Correspondence

Death in a Gene-Therapy Trial

N Engl J Med 2009; 361:1811-1812October 29, 2009

Article

To the Editor:

Frank et al. (July 9 issue)1 do not discuss the issue of therapeutic misconception2 — namely, the belief by a research subject that the investigational agent is actually therapeutic. Admittedly, there was no concrete evidence for this issue here, but on the basis of the nature and timing of events, the issue was relevant and became an important part of the report and recommendations of the Recombinant DNA Advisory Committee of the National Institutes of Health.

Therapeutic misconception for the subject can be addressed during the consenting procedure.3,4 However, therapeutic misconception is also an issue for investigators for whom conflicting commitments can blur the line between research and treatment. Therefore, the protocol itself becomes the main protection for safety in this regard. In addition to recommending screening tests and laboratory requirements before the initiation of therapy, the advisory committee recommended that subjects carry a medical card containing key information about the investigational agent, as well as phone numbers for ready contact with the study's principal investigator. The protocol should clearly state how to proceed in the event of any unforeseen illness.

John A. Zaia, M.D.
City of Hope, Duarte, CA
jzaia@bricoh.edu

Howard J. Federoff, M.D., Ph.D.
Georgetown University Medical Center, Washington, DC

Dr. Zaia reports being a member, and Dr. Federoff reports being chair, of the Recombinant DNA Advisory Committee, which reviewed this adverse event. No other potential conflict of interest relevant to this letter was reported.

4 References

1. 1

   Frank KM, Hogarth DK, Miller JL, et al. Investigation of the cause of death in a gene-therapy trial. N Engl J Med 2009;361:161-169
   Full Text | Web of Science | Medline

2. 2

   King NM, Henderson GE, Churchill LR, et al. Consent forms and the therapeutic misconception: the example of gene transfer research. IRB 2005;27:1-8
   CrossRef | Medline

3. 3

   Kahn J. Informed consent in human gene transfer clinical trials. Hum Gene Ther 2008;19:7-8
   CrossRef | Web of Science | Medline

4. 4

   National Institutes of Health, Office of Biotechnology Activities. NIH guidance on informed consent for gene transfer research. Bethesda, MD: National Institutes of Health. (Accessed October 8, 2009, at http://oba.od.nih.gov/oba/rac/ic/pdfs/temp_pdf.pdf.)
   

To the Editor:

Frank et al. examined the role of a tumor necrosis factor α (TNF-α) antagonist, delivered through an adeno-associated virus, as a precipitating cause of death in a gene-therapy trial. When a patient is receiving a TNF-α blocker, education about the risk of opportunistic infection, especially histoplasmosis and tuberculosis, is a requisite. A survey of infectious-disease consultants in the United States revealed that histoplasmosis occurred more often than tuberculosis in patients receiving TNF-α blockers.1 Perhaps because of the regional occurrence of histoplasmosis in the United States, many physicians may fail to entertain the diagnosis of this infection. Since the presenting clinical features are nonspecific and exposure often goes unrecognized, physicians should include histoplasmosis in such evaluations. The role of reactivation of latent infection, as compared with reexposure, also merits consideration. The authors conclude that the case here “is most consistent with reactivation of histoplasmosis, although a recent primary infection cannot be ruled out.” The reactivation hypothesis is less likely in this case, since the patient resided in a highly endemic area and had received systemic TNF-α blockers for the 4 years preceding the gene-therapy trial. In addition, calcified lesions have not been shown to contain viable organisms when cultured or after inoculation into experimental animals.2

Chadi A. Hage, M.D.
Suzanne Bowyer, M.D.
Martin B. Kleiman, M.D.
Indiana University School of Medicine, Indianapolis, IN
chage@iupui.edu

2 References

1. 1

   Winthrop KL, Yamashita S, Beekmann SE, Polgreen PM. Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Network. Clin Infect Dis 2008;46:1738-1740
   CrossRef | Web of Science | Medline

2. 2

   Straub M, Schwarz J. The healed primary complex in histoplasmosis. Am J Clin Pathol 1955;25:727-741
   Web of Science | Medline