Disclosure in Phase 1 Cancer Trials

Followers of this blog may recall my continuing concern with the way informed consent is obtained in phase 1 trials involving patient-volunteers (typically, these patients have exhausted standard care options and enter phase 1 trials as a final shot at managing their disease). Language used by investigators in these studies is often suggestive of therapeutic benefit, even though meta-analyses of phase 1 studies show that chances of major clinical benefit in phase 1 studies are exceedingly low. In previous posts, I described my own experience with an ethics review committee that actually defended giving patients vague and almost meaningless information about the therapeutic benefits of phase 1 trial participation. Meantime, evidence from surveys indicate that phase 1 cancer patient-volunteers tend to overestimate the probability of therapeutic benefit.

In the July-August 2009 edition of the ethics journal IRB, Shlomo Koyfman and co-authors at NIH offer up a "Consent Form Template for Phase I Oncology Trials." Their recommendations are comprehensive and excellent. Among the items they recommend are:

• use of more therapeutically neutral language, like "research agent" instead of "therapy"

• disclosure of dose escalation design; in particular, the authors recommend that patients be informed about risks and benefits relative to the cohort they are entering.

• a statement (where appropriate) that patient-volunteers will not have the option of adjusting their dose assignment in the study

• a statement that "the chances that this agent will... allow you to live longer [is] very low."

One can quibble with various particulars (I think, for example, discussion of subtherapeutic dosing should be more explicit). But on the whole, these recommendations provide an excellent standard– along with NIH Guidance on Informed Consent for Gene Transfer Research– against which typical phase 1 cancer study consent forms should be measured. (photo credit: banlon1964)

Quack You! Medical Tourism and Stem Cells

In the September 2009 issue of Nature Biotechnology, Jane Qiu reports on a thriving trade in nonvalidated stem cell interventions for incurable illnesses ("Trading on Hope"). The article provides numerous examples of overseas clinics that cater primarily to North American and European clientele in offering pricey, unproven stem cell transplants for incurable conditions like spinal cord injury, Parkinson's disease, and autism. Many of these clinics make extravagant claims in their promotion materials.

Encouragingly, policy makers are beginning to take notice. China, for example, has issued new regulations on clinical application of novel interventions; it requires licensing for clinics that provide unproven stem cells. India has issued guidelines on stem cell research and therapy. As noted previously in this blog, the scientific society ISSCR issued guidelines urging clinicians to offer nonvalidated stem cell interventions to patients only in the context of clinical trials designed to test safety and efficacy. Problem is (according to the article), guidelines are sporadically enforced, if that.

I think there is much more that governments and professional societies can and should do to stem this unethical conduct. Though most of these clinics are located outside of North American and Europe, some overseas clinics have reputable, North American / European scientists and clinicians on their advisory board or have partnerships with biotechnology companies that are based in North America / Europe. Examples include Stemedica (which includes several Stanford and UCSD faculty on its advisory board), and Theravitae (which has involved close collaboration with University of Pittsburgh clinicians), and Vescell (which includes Nobelist Aaron Ciechanover on its scientific advisory board). All of these companies offer stem cell interventions to large numbers of patients outside trials, and make claims that their interventions are effective when, in fact, they remain unproven.

1- Research ethics policies should condemn scientist-clinicians who travel or collaborate abroad in delivering nonvalidated, potentially risky interventions overseas outside the context of a clinical trial. Policies should state clearly the imperative of subjecting nonvalidated interventions to systematic study.

2- Institutions should not allow these clinics to trade on their reputations, and should sanction faculty members who are involved in such activities.

3- professional societies in medical fields (e.g. cardiology) and research areas (stem cells, gene transfer) should steward the standing and credibility of their research field by developing policies and standards that discourage inappropriate activities-- through social pressure-- by providing a benchmark against which the conduct of scientists and clinicians can be judged.

(photo credit: Insert Photographer Here, 2006)

Accelerated Approval: Safe at Any Speed?

