Conference Paper: Full Disclosure of the “Raw Data” of Research on Humans: Citizens’ Rights, Product Manufacturer’s Obligations and the Quality of the Scientific Database

23 10 2009

Dennis J. Mazur
Oregon Health and Sciences University

To read this article and its associated commentaries for free just click on the PDF links below.

Mazur PDF

Commentary 1 PDF - Alicia Hall (California State University, Fresno)

Commentary 2 PDF - Karen Melham (University of Oxford)

In order to post your comment and response, please use the comments box at the bottom of this post. All comments are moderated and will appear shortly after they are submitted.

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Abstract

More work needs to be done across academic boundaries in the area of rights of study volunteers, consumers, and patients related to full and open disclosure of risk information related to medical products and the obligations of product manufacturers to provide this information about their medical products.

While emphasizing risk disclosure to patients in the patient-physician relationship through the concepts of consent and informed consent, society protects the product manufacturer in many ways from its obligations of full and open disclosure of risks related to its medical products. Here, for example, product manufacturers may insist that the academic research and medical institutions and their scientific investigators—involved in securing the study volunteers for study and obligated to carefully monitor all study volunteers during study participation—not disclose new risk information to the public about new drugs being tested on human research volunteers without full permission of the product manufacturer. Here, the product manufacturer assumes it has the legal right to restrict investigators’ and medical institutions’ disclosure of the risks—that these parties see occurring in the study participants who are under their care—through non-disclosure contracts.

This paper reviews the origins of study volunteer, consumer, and patient rights related to risk disclosure and the obligations of product manufacturers related to disclosures related to their medical products. Here, the citizen is the subject of a research study who volunteers his or her participation in order to benefit present and future generations in the development of more accurate scientific knowledge. With this voluntary participation, that same study volunteer agrees to bear the risks of death and morbidity from adverse outcomes that befall him or her during the research study and bears the often heavier burden of risks and effects of unknown mechanisms of action from studies of newly developed drugs. The citizen is not only the study volunteer, but also the consumer and patient listening for new medical products that might be helpful to extend life or at least to improve the quality of life.

But what does it mean to say that the research study participant agrees to bear risks for the goal of development of scientific knowledge and what rights guarantee that the study sponsor, the product manufacturer, fulfills the requirements of free and open disclosure which is necessary for any development of scientific knowledge? In particular, what are the rights accorded to research study volunteers, consumers, and patients for free and open disclosure of risks related to newly designed medical products when product manufacturers’ attempts to bypass their obligations of disclosing risk information to the public related to the new products under study in human volunteers as such risks become known during research trials involving humans? In the United States, the Freedom of Information Act may be used to attempt to garner raw data related to scientific studies from federal regulators, but where is the open disclosure of the raw data held by product manufacturers who are the primary repositories of data related to risk information from these research trials?

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19 responses

23 10 2009
Dennis Mazur

Alicia and Karen,

I want to thank you both for your commentaries on this paper on the notion of informed consent as it related to the “raw data” of clinical science as it applies to medical products.

As we examine “raw data” in human trials research on medical products, it is important to recognize at the outset that raw data (as they are obtained through observations and measurement) on human study participants are essentially non-obtainable without the human study volunteers who participate in the trials. No matter what scientific hypothesis has been developed for research, no matter how creative the (1) study objective, (2) the design methodology, (3) the data collection, (4) data analyzes, (5) data interpretations, and (6) financing of the study itself, one overriding fact remains: the data is only there because of the agreement of the study participant to volunteer his or her time, effort, and willingness to bear the risks of dying or bearing irreversible outcomes impacting their quality of life in the study. While each researcher and the product manufacturer wants to capture his or her ownership of the research study in terms of his or her contribution(s) to any one or more of the above six components of a research trial on a medical product, it is the study participant who is owed the most for his or her unique contribution to the data obtained in the study. Yet, today, even in courts across developed countries, there is little recognition of the contribution of each study participant to the research trial.

