Efficacy of tct and aba in 22 hospitalized treatment resistant patients with schizophrenia
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012Michener InstituteETCR 120Efficacy of TCT and ABA in 22 hospitalized treatment-resistant patients withSchizophrenia: A comparative studyClinical Case Analysis(Modules 3 and 4)Xiomara Arias Fernández
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012Efficacy of TCT and ABA in 22 hospitalized treatment-resistant patients with Schizophrenia: Acomparative studyIntroduction: Relevant factsThis study attempts to help resolve a controversy regarding which of two treatments is better fortreating schizophrenia. It is part of a 22-site multicenter US and Canada study and the WesternCanada University Research Ethics Board (WCU REB) is responsible for reviewing andapprove/disapprove this study .(The original description of the assignment is given at the end of thispaper under the references section).This paper evaluates the clinical study proposed with reference to relevant moral codes andguidelines, identifying the main moral concerns in order to suggest changes that would minimize thesemoral issues and their implications for the wellbeing of participants involved in the study.One of the relevant facts that arise in this study is primarily related to the use of a placebo “washout”. In fact, a placebo run-in period is seen as a potential harm that could negatively affect thewellbeing of the participant and the safety of others. Risk/benefit ratio should be heavily considered.Another relevant fact in this study has to do with informed consent performance. Theseparticipants belong to a vulnerable group since they suffer from mental illness. Without adequatetreatment, while performing the study, symptoms of schizophrenia could worsen to the point thatparticipants may become unable to give their informed consent.A final fact that could raise ethical concerns is the criterion of inclusion/exclusion of potentialparticipants.In regards to the investigator duties and participant rights, firstly, participants have the right not tobe harmed by any procedure involved in the study, and to receive adequate medical care for anyadverse event that occurs. For instance, participants must be given the best possible medical
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012treatments available in the market when side effects arise from the drugs taken as part of the clinicaltrial. It is the investigator’s duty to provide this protection for all subjects. Essentially, according to theHarmonized Tripartite Guideline (ICH) 1(p 9): “The Independent Ethics Committee (IEC) has theobligation to protect the rights, safety and well being of all the subjects involved in a trial”. IEC mustenforce a good communication among all the parts involved in the trial. According to Helsinki principle(²) section B, 1 (p 2): “Physicians in Medical research have the duty to protect life, health, privacy anddignity of the subject who participate in a trial.”Secondly, there is a personal and moral duty of the sponsor, investigators and the participant’slegal representative (if one is needed) to ensure that genuine informed consent is fully accomplished.As mentioned at the introduction of this paper, investigators have an obligation to estimate therisk/benefit ratio to minimize any harm to participants. One of the main duties of The investigator(s) isto design the study in a way that optimize the potential to acquire meaningful results from the studywhile minimizing risk.As it mentioned in the introduction, one of the moral issues is that there is a risk that theparticipants of the study become unable to continuing given genuine consent .If this situation happenthey must be excluded from the study. However, since they belong to a vulnerable population theyshould not be excluded because they have the right to obtain benefits from the study and part of thecriteria of inclusion of the study that states that participants must suffer of the active disease in study.The use of a placebo raises a moral issue in the study, because this may breach the researcher’sduty to minimize harm to the participants. It is unethical to enroll participants in a study .when it may beexpected that their medical condition(s) will worsen.Another moral issue is related to the potential occurrence of adverse events, and raise a question:What standard of care should be provided to the participants who become ill during the study, whether
