Editing Clinical trial (section)

==Ethical aspects==
{{main|Clinical research ethics|Clinical trials publication}}

Clinical trials are closely supervised by appropriate regulatory authorities. All studies involving a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the US, this body is called the [[Institutional Review Board]] (IRB); in the EU, they are called [[Ethics committee (European Union)|Ethics committee]]s. Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions.

To be ethical, researchers must obtain the full and [[informed consent]] of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In addition, the clinical trial participants must be made aware that they can withdraw from the clinical trial at any time without any adverse action taken against them.<ref>{{Cite journal |title=The Ethics of Withdrawal from Study Participation | year=2006 | pmc=9527709 | last1=Gordon | first1=E. J. | last2=Prohaska | first2=T. R. | journal=Accountability in Research | volume=13 | issue=4 | pages=285–309 | doi=10.1080/08989620600848645 | pmid=17849641 }}</ref> In [[California]], the state has prioritized the individuals who can serve as the legally authorized representative.<ref>{{cite web|url=http://irb.ucsd.edu/ab_2328_bill_20020826_enrolled.pdf|title=Assembly Bill No. 2328|access-date=19 November 2007|archive-date=2 December 2007|archive-url=https://web.archive.org/web/20071202102256/http://irb.ucsd.edu/ab_2328_bill_20020826_enrolled.pdf|url-status=dead}}</ref>

In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy ([[Health Insurance Portability and Accountability Act|HIPAA]]) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the "rights, safety and well being of trial subjects are protected".

The notion of informed consent of participating human subjects exists in many countries but its precise definition may still vary.

Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. In [[compassionate use]] trials the latter becomes a particularly difficult problem. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. See also [[Expanded access]]. However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see [[Odds algorithm]]), and then quantified methods may play an important role.

Additional ethical concerns are present when conducting [[Ethical problems using children in clinical trials|clinical trials on children]] ([[pediatrics]]), and in emergency or epidemic situations.<ref>{{cite journal | vauthors = Hayden EC | title = Ethical dilemma for Ebola drug trials | journal = Nature | volume = 515 | issue = 7526 | pages = 177–8 | date = November 2014 | pmid = 25391940 | doi = 10.1038/515177a | bibcode = 2014Natur.515..177C | doi-access = free }}</ref><ref>{{Cite journal|last=Pattinson|first=Shaun D.|s2cid=71853867|date=2012|title=Emergency research and the interests of participants|journal=Medical Law International|language=en|volume=12|issue=2|pages=121–141|doi=10.1177/0968533212465615|url=http://dro.dur.ac.uk/10618/1/10618.pdf|access-date=13 July 2019|archive-date=9 April 2023|archive-url=https://web.archive.org/web/20230409105605/https://dro.dur.ac.uk/10618/1/10618.pdf|url-status=live}}</ref>

Ethically balancing the rights of multiple stakeholders may be difficult. For example, when drug trials fail, the sponsors may have a duty to tell current and potential investors immediately, which means both the research staff and the enrolled participants may first hear about the end of a trial through public [[business news]].<ref>{{Cite news|last=Span|first=Paula|url=https://www.nytimes.com/2020/03/03/health/drug-trial-alzheimers-volunteer.html|title=When a Drug Study Abruptly Ends, Volunteers Are Left to Cope|date=2020-03-03|work=The New York Times|access-date=2020-04-23|language=en-US|issn=0362-4331|archive-date=7 April 2023|archive-url=https://web.archive.org/web/20230407073602/https://www.nytimes.com/2020/03/03/health/drug-trial-alzheimers-volunteer.html|url-status=live}}</ref>

===Conflicts of interest and unfavorable studies===

In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research were not published, the [[Pharmaceutical Research and Manufacturers of America]] published new guidelines urging companies to report all findings and limit the financial involvement in drug companies by researchers.<ref name="moynihanbmj">{{Cite journal |journal=British Medical Journal|volume = 326|issue = 7400|pages = 1193–1196|pmc = 1126054|year = 2003|last1 = Moynihan|first1 = R.|title = Who pays for the pizza? Redefining the relationships between doctors and drug companies. 2: Disentanglement|pmid = 12775622|doi = 10.1136/bmj.326.7400.1193}}</ref> The [[US Congress]] signed into law a bill which requires Phase{{nbsp}}II and Phase{{nbsp}}III clinical trials to be registered by the sponsor on the [[clinicaltrials.gov]] website compiled by the [[National Institutes of Health]].<ref>{{cite web|url=http://www.hhlaw.com/files/Publication/edbf3429-125c-41c9-9442-b552e69b756c/Presentation/PublicationAttachment/972a9053-8c8d-46e4-ac96-ecf4892a8643/Pharma.pdf|title=Hogan & Hartson Update on Pharmaceutical Trial Registration|access-date=2008-06-02|date=2008-03-03|url-status=dead|archive-url=https://web.archive.org/web/20080625192559/http://www.hhlaw.com/files/Publication/edbf3429-125c-41c9-9442-b552e69b756c/Presentation/PublicationAttachment/972a9053-8c8d-46e4-ac96-ecf4892a8643/Pharma.pdf|archive-date=25 June 2008|df=dmy-all}}</ref>

Drug researchers not directly employed by pharmaceutical companies often seek grants from manufacturers, and manufacturers often look to academic researchers to conduct studies within networks of universities and their hospitals, e.g., for [[translational research|translational]] cancer research. Similarly, competition for tenured academic positions, government grants and prestige create conflicts of interest among academic scientists.<ref>{{cite news |url=https://www.nytimes.com/2012/04/17/science/rise-in-scientific-journal-retractions-prompts-calls-for-reform.html |title=Rise in Scientific Journal Retractions Prompts Calls for Reform |work=The New York Times |date=16 April 2012 |access-date=22 May 2018 |archive-date=18 June 2018 |archive-url=https://web.archive.org/web/20180618130136/https://www.nytimes.com/2012/04/17/science/rise-in-scientific-journal-retractions-prompts-calls-for-reform.html |url-status=live }}</ref> According to one study, approximately 75% of articles retracted for misconduct-related reasons have no declared industry financial support.<ref>{{cite journal | vauthors = Woolley KL, Lew RA, Stretton S, Ely JA, Bramich NJ, Keys JR, Monk JA, Woolley MJ | s2cid = 2583905 | title = Lack of involvement of medical writers and the pharmaceutical industry in publications retracted for misconduct: a systematic, controlled, retrospective study | journal = Current Medical Research and Opinion | volume = 27 | issue = 6 | pages = 1175–82 | date = June 2011 | pmid = 21473670 | doi = 10.1185/03007995.2011.573546 }}</ref> [[Seeding trial]]s are particularly controversial.<ref name="Say no">{{cite journal | vauthors = Sox HC, Rennie D | title = Seeding trials: just say "no" | journal = Annals of Internal Medicine | volume = 149 | issue = 4 | pages = 279–80 | date = August 2008 | pmid = 18711161 | doi = 10.7326/0003-4819-149-4-200808190-00012 | doi-access = free }}</ref>

In the United States, all clinical trials submitted to the FDA as part of a drug approval process are independently assessed by clinical experts within the Food and Drug Administration,<ref>{{cite web |url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ |title=Development & Approval Process (Drugs) |publisher=U.S. Food and Drug Administration |access-date=22 May 2018 |archive-date=10 June 2018 |archive-url=https://web.archive.org/web/20180610040253/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ |url-status=dead }}</ref> including inspections of primary data collection at selected clinical trial sites.<ref>{{cite web|url=https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf|title=Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors: FDA Inspections of Clinical Investigators|website=[[Food and Drug Administration]]|date=June 2010|access-date=16 October 2014|archive-date=11 June 2014|archive-url=https://web.archive.org/web/20140611165725/http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf|url-status=dead}}</ref>

In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that [[contract research organization]]s had, by 2000, received 60% of the grants from [[pharmaceutical industry|pharmaceutical companies]] in the US. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results.<ref>{{cite journal | vauthors = Davidoff F, DeAngelis CD, Drazen JM, Nicholls MG, Hoey J, Højgaard L, Horton R, Kotzin S, Nylenna M, Overbeke AJ, Sox HC, Van Der Weyden MB, Wilkes MS | title = Sponsorship, authorship and accountability | journal = CMAJ | volume = 165 | issue = 6 | pages = 786–8 | date = September 2001 | pmid = 11584570 | pmc = 81460 | url = http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=11584570 | access-date = 27 February 2011 | archive-date = 15 April 2023 | archive-url = https://web.archive.org/web/20230415001804/https://www.cmaj.ca/content/165/6/786.long | url-status = live }}</ref>

Despite explicit recommendations&nbsp; by stakeholders of measures to improve the standards of industry-sponsored medical research,<ref>{{Cite journal|last1=Mansi|first1=Bernadette A.|last2=Clark|first2=Juli|last3=David|first3=Frank S.|last4=Gesell|first4=Thomas M.|last5=Glasser|first5=Susan|last6=Gonzalez|first6=John|last7=Haller|first7=Daniel G.|last8=Laine|first8=Christine|last9=Miller|first9=Charles L.|last10=Mooney|first10=LaVerne A.|last11=Zecevic|first11=Maja|date=May 2012|title=Ten recommendations for closing the credibility gap in reporting industry-sponsored clinical research: a joint journal and pharmaceutical industry perspective|journal=Mayo Clinic Proceedings|volume=87|issue=5|pages=424–429|doi=10.1016/j.mayocp.2012.02.009|issn=1942-5546|pmc=3538468|pmid=22560521}}</ref>&nbsp; &nbsp;in 2013, [[Mauricio Tohen|Tohen]] warned of the persistence of a gap in the credibility of conclusions arising from industry-funded clinical trials, and called for ensuring strict adherence to ethical standards in industrial collaborations with academia, in order to avoid further erosion of the public's trust.<ref>{{Cite journal|last=Tohen|first=Mauricio|date=September 2013|title=Credibility of industry-funded clinical trials|journal=The International Journal of Neuropsychopharmacology|volume=16|issue=8|pages=1879–1884|doi=10.1017/S1461145713000461|issn=1469-5111|pmid=23672957|doi-access=free}}</ref> Issues referred for attention in this respect include potential observation bias, duration of the observation time for maintenance studies, the selection of the patient populations, factors that affect placebo response, and funding sources.<ref>{{Cite journal|last=Tohen|first=Mauricio|date=2017-02-01|title=Treatment Guidelines in Bipolar Disorders and the Importance of Proper Clinical Trial Design|journal=The International Journal of Neuropsychopharmacology|volume=20|issue=2|pages=95–97|doi=10.1093/ijnp/pyx002|issn=1469-5111|pmc=5356994|pmid=28927197}}</ref><ref>{{Cite journal|last=Tohen|first=Mauricio|date=2018|title=Severity of symptoms in mania-clinical guidelines and study design implications|url=https://pubmed.ncbi.nlm.nih.gov/29327798|journal=Bipolar Disorders|volume=20|issue=2|pages=171–172|doi=10.1111/bdi.12598|issn=1399-5618|pmid=29327798|access-date=27 May 2021|archive-date=8 April 2023|archive-url=https://web.archive.org/web/20230408221130/https://pubmed.ncbi.nlm.nih.gov/29327798/|url-status=live}}</ref><ref>{{Cite journal|last=Tohen|first=Mauricio|date=2013|title=Credibility of industry-funded clinical trials|journal=The International Journal of Neuropsychopharmacology|volume=16|issue=8|pages=1879–1884|doi=10.1017/S1461145713000461|issn=1469-5111|pmid=23672957|doi-access=free}}</ref>

===During public health crisis===
Conducting clinical trials of vaccines during epidemics and pandemics is subject to ethical concerns. For diseases with high mortality rates like Ebola, assigning individuals to a placebo or control group can be viewed as a death sentence. In response to ethical concerns regarding clinical research during epidemics, the [[National Academy of Medicine]] authored a report identifying seven ethical and scientific considerations. These considerations are:<ref name="Edwards">{{cite journal|doi=10.1146/annurev-virology-013120-013123|title=Ethics of Conducting Clinical Research in an Outbreak Setting|year=2020|last1=Edwards|first1=Kathryn M.|last2=Kochhar|first2=Sonali|journal=Annual Review of Virology|volume=7|issue=1|pages=475–494|pmid=32212920|doi-access=free}}</ref>
{{div col}}
* Scientific value
* Social value
* Respect for persons
* Community engagement
* