Vulnerability and Informed Consent

I spent most of today discussing ethics in clinical trials at a conference produced by Leo Intelligence in San Diego with a fascinating group of people from IRBs, sponsor companies, and CROs.  It was a really good small meeting, and I hope they put it on again next year and give it a chance to grow.

In the morning we reviewed how the relentless drive for new, willing, and preferably treatment naive patients is pushing clinical research out to farther and farther away places, countries that may have weak, stressed or crumbling health care delivery systems that struggle to serve their citizens' basic medical needs.  We discussed some of  the major ethical policy issues of international clinical research, especially in developing countries, such as placebo controls, clinical trials as treatment or even marketing, and vulnerability and consent.  (The slide set for this talk can be found here.)  Some countries have legislated and developed and invested, such as India and Brazil (and other South American countries), many countries of the post-WWII east.  Some countries have grown a clinical research enterprise out of the opportunism of a health crisis, such as Russia and the Ukraine following the Chernobyl disaster.  Even in these countries we see challenges in obtaining truly informed, voluntarily given consent. Cultural differences can take the standard western idea of consent and stand it on its head.  

For example, the Belmont Report's first principal of respect for persons, usually defined as the autonomy of the individual, is considered a universal ethical truth, one which even the ethical relativists can accept as valid for all.  Except that in many non-Western cultures where the collective is valued above individual - where "the needs of the many outweigh the needs of the few, or the one" - the idea of a patient making a decision to participate in a clinical trial based on her self-interest quite stretches the imagination.  

Now consider this same patient, who has little experience making a decision that is not at least informed by or simply made outright for her by another member of her family, and add to that the fact that she cannot read; not her own language and certainly not English.  Then add finally the factor that her physician is an even more powerful figure in her life than her husband or father, and whatever he (or she) says has the weight of the voice of God himself.  Now the idea of slapping a 19 page consent form in front of that patient, getting her signature or mark, and going to sleep at night believing that we have met our obligation to obtain true, voluntary informed consent to participate in a study is truly laughable.

And yet that's what we do.  

And this is not all.  This afternoon's keynote speaker was Andy Mikulak, of Max's Ring of Fire, who gave a patient's perspective of participating in clinical trials.  Andy is not a researcher, or IRB member.  He is a father, and his son Max taught Andy much about participating in clinical trials - right up until the time he died of neuroblastoma at age 7.  Since Max's death Andy has coped with his grief by becoming a patient advocate and raising money and awareness for pediatric cancer research.  Check out the website and click on a couple of videos.  Your eyes will not stay dry.  

Andy gave a short talk intended to explain to us why patients go into clinical trials, and what we could do to make the experience better and more useful for patients.  He said patients go into trials to live, to survive, and sometimes because they cannot get treatment for their serious disease any other way.  He suggested to researchers that if they meet their patients' needs, their own needs for data and results will be met.  He also admonished us for making informed consent forms too complicated.  He said that he and other patient families routinely seek out other patients for 'true' information' about trials, because the sponsor/IRB provided documents are written "to protect the institution first, and inform the patient second".  He said the language used in consents did not meet his needs or those of other patient families: the language was too obtuse and not intended to inform.  There is too much protectionist, defensive language.  And this is not a guy who cannot read beyond the 6th grade level; Andy had no problem discussing the preclinical data of various chemo agents his son was treated with, so the issue was not the level of the language, but that the language was not intended to inform.  

This got a big response from the IRB members in the room, whose nominal role is protect patients, yet some IRBs seem to be a driving force behind the ever-lengthening consents in recent decades.  When I have asked them why, the most prevalent reason seems to be: "we want to anticipate patient questions so in case they don't know what to ask, it's all there in the document."  Fair enough; many patients don't know what to ask or are too timid to ask.  But why then do we not train and then empower the investigator to provide information, to anticipate questions and prompt for them?  Have we completely abandoned the investigator's role in providing risks and other information to patients?  (For information about the learned intermediary and its rise and fall in the pharmaceutical world, as well as clues as to how we became so protectionist, see Perez v Wyeth Labs.) It seems that instead of using the consent form as the documentation of the consent conversation, and the basis for discussion, we are allowing the form to replace the process almost entirely.  

And in the end, studies show that many patients - western and non-western alike - do not understand that they are involved in a study, that they have right to withdraw, what the risks are and that they may receive treatment with a comparator (or placebo).  So clearly the answer isn't to be found by adding more pages to the consent form other than to make the institution's lawyers feel better.  

The plane is boarding.  Next post, some thoughts about where the low hanging fruit might be found; how we can minimize the mistakes that we make and better protect the patients we study.

Informed Consent May Be Compromised & Medical Device reform

In a study published today in IRB: Ethics and Human Research (free abstract, $ subscription for full article), concluded that unrealistic optimism is prevalent among some clinical study subjects  and that it "has the potential to compromise informed consent".  Seventy-two early phase cancer study subjects completed questionnaires designed to assess their level of understanding of the study's purpose as well as to detect signs of unrealistic optimism.  Unrealistic optimism is defined as "specific to a situation and consider (sic) a form of bias...and is distinct from "dispositional optimism, which is a general outlook on life and is neither realistic nor unrealistic".  Questions to reveal unrealistic optimism revolved around the likelihood of particular individual outcomes as compared with other study participants, or the participant's tendency to give greater weight to possible benefits than possible risks.  According to the study's findings, 72 percent of the subjects accurately understood the objectives of the cancer trial in terms of potential benefits to future cancer patients rather than directly to themselves, which means that 28% of respondents did not clearly separate those facts.  The researchers' concluded that we need to improve the informed consent process by "paying more attention to how patients apply the consent information to themselves".  Reporting on the trial is found online at Medical News Today.  


In other news, last week the FDA announced proposed changes to improve the agency's 510(k) program for approving medical devices for sale.  Some of the recommendations include:

• consolidate the terms “indication for use” and “intended use” into a single term, “intended use”; 
• expand its statutory authority to consider off-label use when determining the intended use of a device; 
•  issue guidance on when a device should no longer be available for use as a  predicate;  
•  issue a regulation on its rescission authority;  
•  issue guidance to create a “Class IIb”; and  
•  seek greater authorities to require postmarket surveillance studies as a condition of clearance for certain devices.

The full report is here (PDF).  FierceMedicalDevices reported generally favorable reception of this news by the industry.  We have a long way to go until any of the report's recommendations become regulation, but now at least we have some ideas of which way the agency's thinking is going.  At the same time, the Wall Street Journal carried an op-ed by President Obama discussing the balance between regulator and free market. It all makes for very interesting reading.

Questions

A former GCP student sent me this question today:  "Can you tell me if it is OK for a principal investigator to have his signature Xeroxed onto the ICF for the subject to sign?  This doesn’t seem appropriate to me, but I am having trouble finding anything that says otherwise.  Also, can they sign the ICF in advance of the subject signature, or should it always be after the subject consents to be in the study."

Every class term starts with my passionate admonishment that GCP is more than just knowing the rules, in fact knowing the rules is only a small part of the task.  To understand the rules, we have to think through why those rules exist.  Reading this students' question gave me an unsettling feeling that I am not being very effective at getting this point across.

Whether there is or is not a regulation about pre-signing informed consent forms, whether in ink or by photocopying, stamping, or smoke signals, is entirely beside the point.  The point is not the signature at all.   The point is what the signature represents.  (*Extra credit: is the investigator's signature even required under US regulations?)  My students have all been taught that the signature represents that the investigator's obligations to the patient with respect to the nature of the study, risks and discomforts, alternative treatments, right to withdraw and all the other elements of consent have been met.  Therefore, of course it is unacceptable to pre-sign the form, Xerox a signature onto the form or whatever else this investigator has thought up.



*Answer: No, only the patient's (21CFR 50.27(a)). Under ICH guidelines the consent should be signed by the patient and by the person who conducted the informed consent discussion (ICH E6 4.8.8).

