Phase 0 Trials: A Fait Accompli?

A Reappraisal From a Ten-Year Perspective (1)

by John Otrompke, JD(*)

In 2006, the FDA released a guidance on Phase 0 trials, in which a ‘microdose’ ( less than 1% of the expected dose) of an experimental drug is administered to humans for a very brief period of time (perhaps one week).2

The guidance generated controversy, such as an article raising ethical questions like whether it is ethical to subject humans to the risk of taking a new drug, which has been subjected to less rigorous preclinical research than in a traditional Phase 1 trial, without offering the possibility of enjoying a therapeutic benefit.3

Today, Phase 0 trials occur frequently, without substantive comment.4 In fact, the entire proposal in advance of amending the U.S. Common Rule doesn’t even mention them.5 So ten years out, are Phase 0 trials a fait accompli?

It would seem so. When Prof. Kimmelman wrote his article, his review of the literature found no more than 10 such studies. Perhaps for this reason, the 2007 article raised, but did not attempt to answer, such ethical questions.

But a similar search conducted on PubMed last month returned 1,892 hits for Phase 0 trials, and 544 hits for microdosing; a search on clinicaltrials.gov returned 97 studies. Regulators in Australia(6) and the European Union(7) have given Phase 0 trials their blessing.

Have the ethical issues raised by Prof. Kimmelman ever been addressed? At least one of the ethical questions he raised, whether Phase 0 trials have scientific value, seems to have been answered, at least to the satisfaction of society and the scientific community. 

Another issue, however, has never been sufficiently addressed: whether society is permitting human volunteers to subject themselves to an unquantifiable but substantial risk, to which they cannot truly consent. 

This article takes the position that Phase 0 trials are part of a next-generation tool-box for drug discovery (including genomic browsers, micro-fluidics, biomarkers, gene signatures and other modern techniques) that may one day eliminate animal testing,(8) and cure cancer. While the practice of Phase 0 trials is only likely to accelerate given the administration’s National Cancer Moonshot initiative, the federal government should take the opportunity presented by the proposal to amend the Common Rule(9) to produce a more definitive response to the ethical issues they raise.

What are Phase 0 Trials?

In its 2006 guidance, FDA defines the concept of microdose trials, and lays out how to use them.

In traditional, pre-2006 drug development, clinical trial research was broken down into three phases, preceded by basic, in vitro research, proof-of-concept, and animal testing; Phase 1, in which doses of a medicine were administered to human beings for titration and to further test for safety; Phase 2, in which the experimental medicine is given to larger numbers of patients, to further test for safety as well as efficacy; and Phase 3, the most complete and scientifically rigorous phase, in which the medicine is administered to a cohort large enough to generate statistically significant results, the primary endpoint being efficacy. 

In order to conduct a Phase 1 trial, a drug developer needs to submit an application to FDA. In its guidance, FDA explained that many drug developers submitted vastly more data than necessary to get approval for Phase 1 trials, unnecessarily constricting scientific progress and hindering medical progress.10 

The FDA explained just how little scientific evidence is necessary to justify a Phase 1 trial, and encouraging drug developers to rely on a hitherto under-utilized technique called the Phase 0, or microdose trial. The point was to simplify the process by sorting out the more promising agents by trying them out earlier in humans in a microdose form.

While traditional Phase 1 trials had once been referred to as ‘first-in-human’ studies, with Phase 0 research, this is no longer the case. 

What Ethical Issues Have Been Raised?

What exactly is the ethical difference between Phase 0 and Phase 1? Chiefly, while the likelihood of a human subject receiving a therapeutic benefit from a Phase 1 trial is small, the odds of receiving any therapeutic benefit from a Phase 0 trial are virtually nil, partially because the dose of the experimental drug is so small, and the period of administration is so brief.11

Stepping back, the U.S. government’s three basic watchwords for bioethical regulation may be found in the Belmont Report, the document which informed the creation of the Common Rule: respect for persons, beneficence, and justice. 

Many of the criticisms leveled at Phase 0 trials come from the proposition that risks and benefits faced by human subjects must be proportional. (Prof. Kimmelman expressly excluded consideration of research in healthy people from his consideration, but the FDA guidance said that exploratory studies could be conducted in healthy individuals).12 Unlike in traditional Phase 1 trials, the dose of the experimental agent in a Phase 0 trial is very small. Therein lies the rub. 

First-in-human studies of experimental medicines can pose grave health hazards. The Guidance addresses such concerns by encouraging animal testing in a rather unrestrained way, notwithstanding the burgeoning evidence that animal research does not produce results reliably generalizable to human beings.13 (At the same time, federal agencies are doing significant work in developing alternatives to animal testing through programs like ICCVAM and NICEATM, programs in which FDA is involved, but in which FDA should place greater confidence).14

Therefore, a human individual taking part in a Phase 0 trial often assumes a significant risk, without much likelihood of enjoying a personal medical benefit. An adult might assume a risk to herself or himself for the benefit of others.15 It is assumed that this can be ethically permissible, if the benefit to others is sufficient. But experimental drugs are tested in humans earlier than was the case in traditional Phase I studies, which involved a more rigorous period of preclinical study. Prof. Kimmelman asks us whether the public benefit is sufficient to justify greater individual risk if Phase 0 trials are unlikely to lead to generalizable scientific knowledge, because, for example, the results of Phase 0 trials may never be publicly available. Is it just if human beings are exposed to danger, not to develop generalized knowledge, but to advance the individual development of a privately-owned drug that will ultimately be sold for profit, sometimes at objectionable rates? Is it possible for an individual to consent in a truly autonomous way to willingly participate in such an unequivocally unilateral procedure, and why would they do so?

