ENDO ROUNDS ~ ETHICS Christopher Patriquin PGY3. Ethics Topics for Today Pharmacogenomic Research Gene Therapy Presymptomatic (Predictive) Testing

ENDO ROUNDS ~ ETHICS

Christopher Patriquin PGY3

Ethics Topics for Today

Pharmacogenomic Research Gene Therapy Presymptomatic (Predictive) Testing

Ethics of Pharmacogenomics Objectives:

Identify ethical issues related to research ethics in the field pharmacogenomics.

Identify important information to communicate to participants in pharmacogenomic studies.

Appreciate the potentially sensitive nature of pharmacogenomic information.

Ethics of Pharmacogenomics Case ~ Dr. Smith and Geneticeuticals: In the context of a clinical trial, Dr. S is studying genetic

factors in cardiac disease. Patients are recruited from his practice to participate in

a clinical drug trial (NEW vs OLD) and a pharmaco-genomic add-on study. Pts from N. Africa, Central Europe and Japan are equally split

between the two arms Dr. S is financially supported by the company but does

not receive finders fees Samples are double-coded and compared against pre-

selected genetic markers to determine the efficacy of NEW (produced by Geneticeuticals)

Ethics of Pharmacogenomics Case cont’d... Before sample collection, study participants

consented to both clinical and pharmacogenomic aspects of the study, including future use of samples for “future pharmacogenomic research about cardiovascular disease.”

Informed that because of the exploratory nature of the add-on study and small sample size, those results would not be released; instead, larger studies would be needed first to validate findings

Ethics of Pharmacogenomics Case cont’d... Clinical trial results showed that NEW was as

effective as OLD, and no side effects were experienced

Pharmacogenomic results showed that NEW metabolized more quickly than OLD in 33% of Japanese and 75% of African participants

As such, they would need a higher dose of NEW to produce the same effect as regular OLD doses OLD PO OD = NEW PO TID

Ethics of Pharmacogenomics Case Questions:

Was the consent process sufficient? Consider this question in light of the potential for

conflicts of interest, the inclusion of a pharmacogenomic add-on study in the clinical trial, and the consent to future research.

Should Dr. Smith inform his patients of the results of the pharmacogenomic add-on study? Consider this in terms of the value of the information for

the patient, their expectations and their right to know. Are the ethnicity-related exploratory results

relevant for publication of the study and how should they be communicated?

Ethics of Pharmacogenomics Was the consent process sufficient? Errors were made...

Dr. Smith’s role in consent and recruitment... TCPS cautions against the participation of patients’

physicians as the recruiter (undue influence – art 2.2). Financial support could also cause conflict of interest,

with the conflicting desires of increased income vs. patient care

The TCPS (art 4.1) requires full disclosure of the financial relationship between company and physician.

Even with full disclosure, REBs can still reject a protocol if the conflict of interest is too great (ex. Shares in the Co.)

Ethics of Pharmacogenomics Was the consent process sufficient? Errors were made...

Combined clinical/pharmacogenomic consent... Separate consent forms should have been provided for the

clinical trial and the add-on. Health Canada urges that separate consent be obtained in

cases where pharmacogenomic testing is not essential to the study being conducted:

“[If] testing as a substudy that is not linked, but may be indirectly related to the main clinical trial, consent should be sought separately from consent to the main trial, either by using separate informed consent forms or by using the same form. The participant should have the ability to decline consent to the collection of samples for research use without prejudicing their participation in the main trials.” Health Canada: Submission of Pharmacogenomic Information

Ethics of Pharmacogenomics Was the consent process sufficient? Arguably acceptable...

Broad consent regarding future research... Solidarity and Citizenry are becoming more

prominent ethical principles This future research presents no additional physical

harm, and the psychological harm is minimized due to sample anonymization

Consent was limited to a specific class of research NB: “Blanket Consent” to unlimited research or for an

unlimited amount of time is not acceptable The option of forgoing future research still should have

been offered by Dr. Smith

Ethics of Pharmacogenomics Should the patients be informed of the results of

the add-on study? Must consider whether, when and how...

Communication of research results to subjects is an ethical imperative based on the principle of respect and on the relation of trust between subjects and researchers (Fernandez et al. 2003)

However, especially in the context of experimental genetics, these results should meet certain criteria:

Scientific validity, clinical significance, benefit and absence of an explicit refusal to know before being communicated (Knoppers et al. 2006)

Experimental nature of the add-on study requires that the results be confirmed with larger, more robust evidence before communicating the results to participants.

