WWW Open Letters

Tuesday, April 04, 2006

Follow-up to the March 29 letter on Schering-Plough study P03659 (NCT00160251)

Yesterday afternoon, I participated in a conference call with four representatives of Schering-Plough. They initiated the call after reading my open letter to Schering-Plough of March 29th. This post is not a letter, but a follow-up based on the information gathered in that conference call.

I talked with Ken Banta, Director of Strategic Communications, Robert Consalvo, Media Contact for PEG-Intron, Cecil B. Pickett, PhD, Senior Vice President and President, Schering-Plough Research Institute, and Robert J. Spiegel, MD, Senior Vice President, Medical Affairs and Chief Medical Officer. They addressed my questions, and gave me a clearer understanding of their rational for this study design. Although I still have some concerns about the study design, I was pleased that they were willing to talk with me about the protocol. Here are some of the questions I raised and the answers I received:

* How is "African-American" defined in this trial? Those who define themselves as "African-American" are considered "African-American". A patient can designate themselves as she wishes. It is important to note that several studies have shown that a higher percentage of those who self-identify as African-American are non-responsive to the standard HepC treatment (pegylated interferons and ribavirin) as compared to European-Americans. Schering-Plough acknowledged that the lack of a biological or other measurable means of defining population groups introduces complications in interpreting and applying these data.

* Can people of African-descent participate is this trial if they do not identify as African-American? Apparently so.

* Are African-Americans banned from this trial in an effort to increase genetic homogeneity? "That would be absurd." No, that is not the rationale.

* Are African-Americans banned from this trial because some studies have shown that African-Americans have lower neutrophil counts? No, neutrophil counts are very important when ribavirin is used, but ribavirin is not used in this trial. In addition, neutrophil counts are an inclusion criteria.

I asked if there were specific scientific or safety reasons for excluding African-Americans from this trial. I was not satisfied with their answers even though they were framed in the language of safety and science. For example, since we do not yet know if African-Americans (as a group) will show similar response rates to SCH 503034 as they do to the standard treatment, it seems that they should be included in the trial unless or until safety or scientific concerns suggest otherwise. Also, thorough and ongoing informed consent procedures would ensure that African-American study participants (and all other study participants) are aware of the risk of non-responsiveness over time or at higher doses. It is important to note that I have not reviewed the full protocol for this study. There could be clarifying information in that document, but that information, if it exists, was not conveyed to me during the conversation with Schering-Plough.

My interpretation is that since some studies have shown that African-Americans (as a group) respond differently to the standard HepC treatment (as compared to European-Americans, what about other ethnic groups?), it is more expedient to exclude African-Americans from the low-dose arms of the Phase II study of this new interferon based therapy. (African-Americans will be included in Phase III as mandated by law.) It seems they think this will make the data 'cleaner', but that comes at a cost to African-Americans who could potentially benefit from the low-dose drug in the trial, and it prevents researchers from studying the mechanism and effects of this drug in this population group. (Schering-Plough is currently running a separate single-dose clinical pharmacology study in African-Americans to partially address the latter concern.) It seems they feel they will save time by excluding African-Americans now. By their rationale, all people with HepC will receive a greater benefit if they can bring the drug to market sooner. In addition, Schering-Plough will be able to make money sooner.

Others, particularly the HepC and HIV advocacy groups from whom I first heard about this trial, contend that Schering-Plough's assumptions (African Americans will be more resistant to this drug, excluding them will save time, etc.) may not be correct, and that people's lives hang in the balance now. Given the information I have, I agree with this position.

My current research focuses on ethical and scientifically-responsible uses of race in biomedical research. The information I have suggests that this is not an ethical or scientifically-responsible use of race. As I noted in the original letter, defining 'race' is a complex issue that cannot be accomplished using only biological or scientific means. That makes the concept of 'race' particularly difficult to use in biomedical research, especially since it is a very real social concept that correlates strongly with certain health indicators. It is my position that this study, like many others, misuses the concept of 'race'. Fixing this problem requires a systematic and scientifically and socially-informed change in the way we understand, define and use race. Given yesterday's conversation, I hope that Schering-Plough will be on the leading edge of this change, if for no other reason than it will allow us all to produce better quality scientific and medical data that can be more easily and appropriately applied to individuals and population groups.

Let me express my gratitude again to the Schering-Plough representatives for talking with me about this issue. We may not agree on the immediate solution, but our conversation has helped advance my thought on this complex and important issue. Thank you.


Blogger Kevin T. Keith said...