In relation to informed consent, there is no statement even in current research study informed consent forms that relates to the fact that the research data in a medical product’s study might not be published by the product manufacturer because of the fact that the research trial produces “negative results” about the medical product from the manufacturer’s standpoint. For example, in the case of a study drug, a set of research trials on a product might simply result in the fact that the drug’s effects on humans from a benefit (effectiveness) standpoint are no better than placebo. If this research study is completed before the drug is approved for sales and marketing by regulators, the drug would not be approved. However, if research trials are done post-drug approval and the same results are obtained (drug benefits less than or the same as placebo), the product manufacturer may simply just not publish the results of this post-approval trial for fear of harming the product’s sales in a country.

In considering research today, there is little defining of the rights of study participants as contrasted with the obligations of product manufacturers to study participants, and this needs to change. Considerations of rights of study participants to their own data in aggregate obtained in research trials should be recognized as a minimal duty owed to the research participant by researchers, product manufacturers, courts and legislatures.

Dennis

23 10 2009
Mary Ann

Dennis,

Your points are definitely pertinent to the ongoing debates about television drug advertising to consumers. Historically, I believe it was the case that car manufacturers first advertised to consumers the chance of obtaining credit to purchase a car in the first place. This then led to consumers making assumptions that since they could obtain credit for a purchase, they somehow possessed the capability of actually paying for the car. This was not necessarily the case. With the introduciton of direct-to-conumer advertising of prescription drugs on television, drug manufacturers lead consumers to believe that they need the drugs being advertised before they have even seen their doctor about the problem. Interestingly, given the success of such advertising, consumers are buying into the manufacturer’s logic, and this is not right. What are your perspectives on this point?

Mary Ann

23 10 2009
Dennis Mazur

Mary Ann,

Thank you for your comments. Your point about car sales, credit, and consumer perceptions is an important one. With respect to direct-to-consumer advertising of prescription medicines, such advertising has so far been legalized in only two countries, the United States and New Zealand. In the US, direct-to-consumer advertising has been viewed as a definite benefit by the product manufacturers who purchase the advertising for their product (as sales of its product increase). In terms of consumer interest, two points need to be made.

First, it is definitely the case that a consumer’s or patient’s insurance payers and their managed care organizations are not providing consumers with information about newly approved prescription drugs when the payers and the managed care organizations have less expensive alternatives already on their formulary. Thus, heretofore, access to information about new prescription medicines prior to direct-to-consumer advertising over television was often difficult for most consumers to hear obtain.

Second, while it is the case that consumers may want to hear about “newly developed” medical products related to their treatments (regardless of what their insurance carrier or health maintenance organization want), there is still a lack of quality information contained in direct-to-consumer advertising. In addition, direct-to-consumer advertisements are not previewed by regulatory agencies in the U.S. prior to their airing on television. Since there is no regulatory pre-review of ads in the U.S., the only response the regulatory agency has is after-the-fact of the actual airing of the ad. After the actual ad’s airing on televisions, regulatory agencies can hear and decide whether and when to respond to consumers’, consumer groups’, patients’, physicians’, and others’ complaints about a specific ad’s content.

One possible solution is through the development of high quality screening criteria for pre-review of such ads such that these criteria applied to an ad “before the ad ever airs”. This would be one way to improve today’s ad contents based on scientific evidence, assuming that the criteria selected are based on scientific grounds translated into a language that could be understood by the members of the public who view the ads.

Dennis

23 10 2009
Mary Ann

Dennis,
What are you ideas on how to get consumer feedback on the prescription drug commercials before they are aired?

My suggestion would be to possibly have several groups divided by age and educational level that could view the commercials before they are aired and provide feedback to regulators.

Mary Ann

23 10 2009
Dennis Mazur

Mary Ann.

With your comments on review and assessment of prescription drug ads, you are getting into a set of key questions related to consumers, product manufacturers, and other stakeholders in direct-to-consumer advertising over broadcast airways. To further clarity these issues, let us take note of the following points:

1. In the United States, guidelines for direct-to-consumer advertising of prescription drugs need to fulfill the requirements of the U.S. Code of Federal Regulations. One would need an assessment of this U.S. Code’s criteria for prescription drug advertising in relationship to other stakeholders in the discussion.

2. The list of stakeholders in the direct-to-consumer advertising of prescription medicines is quite long. Stakeholders include consumers, consumer groups, patients, physicians and other health and medical care providers, pharmacists, product manufacturers, advertisers, regulators, legislators, judges, insurers, health maintenance organizations and other health and medical care delivery institutions and organizations, among others.

