Abstract
I argue that behind the 1962 Food and Drug Administration Act we find a combination of two normative principles: a liberal argument for the protection of pharmaceutical markets (in terms of quality control) and a paternalist argument for the protection of pharmaceutical consumers (in terms of drug safety and efficacy). These normative intuitions go hand in hand with the choice of regulatory testing standards: depending on the values the regulator wants to protect, she will avail herself of different testing methods. I explore two potential justifications for regulatory paternalism, in terms of risk aversion and impartiality. I defend our current regulatory arrangement against socialist and libertarian critiques.
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Notes
- 1.
I should warn the reader that I do not presuppose an a priori definition of safety and efficacy: I rather track the public understanding of both concepts in the United States, namely through regulatory decisions. In the policy-making process, medical reformers operationally defined these concepts in terms of the test a treatment should pass in order to be considered safe and effective. As we will see below, prior to 1962, safety was linked to success in a number of laboratory tests; from 1962 onwards, safety and efficacy meant success of a treatment in a randomized clinical trial. Of course, we can adopt tighter definitions of both concepts that would question the adequacy of the testing standard: e.g., randomized clinical trials are notoriously underpowered to detect uncommon side effects, which might be sometimes fatal. For the sake of my analysis, vague as they might seem, it is sufficient to with the operational definitions developed by the medical reformers who crafted American pharmaceutical regulation.
- 2.
Throughout the paper, I will use the following terms as follows. Pharmaceutical liberalism will defend the superiority of markets to organize the production and distribution of drugs. Pharmaceutical socialists will be those who defend instead the superiority of a State-owned pharmaceutical industry. Pharmaceutical paternalists will constrain the freedom of patients to consume drugs, whereas pharmaceutical libertarians will oppose any constriction in this regard. Pharmaceutical libertarians will often rely on liberal (pro-market) arguments.
- 3.
Signed by President Barack Obama on December 13, 2016, the twenty-first Century Cures Act aims at increasing and speeding the production of new medical treatments. Its Title II Subtitle D (“Modern Trial Design and Evidence Development”) invites the FDA to issue guidance that addresses using alternative statistical methods in clinical trials and in the development and review of drugs. The current normative consensus on pharmaceutical regulation discussed in this paper will surely change as a consequence.
- 4.
What counts as a serious adverse effect historically depends on a number of contextual circumstances that I will not discuss here.
- 5.
- 6.
- 7.
- 8.
Adverse selection presupposes an asymmetry of information: variations in the quality of individual goods can be observed by only one side of the market. In principle, the manufacturer knows better the ingredients of a compound and their properties than any buyer.
- 9.
- 10.
Julian Reiss (personal communication) objects that my articulation of the liberal argument presupposes that regulation protects pharmaceutical markets better against adverse selection than more market-oriented solutions, such as expert advice on drugs or privately sponsored assessments. As a matter of principle, we cannot rule out these solutions, but it is worth considering why in our past history none of them has ever worked, despite their apparent simplicity. For instance, it is worth considering why the American Medical Association (AMA) dismantled its pioneering Seal of Acceptance program precisely at a time (the 1950s) in which companies were bringing to the market many great drugs. According to Podolsky (2015, 31–33) the contributing causes were the combined pressure of the own AMA marketing branch, the lack of resources for assessing every drug submitted and litigation against AMA for failed assessments. Precisely the problems we have been discussing regarding the FDA. What institutional setup would allow a private assessment system to overcome these obstacles?
- 11.
“As of the summer of 1969, the Administration had not yet codified its interpretation of the Food, Drug and Cosmetic Act’s requirement for “substantial evidence” of effectiveness. The main criteria for effectiveness had instead been elaborated informally, often in speeches by Joseph Sadusk, Frances Kelsey, and Commissioner James Goddard in the early and mid-1960s. […]The May 1970 rules defined “well controlled studies” in flexible but rigorous terms, explicitly excluding “isolated case reports, random experience, and reports lacking the details which permit scientific evaluation.” (Carpenter 2010, 354).
- 12.
As one of my reviewers observed, it would be possible to appeal to the liberal argument for introducing the 1962 FDA Act rather than (or in addition to) the paternalistic arguments. Indeed, the Act could have been justified in terms of the superior protection it offered against adverse selection. But the actual arguments of the Kefauver-Harris hinged on consumer protection understood in a paternalistic manner. The FDA could have tested the drugs and deliver the assessment to the consumers for them to make the decision about taking potentially risky compounds. But this was a route never taken.
