In this assignment, you will analyze the relationship between ethics and health care research. You will demonstrate your research skills by applying them to an ethical scenario you choose. While most health care managers do not conduct research, being able to evaluate research and apply it to situations, such as the ethical concerns presented in this assignment, are a valuable part of the effective management and adaptable leadership needed in the health care industry.
Select 1 of the following ethical scenarios:
A company uses patient DNA for research without the patient’s knowledge or consent.
A nonprofit organization sells fetal tissue for research. (Note: Do not assume this is illegal; this may be legal in some states or jurisdictions.)
Management invites researchers onto a health care research project who do not have the institutional review board’s (IRB) approval or exemption.
An oncology clinical trials coordinator is conducting a research study and selects a relative who has the cancer under investigation. The relative is placed in the group receiving the experimental drug.
Search the University Library for at least 3 peer-reviewed research articles that relate to the ethical concerns of your chosen scenario or to the process step at which ethical issues may have begun.
15-slide presentation with detailed speaker notes in which you:
Identify the ethical concern and at what step in the scenario the ethical concern(s) occurred.
Explain how evidence-based research can eliminate or minimize ethical concerns in the health care industry.
Compare and contrast research studies and quality-management projects as they relate to the health care industry.
Explain external factors that have an impact on the ethical concern in the scenario.
Include a title slide, detailed speaker notes explaining the content for each slide, and a reference slide. The title slide and reference slide are not part of the count.
Cite at least 3 peer-reviewed references to support your presentation.
Format your citations and references according to APA guidelines.
Research Article Links
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Public attitudes towards the use of primary care patient
record data in medical research without consent: a qualitative
Authors: MR Robling, K Hood, H Houston, R Pill, J Fay and HM Evans
Date: Feb. 2004
From: Journal of Medical Ethics(Vol. 30, Issue 1)
Publisher: BMJ Publishing Group Ltd.
Document Type: Article
Length: 5,154 words
Content Level: (Level 5)
Objectives: Recent legislative changes within the United Kingdom have stimulated professional debate about access to patient data
within research. However, there is currently little awareness of public views about such research. The authors sought to explore
attitudes of the public, and their lay representatives, towards the use of primary care medical record data for research when patient
consent was not being sought.
Methods: 49 members of the public and four non-medical members of local community health councils in See end of article for South
Wales, UK gave their views on the value and acceptability of three current research scenarios, each authors’ affiliations describing
access to data without patient consent.
Results: Among focus group participants, awareness of research in primary care was low, and the appropriateness of general
practitioners as researchers was questioned. There was general support for University of research but also concerns expressed
about data collection without consent. These included lack of respect and patient control over the process. Unauthorised access to
data by external agencies was a common fear. Current data collection practices, including population based disease registers elicited
much anxiety. The key informants were equally critical of the scenarios and generally less accepting.
Conclusions: This exploratory study has highlighted a number of areas of public concern when medical records are accessed for
research without patient consent. Public acceptability regarding the use of medical records in research cannot simply be assumed.
Further work is required to determine how widespread such views are and to inform those advising on confidentiality issues.
Although access to patient records for medical research has come under increasing scrutiny in the UK, the debate has largely been
confined to professional circles, and very little is known about the views of the general public on this matter. (1-4) Researchers face a
confusing situation. On the one hand the 1998 Data Protection Act strengthened the law protecting an individual’s privacy and
implemented stricter controls on the use of personal data. However, the 2001 Health and Social Care Act makes provision for the
disclosure of patient identifiable information in certain circumstances–including medical research–and constituted an advisory group
to consider the processing of such data on behalf of patients and the general public.
Standards for transparency and confidentiality have been set for researchers by the Department of Health, but guidance from the UK
Medical Research Council describes research scenarios where a breach of confidentiality may be permissible under the Data
Protection Act and the Common Law of Confidentiality. (5 6) Further complications arise since such professional guidance has been
criticised by patient groups concerned about the use of patient data without consent. (7 8) Recent court rulings have also raised
doubts about the legality of even anonymised data being used in research. (9)
The acceptability to patients of access to medical records without their consent has frequently been assumed. (10 11) However, the
lack of any evidence about the acceptability of such activities from the potential research subjects–members of the UK public–is
striking. Studies that have been done in primary care relate to the issue of confidentiality of records in routine clinical practice rather
than the use of records for research. (12 13) The aim of this study was to explore issues of importance to the public regarding the use
of primary care records when consent was not being sought. The choice of primary, rather than secondary, care as the context of
investigation was determined by two considerations. Firstly, general practitioners (GPs) are increasingly participating in research in
accordance with the principles of evidence based medicine. Secondly, given the nature of the ongoing relationship between patients
and their general practitioner, there was no reason to believe that patients’ attitudes to confidentiality and consent would be the same
in both settings.
The acceptability of research designs excluding patient consent (to patients, professionals, and the public in general) will reflect the
moral position of those key players. O’Brien and Chantler, for example, identify GPs more with a rights based approach to citizenship
whereas public health and epidemiological professionals may be more aligned with a utilitarian perspective. (14) This paper will
consider the moral issues raised by this empirical study and, in particular, potential sources of tension between differing perspectives.
An exploratory qualitative approach was chosen to identify issues of concern to the public. Focus groups were chosen as they are
especially good for exploring attitudes and experiences. The method actively uses group interaction (both supportive and contrary) to
allow the observation of a range of views, and identify the nature of arguments and counter arguments deployed within a group. (15
16) Eight meetings were held with members of the general public drawn systematically from the register of four electoral divisions in
South Wales, UK. The groups were stratified by gender, geographical setting, and level of deprivation. Gender was chosen as a
stratifying variable to aid rapport amongst participants. Groups were selected to be either urban or rural to reflect different
communities in South Wales and either relatively affluent or deprived to reflect differing socioeconomic circumstances. (17)
Stratification emphasised major factors affecting health status and access to services. Two pilot meetings used participants drawn
from a different electoral division.
Key informant interviews were also conducted with non-medical members of local community health councils. It was thought that the
interviewees might represent lay people with a greater familiarity and interest in confidentiality issues. Bro Taf Local Research Ethics
Committee advised that approval was not required.
Recruitment of sample
As previous focus group work shows variable rates of interest to postal invitations, letters of approach were mailed to at least 100
people per focus group. (18) Up to eight people per group were selected. One non-medical member from each of the four community
health councils in the area covered by Bro Taf Health Authority was approached and interviewed.
Discussion guide and procedure
Each focus group was moderated by two researchers (MR/KH). Upon arrival, participants completed a brief questionnaire, including
details of age, occupation, and awareness of their own GP’s involvement in research. Participants were asked to consider in turn
three scenarios describing the use of patient information for research without informed consent (see box). The extent of breach in
confidentiality was designed (in the eyes of the authors at least) to increase from scenario one to three. Participants were asked to
consider the acceptability and value of each scenario. Prompts were used to explore specific variations for each scenario, including
measures proposed to address confidentiality issues (for example, using a research nurse).
Discussion was recorded and transcribed for analysis. In addition, the assistant moderator made notes during the focus groups and
both moderators discussed their initial observations following the meeting.
Key informant interviews
Each semi-structured interview was conducted by MR using the same research scenarios as the focus groups. Interviews were
recorded and transcribed.
Transcripts were reviewed independently by MR and KH and narrative summaries for each scenario and group were prepared. The
researchers met to agree a summary of the key themes for each scenario. Of particular interest was the level of consensus across
groups expressed towards each scenario, the range of views described, and the arguments put for and against a particular opinion.
The aim of the analysis of key informant interview data was to determine whether any additional issues arose not described already
in the focus groups. A third researcher (RP) provided additional guidance and review of the process.
Role of the funding source
The study was financially supported by the Wales Office of Research and Development who provided constructive feedback on the
funding application and on the final study report but played no role in study design (collection, analysis, and interpretation of data) of
the decision to submit the paper for publication.
Of 1145 people approached, 226 (19.7%) returned the response form, and of these 112 were willing to be contacted further. Between
three and eight people attended each focus group, 49 in total. Thirty two (71%) of the 45 people reporting their age were older than
50, and 36 were in a non-manual social class (table 1). Focus groups lasted approximately 90 minutes and were characterised by
initial clarification of the process and subject matter. Subsequently, participants felt able to debate each scenario within their group,
exhibiting a range of positive and negative views. Analysis exploited the discussion guide to summarise these views by scenario and
by specific prompt.
RESEARCH IN PRIMARY CARE
One of the most striking features revealed by the group discussions were the general assumptions about research, researchers, and
more particularly of GPs as researchers. People had high expectations of confidentiality from their GP and felt a greater level of
control within primary care compared with other settings. Looking at each scenario in detail there is evidence that concern increased
as control was perceived to more away from participants’ own GP and local surgery.
Anxiety increased with more sensitive conditions, such as mental health problems. Serious concerns were expressed about access
by unauthorised external agencies, notably insurance and pharmaceutical companies. Interestingly, participants rarely considered
electronic data within the surgery as being similarly vulnerable to attack. Either way, there was little recognition of safeguards for data
security or, more generally, governance within the research process (for example, ethical review). Adverse consequences from
research using even aggregated anonymous data were described.
In the focus group questionnaire, only seven participants reported being aware of research conducted within their own surgery. This
apparent lack of awareness was reinforced by the group discussions during which doubt was cast about the suitability of GPs to
conduct research and that they may have conflicting interests (table 2). Some participants were concerned that their doctor should
concentrate on providing clinical care–research being viewed as the province of hospitals and pharmaceutical companies.
Justifications for this view included a concern about GPs working in isolation and their heavy clinical load.
SCENARIO 1: SINGLE GP REVIEWING OWN PRACTICE RECORDS
Positive support for the research was often expressed conditionally upon the understanding that data would be anonymised. The
general nature of the data collected (such as childhood infections) was viewed as innocuous and therefore acceptable. Data were
noted as having value, and some participants were even comfortable for its sale if the money went back into the practice.
There was a common wish to be informed about the data collection, firstly out of courtesy and, secondly, to enable patients to opt out
(table 3). The desire for courtesy is shown in the extended interaction at the beginning of table 3. The interaction also illustrates the
value of focus groups in facilitating questioning and debate among participants and exploring opposing views. The adverse
consequences of informing patients were suggested in one group. Informing patients was seen as a way of making patients feel that
they were helping, although the difficulties and cost of processing consent were recognised. Concerns about unauthorised access to
patient data were aired, including individuals being penalised on the basis of their own medical record and also their membership of a
Sharing results through publication was viewed favourably by adding value, credibility, and providing benefit to other population
groups. However, publication without consent could create distrust between the patient and their GP (table 3). Concerns about being
identified were greater when the condition under consideration was rare.
SCENARIO 2: TRANSFER OF NAMES AND ADDRESSES TO RESEARCH TEAM
Initial acceptance of this scenario appeared to be based upon the choice patients had to return a questionnaire once contacted by
researchers, and that only names and addresses were being released. However, a number of concerns were expressed about this
scenario and some felt the approach should come directly from the doctor. The credibility of the “researcher” was questioned amid
concerns about their duty of confidentiality (table 4). Objections arose from participants” lack of faith in computer security–a high level
of computerisation within primary care was assumed and protection against unauthorised access inadequate and difficult to achieve.
To some participants, providing a minimal amount of data in the form of names and addresses appeared to increase this risk.
Using a “research nurse'” to contact patients was favourably greeted. A nurse was viewed as abiding by professional regulations and
had a duty of confidentiality towards patients. A nurse provided accountability and a point of contact. Furthermore, the approach now
came from the practice. However, some saw the doctor alone as the person to provide the approach.
Whereas some participants saw value in additional information being provided, generally participants saw this as the thin end of the
wedge towards full disclosure of confidential data. Particular groups (for example, the elderly) were seen as especially vulnerable.