Ethics of Pharmacogenomics Should the patients be informed of the results of

the add-on study? Must consider whether, when and how...

Patients were explicitly informed that they would not be given the results of the pharmacogenomic testing.

Possibility and method of returning results should always be described in the consent process (Pharmacogenomics Working Group 2002).

Exploratory results of this study had low informational and clinical value, and subjects knew in advance not to expect them due to questionable validity, making individual release inappropriate

Future publication of the general results, if confirmed, is arguably an ethical duty and failure to do so “scientific misconduct” (Knoppers et al. 2006)

Ethics of Pharmacogenomics Are the ethnicity-related exploratory results

relevant for publication of the study, and how should they be communicated? Positive and negative effects are possible...

May identify sensitivities to drugs Can cause stigmatization Must ensure that sample groups are accurately

described (International HapMap Project): Too-narrow categorization invasion of privacy of a small

population subset Too-broad categorization erroneous characterization and

equating of genetics with the social construct of race

Ethics of Pharmacogenomics Are the ethnicity-related exploratory results relevant

for publication of the study, and how should they be communicated? Positive and negative effects are possible...

Genetic differences between, but also within, ethnic groups, and similarities also exist across groups

Pharmacogenomics and personalized medicine may allow for the bypassing of group categorization, but it is still in its exploratory infancy

Race (social construct) should not be a category of analysis in research geographical origins may be more responsible for genetic similarity (IHP):

More information on the Case subjects would be required, such as their ancestral origins (ex. Tribe, country, island, SES, lifestyle factors, etc).

IHP citation guidelines require that a group be described in detail before it is permissible to assign short-form designations, and that criteria for membership in a certain group be explained (ex. Japanese four grandparents must be of Japanese descent, etc.)

Ethics of Pharmacogenomics Are the ethnicity-related exploratory results relevant

for publication of the study, and how should they be communicated? Positive and negative effects are possible...

Race alone is a dangerous category of identification Classifying entire groups with labels (ex. “poor responder”) can

lead to a too-broad population segment being perceived in a certain way (ex. Too expensive to treat/too risky to insure, etc.)

NIH Guidelines (Realizing the Potential of Pharmacogenomics: Opportunities and Challenges) suggest:

If a correlation between a group and a drug is found, further genetic and biological factors must be explored to account for these diffferences

The same research should be performed in other groups to assess for a similar response/effect

Upon discovery of a correlation between race and drug response, additional research (biological, social, behavioural, environmental) should be undertaken

Questions?

Ethics of Gene Therapy

Objectives: Understand the ethical and legal issues

relating to the inclusion of children in clinical studies on gene therapy.

Identify allowable limits regarding the inclusion of children in these clinical studies.


Case ~ Felix has DMD Felix (12M) uses a W/C because of the

progression of his disease. He is told by his specialist, Dr. Williams, that

the diagnosis is certain (dystrophin mutation) and that he is certain that Felix’s muscles will continue to rapidly degenerate

He is aware that steroid-based therapies can help temporarily preserve muscle strength, but there is no proven treatment to directly cure/treat the DMD


Case cont’d... Dr. Williams is also a researcher, and has

a study using ex vivo somatic gene therapy to treat DMD: Myoblasts are removed, modified

genetically to insert normal dystrophin genes, then reimplanted with multiple muscle injections

Still an experimental therapy, with risks including immune reaction to wild type dystrophin, and tumour formation in the genetically modified cells


Case Questions: What special challenges does gene therapy

research pose? Is it ever acceptable to perform gene therapy

research involving children? What are the benefits and harms of such

research, and are they reasonable? Does a child need to assent to his/her

participation in gene therapy research? If he/she dissents, should the decision be

respected?


What special challenges does gene therapy research pose? Must prove effectiveness! (Couzin et al. 2005)

Successful treatment of X-SCID Increased risk of cancer/leukemia and death Still a very experimental therapy with multiple risks Last chance for some otherwise-terminal childhood illnesses

Intervention characterization Listed as ‘experiment’ by some, ‘experimental therapy’ by

others (VERY different goals) “experiment” acquire new knowledge (full stop!)