3. Within this arena of stakeholders, the potential for conflict of interest is rife forcing a search for answers to many new questions. Key questions related to all stakeholders involve the following fact. It is a fact today that some consumer groups receive funding from product manufacturers. Key questions surrounding this fact are the following:

3.1 Should this practice be allowed to continue or be banned entirely within a country?

3.2 If the practice is allowed to continue within a country, what parameters should be used to regulate the practice?

These are examples of a broad range of topics for future interdisciplinary research that is the continued focus of this conference.

Dennis

23 10 2009
Sam Rickless

Dear Dennis,

I wonder whether you have any thoughts about the appropriateness of the reasonable person standard of disclosure. It seems to me that different reasonable people might want to know different things about the possible risks and benefits of a particular medical intervention. Some reasonable people are quite risk-averse, others not so much. Furthermore, if the test is whether a reasonable person in the relevant patient’s position would want to know this or that, there is a question about whether it is reasonable to suppose that the medical intervener could have known what the relevant patient’s position is. Suppose, for example, that the patient is an actor and cares greatly that the medical intervention will not affect the use of his eyebrows, but suppose further that the medical intervener does not know this and could not reasonably have been expected to know this. As it happens, the relevant treatment poses some small risk to the patient’s eyebrows, a risk that most reasonable people who are not actors would be more than willing to take. Should we hold the medical intervener to the reasonable person standard of disclosure?

cheers,

Sam

25 10 2009
Dennis Mazur

Sam,

If we examine Judge Spottswood Robinson’s original use of the phrase “reasonable person standard” in the landmark U.S. federal decision, Canterbury v. Spence, Judge Robinson interprets “reasonable person” in one and only one way: A jury must view the information disclosed by a physician to the patient who has brought the physician to court in terms of “what a reasonable person in that particular patient’s position” would want to know about the medical intervention in question. So the referent of the term “reasonable person” is not the theoretical reasonable person, but the reasonable person in the position of the patient who is considering to either follow the physician’s recommendation on the intervention in question or not. Judge Robinson’s view here is of the traditional patient-physician relationship found in the 1970s in the U.S. where the physician has followed the patient over time and has over that period of care learned quite a bit about what the patient would want from that physician in terms of information.

Interestingly, the House of Lords and the High Court of Australia place a high degree of emphasis on whether the patient in question asked the physician any questions related to the intervention and in turn how the physician answered those questions of the patient. Judge Robinson in Canterbury views informed consent from the perspective of the physician’s obligations of disclosure to the patient without the patient having to ask any questions at all.

Dennis

26 10 2009
Sam Rickless

Thanks, Dennis. That is helpful. But I am still curious. If the standard to which a physician is held is what a reasonable person in the patient’s position would want to know, then this standard places an extreme burden on any physician who wants to protect herself against liability. Arguably, the burden is too extreme. For in order to indemnify herself against potential lawsuits, the physician must extract from the patient *everything* there is to know about the patient’s situation that *might* be relevant to the desirability of the medical intervention at issue. Shouldn’t patients too have certain responsibilities with respect to their physicians, namely to disclose facts about them that *might* be relevant to the desirability of the medical intervention?

cheers,

Sam

26 10 2009
Dennis Mazur

Sam,

You are quite right in terms of the burden that is placed upon a physician under a reasonable person standard.

Interestingly, the main force of the reasonable person standard comes from only one key type of risk: the severe adverse outcome. It is very easy for physicians to say that risks that are in the range of 1 in 10,000 or less do not have to be disclosed because of their low chance of occurence (as they typically might under a professional standard of disclosure). However, the fact of the matter is that severe adverse outcomes at 1 in a 1,000,000 do in fact occur. Take for example the dystonia suffered by a young woman in the United States after receiving an H1N1 vaccine. This is further complicated by the fact that it is reported that typically 50% of physicians do not get regular flu shots themselves in their own care. In my institution, the number is closer to 60% of physicians refusing flu shots. In this situation, in the case of physicians, it seems that physicians are rejecting a nationally recommended intervention, that is, routine regular flu shots, because of the severe adverse outcomes that exist with the regular flu vaccine in their own case. Here, the refusing physicians know the severe adverse outcomes at their low chance of occurrence and refuse the regular flu shot. What should one then say about patients’ who want to know about severe adverse outcomes at low probabilies of intervention when they must decide on a medical intervention?