Providing a general consent in advance for names and addresses was acceptable if sufficient information was provided. Such
consent had to be updated to account for changes in personal and practice circumstances.
SCENARIO 3: TRANSFER OF PATIENT DATA TO EXTERNAL DISEASE REGISTER
Collecting anonymised and unlinked data appeared to be the most acceptable of the three scenarios, although some preferred
consent to be sought. Some considered this an obligatory service, which should be part of the GP contract (table 5). Potential harms
identified included failure to anonymise data adequately and unauthorised access by insurers and employers. Some drew a
distinction between data used for service planning and research, with the latter only acceptable when obtaining consent.
Collecting linked data appeared to enhance its value, although for some participants the ability to prospectively monitor patients
necessitated consent. Transferring personally identifiable data stimulated much concern. For some it ignored common courtesy,
removed personal choice, and reflected a lack of respect for human rights. Indirect harms included economic disadvantage by
reduced house prices in localities highlighted by research. Consent was often seen as mandatory but the threat this posed to
epidemiological work was recognised (table 5).
KEY INFORMANT INTERVIEWS
Three interviewees found the first scenario unacceptable, with concerns about harm to the doctor-patient relationship and wanting the
opportunity for “opting out” of the process. Providing patients with results and a patient committee to review research proposals were
suggested. All interviewees found the second scenario unacceptable, as decisions about the release of patient names and addresses
were being made on behalf of the patients. An approach from the researchers was seen as potentially anxiety provoking. Waiting
room posters to recruit (rather than inform) patients was advocated and seen as preferable to an approach from the nurse.
All four interviewees were unhappy about the collection of unlinked anonymous data in scenario three, although it was considered
more acceptable for service planning. Concerns expressed included the sensitivity of the medical condition and database security.
Consent was generally viewed as obligatory for linked anonymous and personally identifiable data. One interviewee was more
accepting of the latter but still worried if patients discovered subsequently that their records had been accessed.
The acceptability of research requiring access to general practitioner records without patient consent was explored using focus
groups with members of the public and interviews with lay representatives from community health councils. Participants quickly
became comfortable with the group format and a number of patterns started to emerge. Despite support for the aims of the activities
discussed and some approval for such data collection, this exploratory study has raised a number of important areas of concern that
require further investigation.
Recent UK legislation and its interpretation has caused consternation for clinicians, researchers, and patient representative groups
alike? (8 19 20) Its actual and potential impact has been discussed widely amidst concern for damage to the work of cancer registers,
public health surveillance, and broader epidemiological work. (21 22) Justifications proposed for not formally obtaining patient
consent and respective counter arguments have often made assumptions about what patients and the public in general would find
acceptable. (10) Perhaps as may be expected, the picture evolving from the current work is a little more complex.
Members of the public and their lay representatives expressed concerns about breaches of confidentiality that may occur in current
and legitimate research practice. Furthermore, the public may be unaware of current safeguards for research and data security and
may also be dissatisfied with some solutions proposed for minimising breach of confidentiality. It is possible that some of these
concerns are exacerbated by unfamiliarity with both the research process and routine record handling. This would indicate the need
for raising public awareness of such issues, a considerable task assuming low baseline levels of current knowledge.
ETHICAL ISSUES RAISED
Individual rights and utilitarianism
Study participants recognised both the importance of and conflict between personal privacy and societal needs. This was probably
best exemplified in their discussion of the third scenario–the disease register (table 5) but was apparent throughout the focus groups.
O’Brien and Chantler reflect npon this tension within two ethical perspectives–a rights based approach to citizenship and a broad
utilitarian approach. (14) Interestingly, they consider GPs in particular as sharing the former approach but place those concerned with
public health, epidemiology, and other researchers within a utilitarian perspective. A perspective in which actions should be guided by
what produces the greatest good for the greatest number presupposes a basic confidence in the benevolence of one’s government.
(23) It is not difficult to see how an increasingly sceptical public may have difficulties with this.
Whilst utilitarianism permits the interests of the majority to override minority rights, it has been argued that the pursuit of the goal of
social utility is not necessarily morally wrong–if almost everyone’s interests are protected. (24) However, a specification of “almost” is
critical and data from this study would suggest an expanded definition of “interests”–for example, to include certain moral harms.
Study participants recognised several potential harms when patient records are accessed without consent–even if it is solely the
infringement of their human rights. This is generally in contrast with what is often considered the potential for harm in such non-
interventional studies. However, Capron exemplifies such harms when describing the invasion of personal privacy and concomitant
lack of respect for reserve and solitude. (25) Such moral wrongs are committed even when the “wronged” is unaware of their
occurrence. This is consistent with views expressed within our study. The data balance the views of, for example, O’Neill–that
anonymised data cannot result in harm to an individual and therefore does not require consent. (26)
McLean asserts that not obtaining consent neglects the notion that good research must respect the subject. (27) Offering patients the
choice of research participation upholds autonomy, although Warnock prefers what she considers a more precise label–non-
exploitation. (28) For Warnock, the secondary use of anonymised data for a previously unthought of study involves no harm to
subjects and is unlikely to represent exploitation. This may well be contrary to the feeling of those participating in the current study.
The moral balance
It is clear that members of the public recognise the necessity of a balancing act to resolve competing but legitimate interests (for
example, individual versus community). Doyal discusses this moral balance in studies using medical records without consent, where
the moral wrong being done can be set against the benefit to the patient and the public interest. (1) Doyal asserts that the moral
imperative of respecting human autonomy is not applicable in all circumstances and is defended in part by the proviso that there is no
intention to contact patients subsequently (for example, in epidemiological research). There is of course a danger that patients may
unintentionally discover such (moral) abuse. Doyal acknowledges this but was perhaps more forcefully verbalised by our focus group
participants (table 3). The position of concerned study participants is probably best reflected by Hurwitz who considers that there is
insufficient moral warranty for wholesale use of personal data for purposes other than those for which it was originally supplied. (29)
The study provides empirical data both to exemplify the moral issues surrounding confidentiality and consent currently being debated,
and also to cast doubt on some of the assumptions above that are being made on behalf of patients. The health of the debate can
only be improved by results from current (and future) studies, and should help to facilitate a more transparent assessment of the
balance of harms and benefits in individual studies.
The aim of this study was exploratory in nature and not designed to facilitate broader generalisation. Hence, theoretical sampling was
used to maximise sample variation rather than to facilitate group comparisons. Alternative approaches to identifying and approaching
focus group participants were considered–for example, using family practice lists, but were considered inappropriate given the topic
matter. That a large number of people had to be approached for the focus groups is not uncommon using this particular method.
Nevertheless, participants were mostly middle aged or elderly and it is possible that different issues might be important to younger
people or people from certain minority groups. Further targeted qualitative work would be required to determine this.
Focus groups offer advantages over interviews for people who feel they have nothing to contribute or may be intimidated by a one to
one situation. (15) This is particularly useful when addressing issues not previously considered by participants. Focus groups may
also generate more critical comments than interviews and for scenarios where few harms are assumed; it is useful to explore such
perceptions. (30) The approach also allows participants to generate their own questions and discuss issues using their own
vocabulary. Similarly, the interaction and debate within focus groups served to reveal participants’ views capitalising upon the natural
tendencies to discuss, agree, and argue points. Whereas the focus groups allowed the exploration of participants’ viewpoints and
their basis, the aim of analysis was mainly upon describing the range of views expressed.
The focus groups were conducted in an area where the academic general practice unit had conducted a large number of practice
based studies. However, participants were generally unaware that research was conducted in primary care and there were doubts
expressed about the suitability of GPs to conduct research. The special nature of the general practitioner-patient relationship, the
continuity of care afforded in primary care, and also the public perception that research seldom occurs in this context, mark it out for
special consideration in relation to records based research.
KEY INFORMANT INTERVIEWS
Lay patient representatives were interviewed to determine whether issues or concerns were expressed in addition to those raised by
members of the general public. Issues arising in the interviews were generally congruent with those raised by members of the public,
although the scenarios appeared somewhat less acceptable to the lay representatives. The study was not designed to
representatively compare such groups. It does though hint at differences referred to by Turnberg, who feels that the public is
generally happy for personal data to be used for research purposes–and that debate on the topic should encompass a wider public
than those who have claimed to represent them in the past. (31) We agree that the arena for debate should be broadened but value a
balance of perspectives from both the public and also their formal representatives.
The consultation process regarding section 60 of the Health and Social Care Act produced comments that were broadly supportive.
(32) However, the power to allow access to patient information without consent did raise concern among groups representing
patients. The Patient Information Advisory Group constituted to consider such applications for section 60 support has echoed these
concerns, for example, in response to clinician claims that informing patients would be too burdensome. The advisory group points to
the central role of GPs in informing patients about work requiring access to data without consent (for example, the Public Health
Laboratory Service). There is clearly a lot for those working in primary care to do to satisfy the spirit of these recommendations.
Messages for researchers and GPs
Implied consent for access to and use of confidential patient record data cannot necessarily be assumed and the public at least
perceive some harms inherent in that process. (33) Access to medical data has been facilitated by technological progress and data
are now available that would not have been previously accessible. Demand for data across the health service and beyond continues
to grow, as does the potential to exploit it. Consequently, the GP’s role as guardian of this data is now very different. How patients
and the public in general have adjusted to such developments is illuminated by the current exploratory study and should be the basis
of reflection for researchers and policy makers alike. However, how widely held such views are still needs to be determined by a
representative quantitative approach. Such research could usefully inform the work of the Patient Information Advisory Group and
others concerned with balancing wider societal benefit and demands for personal privacy.
Table 1 Demographic characteristics of focus group participants * Variable Category n (%) Age <30 2 (4) 30-39 6 (13) 40-49 5 (11) 50-59 17 (38) 60+ 15 (33) Social class ([dagger]) I 5 (11) II 16 (36) IIINM 15 (33) IIIM 4 (9) IV 1 (2) V 0 (0) Other ([double dagger]) 4 (9) * 45/49 respondents completed the questionnaire. ([dagger]) Using Standard Occupational Classification. ([double dagger]) Could be not classified. Table 2 Research in primary care UDM2: Is that the job of a family doctor would be my concern ... I'm not; sure technically it should be your family doctor in isolation, working alone, would be the right way to do it. There are research bodies, hospitals and universities and things like that. I would have thought personally that would have been a better place to do the research ... rather than the family doctor himself who would appear to be under great pressure to just do the family doctoring. RDM2: The only concern I would have is if the practice was doing too much research because it was getting funded at the loss of patient care. UDMI: I'd like to be informed if they are going to dwell into our medical doctors ... not work as a ... records. Because sometimes only doctor they work in medical schools as well, they go to the hospitals to work. And if they are using our records for same reason or another it would be nice to be consulted. U/R, urban/rural; A/D, affluent/deprived; M/F, male/female. Table 3 Comments from scenario 1: single GP reviewing own practice records UAF2: Well, personally I would like to have had the opportunity. I would probably say 'yes'. I would still like the common courtesy of being asked if I was willing for that to happen. Anon: Exactly. UAF5: I'm like you--I think that would have to be a must to be asked MR: Right. UAF4: But they've got your records and they can look at them any time, so why would it be of any concern to you? UAF5: In as much as research-and they could be using those records within their research and other people are looking at them. UAF4: But it says here your own doctor is going to be looking. So anytime that he can look in your records and see what you've had. UAF5: Yes, but that's you own doctor, that's not any one else involved UAF4: But it says, it says here your own family doctor has decided to look at your medical records. UAF2: But you should expect still common courtesy from our family doctor. UAF4: Well he doesn't look at--ask you every time he wants to look up your records. He doesn't ring you up and say "I'm going to get your file out today ... " and ask you, does he? I mean! RDF5: Maybe it would affect-the results, perhaps how they communicated things to doctors some or... they would withhold say there were more, so I think in some instances it could affect results. UAM5: I worry when its published because once something is in the public domain ... I mean you often see in the papers there will be some pilot study or something that's been grabbed out and sort of put in the papers and you sort of open the paper one day and hidden--people might think "Oh!" You know, it sews a certain mistrust and they think "oh hang on, I didn't think this was going on". Table 4 Comments from scenario 2: transfer of patient names and addresses to external research team RAM3: So presumably the researchers then have got no way of knowing anything else other than a name. So they have got to presumably waste time and money writing to everybody on the list although people below a certain age and above a certain age, perhaps are not really going to be part of the study anyway. UAF5: I would hate the thought of say half a dozen people, researchers looking and going through the notes and saying 'Have you seen this one, wow!' ... People especially going back to mental health problems because people are very sympathetic towards any physical problems but often times, when it comes to mental health problems they see it as a huge joke. UDM3: Everything is done on computer nowadays and computers can be hacked. I mean if it's on a piece of paper in somebody's office that's generally where it stays. But it's not that way anymore. UAF4: Because once you come out of the realms of confidentiality of the doctor, you accept or you hope you have got the confidentiality with your doctor, but once it's out in a wider thing, it's not is it. Nobody owes the same allegiance to you as the doctor-patient. Table 5 Comments from scenario 3: transfer of patient data to external disease register RDM1 : ... do you believe that there could be, certain general practices would have the right to opt out? ... Where the central body can say 'No, no that's part of your agreement. You're GP in that area and we need this information--to have it everywhere. No opting out mate, that's part of what we are paying you for.' ... for the services to be planned database would have to be a full database. We couldn't say have half a dozen people saying 'No. I won't fill in that', We don't want to be part of that', when there are people really being affected. RDM1 : If the final conclusions are proved to be wrong, and it's proved to be wrong because that 10% didn't partake in the final thing we've got to admit that and then as individuals say, 'Forget consent'. But at this moment I think consent has got to be there. RDF5: Strong words to use but it's a bit like human rights isn't it? It's your right not to let that information go into other hands. There's very few things we've got control over and that should be one area that you do have a choice. ACKNOWLEDGEMENTS The authors gratefully acknowledge the contribution of all the people who gave up their time to attend the focus group meetings and themembers of the local community health councils who agreed to be interviewed. We also acknowledge the work of Mrs Kathryn Belby for her administrative support of the study and both her and Mrs Diana Thomas for transcribing the individual and group interviews. Finally, we thank Professor Nigel Stott for his guidance and support at each stage of the study. REFERENCES (1) Doyal L. Informed consent in medical research: journals should not publish research to which patients have not given fully informed consent-with three exceptions. BMJ 1997; 314:1107-11. (2) Al-Shahi R, Warlow C. Using patient-identifiable data for observational research and audit. BMJ 2000; 321: 1031-2. (3) Strobl J, Cave E, Walley T. Data protection legislation: interpretation and barriers to research. BMJ 2000; 321: 890-2. (4) Sankila R, Martinez C, Parkin DM, et al. 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(13) The Bolton Research Group. Patients' knowledge and expectations of confidentiality in primary health care: a quantitative study. Br J Gen Pract 2000; 50: 901-2. (14) O'Brien J, Chantler C. Confidentiality and the duties of care. J Med Ethics 2003; 29: 36-40. (15) Kitzinger J. Qualitative research: introducing focus groups. BMJ 1995; 311: 299-302. (16) Kreuger RA. Analyzing and reporting focus group results. Thousand Oaks: Sage Publications, 1998. (17) National Assembly for Wales. Welsh Index of Multiple Deprivation. http:// www.wales.gov.uk/keypubstatisticsforwales/content/publication/social/ 2000/deprivation/intro_e.htm. (18) Pin R, Prior L, Wood F. Lay attitudes to professional consolidations for common mental disorder: a sociological perspective. Br Med Bull 2001; 57:207-19. (19) Paterson ICM. 'Confidentiality' should be a protecting principle not an excuse for non-co-operation. BMJ 2000; 321: 1031-2. (20) Roberts L, Wilson S. Argument for consent may invalidate research and stigmatise certain patient groups. BMJ 2000; 322: 858. (21) Redsell SA, Cheater FM. The Data Protection Act (1998): implications for health researchers. J Adv Nurs 2001; 35: 508-13. (22) van Teijlingen ER, Rennie A-M, Hundley V, et al. The importance of conducting and reporting pilot studies: the example of the Scottish Births Survey. J Adv Nurs 2001; 34: 289-95. (23) Lachmann PJ. Consent and confidentiality--where are the limits? An introduction. J Med Ethics 2003; 29: 2-3. (24) Beauchamp TL, Childress JF. Principles of biomedical ethics, 4th ed. Oxford: Oxford University Press, 1994. (25) Capron AM. Protection of research subjects: do special rules apply in epidemiology? Law Med Hlth Care 1991; 19:184-91. (26) O'Neill O. Some limits of informed consent. J Med Ethics 2003; 29:4-7. (27) McLean SAM. Commentary: No consent means not treating the patient with respect. BMJ 1997; 314: 1076. (28) Warnock M. Informed consent--a publisher's duty. BMJ 1998; 316: 1002-3. (29) Hurwitz B. Accessing medical records for health services research. In: Doyal L, Tobias JS, eds. Informed consent in medical research. London: BMJ Books, 2001: 230-9. (30) Watts M, Ebbutt D. More than the sum of the parts: research methods in group interviewing. Br Educ Res J 1987; 13: 25-34. (31) Turnberg L Common sense and common consent in communicable disease surveillance. J Med Ethics 2003; 29: 27-9. (32) Department of Health. Health and Social Care Act 2001--Section 60: Summary of responses to consultation on draft regulations. http:// www.doh.gov.uk/ipu/confiden/act/summaryofresponses.pdf. (33) Baker R, Shiels C, Stevenson K, et al. What proportion of patients refuse consent to data collection from their records for research purposes? Br J Gen Pract 2000; 50: 655-6. Summary of focus group research scenarios Scenario 1: Single GP reviewing own practice records GP reviews the records of adult patients to find out how often they suffered from various childhood infections. He is also planning to find out if the infections are related to the subsequent development of a particular common medical condition. His aim is to recognise the provision of services to children in the practice. * Results sent to medical journal for production. * For a rare (rather than common) condition. Scenario 2: Transfer of patient names and addresses to external research team Researchers are running an awareness campaign for all patients in a surgery about a particular condition. They want to find out if the campaign will increase people's knowledge of the condition and change their attitudes. Information on just the names and addresses of patients is sent to the researchers. Researchers contact patients by letter to ask if they would be willing to complete a questionnaire survey. * Patients identified by practice nurse solely employed for research. * Patient told in advance that their data may be used for research. * Additional medical information provided to researchers. Scenario 3: Transfer of patient data to external disease register Surgery (along with other practices nationally) sends information about patients with a newly diagnosed condition to a central database. Information will be used to plan services and for research. * Data provided are linked and anonymous. * Data provided are personally identifiable. Note: Specific prompts and variations used denoted by bullets. M Robling, K Hood, H Houston, R Pill, Department of General Practice, University of Wales College of Medicine, Llanedeyrn Health Centre, Maelfa, Llanedeyrn, Cardiff, CF23 9PN. J Fay, St Bartholomews Medical Centre, Manzil Way, Cowley, Oxford, OX4 1XB. H M Evans, Centre for Arts and Humanities in Health and Medicine, University of Durham, old Shire Hall, Durham, DH1 3HP. Correspondence to: M Robling, University of Wales College of Medicine; [email protected] cardiff.ac.uk Received 5 June 2003 Revised 13 October 2003 Accepted 20 November 2003 Robling, MR^Hood, K^Houston, H^Pill, R^Fay, J^Evans, HM Copyright: COPYRIGHT 2004 BMJ Publishing Group Ltd. http://www.bmj.com/ Source Citation (MLA 9th Edition) Robling, MR, et al. "Public attitudes towards the use of primary care patient record data in medical research without consent: a qualitative study." Journal of Medical Ethics, vol. 30, no. 1, Feb. 2004, pp. 104+. Gale In Context: College, link.gale.com/apps/doc/A114007453/CSIC?u=uphoenix&sid=ebsco&xid=5983d55a. Accessed 2 June 2022. Gale Document Number: GALE|A114007453 http://www.bmj.com/ Disclaimer: This is a machine generated PDF of selected content from our products. This functionality is provided solely for your convenience and is in no way intended to replace original scanned PDF. Neither Cengage Learning nor its licensors make any representations or warranties with respect to the machine generated PDF. The PDF is automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. CENGAGE LEARNING AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGEMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. 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Document Type: Report Length: 8,129 words DOI: http://dx.doi.org/10.2217/pme.09.47 Full Text: Author(s): Mats G Hansson 1 KEYWORDS : bioethics; ethics; hype; informed consent; justice; personalized medicine; pharmacogenetics; race; risk management Developments within pharmacogenetics have received a great deal of attention from ethicists, lawyers and social scientists (for some recent examples, see [1-6] ). One may get the impression that truly new and urgent ethical problems have arisen that need to be sorted out before any large-scale introduction of pharmacogenetics into clinical practice; however, this appears not to be the case. The ethical issues that are suggested to capture our interest are the same ones that have been focused on and debated since the early days of gene transfer and genetic diagnosis. Other issues, such as the casting of roles between scientists, industry and government, have been thoroughly discussed within moral philosophy for centuries. Of course, these ethical issues may still be of relevance to pharmacogenetics but one should keep earlier discussions in mind. This perspective will provide a critical overview of some of the major themes of the ethics debate that are of relevance to pharmacogenetics. One group of ethical issues discussed is related to the handling of genetic information of individuals in association with genotyping for treatment efficacy and the avoidance of adverse reactions to drugs. Here, the old questions concerning third-party access to genetic information are revisited again. Questions regarding privacy are asked, which is also believed to be at stake during the research process when human tissue samples are used together with medical and personal data in order to detect genetic and environmental vulnerabilities. Another group of issues is related to the stratification of patients according to genotype with concerns regarding individuals whose genetic responses to common drugs fall outside the range. As suggested by Dorothy Wertz, "the cost of drug development raises questions of government, industry and insurance company responsibilities to individuals whose pharmacogenetic responses are in a minority"  . I will not go into these issues in any detail, but will point out some of the solutions and consensus views that have emerged over the years. Instead, I will use the major part of this article to elaborate on some of the themes in discussion with regard to the framing of the ethical discussion of pharmacogenetics. A lasting impression when reading the ethico-social literature on pharmacogenetics is that ethical concerns are often only indirectly related to the health and well-being of current and future patients. Concern has been expressed regarding the role of the pharmaceutical industry, commercialization, justice and the meaning and role of race in association with genotyping [7-10] . I do not regard these issues as uncontroversial and I will comment on some of them, but it seems to me that this framing of the ethics debate may risk losing the arguably