If I understand their response correctly, it is known that self-identified African-Americans as a group have a higher concentration, compared to the population as a whole, of people for whom the standard treatment for HepC simply does not work. The trial sponsor is apparently concerned that including that population in the Phase II study will thus be more likely to enroll people for whom the experimental drug will also not work. (This assumption seems questionable to me, since they state they are not using one of the two drugs found in the standard treatment, but they may just be erring on the side of caution by removing any known source of subjects who might not be responsive to the treatment.)

The scientific rationale for the exclusion of this group would seem to be tied to the purpose of a Phase-II study. Studies of that type are intended to find a standard effective dose for a new drug that has already passed Phase I trials (which merely prove it is safe, not that it is effective), and to eliminate drugs that are not effective at any dose. The Phase II study tells doctors what dosage of the drug to prescribe in later Phase III studies, aimed at proving the drug is actually effective against the disease when compared with existing therapies. Phase II studies are conducted by giving a group of volunteers different doses of the drug, ranging from very low to above the expected effective dose, and seeing what percentage of subjects show a clinical response at each level. By definition, many of the study participants will be getting doses too low to be effective, and will show no response, and in practice there is never 100% responsiveness among subjects at any dosage level, no matter how high.

Under these circumstances, having a percentage of absolute non-responders in the study population - people who will not show benefit from the drug no matter what, for reasons of their own biology, not the pharmacodynamics of the medication - would certainly decrease the observed response rate noticeably. Phase II trials typically enroll only a few hundred people, usually divided into a number of different dosage groups. If, for instance, each group had 50 subjects, of whom, say, only 40 were expected to respond in the optimal-dosage group, having only one or two non-responders in each group could depress the apparent response rate up to 5% in the high-response group, and more in the low-response groups. This gives an inaccurate picture of the drug's effectiveness, and possibly mis-identifies the correct useful dosage. (To put that another way: it would correctly measure the response rates to the drug among the population as a whole, but underpredict them among the population for whom the drug might possibly be useful in the first place - the population who are not absolute non-responders.)

It makes sense to me to get the response number correct in the treatable population in order to understand how the drug can be used when it can be used at all, and then seek alternate therapies for those in whom it simply cannot be used. It is in the interests of everybody - the manufacturer, clinicians, patients, and even preliminary trial subjects - to know what the actual response rate to the drug is among the patients who are eligible to use it, and trials among that population are the only way to establish this.

From what I understand, it seems to me that the manufacturer's stated reason for excluding self-identified African-Americans from the trial - that that group includes likely non-responders who would skew the data for the actual target population - is reasonable on its face. The real question seems to me not whether that effectively excludes potentially responding African-Americans from the study (it probably does), but whether the manufacturer's assumption that African-Americans are likely non-responders to this drug (on the basis of non-response to a different drug) is reasonable. On that I have no opinion. I do suspect, however - on the basis of incomplete information, it's true - that the harm of excluding this group on the basis of a reasonable assumption about non-responsiveness would be less than the harm to all potential patients from having incorrect dosing information.

Assume this trial enrolls 300 people, and African-Americans would have been included at a level proportionate to their representation in the general population; that would give 12%, or 36, African-Americans in the trial, probably half of whom would have been in groups with dosages too low to be effective in the first place. So the impact of the exlusion is to prevent perhaps a few dozen patients from accessing an experimental drug that will almost undoubtedly not work for many of them anyway. The harm from not excluding them - again assuming the prediction of non-responsiveness in some of them is reasonable - would be that no one would ever know the actual, correct dose/response rates for the treatable population (including the thousands of patients in the Phase III study and the potentially millions who might use the medication if it proves effective - many of whom in both cases will be African-American). Giving the drug to a handful of African-American non-responders in Phase II would mean no African-American in Phase III or later, or anyone else, could be certain they were getting the right dose, or that the experimental results which proved the drug effective in the first place were even correct (again predicated on a reasonable assumption about non-responders). I don't see how that can be defended, and I also don't see that the patients' and advocates' perception that a Phase II study should be regarded as a treatment plan for their benefit - which it is not - should skew the design of the study to the detriment of every other person who ever uses the drug.

I am concerned about the leap from non-response to ribivarin to non-response to this new drug, but that is a technical question, not an ethics or policy question. I am aware of the systematic exclusion of important social groups, including ethnic groups, women, the elderly, and so forth, from clinical studies and the harmful clinical and social impact that has. I am also sympathetic to the desire among many patients to participate in early-phase studies as a means of access to new treatments. But I do not think study designs should be compromised out of deference to patients' desires (desires based on no rational belief that the drug will even help them - since the appropriate studies to prove that have not been done yet). I also do not think that systematic exclusion for reasons that materially affect the reliability of the study for all groups is unfair, even when it falls on an already disadvantaged group.