To really answer these questions, it would be necessary to quantify the risk to which those who volunteer for Phase 0 trials are subjecting themselves. Are human volunteers experiencing more adverse events than before? Are any Phase 0 volunteers enjoying pharmacological benefit? 

Bioethicists have commented that this is a difficult calculation, because it is difficult to keep track of adverse events encountered by volunteers in clinical trials. These concerns may have been partially alleviated by the expansion of the ClinicalTrials.gov database, which was expanded again this month.16 According to the agencies, the database can be searched for adverse events.

Ten years on, federal regulators and the not-infallible scientific community seem to have concluded that Phase 0 trials present enough promise to justify the individual risk to human volunteers. (Concerns that the benefit is private could perhaps be better addressed by efforts to reform the phenomena of commerce more generally). 

It may be that the outcome of the Cancer Moonshot Initiative will ultimately determine whether the sacrifices made by individual human beings were worthwhile.

Conclusion

Some say that the focus of bioethical regulation in the U.S. has shifted from informed consent to an emphasis on access to experimental medicine. In light of the observations and conclusions contained above, Phase 0 trials are indeed a fait accompli, for the time being at least; but because the history of medical ethics in the last century has been reactive in nature, that could change.

Probably the most important document of research ethics since the turn of the century is the notice of proposed rulemaking to amend the Common Rule.17 The NPR doesn’t explicitly mention Phase 0 trials, but several aspects of its language may bear on some of the ethical concerns discussed above.

Therefore, a subsequent article could explore how that language ameliorates or aggravates the concerns mentioned above.

* John Otrompke, JD, is a bioethicist and medical journalist. A graduate of DePaul University College of Law, with a certificate in health and hospital law, he was a 2015 faculty recruitment applicant at the Association of American Law Schools. He has never been engaged in the practice of law. He blogs at www.otrompkescommentaries.blogspot.com. He can be reached via email at John_Otrompke@yahoo.com

Notes

1. The author wishes to thank Prof. Barbara Evans, JD, PhD, of the University of Houston Law Center, and Prof. Seema Shah, JD, association professor at the Truman Katz Center for Bioethics at the University of Washington for their many helpful comments. Any errors are my own.

2 Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies (January 2006).

3 “Ethics at Phase O Clarifying the Issues,” J. Kimmelman, 35 J.L. Med. & Ethics 727 (2007). Prof. Kimmelman raised, but did not answer a number of such ethical questions. See also, “Phase 0 trials: a platform for drug development?”, editorial, The Lancet (July18, 2009), p. 176.

4 For exceptions, see: “Note: The FDA Clinical Trial Process: Effectuating Change in the Regulatory Framework Governing Clinical Trials to Account for the Historical Shift from ‘Traditional’ to ‘New’ Phase I Trials,” J. Aldest, 18 Health Matrix 463 (2008), pp. 474-477; “First-in-Human Trial Participants: Not a Vulnerable Population, but Vulnerable Nonetheless,” R. Dresser, 37 J.L. Med. & Ethics 38 (2009), p. 39 et seq; “Recommendations for Nanomedicine Human Subjects Research Oversight: An Evolutionary Approach for an Emerging Field,” L. Fatehi, 40 J.L. Med. & Ethics 716 (2012), p. 732-735; “Revising the Regulation of Stem Cell-Based Therapies: Critical Assessment of Potential Models,” B. Von Tigerstrom,  70 Food & Drug L.J. 315 (2015), p. 330.

5 Federal Register, Notice of Proposed Rulemaking, p 539334 (September 8, 2015)

6 “Regulatory Challenges of Synthetic Biology Trials and Other Highly Innovative Investigational Products,” L. Eckstein,  15 Macquarie L.J. 65 (2015), n.12.

7 “Position Paper on Non-Clinical Safety Studies to Support Clinical Trials with a Single Microdose,” EMEA Committee for Proprietary Medicinal Products (23 January 2003).

8 "Early Microdose Drug Studies in Human Volunteers Can Minimise Animal Testing: Proceedings of a Workshop Organised by Volunteers in Research and Testing.” Combes R, et al. 19 Euro J Pharma Sciences 1, pp 1-11 (2003).

9 See, for example, “Significant Changes to Institutional Review Boards Proposed,” J. Otrompke, IEEE’s Pulse Magazine, November-December 2012.

10 Guidance, supra n. 1 (p. 2, n. 4).

11 However, the guidance assumed that some exploratory studies might theoretically “induce pharmacologic effects.” Guidance, supra n.1 (p. 9).

12 Guidance, supra n.1 (p. 5).

13 Animal Research in Medical Sciences: Seeking a Convergence of Science, Medicine, and Animal Law,” J. Pippin, 54 S. Tex. L. Rev. 469 (2012-2013).

14 The author of this present article generally opposes animal testing, because even if it saves human lives, human beings do not adequately compensate the animals, individually or as a species, who are sacrificed.  

15 See, for example, “Research into a functional cure for HIV in neonates: the need for ethical foresight,” S. Shah, et al, Lancet Infect Dis. (2014 September).

16 FDA Amendments Act of 2007,  section 801. According to FDA, this regulation takes effect in January 2017. “The final rule considers all interventional clinical trials with one or more arms and with one or more pre-specified outcome measures to be controlled clinical trials.” Final Rule, Federal Register p. 64982 (Sept. 21, 2016).

17 Note 3, supra.