most important ethical perspective in medical research and drug development - the perspective of current and future patients wanting medical treatment that is both effective and carries low risks of adverse effects. The 'social' framing of the ethics discussion is well illustrated in a comprehensive paper by Adam Hedgecoe and Paul Martin  . They claim that: "By creating a more complete picture of the process of technical change in biotechnology, as well as carrying out empirical research on the ethical, legal and social issues raised by emerging genetic technologies, social scientists such as ourselves are also helping - construct and shape the future"  . This is an important remark; there are no neutral accounts. Hedgecoe and Martin recurrently state that the area of pharmacogenetics is 'highly controversial' and that it raises 'controversial ethical issues'. However, unfortunately, they neither explain what it is that makes this kind of biotechnology controversial, nor do they make any suggestion as to how the alleged ethical controversies should be understood. The 'controversies' seem to be taken for granted, belonging to a necessary framing of the issues that are needed in http://dx.doi.org/10.2217/pme.09.47 order to proceed with a sociological analysis. In any case, they are honest about their normative interests and this is good. Sociologists feed on controversy, real or imaginary. In this perspective, I will also take a normative stance. Ethicists feed on conflicting interests and the task of balancing interests that are at stake for different parties. I will discuss the ethics of pharmacogenetics from the perspective of current and future patients' interests in sufficiently safe medicines. According to this view, the patients are the primary stakeholders. Drug efficacy:safety ratio is decisive from the patient's perspective Hedgecoe and Martin invest a great deal of energy in imposing a superficial structure on the technological development within pharmacogenetics. They claim that there are two 'visions' guiding the field: "In the first vision, pharmacogenetic variations are focused on drug metabolism and are independent of disease-causing genes. Here the emphasis is on the safety of the drug. In the second, the introduction of pharmacogenetics is centered on the genes associated with disease and will lead to changes in how common diseases are classified. Here the emphasis is on drug efficacy"  . There is certainly room for many different focal points in pharmaceutical science and genetics research. However, any vision regarding increased efficacy that does not take potential adverse effects into account is doomed to fail. The ambition of all drug- development projects is to find a favorable balance between efficacy and safety for targeted patient groups, and this is also the concern of the regulatory authorities. I will come back to the issue of setting the balance later. More important is that, from the patient's perspective, this sociotechnical framing is entirely superficial and of little interest. Any medication, with or without pharmacogenetics, has the purpose of providing a benefit to the patient with as little risk of negative side effects as possible. There is, to my knowledge, no drug that has only beneficial effects with no risk of adverse reactions. Before pharmacogenetics, the doctor tried to master the efficacy:safety ratio for the individual patient with the help of rather blunt instruments, often only adjusting the dosage on a trial and error basis. In some instances a higher risk may be justified, for example, in life-threatening situations when no alternative treatment is available. In other cases, safer drugs may be available, but any drug involves some kind of risk-taking on the part of the patient. The important point is that, from the patient's perspective, keeping efficacy and safety concerns together is absolutely essential. The encouraging vision that is now being established in pharmacogenetics is that we may move from trial and error to evidence-based personalized medicine in clinical practice. I will not review the current status of pharmacogenetic research and its clinical significance in different areas of medicine. Several recent reviews from the field of pharmacogenetics point at significant possibilities for treatment, even though there is an indicated need for more research [12-14] . Instead, I will give a concrete example of what pharmacogenetics can achieve for patients in clinical practice. Abacavir The antiviral drug abacavir (Ziagen® , GlaxoSmithKline, London, UK ) is a nucleoside reverse transcriptase inhibitor that is used in HIV treatment. It has demonstrated efficacy, few drug interactions and a favorable long-term toxicity profile  . However, many doctors hesitate to prescribe this drug owing to the risk of hypersensitivity reactions. These immunologically-mediated reactions affect 5-8% of patients, with skin rash, fever, gastrointestinal and respiratory symptoms occuring during the first 6 weeks of treatment. As described by Simon Mallal et al. , the symptoms of these reactions to abacavir are nonspecific and are difficult to distinguish from concomitant infection, a reaction to other drugs or inflammatory disease  . This implies that the doctor may hesitate to prescribe the drug or discontinue an effective treatment in cases where the symptoms have nothing to do with the antiviral drug. In 2002, it was found that the hypersensitivity reactions were strongly associated with the presence of the HLA-B*5701 allele [16,17] . Several retrospective and prospective studies were carried out, but overall, the evidence was not sufficient for introducing the screening of patients into clinical practice. Besides methodological limitations, Mallal et al. refer to clinical overdiagnosis that "has led to a substantial overestimation of the prevalence of hypersensitivity reaction over the true prevalence of immunologically mediated hypersensitivity reaction. This is particularly true in racial groups with a low carriage frequency of HLA-B*5701 , in which false positive clinical diagnosis has resulted in the erroneous conclusion that the test lacks sensitivity"  . A prospective, randomized, multicenter, double-blind study (Prospective Randomized Evaluation of DNA Screening in a Clinical Trial [PREDICT-1]) has now provided evidence that screening for the HLA-B*5701 allele before treatment with abacavir will significantly reduce the incidence of hypersensitivity reactions  . It was found that in predominantly white populations, 94% of patients do not carry this allele. Therefore, a pharmacogenetic test can prevent these toxic effects and patients need not stop taking a beneficial drug if their symptoms are not truly due to hypersensitivity. For now, this is one of the clearest examples of the effect of pharmacogenetics on evidence-based clinical practice and, again, it is a reminder that benefit and safety concerns must be kept together. Whether or not this scientific evidence implies a 'bipolarization' of race and is, for this reason, ethically problematic is a theme I will return to  . It should definitely have consequences for the regulation of drugs and risk assessment. I will address these questions in turn, but first, I want to highlight a recurrent theme in the bioethical, legal and social science literature on genetic medicine - the question of hype. Is there hype & who is the 'hypist'? Exaggerations and unsubstantiated claims in medical science should not be taken lightly. Vital patient interests are at stake and the promotion of these kinds of accounts may further give nourishment to false ideas regarding drugs that are free of risks or adverse effects. The example of abacavir provides evidence of what we may realistically expect in pharmacogenetics and thus, a description that is not fit to be labeled 'hype'. Hyperbole in this context is a description that exaggerates the potentiality of cure with unsubstantiated claims of treatment effect while downplaying the risks and the significance of adverse reactions. Oonagh Corrigan seems confident that there is hype in pharmacogenetics. In a critical account of the Nuffield report on ethics and pharmacogenetics, she concludes that the report fails to "analyze the political and economic context surrounding the much publicized hype surrounding pharmacogenetics research and development"  . However, it is not clear who is the author of the 'publicized hype' - the biomedical scientists or their social counterparts, or both. It is an important and legitimate part of science to try to promote ideas, but if the promotion is exaggerated, it is believed to undermine public trust and financial support in the long run [19,20] . Michael McDonald and Bryn Williams-Jones have argued that this is what happened to gene therapy: "When legitimate promotion became hype, followed by very public failures of clinical trials venture capital and government sponsors withdrew from the field. The result was that scientific research suffered, and the public and other stakeholders were left holding an empty bag of promises"  . According to the witnesses in social science, enthusiasts within the academic and business fields of genetic medicine are guilty of too much speculation and unsubstantiated claims  . The sociological analyses of these expectations have focused on how key actors communicate visions regarding the future prospects of a new technology in the media  . The key actors represent several different interests, for example, industry, government, the medical profession and patient groups, and visions are seen as co-constructions whereby each actor is actively helping to shape the trajectory of an emerging promising technology  . Even bioethics is suggested as a helpmate, actively recruited by pharmaceutical companies and the biotechnology scientific community in order to serve as a 'political broker'  . A basic message in these sociological analyses is that industry, the medical profession and patient groups are responsible, not only for providing hope, but also for producing hype. An investigation of the social aspects of new medical technologies is vital, in the sense that it is not enough to increase understanding of the scientific rationale and applicability of a technology; one must also understand more about the society in which this technology is to be applied. However, as can be seen from the sociological accounts presented in this perspective, there are no neutral accounts of the use of new medical technologies. As Mary Dixon-Woods et al. have recently argued, the ethical, legal and sociological accounts of medical research that influence the debate describe this research as operating in opposition to the norms and interests of the general public  . Dixon-Woods et al. studied the use of human tissue in biomedical science and conclude that "in much recent social science, anthropological and sociolegal studies, the use of human tissue for research is deeply troubling"  . They argue, using several examples [26-28] , that a large body of the academic literature has been activist in its commentary on biomedical research and genetic medicine. An account of 'social unease' in biomedical research is given, arguing for the existence of a public crisis of confidence. One example given in the legal accounts is a perception of the general population as individuals "who feel disenfranchised from, and disempowered by, the modern machinery of research-"  . As suggested by Dixon-Woods et al. , some of this 'social unease' work seems to be more consistent with a 'horror' genre than with social science  . Accordingly, one may suspect that it is not only scientists and industry that are producing hype rather than well-informed hope. Bioethicists as well as anthropologists, social scientists and lawyers, among the sceptics, may be equally guilty. Without sound arguments, they define genetic medicine as deeply controversial and provide unsubstantiated claims about public perceptions and attitudes. One characteristic feature of the sociological accounts seems to be that the patient completely falls outside the picture, something that, in accordance with my declared normative interest, is ethically problematic. The patient's perspective disappears when the broader picture of political and social theory is painted. One example is a description of the endeavors of pharmacogenetic research in the following terms: "The legitimacy of such projects has been linked to national prestige and images of the nation, the purity of scientific Endeavour, the entrepreneurial spirit, medical progress and the public health"  . Nowhere in this description is there a hint of the possibility that a driving motive in pharmacogenetic research is the need to develop treatments that try to optimize the efficacy:safety ratio for groups of patients with a specific genotype. I am not claiming that the scientists are not guilty of exaggerations and unsubstantiated visions but, in terms of the publicized hype, social scientists may be equally guilty. More realistic accounts are preferable and it is not unlikely that the extra public attention incurred by the 'hypists' will lead to the overregulation and premature withdrawal of new drugs from the market. One illustrative example of this may be the recent gene therapy trial involving ten children suffering from X-linked severe combined immunodeficiency syndrome (SCID-X1) in France  . It is conceivable that, owing to a great deal of publicity regarding gene transfer and unrealistic hopes of cure without adverse effects, the study was discontinued after it was learned that two children had developed leukemia as a side effect. However, the treatment had beneficial effects on the childrens' immune systems and some of the children and their parents wanted to continue the trial. It is not difficult to imagine that life in plastic bubble tents with an extremely poor prognosis may be regarded as a worse scenario than the cancer risk. For those SCID-X1 patients who do not have a HLA-identical sibling or an unrelated fully HLA-matched donor, the efficacy of gene therapy may be superior to other available treatments  . Risk:benefit ratios should always be compared with existing alternatives. Regarding gene transfer for SCID diseases, it has been suggested that the immunodeficiencies of the patients need to be molecularly characterized in order to guide treatment  . Here, as in pharmacogenetics, it is a matter of finding the right patients where a favorable balance of benefits against risks may be attained. I will now elaborate on the consequences of this for the regulation of pharmaceutical products. Need for a life-cycle approach in the risk management of drugs The antiviral drug abacavir is a good example of the realism of pharmacogenetics and the new possibilities of defining genetic subpopulations with an optimal benefit:risk balance. This may accelerate the drug-discovery process and provide early market access of new drugs that fit these specifically defined groups of patients. One implication of this development is that the drug is only tested on a small and genetically homogenous group of patients. As pointed out by Kathinka Evers, a consequence of this is that drugs may be marketed with less premarketing exposure and less information regarding adverse reactions for other populations, for example, the risk of nonprescribed use  . However, from the perspective of the patients who may benefit from the drug, a solution that requires an overall assessment of adverse reactions before marketing is not preferable, particularly if the drug responds