Also, bear in mind that physicians are the one seeing the patients with flu symptoms, thus, not only are they refusing regular flu vaccination on the basis of chance of severe adverse outcomes of low probability befalling them, but they are the ones caring for the flu vicitims and possibly transmitting the disease when contacting patient who do not have yet have the flu.

Dennis

26 10 2009
Jerry Suls

Mazur’s paper really helps to provide a grounding for contemporary debates about research ethics and use of research data.

Although I was a Chair of a university IRB, I was not fully aware of the history of the consent of consent and informed consent. I do believe the question of research generalizability will continue to be problematic. The line between research and pedagogical demonstrations is a fuzzy one. I also have learned recently that some institutions allow instructors to collect data purely as demonstrations but then request permission to treat the data as generalizable and thereby publishable- this seems like a questionable practice.

26 10 2009
Dennis Mazur

Jerry,

Your point about the need to establish criteria for distinguishing “a scientific research study conducted on human study participants” and “pedagogical demonstrations” is a key point. It emphasizes the failure to adequately define research on humans in general. It also points to the need for further clarification of “research studies on human participants related to risk”.

In many institutions, such a pedagogical demonstration would need to come to an institutional review board (IRB) and a determination made by that IRB before the project ever starts. The IRB would make a determination of whether the project is itself a “minimal risk study” or not.

This distinction–whether the study is “minimal risk” or not?–is itself a determination made by the IRB, not the researcher, the research team, or the product manufacturer. Indeed, in many institutions, the submission of a pedagogical study for permission to submit for publication in a research journal would be a “red flag” that the researcher, the research team, and the product manufacturer are in need of “re-education” by the IRB that projects need to come to the IRB for determinations whether they are (1) research or not and (2) if research, whether minimal risk or not, all prior to their inception, not after their completion.

I further discuss such distinctions pertinent to IRB review in a book where I share my experiences as chairperson of two IRBs (one institutional; one regional) published by Johns Hopkins University Press,

Evaluating the Science and Ethics of Research on Humans:
A Guide for IRB Members.

Jerry, as you have suggested, the need for further clarification of concepts can only further help IRB in their task of protecting human study participants. This task is an important one for cross-disciplinary studies which remains the focus of this conference.

Dennis

27 10 2009
Paul

Dennis,

I feel that both informed consent and communication about risk are very important topics today. This is especially true for people who are at high risk and are not knowledgeable about their own medical conditions. As well, they are not knowledgeable regarding what they should to to be more alert about what they themselves can do. Key here is communication in a way that patients can understand what is being said to them.

Dennis, do you have any thoughts on this?

Paul

27 10 2009
Paul

Paul,

I agree with you regarding the difficulties that exist in the areas of risk communication both in general in society and particularly in the patient-physician relationship.

Let us focus on risk communication in the patient-physician relationship.

If we break down medical risk at a first level of analysis, one has (1) the actual risk itself in terms of an outcome (that is, an adverse outcome), and (2) the chance (probability) that the risk will occur.

In the case of risk as an “adverse outcomes”, let us take the case of the term “stroke”. When many patients consider the term “stroke”, they think primarily of motor paralysis or speech paralysis or massive stroke leading to death. However, a blockage can occur to any artery leading to any organ in the body, and damage to the organ supplied by the artery. Thus, “stroke” as defined by blockage of an artery (or arterial occlusion) can occur, not just in the brain, brainstem, and spinal cord, but any organ in the body.

In the case of chance (probability), my colleagues and I have found that the majority of patients in our studies do not want physicians to use “numbers” when the physician discloses risks to them. Instead, the majority of patient prefer to use qualitative expressions of chance (probability) such as “rare”, “probable”, “possible”, and the like. The problem here is that these patient do not immediately recognize that different reasonable person can assign very different numbers (where there may be magnitudes of difference) to the same verbable proability term. For example, depending on the context, a reasonable person could assign any one of following numbers to the term “rare”: 1 in 10, 1 in 100, 1 in 1000, 1 in 10000, 1 in 1000000, and so on.

