April 2012

Placebo: Wrong then, wrong now

Scherzer The issue of placebo use in clinical trials for GIST patients has resurfaced once again as Infinity Pharmaceuticals proceeds to implement a phase III trial for IPI-504, for patients with refractory GIST.

The Life Raft Group first addressed the issue of placebos at a board of directors meeting in November 2003 when eight directors and LRG members agonized and debated the merits of a Pfizer clinical trial for SU11248 (Sutent) that included a placebo in its protocol (A photo of this group can be found on page five of our March 2004 newsletter in a eulogy to Dean Gordanier, the first of three members of this group to die from GIST). In January 2004 our editorial headlined, “Placebo use in Pfizer trial is simply wrong”. In August 2004 our front page article headlined, “More placebo clinical trials predicted for cancer patients-Patient advocacy concerns presented about potential ethical dilemmas”. Once again we shared our concerns and made the following major points:

"Nothing about us, without us", stealing a mantra from our colleagues at ECPC (European Patient Cancer Coalition).

The burden of proof must be upon those proposing to use a placebo.

If a drug being tested is likely to produce stability rather than tumor shrinkage, then how could any progression which occurs due to a placebo be reversible?

This new trial comes a step closer to addressing our concerns. We note that the trial protocol attempts to strengthen the monitoring of participants to enable earlier cross-over to the trial drug for those progressing on the placebo. We note that the use of a placebo may well reduce the number of trial participants needed and that this may expose fewer patients to the unknown risks of an unproven drug. We note that the smaller number of participants may mean a shorter trial period and, should the trial demonstrate drug efficacy, that this may allow earlier approval for the drug and earlier access to it by GIST patients.

Finally, we note that Infinity is a progressive company with a high degree of transparency and a sincere motivation to do right by patients. We appreciate that the company plans to help trial patients with transportation costs. We appreciate the time and attention we have been accorded from the President, Julian Adams, on down.

We have once again invested a considerable amount of time and energy investigating the complex issue of Data from IPI-504 phase I trial. placebos and deliberating what our position should be. We are particularly indebted to the comprehensive work of the Canadian National Placebo Initiative published in July 2004.

We do understand the challenge posed to a pharmaceutical company to design a clinical trial which can demonstrate the safety and efficacy of a new drug to the satisfaction of government regulators. This must be done while still meeting the financial needs of its investors and the medical needs of the patients for whom the drug is intended. This is no small task, particularly for smaller companies.

We are also particularly sensitive to the realistic world of drug development and the need to encourage companies to invest in drugs for a rare disease like GIST.

What is at stake today is not just the Infinity trial but the precedent that it sets for others to come. We could continue to weigh the pros and cons indefinitely and engage in an ongoing lively dialogue with a vast community of ethicists, scientists, scholars and others regarding a subject that brings great passion to the table, but the time is once again at hand to take a position.

The Life Raft Group respectfully disagrees with the use of a placebo in the Infinity clinical trial for IPI-504.We feel that the burden of proof for using such a placebo, which must be assumed by those proposing it, has not been met for the following reasons:

Differences in criteria, in judging tumor response/progression 1. Poor Science: There is a sufficient body of knowledge that removing a GIST patient from whatever treatment they are on may accelerate the cancer progression. Hence, the issue is not whether a drug is better than nothing, but whether it is better than the current treatment. We are also concerned that the RECIST criteria being used to demonstrate progression is not the best methodology available and has in fact been discredited by a number of GIST specialists over the past few years. CHOI criteria, on the other hand, identifies progression sooner and could be substituted for RECIST1,2.

2. Irreversible Disease Progression: Early data strongly suggests that the major benefit of IPI-504 may be tumor stability rather than tumor shrinkage (Figure 1). Should that be the case, we submit that the progression required to qualify for cross-over to the drug may well be irreversible and therefore is potentially life-threatening.

3. Failed Ethics: Many ethicists hold that placebo use cannot be justified solely on scientific grounds. We agree, especially in the case of terminally ill cancer patients whose judgment may be clouded. Indeed, a placebo-based trial exploits their vulnerability3. The Life Raft Group remains committed to its mission to ensure the survival of every GIST patient. We cannot condone a situation in which terminally ill patients and their families are asked to choose between a placebo and a drug which might save their lives.

4. There is an alternative to this placebo protocol: Although it may take more patients, time and money, there is no disagreement that a clinical trial for IPI-504 could be created with current best treatment substituting for a placebo.

In an October 2006 article on the efficacy and safety of sunitinib4, and which was co-authored by George Demetri, the sunitinib principal investigator, the authors commented that “subsequent preliminary data suggest that discontinuation of imatinib in patients with GIST increases risk of disease progression and is associated with accelerated disease progression in some patients…With this perspective, continuing imatinib despite progression might have served as an alternative approach for the (placebo), for reasons of patients’ well being and because discontinuation of imatinib therapy might not represent the most current standard of palliative care. In the absence of a trial directly comparing sunitinib with continuing imatinib treatment after imatinib failure no definitive conclusion about the superiority of switching to sunitinib can be reached.” We would submit that his words hold true for this new clinical trial as well.

Please see Jim Hughes’ article on this trials’ protocol for more information.

Citations

1. Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, et al. Response of gastrointestinal stromal tumors (GISTs) to imatinib by Choi criteria and response evaluation criteria in solid tumors (RECIST) as surrogates for survival and time to progression. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 9506.

2. Benjamin, RS, Haesun C, Homer MA, et al. We Should Desist Using RECIST, at Least in GIST. Journal of Clinical Oncology. 25: 1760-1764, 2007.

3. National Placebo Initiative Final Report. CIHR, July 2004.

4. Demetri GD, van Oosterom AT, Garret CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. The Lancet, October 2006.