to a great medical need. Hans-Georg Eichler et al. recently proposed a better solution  . They recognize a mounting challenge for the regulatory authorities in the need to balance early market access to new drugs with the need for comprehensive data on the efficacy and safety of the drugs. This problem is general and does not only concern pharmacogenetics. As they point out, all regulatory decisions are taken under conditions of uncertainty and, as I discussed earlier, there is no drug that carries no risk of adverse effects. Raising the bar will exclude patients from beneficial treatment, and lowering it may imply inflicting unknown risks on patients. The solution that Eichler et al. suggest is that the regulatory authorities start applying a life-cycle approach to risk management by which benefit:risk data are also collected and monitored following post-market decisions and presumably during the entire lifetime of the drug. Rare drug adverse reactions will almost always be identified after broad use. Such a reaction should not automatically result in the drug's withdrawal, but in balancing the judgment of the risks versus the benefits. Eichler et al. point to the need for regulatory authorities to further develop post-marketing risk management systems. They hope that this "proactive approach will inform more 'learning-confirming' cycles throughout the drug's life-cycle and into the post-marketing phase. This in turn is expected to allow regulators who are faced with an increasingly risk-averse environment to continue granting early (limited) approval by conducting repetitive benefit/risk assessments"  . It is likely that developments in pharmacogenetics will force the pace of this change in regulatory approach. Clinical trials will include a hypothesis for overall treatment as well as a hypothesis concerning the effect in a genetic subpopulation. This will not solve the problem associated with nonprescribed use; however, this problem is not unique to pharmacogenetics. Arguably, patients also need to assume some responsibility for taking the advice of doctors and reading the packaging information. Tailoring does not imply individualizing The metaphor 'tailoring' is frequently used by both scientists and in sociological criticism when describing the visions of pharmacogenetics. Corrigan states that "developments in this field will eventually move away from a 'one-size-fits-all' approach - to the tailoring of new medicines to an individual's genetic profile"  . There is room for a misconception here, since genotyping is only one limited route for specifying the phenotype of an individual. There are many polymorphisms, epigenetic factors and environmental conditions that must also be understood and mastered before the characteristic metabolic reactions of an individual can be accurately predicted. Even biological chance may play a significant role, particularly concerning late-onset conditions and diseases. Caleb Finch and Tom Kirkwood presented a strong argument on this by mating brothers and sisters of the nematode Caenorhabditis elegans for 100 generations, acquiring nearly identical genotypes  . Despite strictly controlled environmental conditions, for example, humidity, temperature and nourishment, the result was great variation regarding late-onset diseases (after reproductive ages) and death. In my view, personalized medicine does not necessarily imply a unique drug profile for each individual. To continue the metaphor, as in fashion, few individuals can afford their own individual tailor. However, this does not imply that one needs to settle with 'one-size- fits-all'. An individual can still select in accordance with a personal profile of taste, a selection that in practice may fit several others. The great challenge for personalized medicine is to understand not only the biological variations (genotype, epigenetic factors or biological chance) but also the role of gene-environment interactions and how different environmental conditions and lifestyle factors influence health - that is, both the efficacy of a drug and its adverse reactions. Mastering gene-environment interactions: the great challenge for personalized medicine In order to fit the profile of individual patients, the approach to health-related risk information needs to be multidimensional. An individual who has suffered from an acute myocardial infarction carries the greatest risk of suffering a new infarction. As described earlier, for some diseases and drugs there is a known genetic risk that is communicated to a patient on the basis of a genetic test. Risk information may also be based on the measurement of protein or lipid levels, for example, serum cholesterol and apolipoproteins, or the measurement of blood pressure. Other risk factors are related to lifestyle, for example, smoking, physical activity, dietary patterns and psychosocial factors such as depression, a sense of control or perceived stress. The absolute risk faced by an individual is a combination of genetic and environmental factors as well as individual psychosocial factors. There is a growing body of information regarding the modifiable risk factors related to lifestyle. According to the INTER-HEART study (a prospective, randomized, double-blind and powered study, designed to evaluate the clinical utility of HLA-B*5701 screening in the management of abacavir), nine modifiable risk factors account for 90% of the population-attributable risk, for example, smoking, apolipoproteins and psychosocial factors  . A total of 85% of all cancers are not hereditary, but rather bear strong associations with lifestyle factors. For Type 2 diabetes, almost the entire absolute risk is related to lifestyle. The variation can be described with the help of Figure 1. For group I, treatment may be available, but the individual can do very little to control his or her risks. Research on the psychological effects of genetic risk information is still important, as is the development of counseling and care. However, from both an individual and a public health perspective, it is now urgent to also direct the research attention to epigenetic and environmental factors, to psychosocial factors and to what affects health-related behavior. In group IV, individuals can control their risk by changing specific behaviors, for example, quitting smoking, drastically reducing sun exposure or losing weight. For groups II and III, there are now well-known modifiable risk factors that, if controlled, may reduce the relative risk to the individual. In groups II-IV, one finds diseases with a high frequency among all populations, for example, cardiovascular diseases, various forms of cancer and Type 2 diabetes. Adverse lifestyle characteristics and modifiable risk factors are now well understood for these diseases. However, one should keep in mind that even if both the genetic and environmental risk factors are known, it is also well known that a change in behavior is not directly correlated to information regarding health risks. Health promotion activities present a substantial unrealized potential, since individuals at risk do not change their lifestyle or health-related behavior as a result of risk information, for example, changing diet, starting to exercise, limiting sun exposure, quitting smoking or taking prescribed medicine. A major challenge for personalized medicine from the perspective of patients' health and well-being is to understand why currently known modifiable risk factors develop in some individuals and to identify approaches for preventing or reducing their development. Ethical problems related to the research process: biobank ethics Pharmacogenetic research uses population-based blood/tissue sampling for the study of genetic variation, and gene-environment interaction studies require large biobanks and access to medical and personal data. One example is the use of archived pathology biobanks for the evaluation of genetic polymorphisms in order to determine whether there is a genotype-phenotype correlation  . Selection of informed consent procedures is believed to constitute a special ethical problem that is intrinsic to pharmacogenetic research [38,39] . However, a great deal of ethics research has been conducted on the specific problems related to informed consent and the confidentiality of personal information, the two main questions in the ethics of biobanking. In a recent review of this research, it was concluded that, regarding these themes, different arguments have been proposed and challenged in the literature to the extent that it is now possible to see the beginning of a concordance and some emerging trends related to the central issues  . For previously collected human biological material, no consent is needed, provided that the material and data are safely coded, securely stored and only accessible to authorized individuals, and that the original donors have not explicitly said 'no' to future use  . For new collections of samples and data, the current and generally preferred solution is to obtain broad or general consent for future research, again provided that the material and data are coded and securely stored and that there is a viable option for the donor/participant to withdraw from the study  . Regarding nomenclature in coding, the European Medicines Agency (EMEA) proposal has now become the authoritative nomenclature version in Europe, with agreement from the USA and Japan  . The question regarding whether and how to return information, research results or incidental findings to donors of tissue material is still the focus of intensive discussion, and a couple of helpful analyses and suggestions have recently been published [43,44] . Ethnicity/race may serve as a proxy but elaboration is needed in pharmacogenetics As previously mentioned, abacavir was demonstrated to have an effect without causing any hypersensitivity reactions in 94% of a predominantly white population who did not carry the HLA-B*5701 allele. Perhaps more famous, regarding the potential link between pharmacogenetics and ethnicity/race, is the heart failure drug BiDil ® (NitroMed Inc., NC, USA), which was approved by the US FDA in 2005 for use in a self-identified black population. The original study did not demonstrate any significant efficacy for the general population, but when the data were re-examined, it was found that the efficacy was better in a subsample of African-Americans  . This led to a new trial being conducted with 1050 self-identified black patients with severe heart failure who had already received the best available treatment. Patients on BiDil experienced a 43% reduction in death and a 39% decrease in hospitalization for heart failure compared with those who were given a placebo, as well as a decrease in their symptoms of heart failure  . In a critical remark on this move towards a 'medicalization of race', Troy Duster argues that if one wants to categorize patients in clinical trials according to race, this would require the researcher to make a clear specification of the boundaries of the relevant population  . Without such a design, one does not truly know if the drug has a greater effect on African-Americans than on white populations. Duster believes that the approval of BiDil promotes the view that racial differences in health are owing to biological differences and that the significance of environmental factors, for example, employment, housing conditions and psychosocial stress, is underestimated. Søren Holm is also critical of the approval of BiDil on these grounds, asserting that race is a poor proxy of pharmacogenetic knowledge. His argument is also related to the definition of race and the reliance on self-definition. He states that: "Various estimates for the average percentage of non-African genetic material in African-Americans range from 16-26% and - the amount of non-African genetic material in a person self-identifying as African-American may range from 0-80%"  . The reason for this is the continuous migration of human populations over time and the increasing mixing of genetic material and cultural traditions. Thus, race and ethnicity are critical and rather loose concepts. However, from the patient's perspective, the evidence is rather appealing. The possibility of prescribing abacavir without risk of reactions of hypersensitivity represents a clear benefit for a large group of patients. A 43% reduction of death and a 39% decrease in hospitalization for black patients with heart failure and with no alternative therapy available is clearly of great ethical significance. These figures contradict Holm's assertion that race is not a good proxy for pharmacogenetic knowledge. More evidence exists that points in the direction of using race or ethnicity as good proxies. One further example is the anticoagulant Exanta® (melagratan/ximelagatran, AstraZeneca, London, UK), which was withdrawn from the market by AstraZeneca in 2006. The withdrawal was triggered by an adverse event report of serious liver injury, but there were no previous clinical signs that indicated this effect. Long-term treatment with this oral direct thrombin inhibitor resulted in elevated levels of serum alanine aminotransferase in some patients, but there is now evidence that these adverse reactions and the serious liver injury did not affect all populations. The presence of a certain allele has a geographic distribution with a carrier frequency of approximately 11% in Scandinavia versus 0.3% in Japan  . On this basis, at least a preliminary conclusion may be that the decision to withdraw the drug was premature; an Asian population would presumably have benefited from Exanta. As a Scandinavian, I would not feel discriminated against on these grounds. Ethnicity and race may accordingly serve as good proxies in pharmacogenetics, but more work needs to be carried out in order to describe different at-risk populations based on genotypes. One also needs to take cultural differences and environmental effects into consideration. An individual's coping capacity in situations of stress is a good example for the need of a broad approach. The ability to cope with stress is essential for health and failure in this capacity may increase one's susceptibility to psychopathology. It has recently been demonstrated that early epigenetic events in the stress-coping machinery may influence the capacity to cope with stressful events later in life  . In rats, maternal deprivation through the separation of mother and pups for 24 h during the first weeks of life has been demonstrated to have long-lasting consequences on the stress-coping system of the pups  . Recently, Bastiaan Heijmans et al. presented the first data that show empirical support for the hypothesis that epigenetic changes caused by environmental conditions early in human life can have effects throughout life  . Individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944-1945 following a food embargo imposed by the Germans had, six decades later, less DNA methylation of an imprinted gene compared with unexposed same-sex siblings. One can expect genetic epidemiology to uncover more of these gene-environment interactions, and subsequently, an increasing challenge in pharmacogenetics is to define, not only different genotypes, but also the effect of epigenetic changes earlier in an individual patient's history. Leave questions about justice to the authorities & politicians Questions concerning justice are a legitimate ethical concern from the perspective of disadvantaged individuals. As described at the beginning of this article, Dorothy Wertz suggested that "the cost of drug