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012as a consequence of using the new drug or as a result of the primary treatment withdrawal?A final issue is the possibility that some individuals who belongs to a vulnerable group (i.e., pregnantwomen) could be inappropriately excluded from the research and thus be denied of a potential benefitfrom the studyIn relation with the changes to be considered in this case, first, there must be complete disclosureof the risks - this is required in order for informed consent to be meaningful. Full disclosure ismentioned in article 3.2 (p30) of The Tri-council Policy Statement (TCPS)(3 ). Second, because of therisk regarding participants’ health and safety, the use of a placebo in this study contravenes theHelsinki (²) and the non-maleficence (4) principle. The participant must be fully informed in detail aboutthe purpose of the trial to avoid the assumption that they will receive health benefits from participating,when in reality they will be kept from taking any beneficial drug during the placebo run. Further,participants’ level of risk is high since the benefits of the trial drug have not yet been proven. In thisregard, the declaration of Helsinki (²) in section 3, 17-20(p 23) emphatically states that “Medicalresearch is only justified if ... the populations benefit from the results of the research”. Based on theTCPS 3 core principles and article 3.1, (p 28) and on Belmont (5) principle of respect for persons and theirautonomy, it would be necessary to ensure that participants be able to give informed consentthroughout the duration of the study, and/or allow the subjects to potentially withdraw from the study ifnecessary, without undermining their wellbeing. Since the core of the consent process is to clearly andprecisely inform of the trial process as a whole and also to protect the participants, they need tounderstand the purpose and the potential consequences of the study thoroughly, not only at thebeginning of the process but also during the investigation itself by monitoring consent. Although thisobligation seems difficult to accomplish since participants could be argued to have limitedunderstanding of technical and scientific terminology, this shouldn’t be a problem, since according toSection 2.2 of The Nuffield Council of Bio Ethics 6 (p 11) “Researchers must do their best tocommunicate information accurately
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012and in an intelligible and appropriate way, taking in account of local knowledge and beliefs” .Supplementary documentation should be available for use according to every particular case, includingthose in which participants’ lack of technical knowledge about the informed consent could pose aproblem. In these instances, rather than ask the subjects to sign the forms, it may be more appropriateto have a witness (e.g., a relative) who verbally agrees with the investigation and its procedures.Further, misunderstandings can be remedied by ensuring that genuine consent is given, and that lackof consent is eliminated. This seems to be particularly important if any of the participants lose capacityto give consent during the course of the trial due to worsening of their schizophrenia.On the other hand, and although it is expected that there would be at least one member withdocumented expertise in the WCU REB to understand the study technical definitions, it may be suitableto provide training to all members who are relatively new, such as Ms. Jeffrey, who doesn’t have theexpertise to understand the study terminology used in the consent.Based on the Belmont principle (5) of Beneficence, the Utilitarian Ethical Theory (7) and also onthe US Federal Code Regulations (CFR) 8 title 45, 46.111(1, 2, b), it would be necessary to assess theprojection of study benefits in terms of medical advancements (risk/benefit ratio). Furthermore besidethis, adequate medical care should planned ahead to be given to the trial participants who eventuallycan result injured by any procedure in the study and additional safeguards must be provided.Based on the Belmont principle (5) of Justice and TCPS (3) guidelines it would be necessary toevaluate the reason(s) why pregnant women are excluded from this study. According to TCPS 3 (p 49)Article 4.3: “Women shall not be inappropriately excluded from research ... because...they arepregnant...Exclusions should be made on the basis of clear criteria...”.Also CFR (8) title 45, 46.111(3)provide that selection of the subject participant must be equitable, being especially cognizable aboutvulnerable population such as pregnant women.Finally, if perceived risk to participants is too great, and the study has not been adequatelydesigned to minimize these risks, the study may not be ethically acceptable. In such cases it may be
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012possible to reconsider the research question and look for another design that fulfills the ethicalrequirements .( According to The CFR 8 in 46.112 , WCU REB would be in capacity to make furtherreviews of the study and may approve/disapprove it. )WCU REB in accordance with IHC guidelines ¹(pp11, 12) 3.3.7 and 3.3.8 (a) should approve any appropriate amendment and maintain continuouscommunication between investigators in order to ensure that participants’ wellbeing is protected,complying also with Helsinki(2) declaration, part B, 13 .All the criteria appointed by CFR( 8) in section46.111 must be analyzed by the WCU REB at the time of approve this study, particularly exertingcooperative research as expressed by the CFR( 8 ) in section 46.114.