- 13.
The construction of the FDA regulatory reputation went far beyond Thalidomide though: see the fifth chapter of (Carpenter 2010) for a full account.
- 14.
The view that the degree of safety of a treatment must be viewed in light of its therapeutic value emerged at the FDA during the 1950s. So far, the FDA had acted as a liberal regulator that checked for quality and safety, but left to the prescribing physician the assessment of a treatment’s therapeutic value. The emerging view wanted to conduct a centralized assessment using RCTs as a standard (Carpenter 2010, 150-ff). The justification for this was a superior degree of protection for the patient, provided by a paternalistic regulator.
- 15.
See (Senn 2008) for a discussion in terms of the bias-variance trade-off.
- 16.
- 17.
For an analysis of how the fight against pharmaceutical marketing drove the adoption of RCTs in the United States see, most recently, (Podolsky 2015).
- 18.
Julian Reiss rightly objects again that a regulator may not be the only alternative and that less interventionist alternatives are conceivable. However, we have had experience of some of these approaches under our current regulatory regime and their degree of success is sobering: see, for instance, (Jain 2007).
- 19.
“To get an approximate idea of the current situation in all specialties, the author reviewed the summaries of original investigations which appeared in the 1959–60 Year Book of Drug Therapy. Out of 394 summaries which gave adequate information about the plan of the study, 225 (57%) related to reports without any explicit comparison with the results of another treatment in similar patients. Every section of the Year Book contained reports which ignored the hard fact of unpredictability and simply described the course followed by patients while they were being given a drug. All of this evidence suggests that a great part of the so-called clinical evaluations of new drugs is unscientific, lacks adequate provisions to eliminate bias, and cannot be objectively judged” (Sheps 1961, 651).
- 20.
In my view –and I follow Carpenter, once more, here–, both regulatory RCTs and the FDA itself have been reasonably effective so far at fulfilling their main mission: keeping out of the market unsafe compounds. The main evidence for this claim is the number of treatments withdrawn from the market for serious adverse effects (Carpenter et al. 2008). That is, the sort of Thalidomide scenarios that the 1962 FDA Act was aimed at preventing. In this regard, if either the evidence or the committees had been biased, the harm has not big enough to threaten the regulatory authority of the FDA.
- 21.
For instance, in trials with subjective outcomes, it has been shown that using an assessor who is not blind to the treatments received by patients overestimates the treatment effect. Yet, blinding is not implemented in a systematic manner: see (Hróbjartsson et al. 2012).
- 22.
In the last quarter of the nineteenth century, a majority of the medical profession thought unethical to patent drugs: not disclosing their composition and exploiting them commercially for private benefit (Gabriel 2014).
- 23.
Kristin Peterson’s etnography shows how the lack of enforcement of the pharmaceutical regulation in Nigeria (based on a British system) led to the proliferation of all sort of fake and defective drugs in West Africa. For Peterson, this should be mostly blamed on the neoliberal policies implemented in Nigeria. For our purposes, her case study illustrates instead to what extent minimally regulated markets (without checks for safety and efficacy) can generate a credible signalling system about drug quality. Of course, this particular case does not prove that such signalling systems may not emerge. It just illustrates once more that, at least to the extent of my knowledge, we have not seen these systems emerge in our recent pharmaceutical history.
- 24.
Even if countries like the UK there are public subsidies for hiring private forensic experts, the costs of RCTs are in a totally different order of magnitude –in the latest guideline “unusually large” forensic costs are those over £5000.
- 25.
On the epistemic problem of choosing expert advice when statistical evidence is involved, see (González De Prado Salas and Teira 2015).
- 26.
Apart from the accelerated approval track discussed above, the FDA also fast tracks breakthrough therapies, improving on current standards of treatment, and grants priority reviews, which gives approval on an application within 6 months.
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Acknowledgements
I am grateful to the editors, Bennett Holman and Julian Reiss for their detailed comments on a previous draft. My research was funded by the grant FFI2014-57258-P The paper was written during my stay at the Instituto de Investigaciones Filosóficas (UNAM, Mexico) with a PREI grant that I gratefully acknowledge. I thank Atocha Aliseda and various audiences at UNAM for their insightful discussion.
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Teira, D. (2020). On the Normative Foundations of Pharmaceutical Regulation. In: LaCaze, A., Osimani, B. (eds) Uncertainty in Pharmacology. Boston Studies in the Philosophy and History of Science, vol 338. Springer, Cham. https://doi.org/10.1007/978-3-030-29179-2_18
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