development raises questions of government, industry, and insurance company responsibilities to individuals whose pharmacogenetic responses are in a minority"  . Questions regarding global justice and the distribution of limited healthcare resources have been recurrent themes in the ethics literature focusing on pharmacogenetics (e.g., [3,6,9,33] ). Holm asks if the development of pharmacogenetics will benefit low- and middle-income countries  . These questions are of great importance, but it is of equal importance to address them to the right audience. In my view, it is wrong to ask the scientists or the pharmaceutical companies to answer these questions. It is not their task, and neither is it their task to be concerned about societal implications regarding scientifically-based definitions of genotypes and 'epigenotypes'. Individual scientists and company executives may feel a moral duty to contribute to a just world and to help those who have been disadvantaged owing to earlier injustice from the rich and powerful in particular. Sentiments like these are commendable but are entirely private concerns and nothing that can be imposed on these individuals by society. The reason for this casting of roles has been described in detail by John Rawls in his theory of justice as fairness  . Rawls' idea is that specific moral duties for individuals require specific kinds of moral bonds, such as the relationships between a wife and husband and mother and child, as well as between siblings, friends or colleagues. He also acknowledges altruistic feelings reaching fellow humans across long distances in time and geography. However, these kinds of individual moralities are not transferable to the duties we have as institutions, universities, companies and so on. The chief interest of a university is to provide scientific evidence based on sound research. In addition to this, pharmaceutical companies must also deliver drugs with favorable efficacy:safety ratios, and in order to do so they must also make money in competition with others. Rawls' question is: how would we like to organize a just society if we were ignorant of our positions and our specific interests? His fundamental answer to this question is that without knowing anything about our own or others' needs and interests, we would go for a society with just institutions that distribute resources to the advantage of all, and that unequal distribution is only acceptable - as it may sometimes be unavoidable - if the worst placed members of society reap a benefit. Justice is then a question of organizing just institutions, for example, for patenting, drug approval, the licensing of drugs, the ethical review of research projects, supervising health delivery, giving aid to the poor and so on. As individuals we have a moral duty to promote the organizing of such institutions in society. Pharmaceutical companies have no moral duty to subsidize certain drugs or to treat certain groups of patients more favorably than others. The obvious reason for this is that we do not want these decisions to be taken into the secret boardrooms of large multinational companies. We want them to be taken by governments, parliaments and public authorities, institutions that are accountable and transparent and where the individuals can be cast out of office at the public's will if they do not do what is expected of them. Sweden has provided a good example of this casting of roles regarding the use of genetic information by different parties, one of the much debated ethical issues in association with genetic medicine. A Swedish Parliamentary Commission reasoned that an essential part of the public trust in medical research using genetic and other kinds of sensitive medical information depends on patients and research subjects being aware that third parties are prohibited by law to request or inquire about genetic or medical information from an individual, with the exception of in specified medical situations  . The Commission's proposal is now incorporated into a law on genetic integrity  . The law states that no-one may stipulate, as a condition for entering into an agreement, that another party should undergo a genetic examination or submit genetic information about themselves. There is also a general prohibition that without support in law, genetic information may not be sought or used by anyone other than the person the information is about. This even applies if the individual in question has given their consent to such an investigation for its use, but not if they themselves have requested it. According to this law, there cannot be any legitimate area of application in the general field of genetic information, apart from the medical field, the judicature and other areas that are subject to special regulation, including the use of genetic information by insurance companies. This prohibition is not applicable to genetic information that is sought for medical purposes, for scientific or genealogical research or in order to obtain evidence in legal proceedings. For criminal investigations and insurance purposes, other regulations are in place. Illegitimate requests for, or use of, information may still be a problem, but this risk is minimized since according to the law, such actions constitute criminal offences. The prohibitions are enforced by a scale of penalties that include fines or a term of imprisonment not exceeding 6 months. From a patient's perspective, the law is of great significance. With these strict requirements regulating potential misuse by third parties, cumbersome restrictions on genetic research may be lifted, creating a more favorable climate for medical research that may benefit current and future patients. The Swedish law on genetic integrity is a good example of how social roles may be cast in pharmacogenetics. Conclusion Pharmacogenetics has started to deliver promising results that have decisive influence on the possibility of doctors prescribing drugs with more beneficial efficacy:safety ratios for patients. Exaggerations of results and unsubstantiated claims should be avoided by both scientists and their ethical and social examiners. The developments within pharmacogenetics will call for a more rapid movement among regulatory authorities to adopt a life-cycle approach in the risk assessment and benefit:risk monitoring of new and old drugs. Although controversial, race, ethnicity and cultural conditions can be good proxies for the assessment of efficacy and the risk of adverse reactions to drugs, but pharmacogenetics needs to develop more finely-tuned instruments for genotyping and epigenotyping. In order to serve as personalized, medicine also needs to take into account the health-associated risks that are modifiable through changed lifestyle. Questions regarding informed consent and the confidentiality of data in association with pharmacogenetic research are approaching consensus within the scholarly literature. Questions about global justice and access to new and more efficient drugs are central for the societal institutions to handle with thoughtful legislation that will not hinder research that may benefit current and future patients. Future perspective Pharmacogenetics promises realistic improvements in tailoring efficacy/safety concerns in medical treatment to the needs of groups of individuals with specific genotypes. A challenge in the implementation of a personalized medicine, which should be taken seriously in multidisciplinary settings, is to include research on the role of epigenetic factors and how individuals react to modifiable factors related to health. Concerns about inequalities based on race or ethnicity, as well as concerns about justice, should not be taken lightly, but this is not something that scientists should focus on. Overall, there is a need for bioethics that is well informed in science and in clinical practice, hopefully remembering that saying 'no' to new developments in medicine and biotechnology is of equal moral significance to saying 'yes'. Executive summary * There are no neutral social or ethical accounts of pharmacogenetics. * The most arguably important ethical perspective is related to the interests of patients wanting medical treatment that is both effective and carries low risks of adverse effects. * Exaggerations and unsubstantiated claims should be avoided by scientists as well as by sociologists and ethicists. * Regarding human tissue sampling, an international consensus is emerging concerning information and consent procedures. * A life-cycle approach in the risk management of drugs is called for. * Genotyping is essential for a personalized medical approach but so is the assessment of epigenetic and environmental factors. * Even if controversial, race, ethnicity and cultural conditions can be good proxies for the assessment of efficacy and the risk of adverse reactions to drugs. * Concerns regarding racial inequalities and justice should be addressed by political and legal authorities, although they are not a primary concern in pharmacogenetics. CAPTION(S): Figure 1. Relative importance of genetic and environmental factors affecting an individual's prospect of modifying his or her health risk. The numeral I at the left of the figure represents diseases in which an individual can do very little to control his or her risk. At the other extreme, IV on the right, we find diseases where almost the entire risk may be managed if the individual changes health-related behavior. Bibliography Papers of special note have been highlighted as: * of interest ** of considerable interest 1 Wertz DC: Ethical, legal and social issues in pharmacogenomics. Pharmacogenomics J. 3, 194-196 (2003). 2 Moldrup C: Ethical, social and legal implications of pharmacogenomics: a critical review. Community Genet. 4(4), 204-214 (2001). 3 Marx-Stölting L: Pharmacogenetics and ethical considerations: why care? 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Oxford University Press, Oxford, UK (1972). 53 SOU 2004:20: Genetik, Integritet Och Etik. Slutbetänkande av Kommittén Om Genetisk Integritet . Statens Offentliga Utredningar (Swedish Governmental Report), Stockholm, Sweden (2004). * Websites 101 US FDA: FDA approves BiDil heart failure drug for black patients www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108445.htm (Accessed 24 June 2009) 102 Lag (2006:351) om genetisk integritet mm www.notisum.se/rnp/sls/LAG/20060351.htm (Accessed 24 June 2009) Author Affiliation(s): 1 Centre for Research Ethics & Bioethics, Department of Public Health and Caring Sciences, Uppsala University, PO Box 564, SE 75122, Uppsala, Sweden. [email protected] Acknowledgements The author acknowledges the valuable suggestions from the anonymous reviewers to an earlier draft of this article. Financial & competing interests disclosure The work on this paper has been carried out within the format of the author's permanent position as Professor at Uppsala University. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Mats G Hansson Copyright: COPYRIGHT 2010 Future Medicine Ltd. http://www.futuremedicine.com/loi/pme Source Citation (MLA 9th Edition) Hansson, Mats G. "Taking the patient's side: the ethics of pharmacogenetics." Personalized Medicine, vol. 7, no. 1, Jan. 2010, pp. 75+. Gale Academic OneFile, link.gale.com/apps/doc/A245813211/AONE?u=uphoenix&sid=ebsco&xid=9bf69aed. Accessed 2 June 2022. Gale Document Number: GALE|A245813211 http://www.futuremedicine.com/loi/pme Disclaimer: This is a machine generated PDF of selected content from our products. This functionality is provided solely for your convenience and is in no way intended to replace original scanned PDF. Neither Cengage Learning nor its licensors make any representations or warranties with respect to the machine generated PDF. The PDF is automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. CENGAGE LEARNING AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGEMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the machine generated PDF is subject to all use restrictions contained in The Cengage Learning Subscription and License Agreement and/or the Gale Academic OneFile Terms and Conditions and by using the machine generated PDF functionality you agree to forgo any and all claims against Cengage Learning or its licensors for your use of the machine generated PDF functionality and any output derived therefrom. 'Someday it will be the norm': physician perspectives on the utility of genome sequencing for patient care in the MedSeqProject Authors: Jason L Vassy, Kurt D Christensen, Melody J Slashinski, Denise M Lautenbach, Sridharan Raghavan and Jill Oliver Robinson Date: Jan. 2015 From: Personalized Medicine(Vol. 12, Issue 1) Publisher: Future Medicine Ltd. Document Type: Report Length: 7,049 words DOI: http://dx.doi.org/10.2217/pme.14.68 Full Text: Author(s): Jason L Vassy [*] aff1 aff2 aff3 , Kurt D Christensen aff3 aff4 , Melody J Slashinski aff5 , Denise M Lautenbach aff3 aff4 , Sridharan Raghavan aff3 aff6 , Jill Oliver Robinson aff7 , Jennifer Blumenthal-Barby aff7 , Lindsay Zausmer Feuerman aff7 , Lisa Soleymani Lehmann aff2 aff3 aff6 , Michael F Murray aff9 , Robert C Green aff3 aff4 , Amy L McGuire aff7 Keywords: genomics; high-throughput nucleotide sequencing; pharmacogenetics; physician's practice patterns; qualitative research The claim that genomics will revolutionize the practice of medicine has been the subject of hope and hype, promise and skepticism [1-3 ]. Routine testing for genetic conditions such as phenylketonuria has been a part of clinical care since the 1960s, and today many general practitioners have at least some experience with targeted genetic testing for conditions such as cystic fibrosis, hemochromatosis and factor V Leiden thrombophilia [ 4-6 ]. However, the sequencing of the human genome in 2003 enabled genome-wide analyses of unprecedented scope and resolution, such that most variation in the human genome can now be analyzed with a single test. Genome sequencing has demonstrated clinical utility in specialized settings, including the diagnosis and management of rare diseases, infectious disease outbreaks and cancer [7-11 ]. However, the widespread uptake of genomics into general practice has not yet occurred, in part because of an absence of evidence for its clinical validity (how accurately the test detects or predicts a health outcome) and clinical utility (how likely the test is to improve medical decision-making and health outcomes) [12-17 ], particularly among generally healthy patients. At the same time, some thought leaders as well as industry and patient advocacy representatives have voiced the promise that genomics may usher in an era of personalized medicine [2,18-20 ], in which even healthy individuals undergo sequencing as a part of routine preventive medicine and medical care. Many of the articulated values overlap with movements calling for increased patient engagement in healthcare, including giving patients greater access to their health information and more active roles in medical decision-making [21,22 ]. Because genome-wide testing in these settings has not yet met the standards for clinical use generally required by clinicians, professional organizations and payers, some individuals have bypassed the healthcare system and turned to direct-to-consumer (DTC) products such as 23andMe's Personal Genome Service (PGS) to learn more about the health implications of their genomes [23-25 ]. These products have presented clinical challenges for providers and regulatory challenges for the US FDA, which in November 2013 instructed 23andMe to stop marketing Personal