Beneficial to others with same characteristics eventually “experimental therapy” acquire new knowledge while providing

benefit to the patient (save life/improve health) Applied only to one patient with the goal of immediate treatment

Our case appropriately qualifies as experimental therapy.


Is it ever acceptable to perform gene therapy research involving children? Yes

Declaration of Helsinki/CIOMS – vulnerable people should not be included in research unless it is indispensable to the improvement of their health, and it cannot be done with people capable of providing consent

CIOMS – participation of children is indispensable for conducting effective research into childhood disease (CIOMS/WHO 2002, dir 14)


Is it ever acceptable to perform gene therapy research involving children? Yes

Canadian Guidelines (MRCC/CIHR 1990, TCPS 2005) Diseases that lend themselves best to these studies are

generally fatal at a young age chance to intervene early Children should no be automatically excluded from studies that

could be beneficial to them due to their inability to legally consent:

“A dilemma exists in that the most likely diseases to be considered for gene alteration are severe, progressive and fatal in childhood (e.g. immune deficiencies). Early treatment for maximal effect means the subject is less able to give free and informed consent because of immaturity. Furthermore, long-term effects are unknown in this age group. However, if research is restricted to those who are able to give consent, many severely affected children would be excluded” (TCPS 2005, art 5.3)


What are the benefits and harms of such research, and are they reasonable? Every research project “must be preceded by careful

assessment of predictable risks and burdens ... in comparison with foreseeable benefits.” (DoH art 18)

Research must be stopped when risks are seen to outweigh potential benefits (DoH art 20)

CIOMS Guidelines: Ensure equilibrium between potential risks and benefits, and ensure

minimization of risks Interventions offering direct benefit to research subjects must have

risks justified in context of expected benefit Interventions offering indirect benefit must have reasonable risks

considering the significance of the knowledge obtained Research subjects cannot be exposed to anything beyond minimal

risk, comparable to that of a routine medical procedure Risks can be increased if there are overriding medical reasons to do

so, following REB approval


What are the benefits and harms of such research, and are they reasonable? TCPS (art 2.5)

Research cannot expose children to more than minimal risk unless there is potential for direct clinical benefit.

Involvement of children with incurable diseases requires “special reflection” but no specific guidelines.

Civil Code of Quebec Children can participate in research “when there is an

absence of serious risk” for their health, and when there is benefit for “their health or the health of other children possessing the same characteristics, illness and handicap.”

Limits the degree of allowable potential risk, and does not take into account the overall equilibrium


What are the benefits and harms of such research, and are they reasonable? Our Case

Proposed therapy is not a proven treatment Determining equilibrium of benefits/risks

subjective, and may vary from REB to REB Some may focus more on benefits (possible life

extension and/or symptomatic improvement), whereas others could emphasize the risks (increased rate of leukemia, immune reactions and death).

TCPS would provide grounds to allow it, whereas an inability to ensure an “absence of serious risk” would not allow this experimental therapy to be given in Quebec.


Does a child need to assent to his/her participation in gene therapy research? If a child dissents, should his/her decision be respected? Assent is based on the principle of respect, making it

possible for children to exercise autonomy within their capacity

International guidelines (DoH, CIOMS, UNESCO) require the assent of children capable of understanding the consequences of the research project

Assent must be obtained after consent from the parents or legal representative (CIOMS) Research question, methodology, risks & benefits must be

explained to the child in appropriate language Continuing process (like consent) and requires renewal over the

course of the research, especially with significant changes


Does a child need to assent to his/her participation in gene therapy research? If a child dissents, should his/her decision be respected? Dissent must be respected unless refusal is harmful to

his/her health, but can be superseded in certain situations: Child is too young, immature or incapable of understanding the

project When the research project is the only possible intervention, and

offers hope of benefit for the child TCPS (art 2.7)

Even if children are too young/immature to consent, they can still “express their wishes in a meaningful way.”

Consent of the parents should be obtained before assent is sough in the child

Dissent of the child excludes him/her from the research

Questions?

Ethics of Presymptomatic Genetic Testing

Objectives: Understand the issues to consider when addressing a

request for predictive (presymptomatic) testing for genetic disease Ability to treat the disease, value added for patients by knowing

their status, value added for society by this knowledge, and the potential harms.

