960) and the Environmental Planning Law (Raumordnungsgesetz: ROG, 22.12.2008), both referring to the concept of environmental sustainability in § 2 Abs. 2 Nr. 6 ROG and §§ 1 Abs. 5, 1a BauGB, respectively; the ‘Federal Law for the protection of the environment’ (‘Gesetz über Naturschutz und Landschaftspflege’: Bundesnaturschutzgesetz: BNatSchG 29.07.2009), which refers to the duty to anticipate any damage to the landscape and environment in §§ 13 ff. and §§ 22 ff. Also important is the Law for Waters Protection: Gesetz zur Ordnung des Wasserhaushalts (Wasserhaushaltsgesetz – WHG: 31.07.2009). The Medicines Act (‘Gesetz über den Verkehr mit Arzneimitteln’ or ‘Arzneimittelgesetz’ – AMG: 24.08.1976), which will be the main topic of my discussion, transfers the authorisation conditions stipulated by these norms in the licencing requirements for drug approval (§ 5). In this case, it is not the protection of the environment, but rather of the health of drug consumers, which grounds the precautionary attitude.

2. ‘Fear-heuristics’ corresponds to the maximin strategy in decision theory, that is, a strategy based on the choice of the action that leads to the least worst harm, independently of its probability. Probabilities and expectations are neglected to the extent that the potential harm is catastrophic and irreversible. This approach is ethically grounded on the ‘imperative of responsibility’, which expands the ethical sphere beyond the rights and duties towards the fellow man and extends it to preserving the environment as to allow future generations the same conditions we live in (Jonas 1984, p. 63 ff.). This is also the basis for the principle of ‘sustainable development’, according to which natural resources should not be exploited in such a manner that they are no longer disposable for future generations. Tellingly, the word ‘sustainability’ in German is also expressed through the term ‘Zukunftsfähigkeit’ (future capacity).

3. Available at http://www.//www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp&mid=WC0b01ac058058f32c

4. Phocomelia is a severe congenital pathology characterised by the absence of the proximal portion of a limb or limbs: hands or feet are directly attached to the trunk by a small, irregularly shaped bone.

5. This shift has been mainly caused by an increased ecological culture in Germany, which has gradually penetrated into the European Union (EU) legislation. An implicit endorsement of the precautionary approach at the EU level traces back to the Single European Act, signed on 17 February 1986, which introduced article 130, devoted to environmental policy, in the Treaty establishing the European Community (TEC, 1974 – amendment of the Treaty of Rome, signed on 25 March 1957 as the founding Treaty of the European Economic Community). This article has been renumbered Article 191 of the Treaty for the Functioning of the European Union in the consolidated version of the Lisbon Treaty (signed on 13 December 2007 and entered into force on 1 December 2009). An explicit recognition of the precautionary principle as a guiding principle of European environmental policy has been endorsed in the Communication from the Commission on the Precautionary Principle: COM (2000) 1. The legal literature emphasises the distinction between the adoption of ‘precautionary principle’ in European policy versus US., Canadian and Australian adoption of a ‘precautionary approach’ (see Sanden 2006). This is a fundamental distinction from a legal perspective both from a formal point of view and also with respect to substantive issues, in that a legal principle has a specific binding force and also because the ‘precautionary approach’ generally amounts to a cost-benefit analysis where causal uncertainty is incorporated in the risk estimation without, however, being explicitly acknowledged (see Osimani et al. 2011). The shift from a danger prevention to a risk prevention system in pharmaceutical regulation has been particularly abrupt in Germany because of the sharp historical divide created by the German Medicines Act (one of the most articulated and complex laws concerning marketing approval for pharmaceuticals in Western countries). Other European countries have followed this trend only slowly and did not necessary follow the hard law path. As pharmaceutical approval is becoming more centralised at the European level, the precautionary approach becomes part of the regulatory system. In the United States, the 1962 Law (also known as Kefauver–Harris Drug Amendments) established several restrictions to drug approval, as well as the introduction of Good Manufacturing Practices. However, it did not consider the problem of how to deal with risk safety signals after drug approval during the phase in which there is no established proof of causal connection. After that date, the powers of the US Authority over drug marketing (FDA) have been increasingly strengthened (see, for instance, the introduction of Good Laboratory Practices ensuring product safety and quality by means of strict regulation of clinical trials and evidence collection). At present, especially after the Food and Drug Administration Amendments Act – signed into law in September 2007 and effective since March 2008, pharmaceutical approval and pharmaco-surveillance has been further disciplined: see, for instance, the introduction of Risk Evaluation and Minimisation Strategies (REMS), which can be requested for drugs having a context-sensitive risk–benefit balance, that is, drugs whose associated adverse reactions are especially severe, but under particular conditions of use and in considerations of specific indications, are better left in the market (see, for instance and precisely, Thalidomide for leprosy). REMS supersede in this sense Risk Minimisation Action Plan previously introduced in a non-binding Guidance for Industry. In Germany, the introduction of the principle of ‘well-founded suspicion’ has meant the relaxing of the causal assessment from certain to probable. Pharmaceutical regulation in the United States and FDA guidelines for the industry are rather concentrated on the maintenance of a favourable risk/benefit balance. The different options available when safety signals arise (use restriction, introduction of special contraindications and precautionary information, access restriction) are elected in consideration of possible benefits and drawbacks implied by each, with no explicitly separated consideration of the degree of causal assessment between suspected drug and detected signal. Also, there is no corresponding notion to ‘development risk’ in FDA drug surveillance regulation. The closest one is that of ‘new safety information’.

6. This risk/danger opposition, developed within the debate concerning environmental law in Germany (see first section), should be distinguished from sociological characterisations, which rather focus on the pragmatic implications and ethical tags associated with these terms (see Heyman et al. 2010, pp. 25–27). However, they share analogous semantic traits in that, in subjective terms, a danger is something that ought to be avoided (it is an absolute)), while a risk may be taken if it is associated with a high enough probability of benefit (it is a relational phenomenon characterised by a risk–benefit evaluation). The key difference between the legal and sociological perspectives lies in the focus on the different kinds of factors contributing to this distinction (for instance, the organisational and power-related processes that give rise to different views in the sociological approach). I thank an anonymous reviewer for drawing my attention to this important analogy.

7. The membership to an institution/organisation and the associated sense of shared responsibility is connected with risk acceptance (Hart 1998, p. 193). As a consequence, both the authority and the pharmaceutical firms – as expert and complex institutional/organisational entities with decision-making powers – tend to set the acceptability threshold lower than a lay decision maker would do. The legal level of drug risk acceptance is, therefore, ‘structurally’ lowered in comparison to the lay level of acceptability (Hart 1998, p. 193). This demands a counterforce to balance the risk proclivity of administrators and pharmaceutical entrepreneurs (Hart 1998, p.102). Actual drug regulation does not provide any substantial means for the involvement of the public or target groups in drug risk policy and decision making (Francke and Hart 1999,p. 207).