Genome Service as a health-related product, citing a lack of documentation of its analytic and clinical validity for this purpose [24,26 ]. DTC genomics products often use arrays of only hundreds of thousands of preselected common variants, called single-nucleotide polymorphisms (SNPs), some of which have association with human disease. Whole-genome sequencing (WGS), which reads more than 99% of the three billion base pairs in an individual's genome, has the capacity to reveal uncommon or even unique variants, much of which have uncertain clinical significance for an individual [17,27,28 ], but some of which can be highly diagnostic. The cost of sequencing has fallen considerably, making it feasible for WGS to replace more targeted genetic testing in the near future. However, the evidence for its clinical utility and cost-effectiveness in general patient populations lags behind [ 29 ]. Many health insurers are not reimbursing the costs of sequencing even for individuals with suspected rare genetic conditions, citing its uncertain impact on patient management [30 ]. To a large extent, the clinical integration of these technologies will depend on how useful practicing physicians perceive them to be for improving patient care. In a climate of clinical and regulatory uncertainty for the future of genomics, the voices of practicing clinicians will therefore be important for shaping policy and setting research priorities. To that end, we asked physicians http://dx.doi.org/10.2217/pme.14.68 participating in a research study of the clinical integration of genomics to describe their perceptions of the clinical utility that widespread uptake of genome sequencing might have for patient care. Materials & methods Study overview We report here data from the MedSeq Project, a pair of randomized controlled trials of WGS in the clinical care of healthy adult primary care patients and cardiomyopathy patients [31 ]. In this study, both physicians and patients were research subjects who were studied with serial surveys and interviews during the project. In this report, we use mixed methods to describe the physician participants' perceived utility of WGS for patient care at enrollment. The Partners Human Research Committee and the Baylor College of Medicine Institutional Review Board approved this study. Setting, study design & participants Eligible MedSeq Project physician participants included any primary care physician (PCP) or cardiologist actively seeing patients in a clinic setting in a single large urban network of academic hospitals and outpatient practices. Physicians were invited to enroll in the MedSeq Project as described previously [31 ]. Physicians were told that they would each be asked to identify potentially eligible patients and that research study staff would aim to recruit 8-12 patients per physician. For the primary care trial, eligible patient participants were generally healthy adults aged 40-65 years without an indication for genetic testing. The PCPs used their judgment to determine whether each patient was 'generally healthy,' although patients with cardiovascular disease or diabetes were specifically excluded. For the cardiology trial, eligible patient participants had a diagnosis of hypertrophic or dilated cardiomyopathy and may have undergone prior or concurrent targeted genetic testing for their condition. All patient participants were to undergo a family history assessment; half were randomly assigned to additionally undergo WGS and have the results interpreted on a genome report delivered to their physicians. A disclosure visit between each patient participant and his or her physician participant allowed the two to discuss the findings of the family history report alone or the combination of the family history and WGS reports. After physician enrollment but before patient enrollment, the MedSeq Project PCP and cardiologist physician participants underwent a genomics educational curriculum comparable in duration and scope to other continuing medical education (CME) offerings required for maintenance of certification. This curriculum consisted of two 1-h in-person group classes taught by medical geneticists and genetic counselors and 12 self-paced online modules, designed to take about 4 h total. The curriculum used case-based examples to cover general genetics concepts such as inheritance patterns, an overview of Mendelian conditions, genome-wide association studies and pharmacogenomics. Diseases illustrating key concepts included breast cancer, cystic fibrosis, familial hyperlipidemia and atrial fibrillation. Potential future clinical uses of WGS were not specifically discussed. Physician participants received 6 h of CME credits for completing the curriculum and financial compensation for study participation [31 ]. Measurements The MedSeq Project collected data on many patient and physician outcomes, including attitudes and preferences, psychological and behavioral impact and healthcare utilization, assessed at multiple time points during the study [ 31 ]. Here, we present data from two instruments administered to the MedSeq Project physician participants at enrollment. After the educational curriculum, physician participants completed a survey measuring their perceived utility of family history and genome sequencing information for clinical care. Specifically, physicians were asked to rate on a scale from 1 to 10 ('Not at all useful' to 'Extremely useful') how useful they thought family history and sequencing information would be for 'managing [their] patients' health' at two times: 'now' and 'in the future.' Also after the educational curriculum, but before any disclosure visits with their patients, physician participants underwent in- depth individual semi-structured interviews conducted by nonphysician interviewers trained in qualitative methods. The interview guide included domains about physicians' motivations for study participation, attitudes and expectations for genome sequencing and its utility for clinical care. Question prompts included how physicians felt about 'WGS becoming a part of clinical care' and how WGS results might 'influence [their] approach to patient care.' Interviews lasted about 45 min and occurred between March and December 2013. Interviews were audio-recorded and transcribed verbatim. Analysis We used mixed methods to describe the physicians' perceptions of the utility of WGS and family history information for clinical care. We used paired t -tests to compare the present and future utility ratings of WGS and family history information from the physician surveys. We analyzed interview data using thematic analysis [32 ], following standardized procedures for team-based qualitative analysis [ 33 ] and consensus-coding [34,35 ]. Interview data were stored and managed using ATLAS.ti version 7 software. A comparison of PCPs and cardiologists was not a focus of these analyses. Results Eighteen physician participants were recruited to the MedSeq Project (Table 1). Physicians rated family history information to have higher utility than WGS now, but they rated the two to have similar utility in the future (Figure 1). They anticipated that the utility of WGS would increase in the future (Δ = 2.9, p [less than] 0.001) but the utility of family history information would remain stable (Δ = 0.6, p = 0.08). From interview data, we identified three major themes physicians discussed in describing their perceived utility of WGS for the practice of medicine: its lack of current clinical utility, its inevitability and contexts in which WGS might achieve utility. Table 2 shows quotes illustrating these themes. In expressing these perceptions, physicians often used analogies to current medical testing or more familiar clinical scenarios. Lack of current clinical utility Physicians did not think that the widespread clinical integration of WGS was appropriate at present, citing a general perception that it would not change their clinical care of the majority of their patients. The nature of WGS data was often given as a reason for its limited clinical utility: it was seen to have uncertain disease associations with limited implications for clinical management. Physicians also described WGS results as probabilistic, although they acknowledged that this quality was not unique to WGS. One commented. "Medicine is used to using imperfect information-it does it all the time. In fact, I don't think there's any such thing as a perfect set of data in medicine because you are trying to take the general and apply it in the individual. And that is always fraught because there's no such thing as a probability when the individual is concerned. You have to actually make a binary decision. You either have to treat them or not treat them, take the lesion out or leave the lesion in" (C08). Physicians cited the potential for patient harm as another limitation to the clinical utility of WGS, often invoking the concern that its uncertain interpretation would lead to a cascade of further diagnostic tests carrying their own risks and costs. Inevitability Despite its current limitations, physicians generally expressed a sense that the widespread clinical integration of WGS was inevitable in the near future. When asked his opinion about WGS becoming a routine part of clinical care, one physician responded, "Well, that's sort of like saying, 'So what do you think about getting cholesterol tests on people?' I mean, it's a reality, and I think it's going to happen" (C18). Physicians did not generally elaborate on why they thought WGS would inevitably be a part of clinical care. Contexts of potential clinical utility Addressing the limitations above was seen to be a prerequisite for the clinical integration of WGS. Mirroring the quantitative survey results, one physician commented, "I think for a long time there will be too many genes and not enough correlation to disease, and that ratio will have to gradually change so that we understand more about the specifics" (P05). Physicians described four clinical contexts in which WGS might be useful for patient care: complementing other clinical information, risk stratification, motivating patient health behaviors and pharmacogenomics. Complementing other clinical information Physicians envisioned using WGS results to complement family history and other clinical information about individual patients. They described its potential to explain disease patterns within families, but they felt that they might minimize the clinical significance of WGS results not supported by observed family history. Many emphasized the importance of contextualizing WGS findings to the specific circumstances of individual patients, including their ages, health behaviors, family histories and other lab test results. Risk stratification Physicians would find WGS clinically useful for widespread implementation if it helped them distinguish low-risk from high-risk patients and if that stratification resulted in specific changes in clinical management, such as disease surveillance frequency and therapeutic choice. Physicians often described this concept in the setting of current health screening tests, such as colonoscopy and mammography. Motivating patient health behavior Physicians responded that WGS results might motivate patients to adopt healthier lifestyle habits, undergo screening tests already recommended for them and be more adherent to pharmacotherapy. Some physicians described WGS as empowering to patients in this regard, while others described WGS as a tool for physicians to use in persuading patients to adopt healthy behaviors. One physician responded that the low disease variance generally explained by genetics would paradoxically lead to an emphasis on non- genetic causes and increase patient motivation, stating. "When you start talking about the diseases that I deal with most commonly-atrial fibrillation, coronary heart disease, hypertension-and we have these genetic risks that are a limited percentage of the variation that gets explained, it really just emphasizes the importance of all the lifestyle modifications" (C18). Pharmacogenomics Physicians articulated a hope that WGS information would lessen the inefficient trial-and-error nature of pharmacotherapy, improving efficacy and minimizing adverse events. Still, some reported that the field of pharmacogenomics has the same limitations as genomic medicine overall, with unclear significance for medical decision-making. Discussion Physician participants of a study of WGS cited the complex and uncertain nature of its data, coupled with its potential for harm, as reasons for why genome sequencing is not yet ready for widespread clinical integration. Although they did not use the terms explicitly, physicians often invoked the uncertain clinical validity and utility of sequencing for use in their general patient populations. These physicians related WGS to common primary care scenarios in envisioning the future clinical utility of genome sequencing. They acknowledged its potential use as a screening test in routine health maintenance among asymptomatic individuals, as a complement to or replacement for current modalities such as colonoscopies or prostate-specific antigen (PSA) testing. They anticipated that such screening might one day help them target more intensive monitoring or treatment to patients at highest disease risk. They expressed a hope that sequence results might motivate healthy behaviors among their patients. They also looked forward to a pharmacogenomics-based body of evidence that would guide more effective pharmacotherapy, although they had the sense that such evidence does not yet exist. Despite the current limitations of genome-wide testing in healthy adults, physicians were generally pragmatic about its use. Many saw genome sequencing as just one of many tools for use in medical decision-making that might complement or even be superseded by other clinical information or by the larger context of an individual patient. To our knowledge, this is the first study examining practicing physicians' views on the widespread use of genome sequencing in clinical medicine, but our findings are consistent with prior work around more limited genome-wide technologies. Concerns about the clinical utility of SNP-based arrays have been reported in surveys and focus groups of general practitioners [4,36-40 ], including a group of PCPs who had undergone this testing themselves [ 41 ]. Early focus groups of family physicians expressed concerns about the complexity and uncertain clinical management of genetic cancer susceptibility testing [36 ], and focus groups a decade later echoed similar concerns about personalized genomic medicine more broadly [40 ]. The potential uses for WGS elicited in our interviews mirrored those anticipated for SNP array testing, such as risk stratification to inform disease surveillance frequency and treatment intensity [4,39,42 ]. Survey data suggest that physicians see genome-wide testing as one possible way to motivate their patients to make health behavior changes but, at the same time, are uncertain about its efficacy in doing so [ 4,43,44 ]. Of note, randomized trial evidence to date generally suggests that testing for genetic susceptibility to diseases such as diabetes and lung cancer does not improve health behaviors such as dietary habits, physical activity and smoking cessation [45-48 ]. The study physicians similarly expressed an enthusiasm for pharmacogenomics seen in prior surveys [41,49 ] but also skepticism for its clinical utility, this even before the high-profile publication of studies calling into question