Appreciate the ethical concerns created by predictive testing for genetic disorders in children, in particular, respect for autonomy

Understand the uncertainties in predicting patient affectation status due to the limitations of currently available clinical and laboratory tools

Appreciate the potential personal and social implications of molecular genetic testing for asymptomatic children


Case ~ 3M with a family history of retinitis pigmentosa (RP)

Brought to the eye clinic by his parents No apparent eye problems Father (40) has retinitis pigmentosa which onset

at age 20, starting with decreased night vision Peripheral vision now quite reduced, although

straight-ahead vision is still normal Three other affected family members, with

pedigree suggestive of AD inheritance “Will our son get RP?”


Case Questions: What are the considerations about predictive

presymptomatic testing? What are the considerations about the disease? Are there potential harms from predictive

testing? Are there special considerations for children? Is there policy or empirical research to guide the

clinician? How can clinicians best proceed in a non-

directive fashion?


What are the considerations about predictive presymptomatic testing? Is the request feasible? Is the request indicated?

Moot if no test is available. If treatment or prevention is available (ex. BrCa, OvCa, RB,

hypercholesterolemia), testing is indicated. Variable genetic expression and disease penetrance may

render even highly sensitive and specific tests less powerful Presymptomatic periods may also be variable

For retinitis pigmentosa, electroretinograms are often abnormal before it is picked up on clinical exam, and expression of disease onset is variable, with occasional non-penetrance Mild electroretinographic changes may indicate early disease

or an asymptomatic carrier, and results are most difficult to interpret in the presymptomatic period


What are the considerations about the disease? Predictive testing is justified when a disease is treatable or

preventable Many countries test for neonatal diseases even without specific

consent because overall benefits outweigh minimal testing risks Urgent treatment may have significant impact!

Issues may arise if parents refuse testing, even if medically indicated, or if other family members may benefit from testing Important to address thoughts/knowledge on information sharing

and explore underlying motivation behind refusal Benefits are less certain with untreatable diseases, and

knowledge of affectation status can create significant psychosocial stress Currently no cure for RP Some individuals will express positive attitudes, citing the potential

for future treatment options, accurate and/or earlier diagnosis, and identification of carriers


Are there potential harms from predictive testing? Yes Risks to testing are possible with either positive

or negative results for adult-onset disorders Testing positive for untreatable diseases can lead

to MDD/suicide, discrimination (socially/insurance) Testing negative for untreatable diseases can lead

to guilt, if other family members are affected, or if anticipated travel plans must be cancelled/rethought

Surprise non-paternity!


Are there special considerations for children? Balance present and future autonomy Balance childhood privacy rights with parental

interests Potential harms to predictive testing, so

children must assent to testing in a measure appropriate to their level of maturity, and experiences of illness and treatment

Without a clear therapeutic benefit, parents must be educated as to the risks/benefits of the testing if they have not been considered


Is there policy or empirical research to guide the clinician? CPS and AAP suggest joint decisions be made between physicians

and parents for the very young Clinical Genetics Society (UK):

“Predictive genetic testing of children should generally not be undertaken... [however] for some disorders there is insufficient evidence to recommend for or against [and] if the child stands to gain some health benefit from predictive testing, then it is obviously good practice to make the testing available.” (CGS Working Group 1994)

Mezer et al. (2007) For RP specifically, 67% of unaffected individuals and 44% of affected

individuals supported prenatal testing for AD RP 57% of affected individuals reported significant emotional stress in

recollecting predictive testing experiences as children Furu et al. (1993)

Only 20% of patients with RP and their relatives recommended testing children

Pawlowitzki et al. (1986) 61% of patients with RP perceived potential dangers in molecular

diagnostics, but 90% also perceived potential advantages


How can clinicians best proceed in a non-directive fashion? Before predictive testing, formal genetic counselling

should be undergone to optimally inform patients and family about risks, benefits and expectations

Adults may choose not to have genetic testing If there is no clinical urgency and no identifiable

therapeutic benefit to testing, deferring childhood testing is suggested until they are of an age where a more complete understanding of the procedure is possible

Counselling after testing is also extremely important, especially to screen for adverse reactions

Questions?

Documents

ENDO ROUNDS ~ ETHICS Christopher Patriquin PGY3. Ethics Topics for Today Pharmacogenomic Research Gene Therapy Presymptomatic (Predictive) Testing