Drug regulatory authorities like the FDA have a mandate to protect public health by requiring and evaluating evidence of safety and efficacy before licensing new drugs for commercial sale. But for decades now, patient advocates have argued that FDA bureaucracy kills by keeping promising drugs from the IV's of terminal patients. In response to these criticisms, FDA and others have created new pathways for drug approval whereby drugs can be partially approved for sale on the basis of smaller, Phase 2 trials using surrogate endpoints (tumor shrinkage) instead of survival– provided drug companies confirm efficacy in subsequent trials.

This pathway, called "accelerated approval," is controversial because it allows companies to sell drugs whose efficacy and safety is not yet well established. True- the companies are obliged to run confirmatory studies, but a) how will confirmatory trials enroll enough subjects if patients know they might be randomized to standard, ineffective drugs, and they can get the drug outside a clinical trial? b) drug companies will not have sufficient incentive to run confirmatory studies once their drug is provisionally approved. c) drug companies stand to make lots of money selling unproven drugs to desperate patients in search of a cure.

In the most recent issue of Journal of Clinical Oncology, Elizabeth Richey and coauthors put these concerns to the test in an analysis "Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs." They find that:

• a very large percentage of new cancer drugs are initially approved under "accelerated approval." (37% approvals between 1995 and 2008)

• 63% of drugs receiving accelerated approval have their clinical benefit confirmed in subsequent studies

• drugs involving very rare cancers are often not subjected to confirmatory testing (42%); drugs for more common cancers are tested in confirmatory studies typically (71%-- though the percentage I calculated from their figures is actually higher- 86%)

• drugs receiving accelerated approval are twice as likely to receive black box warnings compared with drugs approved by the standard mechanism (21% vs. 10%)

• about half of non-orphan drugs approved under accelerated approval (47%) become first line treatment regimens in the National Comprehensive Cancer Network.

The authors see the glass half full on accelerated approval: to the title question of their article, the authors answer "Improved Access to Therapeutic Breakthroughs." (photo credit: Marxpix 2008)

Ted Kennedy: 1932 - 2009

Ted Kennedy, who died two days ago, championed many of the issues covered in this blog, among them access to health care, funding for research, and a strong drug regulatory system. To those who care deeply about these issues, his indefatigable advocacy will be missed.

Among the many landmark laws and regulations that owe their origin to Kennedy are U.S. policies on human protections. Way back when, as a freshman Senator, Kennedy chaired Senate hearings that revealed human research abuses like those committed in the Tuskegee Syphilis Study. He went on to introduce some of the first legislation calling for formal regulation of human research. His initial bill would have given the federal government broad authority to regulate both public and private research. However, it was ultimately overtaken by a weaker bill that called for the creation of a National Commission. Ultimately, Kennedy supported the latter bill under the condition that the Department of Health, Education, and Welfare (now HHS) issue regulations. The reports of the National Commission continue to have a towering influence over research ethics, and the regulations following from this law (45 CFR 46) are virtually unchanged today (photo credit: John Mcnab 2007)

Everything You Always Wanted to Know About Clinical Research in China, But Were Afraid to Ask

After scandals involving tainted toothpaste, poisonous pet food, adulterated milk, contaminated heparin, and counterfeit medicines, and a thriving trade in organs, one shudders to imagine how well human subjects are protected in drug studies performed in China. Apart from an occasional report in the medical literature, there is little easily accessible information about Chinese human protections: the regulations and laws, compliance and enforcement, and professional standards. This information would be interesting in its own right; however, it is all the more essential given trends towards trans-national trials.

A recent report issued the Medical Research Council (UK) provides some indication of China's system of human protections, and how researchers in countries like UK might proceed when locating trials in China. The executive summary finds that Chinese regulations substantially parallel those of the International Committee on Harmonization (ICH). Informed consent and independent ethics review is required for any study. However, the UK and China "differ greatly in their approaches to enforcing guidelines for the conduct of research at the national level. In China, although there is some scrutiny of clinical trials, there is comparatively little inspection or review of compliance." Other intriguing mentions are concerns about undue inducement in China: "the high costs of healthcare and medicines, and the dependence on local providers means that particular attention [for UK researchers pursuing studies in China] must be given to potential inducements to participate in research. Collaboration with China may offer attractive opportunities for large-scale recruitment, but potential UK collaborators must be alert to the risk that unethical inducements may be offered to potential participants. ... given the high cost of accessing health care in China, a ‘free health check’ may be a relatively greater inducement than it would be deemed to be in the UK."