the clinical utility of warfarin pharmacogenomics [50 ]. Nonetheless, physicians in this and previous studies predict that genomics will become increasingly important for general medical practice in the future [4,42 ]. This study is limited to one network of academic primary care and cardiology practices, although the physicians represent a diverse range of demographics and training. These analyses are derived from a research study setting; however, at present, that is the only experience that most physicians, and particularly PCPs, have with WGS [17 ]. Moreover, the MedSeq Project aims to model the real- world integration of genome sequencing into general medicine. Specifically, we provided genomics education similar in duration to other CME opportunities and then studied how physicians perceived WGS. Our interviews demonstrate that these physicians are not necessarily early-adopting genome sequencing enthusiasts, but, rather, pragmatic clinicians who might represent the future of genomic medicine in patient care. The specific CME we provided almost certainly influenced the physicians' responses, but given its brief nature, we argue that these physicians may represent the future genomic medicine practitioner: not a genetics specialist but a physician given an introduction to genomics through both didactic and practical experience. Although our sample size limits the conclusions that can be drawn from our quantitative physician surveys, it was sufficiently large to enable the richness that is the strength of qualitative data [51 ]. However, our findings may not be generalizable to other physicians and other practice settings, particularly outside the research context. Although we provide a description of the experience of one group of physicians with genomic medicine, additional research in more diverse practice settings will be necessary to inform the future of genomics education, practice and research. The recent conflict between the FDA and 23andMe illustrates the importance that policy-makers place on the clinical validity and utility of new genomic technologies. WGS will likely be held to the same standards. In late 2013, insurer Blue Cross and Blue Shield concluded that exome sequencing can be diagnostic for certain patients but still not have an impact on disease treatment or outcomes [52 ]. In January 2014, Blue Cross and Blue Shield of North Carolina issued a policy that it would not cover WGS, considering it investigational and lacking in utility. The rise of DTC genomics products, on the other hand, reflects the growing interest of some patients in personalized medicine and engaging in their own healthcare. This tension between evidence-based and personalized approaches is not unique to genomic medicine, but nowhere is the uniqueness of each patient made more concrete than in his or her DNA sequence. To inform this debate, our study gives insight into the potential benefits and pitfalls that physician stakeholders perceive in increasingly integrating genome-wide testing into clinical care. Even before the FDA letter to 23andMe in November 2013, these physicians expressed concerns about the clinical validity and utility of the broad application of WGS. In the policy debate around genome-wide testing, it is important to recognize that physicians still use the language of evidence-based medicine to describe the application of genome sequencing to patient care. Given the unprecedented scope and uncertainty of WGS results, applying an evidentiary framework based on traditional comparative effectiveness metrics presents considerable challenges. At the same time, physicians describe a kind of personalized medicine when talking about the utility of genome sequencing, although this means interpreting a patient's WGS results in the context of their family history and other risk factors at least as often as it means medical decision-making based on one's genomic profile alone. It is unlikely that physicians will widely adopt genome sequencing unless policymakers can develop a framework that balances the competing demands of evidence-based and personalized medicine. In addition to framing the policy debate, the recognition that practicing physicians feel this tension when envisioning the future of genomic medicine will also shape a research agenda to develop the appropriate methodologies, metrics and standards to determine the role that genome sequencing should play in clinical medicine [16,53 ]. In contributing their perspectives to defining the thresholds that genome-wide testing should meet for clinical integration, physicians will minimize their risk of being excluded from the relationships between patients, their genomes and their health. Conclusion Practicing physicians given CME-level training in genomic medicine use the language of both evidence-based medicine and personalized medicine in describing the utility of genome-wide testing in patient care. The promise and limitations of genome sequencing identified by these potential users of this new technology should help shape the policy and research agendas around its integration into clinical practice. Future perspective Rapid advances in genomic technology and discovery in the last few years will almost certainly change the way that medicine is practiced in the next decade. However, the nature and extent of that impact remains to be defined, including the specific clinical contexts in which physicians find genome sequencing to improve medical decision-making and improve the care of their patients. Determining the clinical utility of genome sequencing across the spectrum of healthcare settings remains a next frontier in genomic medicine. Table 1. Characteristics of physician participants recruited to the MedSeq Project. PCPs (n = 10) Cardiologists (n = 8) Total (n = 18) Mean age, years (SD) 53 (9) 50 (9) 52 (9) Women (n) 5 2 7 Nonwhite race/ethnicity (n) 2 2 4 Genetics training[dagger] (n) 1 4 5 [dagger] Number responding 'yes' to the question "Have you ever had genetics training beyond the typical medical school curriculum?" PCP: Primary care physician. Table 2. Illustrative quotes from MedSeq Project physician participants about their perception of the utility of whole-genome sequencing in patient care. Domain Illustrative physician quotes Lack of clinical utility Nature of WGS data "Nobody knows really what to do with the information and knows what it is and what it isn't-" (P17) "I think there's so many mutations with unknown consequence. There's so much variability in the expression of some of the gene mutations so that even if you have them you may or may not have disease outcome with it. There are so many modifiers to it." (P15) Potential for harm "It's like doing a CT scan and finding a nodule and not knowing what it means. And the next thing you know you have a biopsy, and then you have a complication from the biopsy. Then the results from the biopsy are ambiguous again." (C07) "Like PSA testing and mammography, you might end up doing tests and procedures and treatments that are really not indicated because we don't really understand what it means." (P01) "You may tell the patient that he's not at high risk of something when he may be-so I am concerned we can make serious mistakes that may haunt us in the future because we misinterpreted something." (P10) Inevitability "I don't know when, but I'm sure sometime in the future it will become very much a part of what primary care physicians do. It will be just one of the tools in their toolbox that's available for taking care of patients." (P19) Contexts of utility Complementing other clinical information "We tell patients, 'Don't smoke, let's lose weight. Let's look back at that cholesterol-it's average. But, given the genetics- And then let's look at your family history. There was this one aunt.' When you pull it all together, you say, 'You know what? Maybe go on a statin. Maybe go on a little bit of aspirin.'" (P13) "I would take the genetic sequencing information and definitely correlate it to the family history-Separate from that I think that it can actually be dangerous. I think if you look through family histories, that's where the information carries its greatest value." (P15) Risk stratification "If it turns out that we don't have to do colonoscopies every 10 years on 100% of the people, maybe that will save a lot of money. If we know who we really should be doing PSA's on, or mammograms on, instead of doing them on everybody, we can stop creating a lot of harm and disability." (P01) "I look at this just like I look at risk in general. It's one other thing that might push me to be more aggressive in protecting someone against cardiac disease, Alzheimer's. For what impact we can have on those diseases that is, which is probably modest. But if someone were to have risk factors that suggested a higher risk for heart disease, I'd probably be more likely to put them on a statin, on an aspirin, do a stress test-do things that would be more proactive." (P15) "Whether it's from cholesterol, coronary artery disease, arrhythmias, hypertension, heart failure-I think there's going to be a wealth of areas that I deal with on a daily basis, that we will be able to focus our treatments to people who really need it and be able to reassure people who really don't." (C09) Motivating patient health behaviors "People today want to be more in control of their health. And [WGS] will enable them to do that. They'll be able to take something to their doctor and say, in addition to 'I had my appendix out, and I have chronic irritable bowel syndrome, and I get a lot of headaches,' 'By the way, this is my whole genome sequence, and these are the ones I was positive for. I need you to keep an eye out for these.' So it gives a patient a lot more power and control, which I think is very important." (P01) "You get a lot of information that may not be immediately useful and could potentially make some patients anxious. Although, you can always turn that around and use it to prod them to alter their behavior in a more healthy way. So I suppose one could leverage fear into something constructive." (P11) "I think maybe showing something concrete sometimes does work for the patients. I think that seeing results, seeing a paper, may make them change and be more compliant to come and get their mammograms and colonoscopies, which they have postponed and don't want to have done." (P10) Pharmacogenomics "One thing I do look forward to is knowing more about the pharmacogenomics because with basically everything we prescribe-blood pressure medications, anti-depressants, all this stuff-you're just guessing. And you're starting with the basic first- step evidence-based stuff, but you don't know. It would be nice if you just knew this is a patient who needs this SSRI because we know that it's a waste to try the first three steps-just go to the one that you know would work." (P17) "I'm sure many of the drugs that the future doctor uses will be throughput onto their genome to figure out the dose and the drug that's going to work best. That's very exciting, but it's a long way away." (P05) "I wonder about the usefulness of some of the pharmacogenomics associations, because I don't see them. The studies that have been done looking at the pharmacogenomics for warfarin dosing have been at best inconsistent, at worst disappointing, and so it really isn't endorsed as being useful." (C18) Primary care physicians and cardiologists are designated by 'P' and 'C,' respectively. PSA: Prostate-specific antigen; SSRI: Selective serotonin-reuptake inhibitor; WGS: Whole-genome sequencing. Executive Summary * After brief continuing medical education (CME) in genetics and genomics, primary care physicians and cardiologists without specialized genetics training rated genome sequencing to have lower utility for current patient care compared with family history assessment. * Physicians perceived the current limitations in the clinical utility of sequencing to include the uncertain interpretation of sequencing data and its limited ability to change clinical decision-making. * Nonetheless, physicians expected the clinical utility of genome sequencing to increase in the future, matching that of family history. * Physicians perceived the potential uses of sequencing to include complementing other clinical information; improved risk stratification of patients, leading to better preventive efforts, motivating patient behavior change and tailoring pharmacotherapy to patient genotype. * Practicing physicians given CME-level training in genomic medicine use the language of both evidence-based medicine and personalized medicine in describing the utility of genome-wide testing in patient care. * The promise and limitations of genome sequencing identified by these potential users of this new technology should be added to those of other stakeholders to help shape the policy and research agendas around its integration into clinical practice. CAPTION(S): Figure 1. Physician perception of present and future clinical utility of family history and whole genome sequencing, rated on a scale from 1 to 10 ('Not at all useful' to 'Extremely useful'). Values shown are mean (SD) utility ratings. p-values correspond to paired t -tests. References Papers of special note have been highlighted as: * of interest; ** of considerable interest 1 Green ED , Guyer MS . Charting a course for genomic medicine from base pairs to bedside . Nature 470 ( 7333 ), 204 - 213 ( 2011 ). 2 Evans JP , Meslin EM , Marteau TM , Caulfield T . Genomics. Deflating the genomic bubble . Science 331 ( 6019 ), 861 - 862 ( 2011 ). 3 Evaluation of Genomic Applications in Practice and Prevention (Egapp) Working Group. The EGAPP initiative: lessons learned . Genet. Med. 16 ( 3 ), 217 - 224 ( 2014 ). 4 Bernhardt BA , Zayac C , Gordon ES , Wawak L , Pyeritz RE , Gollust SE . 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Author Affiliation(s):  Section of General Internal Medicine, VA Boston Healthcare System, Boston, MA 02130, USA  Division of General Medicine & Primary Care, Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA  Department of Medicine, Harvard Medical School, Boston, MA 02115, USA  Division of Genetics, Brigham & Women's Hospital, Boston, MA 02115, USA  School of Public Health & Health Sciences, University of Massachusetts, Amherst, MA 01003, USA  General Medicine Division, Massachusetts General Hospital, Boston, MA 02114, USA  Center for Medical Ethics & Health Policy, Baylor College of Medicine, Houston, TX 77030, USA  Center for Bioethics, Harvard Medical School, Boston, MA 02115, USA  Geisinger Health System, Danville, PA 17822 4910, USA Author Note(s): *Author for correspondence: [email protected] [double dagger] Authors contributed equally Financial & competing interests disclosure This work was supported the US National Institutes of Health (U01-HG006500, U19-HD077671, L30-DK089597, F32-HG006993). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Ethical conduct The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. Copyright: COPYRIGHT 2015 Future Medicine Ltd. http://www.futuremedicine.com/loi/pme Source Citation (MLA 9th Edition) Vassy, Jason L, et al. "'Someday it will be the norm': physician perspectives on the utility of genome sequencing for patient care in the MedSeqProject." Personalized Medicine, vol. 12, no. 1, Jan. 2015, pp. 23+. Gale Academic OneFile, link.gale.com/apps/doc/A412067338/AONE?u=uphoenix&sid=ebsco&xid=d4b9cc52. Accessed 2 June 2022. Gale Document Number: GALE|A412067338 http://www.futuremedicine.com/loi/pme
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