Principles at stake
Underlying the question of how off-label use should be addressed by regulators are some fundamental principles of science
and law. In science, the highest value is placed on the well-controlled scientific experiment, which is the principal basis
for FDA approval. Science, however, also values empiricism. Scientific advancement requires continuous generation of new hypotheses,
which often result from empirical trial and error experimentation. Balance between empiricism and rigorous testing is inherent
in the scientific process. In the case of off-label usage, what information should be available to doctors about empirical
testing of off-label uses, until and unless these uses reach the hypothesis testing phase, and who should be able to provide
that information? Presently, there are no answers to these questions because there is no longer a Section 401, a Part 99,
or a final FDA guidance document.
What is clear is that off-label use is a significant and important part of medical practice. In certain areas of medicine
such as oncology, in which there are numerous types and subtypes of cancers that may affect very small populations, the likelihood
that products would ever be approved for all relevant uses is remote. The economics of drug development simply make this unrealistic.
As stated in a recent position paper on off-label use by the European Society for Medical Oncology (ESMO), "The off-label
use of drugs in oncology has been estimated to reach 50% or even more. Often these uses of drugs, although off-label, are
fully 'evidence based' and therefore fall within the state of the art" (5). ESMO further explains that in some instances,
high-level clinical data are "difficult to reach even for treatments which are likely effective (this may be the case of rare
diseases, which do not lend themselves to large clinical studies)."
Although FDA appears to be trying to address the issue of off-label use and promotion through guidance, the effort may not
be enough. Since the release of the draft guidance in February, there have been suggestions that final implementation of the
guidance may result in renewed litigation. It is also not yet clear what response the public draft guidance will garner from
Congress. It is possible that the agency's efforts to address off-label use through guidance may not survive congressional
or court scrutiny. The solution may well require new legislation enabling a retooled version of Part 99. Key aspects that
should be considered, which are not currently included in the draft guidance, are the option of FDA to pre-review off-label
materials and the types of audiences who could receive the off-label information. Regardless of whether FDA issues a final
guidance, the importance of off-label use issues to public health, and the considerable polarity in opinions on the subject,
suggest that a public process is needed, with involvement of regulators, regulated industry, healthcare providers, and patients.
For the past decade, the handling of off-label use has rebounded from Congress to the Executive Branch to the courts and back.
It is time to take the lessons learned and adopt a reasoned approach, with limitations that will withstand court scrutiny
and that will address the central issue of off-label use without compromising law or medicine.
Janice M. Hogan is a biomedical engineer and partner at Hogan & Hartson, JMHogan@HHLAW.com
1. Pub. L. 105–115.
2. 21 CFR 99.
3. Memorandum of Meeting between FDA and Sidley & Austin, April 13, 2007,
4. Letter from Rep. Waxman to the Honorable Andrew C. von Eschenbach, Rockville, MD, Nov. 30, 2007, available at http://oversight.house.gov/documents/20071130102744.pdf, cessed Mar. 5, 2008.
5. P.G. Casali, "The Off-label Use of Drugs in Oncology: A Position Paper by ESMO," Annals of Oncol. 18 (12), 2007, 1923–1925. PT