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012References(¹) International conference on harmonisation of technical requirements for registration ofpharmaceuticals for human use. ICH Harmonised tripartite guideline validation of analytical procedures:Text and Methodology Q2 27 October 1994 (Complementary Guideline on Methodology dated 6November 1996 incorporated in November 2005)http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf(²) World Medical Association Declaration of Helsinki Ethical Principles for Medical Research InvolvingHuman Subjects (p4, Section C, 29). Additional principles for medical research combined with medicalcare. At http://www.fda.gov/ohrms/dockets/dockets/06d0331/06D-0331-EC20-Attach-1.pdf(3) Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council ofCanada, and Social Sciences and Humanities Research Council of Canada, Tri-Council PolicyStatement. Ethical Conduct for Research Involving Humans, (Chapter 1 (pp8, 10) Chapter3 (pp 27- 45)December 2010At http://www.pre.ethics.gc.ca/pdf/eng/tcps2/TCPS_2_FINAL_Web.pdf(4) Omonzejele, P. F. Obligation of non-maleficence: moral dilemma in physician-patient relationship (p23) JMBR: A Peer-review Journal of Biomedical Sciences Vol. 4 No.1 pp-22-30; June 2005At http://www.bioline.org.br/pdf?jm05003(5). Gov. U.S Department of Health and Human Services (HHS). The Belmont Report. April 18,1979.(Internet September 2012)Athttp://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012(6) The Nuffield Council of Bio Ethics. Research related in Developed countries. Chapter 2Consent.(p11);2002 Athttp://www.nuffieldbioethics.org/sites/default/files/files/HRRDC%20Follow%20up%20Chapter%202%20-%20Consent.pdf(7) Beauchamp t, Bowie N., Arnol, D.Ethical Theory and business 8thEd. Normative ethical theories.Utilitarian theories (p 18) Lavosier; 19958) The US Federal Cod Title p45 Public Welfare, Part 46 Protection of Human Subjects Athttp://ecfr.gpoaccess.gov/cgi/t/text/textidx?c=ecfr&sid=cda3365ad224bf252867e02264d67e71&rgn=div8&view=text&node=45:184.108.40.206.220.127.116.11&idno=45
ETCR 120 Ethical case analysis #1 Xiomara Arias FernandezETRC 120 October 7 2012Ethical case analysisCynthia Jeffrey is a new member of the University of Western Canadas research ethics Board (REB).Her orientation session to the new Tri-Council Policy Statement and to the REBs responsibilitiesseemed straightforward, but as she considers the most recent proposal on the REBs agenda, sheknows that they face a difficult decision. The proposal from Dr. Cecil Tan, a senior researcher in thedepartment of Psychiatry, appears to contravene some sections of the Policy Statement. However, thestudy is part of a 22-site multicentre US and Canada study sponsored by a major internationalpharmaceutical firm and cannot be modified for UWC alone; the REB appears to have the choice ofaccepting it without change or forcing Dr. Tan to withdraw from the study.The study is a clinical trial of TCT, a new drug for the treatment of Schizophrenia. The study willcompare the efficacy of TCT against that of ABA, a widely used antipsychotic drug, on hospitalizedtreatment resistant patients. 22 subjects from a nearby hospital are to be selected according to strictcriteria defining the activity and duration of their schizophrenia, with exclusions for pregnant women andother contraindicated conditions such as hypertension and known history of adverse reactions toantipsychotic. Response to the ten-week treatment with TCT or ABA will be measured by scores on twoaccepted psychiatric scales that will require blood analyses, ECGs, and other diagnostics throughoutthe study.Because 25% of schizophrenic patients have been shown to respond to placebos, the sponsor requiresan initial placebo run-in period (also known as "placebo washout") for all subjects to establish baselinepatient ratings without treatments. During the run-in, the medication of all subjects is to be discontinuedfor two weeks and to be reinstated if severe problems arise. Dr. Tan has already been questionedabout the placebo run-in, but he and the sponsor argue that the standard treatments have potentiallyserious side effects and the period of treatment withdrawal is short. Dr. Jeffrey is unsure whetherwithholding standard treatments is unethical in this situation, particularly since the risk of subjectsharming themselves or others intensifies without treatment.Although the rest of the REB has not yet considered it, she is also concerned about the ability of thesubjects to give free and informed consent to the research, given that a criterion for selection is theirhospitalization for at least one year with active schizophrenia. The consent form provided with theproposal is long, quite technical, and difficult for her to understand, and she wonders whether a patientsuitable for the study could grasp its meaning and freely agree to the trial.Discuss this case with reference to guidelines, policies and codes referred to in modules 3 and 4.