I appreciate your concern in this instance, but, allowing for my reservations about the fundamental clinical assumption being made here, I am not convinced you've made your case on ethical grounds.

April 05, 2006  
Blogger Karama said...

Thanks for writing, Kevin.

As it seems you realize, this is a complex scientific issue. It is, I argue, also an ethical one. I am proposing that we treat our research on humans as rigorously as we do research on organisms like Drosophila melanogaster, Caenorhabditis elegans, Danio rerio, Saccharomyces cerevisiae, Schizosaccharomyces pombe and others. Recent advances in population and molecular genomics and bioinformatics allow us to do so. Ethical principles like beneficence, nonmaleficence, integrity, and responsible conduct of research require we do so. This will not only produce an ethically grounded discipline of research, but it will also produce higher quality, more useful data. It's a big change though, one that requires a significant, socially and scientifically-based modification in the ways we think about human populations.

Thanks again. I hope you enjoyed your visit to Open Letters. You may also want to check out the companion blog So what can I do.

April 06, 2006  
Blogger TEST FOR ALL, CURE FOR ALL said...

Johanna Koskinen

As executive director of the Hepatitis C Multicultural Outreach, and an African-American, I am offended that Shering-Plough has been in on-going discussions about this issue, never once inviting our organization into the forum.
To date, all I've heard is how the "hep C community" has simply dismissed the outrage against this exclusion,not once stepping up to the plate to express their reasonings behind their "lack of concern." These organizations - some of which I have been involved with - are a disappointment to me and others who believed they were representing ALL people, and not a select few.

One of the reasons our organization was established had to do with the many MANY hep C organizations who so easily cut and paste buzz words into their mission statement, in order to fit the criteria necessary to be funded by pharmaceutical and government entities. It was clear to us last year that the minority focus would be hard and harsh, as groups who rarely ever interact with African Americans, would all of sudden claim, "Some of my best friends are,..." and the ever popular, "Why can't we just represent everyone?" Funny, how they are silent to this new -but old - reality, that where hep C is concerned, you can't stand for everyone, if you only acknowledge a few.

So now we have this exclusion issue. Where are the organizations? Where are the people who piled into the Regency Hotel last year for the Viral Hepatitis Conference in Washington D.C.? Where are the passionate advocates who spent a week sitting in on presentations, standing up and applauding for new ideas, insisting they would not lie down for anything less than a cure for hep C? Only now do I realize that they were never really that specific as to whom they were advocating for, except when it came time for them to publicize themselves.

Yes, I'm offended that our organization wasn't contacted about this exclusion, but I'm not surprised in the least. And we are in the midst of a formal response to this study, because though we don't necessarily question their methods in this one trial, we do question how they dismissed the opportunity to have another trial run right alongside this one, with the focus on those they've excluded.

So, the bottom line is that Shering-Plough is engaging in the social act of "Racialism" - the act of separating groups in order to arrive at a positive or a desired result. It the terms of scientific inquiry, I think it's called a "single-blind" experiment, which can be just as legitimate. The question remains, "Who is served?" Forgive me for answering my own question, but,
"When few are selected, it's the few who will be served."

April 07, 2006  
Blogger James Learned said...

Justifications Vary Depending on the Audience
James Learned
Hepatitis C Action & Advocacy Coalition (HAAC)

This post is a response to Karama’s write-up of her April 3 conversation with Schering-Plough representatives. I’d also like to clarify a few things that Kevin T. Keith brought up in his thoughtful post.

On March 17, 2006, a few of hepatitis C communiity advocates (including me) participated in a teleconferece with Schering-Plough representatives. Following that unsatisfactory teleconference, we issued a press release and backgrounder concerning the unusual exclusion of African-Americans from participation in the company’s Study P03659: PEG-Intron/REBETOL vs. PEG-Intron/SCH 503034 With and Without Ribavirin in Chronic Hepatitis C HCV-1 Peginterferon alfa/Ribavirin Nonresponders: A SCH 503034 Dose-Finding Phase 2 Study. (See

During our March 17 conference call, a Schering-Plough representative clearly stated that the company wanted “genetic homogeneity” in the Study P03659 population (whatever that means). Yet when Karama spoke with Schering-Plough representatives in April, she asked, “Are African-Americans banned from this trial in an effort to increase genetic homogeneity?” The Schering reply: "That would be absurd."

It’s also telling that, according to Karama’s post, the Schering representatives stated that neutrophil counts were not an issue in the company’s decision to exclude African-Americans from the trial. We were given an entirely different story in March. In fact, the likelihood of low neutrophil counts in African-Americans (which are generally lower, although not dangerously so), was the only safety reason offered by the Schering-Plough reps for the exclusion during our conversation. One ribavirin side effect for many people (not only African-Americans, of course), is neutropenia, which can lead to the immune system’s inability to deal successfully with some bacterial infections. If neutropenia occurs during treatment, the ribavirin dose is often lowered (which often means that the patient is less likely to achieve a successful response to treatment), Epogen injections are used to increase white blood cell counts, or, sometimes, the person stops treatment - one more injection is often one too many!

All that I can walk away with faced with these clear contradictions dependant, it seems, on whom company representatives are speaking with and when, is that no one outside of the company has yet to hear anything that remotely justifies the exclusion on a scientific and/or satety basis. Schering-Plough representatives have told at least some reporters interested in the issue that African-Americans were excluded from the Phase II trial because they were more likely to develop resistance to the experimental drug. There is no evidence that I am aware of to support this. Rather, it seems a smart move to confuse people by equating drug resistance to lower response rates.

Kevin T. Keith based much of his post on the assumption that ribavirin isn’t being used in Study P03659. In two of the six ongoing arms, however, ribavirin is being used. Interferon is used in every arm of the study. Mr. Keith also assumes, based on no research that I know of anyway, that ribavirin is the drug responsible for lower overall response rates in self-identified African-Americans. Based on published studies, however, interferon seems to be the culprit that results in the lower overall response rate, not the ribavirin (although ribavirin may also play a role).

It’s important to understand that Study P03659 is specifically designed for non-responders -people who have already gone through at least one full course of interferon plus ribavirin without success and who have HCV genotype 1, the HCV genotype that is least likely to respond to current treatment. Since self-identified African-Americans are, indeed, harder to treat in terms of lower overal response rates, this population absolutely qualifies for this Phase II trial as long as the individuals are eligible based on the other exclusion and inclusion criteria.

Although the primary goal of a Phase II trial is to identify the dose of the experimental drug that is both safe and effective, the effectiveness of the drug in all of the arms, particularly the dose that is most effective, is presented by the researchers and paid close attention to by healthcare providers, people with the relevant disease or condition (in this case, chronic HCV infection), advocates, and, not least, company stockholders.

Efficacy results are usually reported even after Phase I trials, although these trials involve very few people who take the experimental drug for a very short time. Two Phase I studies of SCH 503034 involved people with chronic HCV infection. In one of the Phase I studies, most of the participants took the experimental drug alone (as monotherapy) for 14 days. Other participants took placebo. (SCH 503034 Protease Inhibitor Monotherapy in Hepatitis C Virus Genotype-1 IFN-a Non-Responders). The other Phase I trial that included people with chronic HCV infection also involved a small number of participants over a short time. Participants took SCH 503034 monotherapy, pegylated interferon alfa 2b monotherapy, and/or the two in combination. (SCH 503034 HCV Protease Inhibitor Plus PEG-IFN a-2b in HCV-1 PEG-IFN a-2b Non-responders).

These small Phase I trials’ efficacy and safety results were reported at the 56th Annual American Association for the Study of Liver Diseases (AASLD) Conference in November 2005. The results are certainly interesting to those of us who recognize the need for better HCV treatment.

Visit the following websites to see the results of these Phase I studies and note the efficacy data that was presented (for what it’s worth):

National AIDS Treatment Advocacy Project (NATAP) at The results of these Phase I trials as presented at the AASLD conference, including slides, are available on the site. and

HCV Advocate: and

The larger question is how and why this trial was approved by so many Institutional Review Boards. Were the company’s smoke and mirrors effective with supposedly qualified reviewers? If so, why? Except for participants in the trial, no one in the patient community has seen a copy of the actual study protocol as far as I am aware. Schering-Plough has refused to share it with those of us who have raised concerns about the design.

As Johanna Koskinen eloguently wrote, “…the bottom line is that Schering-Plough is engaging in the social act of ‘Racialism’ - the act of separating groups in order to arrive at a positive or a desired result.”

April 25, 2006  
Blogger Karama said...

You may want to check out this full-length article in the NJ Star-Ledger: "Race and medicine: Beyond black and white: Dispute between AIDS advocates and Schering-Plough scientists highlights conflicts in research" by George Jordan, which appeared on Sunday, April 30, 2006.

May 01, 2006  

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