Clinical Trials in Patients with Resected Stage IIB and III

Melanoma

Craig L. Slingluff, Jr., M.D.

Professor of Surgery, University of Virginia

Director, Human Immune Therapy Center, UVA

Co-chair, Melanoma Committee, ECOG

Vice-chair, Melanoma Committee, ACOSOG

NIH funded investigator on multiple investigator-initiated clinical trials. R01 CA57653, R01 CA78519, R21 89937

UVA-Mel39• A synthetic peptide vaccine trial in patients with

stage IIB-III melanoma was proposed (IND 9847) for patients who refuse IFN or are not candidates for IFN

• The FDA ruling:– patients who simply refuse IFN are not candidates.

– patients who have refused IFN and who are 6 months or more after definitive surgery are no longer considered to be IFN candidates.

– Thus, patients who refuse IFN can enter this trial once 6 months have elapsed.

Risk of opening trials to those who refuse IFN

The only salient argument for legislating against the freedom of patients to decide to enter a clinical trial after refusal of an approved therapy is that patients may be exposed to risk of obtaining inadequate information about the standard therapy because of real or perceived bias on the part of some clinical investigators.  

The process of informed consent• However, the process of informed consent for clinical

trial entry is based on the belief that patients can be informed adequately to consent to clinical studies that may have unknown benefit and known or unknown risks.

• To argue that informed consent cannot provide adequate protection of patients who choose not to take an approved therapy, is tantamount to arguing that informed consent cannot provide adequate protection of patients in any setting.

Proposal for phase II trials in patients eligible for HD-IFN.

A tenable policy for design of phase II clinical trials in patients who may be eligible for an FDA-approved therapy should assure patient protection while also ensuring freedom of self-determination by patients. My suggestion is thatpatients eligible for a standard therapy should be required to study and to document understanding of an FDA-approved document detailing the risks and benefits of the FDA-approved therapy.

Benefits of system for informed consent

• Ensure that no patient who is eligible for an FDA-approved therapy would refuse that therapy and enter a clinical trial without receiving acceptable information about the standard therapy.

• Lead to more uniform information dissemination about the standard therapy than is currently provided to patients who refuse that therapy.

• Permit patients the freedom to choose the management they find most consistent with their priorities (survival and quality of life).

• Increase the proportion of patients whose therapy is regulated and monitored by the FDA, thereby improving patient safety generally.

Alternate recommendation: Shorten wait after refusal of IFN

• If the FDA develops a policy that it will not allow any patients to enter phase II clinical trials who are candidates for an FDA-approved therapy, then it is requested that this policy be applied strictly, based on the conditions in which the drug was originally tested.

• The clinical trials of HD-IFN have restricted entry to patients treated within 56 days of definitive surgical therapy. More recent trials permit entry up to almost 3 months after definitive therapy.

• There are no conclusive data addressing the therapeutic value of HD-IFN administered more than 3 months after definitive therapy.

• Thus, it is requested that the FDA allow entry of patients onto experimental phase II trials 3 months after definitive therapy (rather than 6 months). 

Summary• Patients have the right to refuse any or all standard therapy, for any

disease, because of their personal goals related to quality of life issues, toxicity, or other perceptions of the effects of that therapy.

• Patients who choose not to take an approved therapy, after adequate information is provided, should not be excluded from trials that other patients with the same stage disease are allowed to enter. This can be accomplished with informed consent.

• To disallow that freedom interferes with patient rights and also is harmful to investigation of new therapies, which are sorely needed for melanoma and for most cancers.