A perusal of the Chinese regulations- at least the ones provided in this report- indicate the following:

• China places heavy emphasis on procedure (e.g. IRB review) and informed consent, rather than substance (e.g. prohibitions on certain practices; definitions of minimal risk; categories of patients)

• China seems to take a very permissive stand (like ICH) on the use of placebos. Indeed, there is no mention of studies involving placebo.

• There is no mention of justice considerations- for example, post-trial access or responsiveness.

(photo credit: 2 dogs, 07/03/25 12:32:09 Shanghai, 2007)

Help Wanted, Part 2

So, what are some of the intriguing ethical questions of Kolata's August 2d article? Here is one: when researchers conduct studies and ethics committees review protocols, resource allocation is an important consideration. If, as Kolata alleges, mediocre trials siphon eligible patients away from good trials, then there is a case to be made that IRBs and investigators need to ponder carefully the effects proposed trials will have on other studies- even when proposed trials have a favorable direct benefit-risk balance for volunteers who enter them.

Second, if resource allocation is a key consideration in realms where patients are scarce, investigators (and IRBs) need reliable criteria for assessing the broader social value of study protocols. They further need some way of being able to compare one protocol against a body of others that are either underway or in the pipeline. The current system provides no straightforward way of doing this.

Third, if 50% of trials fail to recruit sufficient numbers to produce meaningful results, investigators, IRBs, DSMBs, and granting agencies are doing a lousy job ensuring high ethical standards in human research. It is well established that, for any study to redeem the burdens that volunteers endure on enrollment, it must produce valuable findings. It is disturbing, to say the least, that many volunteers enter studies that go nowhere, and that investigators, IRBs, and funding agencies are not realistically projecting recruitment.

Last, Kolata suggests that many cancer trials are merely aimed at "polishing a doctor's résumé." It would make a useful contribution to the field of cancer research- and bioethics- to measure the frequency of this practice. Meantime, this inability of IRBs to detect this kind of conduct, and stop it in its tracks, signals an important deficiency in human protections. Which leads me to my next post... (photo credit: ziggy fresh 2006)

Help Wanted- For the War on Cancer

Earlier this week (Aug 2), Gina Kolata of the NYTimes ran a fascinating story about challenges recruiting patients to cancer clinical trials. The story contains interesting facts, credible claims, analysis, and unfortunately, some misleading conjectures. The problem of patient recruitment also invites some hard headed ethical analysis.

First the facts. According to the article, one in five National Cancer Institute-funded trials fails to enroll a single subject; half fail to recruit enough to produce meaningful results. Now some credible claims: many trials are "aimed at polishing a doctor's résumé, and produce meaningless results; many oncologists avoid cancer studies because they can be a money loser, and many patients shy away from trial participation- particularly when their cancer is less advanced and they can obtain treatment outside of trials.

The article, however, is swathed in some misleading conjectures. The article makes the suggestion that problems with recruitment are "one reason" and "the biggest barrier" to major strides in the "war on cancer" (hence the recruitment poster in the graphic above). Hard to reconcile this with Kolata's contention elsewhere that many trials are useless. It's also hard to square the claim with Kolata's point, earlier in the article, that trials involving really promising drugs usually have no problems with recruitment. In one famous case, a Phase 1 trial testing endostatin at Harvard received 1000 inquires from patients for 3 slots in the trial (Pop quiz: see if you can guess which New York Times reporter wrote an article on endostatin that many commentators criticized for sensationalizing the drug's promise?). Third, with only about 1 in 20 cancer drug candidates making it from phase 1 tests to FDA approval, a reasonable question to ask is whether preclinical researchers are validating their drug candidates properly. And finally, the article makes no mention of the fact that many studies have exceedingly narrow eligibility criteria. Many patients may be solicited for trial participation- but only a fraction meet eligibility criteria.

Still, Kolata's article is enlightening and raises a number of intriguing questions that demand ethical analysis. I'll discuss some of these in my next posting (photo credits: Joan Thewlis, 1918 Recruitment Poster, 2009).