Paul, great question!!!

Dennis

27 10 2009
Dennis

Paul,

I agree with you regarding the difficulties that exist in the areas of risk communication both in general in society and particularly in the patient-physician relationship.

Let us focus on risk communication in the patient-physician relationship.

If we break down medical risk at a first level of analysis, one has (1) the actual risk itself in terms of an outcome (that is, an adverse outcome), and (2) the chance (probability) that the risk will occur.

In the case of risk as an “adverse outcomes”, let us take the case of the term “stroke”. When many patients consider the term “stroke”, they think primarily of motor paralysis or speech paralysis or massive stroke leading to death. However, a blockage can occur to any artery leading to any organ in the body, and damage to the organ supplied by the artery. Thus, “stroke” as defined by blockage of an artery (or arterial occlusion) can occur, not just in the brain, brainstem, and spinal cord, but any organ in the body.

In the case of chance (probability), my colleagues and I have found that the majority of patients in our studies do not want physicians to use “numbers” when the physician discloses risks to them. Instead, the majority of patient prefer to use qualitative expressions of chance (probability) such as “rare”, “probable”, “possible”, and the like. The problem here is that these patient do not immediately recognize that different reasonable person can assign very different numbers (where there may be magnitudes of difference) to the same verbable proability term. For example, depending on the context, a reasonable person could assign any one of following numbers to the term “rare”: 1 in 10, 1 in 100, 1 in 1000, 1 in 10000, 1 in 1000000, and so on.

Paul, great question!!!

Dennis

29 10 2009
Mary Ann

Dennis,

Expanding on the comments above, as a CRNA explaining the risk of Anesthesia to a patient I would compare the risk to the patient as if he were traveling a certain distance either by car or plane. This seemed to make it more pertinent and understandable for the majority of patients.
Any thoughts?

Mary Ann

29 10 2009
Dennis Mazur

Mary Ann

Thank you for your comment. In my own thinking on risk, in particular, medical risk, there are pluses and minuses to using “relative risk” comparisons in provider-patient communications.

Let us take the example of the risk of riding in a car. The risk of driving in a car is itself a “relative risk”, that is, the stated estimate of the risk of getting in an automobile accident a specified distance away from one’s home is relative. This risk is relative to:

+ Driver-related factors: (1) the age of the driver, (2) the cognitive status of the drive, (3) the driver’s blood alcohol level among other factors

+Vehicle-related factors: (1) the age of the car, (2) the car’s physical condition among others

+ Road-related factors: e.g., the amount of gravel on the road

+Weather-related factors: e.g., the iciness of the road

+The distance traveled away from home.

On the physician’s side of the communication, when a physician compares one risk estimate (for example, the risk of dying during anesthesia) to another risk estimate (for example, the risk of dying while driving a car a specified distance from one’s home), the physician may have a numerical estimate of risk in his or her mind regarding the risk of anesthesia, however, it is not necessarily clear to the patient if this physician estimate is based on:

++ Studies of anesthesia and risk occurrence published in peer-reviewed medical journals (let us call this “average risk” in or across scientific studies),

or

++ The average risk number as it applies to the patient in question (let us call this the “unique patient risk”.

On the physician’s side of the communication, hearing the number for the risks of dying during and after anestesia from the physician, the patient does not know the origin of the number in question unless the physician clarifies that number’s origin for the patient.

Finally, when a patient or a physician join in a relative risk communication comparing the “medical risk of anesthesia” to “driving a car”, it is not clear which of the above driver-, vehicle-, road-, weather-related, and distance-traveled factors the patient and the physicina have in mind.

More interdisciplinary work is needed on the topic of “relative risk” in informed consent but also across all domains of human activities so well-covered in this conference.

Dennis

30 10 2009
vlafaye

Greetings from The Management. We’re thrilled that you’ve found such fruitful grounds for discussion and exchange. You’re welcome to continue here after today.

30 10 2009
Dennis Mazur

Thank you for the opportunity to engage other in this wonderful conference!!!

Dennis
Dennis Mazur

30 10 2009
vlafaye

You’re very welcome, Dennis. It’s been a great experience for us too, and one which we hope to repeat! Vanessa

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