Air France and Coast Fallout

AccessCR links to a piece from Epoch Times about fraudulent trials producing clinical data for some of the more popular asthma drugs out there, like Serevent, Singulair, Flovent, etc., etc., according to charges brought by a former sub-investigator on the trials named Dr. Robert Davidson. According to the piece,"Davidson charges that during aggressive recruitment schemes in the late 1990s, patients with abnormal EKGs, multiple risk factors for coronary artery disease, arrhythmias, pulmonary embolisms, rheumatic fever histories, acute illnesses, and even pituitary tumors were enrolled with impunity in trials that earned investigators as much as $10,000 per patient."

The article quotes FDA inspection reports that cite dry-labbed patient diary cards, investigators who were advised not to state the risks to potential subjects, investigators pressuring patients to participate against their wishes, patients enrolled in clear violation of entry criteria, and on and on. I searched the FDA's warning letter listings but was unable to turn up the documents, so I will have to take Epoch Times at their word. FDA has since mandated new safety warnings in the labels of several of these drugs.

Yikes. I often use the analogy with my students of plane crashes. Transportation safety people study plane crashes because in doing so they learn to make air travel safer than by studying the hundreds of thousands of flights that go off unremarkably every year. However focusing on air crashes, especially in today's intense news cycle, can make them seem a lot more common than they are, and the public can lose sight of the fact that airplanes simply do not fall out of the sky without warning or reason, although after what happened to Air France this week, that possibility seems frighteningly more likely than it should. In teaching future clinical research professionals, we focus on the bad things, like Robert Fiddes, or the Jesse Gelsinger case, so we can learn what to be on guard for, and it can seem like there are only bad things and bad actors. This story adds fuel to that fire.

AccessCR is a nice resource out of Australia whose biweekly email updates should be of interest to clinical research professionals. It is free. According to their website they offer international perspectives on regulatory issues, public perceptions, trials discontinued for whatever region and regional news from the hot emerging markets as well as the more tired old ones, and industry news, all conveyed with a bit of unmistakable Aussie flair. I read it as soon as it comes out.

In other news, there were signs this week of fallout in the US IRB space from the Coast affair. Over a small technicality, all of a sponsor's study screening activities in entire state were brought to a screeching halt. I can't share much detail without disclosing potentially proprietary information, but it seems very clear - at least to me - that the IRB over-reacted to their own mistake in approving a consent several months ago without certain technical elements having to do with state privacy laws and went into box-checking mode, rescinding their previous approval and shutting down patient screening activities until those elements - none of which had anything to do with safety or procedures or even confidentiality of patient information - were added. The best part was that, again according to state law, which the IRB was unable to cite upon request, these elements needed to be presented in the consent document in - wait for it - 14 point font. Yes. Patient screening activities suspended not for safety concerns, but for font size. I fear that we are in store for much more of this kind of over-reaction and box-checking mentality from US IRBs if they even think that what happened to Coast could happen to them as well. And why couldn't it? In a Kafka-esque world such as Coast found themselves, anything is possible.

Informed Consent, Helsinki and Conflict of Interest

The Pfizer Trovan Case, Still

The New England Journal of Medicine has a piece this week on the problems of informed consent in the increasingly globalized environment of clinical trials (h/t D. Karpf). The article specifically unpacks the ethical rationale for the January 2009 opinion in the case of Abdullahi v Pfizer by the U.S Court of Appeals for the Second Circuit which covers New York, Connecticut and Vermont (and is the current home of Judge Sonia Sotomayor, thought by many at this writing to be on Obama's shortlist for Justice Souter's recently vacated Supreme Court seat). The case is brought by the families of young victims from the now-notorious 1996 Pfizer Trovan trial in Kano, Nigeria.


The facts of the case are these: during an outbreak of meningitis, Pfizer brought non-local physicians to the Kano Infectious Diseases Hospital to conduct a trial of its antibiotic Trovan against a low dose of US-marketed Rocephin. The study participants were 200 sick children, half of whom received Trovan; the oral formulation of Trovan had not been previously tested in a pediatric setting. The dosing portion of the trial lasted two weeks at which point the Pfizer team decamped, leaving no continuing safety monitoring or care. Eleven children died, five randomized to Trovan and six to Rocephin; other children became blind, deaf, paralyzed or brain-damaged, according to case documents. The families allege these results were directly related to the trial. The families specifically allege that Pfizer and the Nigerian government, working together, failed to secure informed consent of either the juvenile participants or their parents and 'failed to disclose or explain the experimental nature of the study or the serious risks involved' and failed to inform them of the availability of effective alternative treatment that was available at the hospital from Medicins sans Frontieres.


Pfizer managed for several years to avoid having the case heard at trial by successfully arguing that there exists no international norm requiring physicians to obtain informed consent, thus eliminating all question as to why the public holds the pharmaceutical industry in such contempt. My GCP students could tell you after the first class meeting, and it turns out the Second Circuit agrees, that there most certainly is an international norm for requiring informed consent, in fact there are several. The Appeals Court reversed the trial court's dismissal of the US lawsuit (once the case finally made it to trial following a report by the Nigerian Ministry of Health concluding the study had violated Nigerian law), and sent the case back to trial, citing the following codes: The Nuremberg Code of 1947, the International Covenant on Civil and Political Rights of 1976, the Declaration of Helsinki (more on this in a minute), and CIOMS' International Ethical Guidelines for Biomedical Research Involving Human Subjects. All of these state, in one way or another, that the investigator must obtain voluntary, freely-given informed consent before subjecting a human to experimental treatment.


The court found these norms not only international, but universal, and specific. It noted that while 'promoting the global use of essential medicines can help reduce the spread of contagious disease,' to conduct clinical trials in 'other countries' without informed consent 'fosters distrust and resistance... to critical public health initiatives in which pharmaceutical companies play a key role'. You don't say. Evidence of this mistrust was found right back in Kano, where the local population boycotted international pharmaceutical companies' efforts to provide polio vaccinations during the 2004 epidemic, dealing a serious blow to worldwide efforts at polio eradication.



Whither the FDA and Helsinki?

I also came across a comment published earlier this year in The Lancet worrying about the abandonment by the FDA late last year of the Declaration of Helsinki as the basis for acceptance of foreign data in US marketing applications. The PDF download is here. The new basis for acceptance is the ICH Good Clinical Practice Guideline. The authors are not impressed with the FDA's rationale for this switch, stating that the ICH GCP guideline lacks 'moral authority' due to the fact that its signatories are fewer and more, well, Western, and that the guideline focuses on regulatory harmonization than on clinical trial conduct.


Anybody who has been paying attention for the past decade knows that the issue here really is the use of placebo controls in clinical trials: Helsinki has steadily moved away from their acceptability, with most emerging nations' health authorities following suit, while the FDA maintains that placebo controls are necessary for scientific rigor and can be made safe for patients if designed correctly and monitored appropriately. I am pretty sure we are not going to settle this question here, but I was struck by the authors' assertion that the GCP guideline lacks moral authority. This comes as a bit of a surprise to all of us who teach GCP around the world and to the many industrialized nations of the world for whom the ICH guideline is the accepted standard for clinical trial conduct and is the model for the GCP regulations of many emerging nations.



Here is Somebody You Don't Want to Be

Getting caught, with good reason, in the never-ending swirl surrounding the use of anti-psychotics in pediatric patients is this University of Texas researcher. She initially attracted the white hot light of US Senator Chuck Grassley's scrutiny by reporting having received $600 from pharma companies, but neglecting to mention the $230,000 paid to her by GSK. The real problem is not about the financial disclosure or lack thereof. The real problem is the fact that this physician was paid these fees apparently for co-authoring the 1998 sponsor-ghostwritten report on the Paxil pediatric study #329 which stated that Paxil was both safe and effective in children when in fact, as it turns out from internal emails, the company already knew at the time the study was negative. Dr Wagner was also paid for speaking appearances on behalf of the drug and the study in a variety of venues, some posh. The Alliance for Human Research Protection has a complete rundown, here, including the internal company memos. Ouch.


Last night my GCP class discussed the idea of rules, of breaking the rules, and the concept of the slippery slope. I feel better about the future on this industry when I know it is going to be in the hands of people who get that concept.


Here is what happens when we don't get it. I recommend reading this on an empty stomach.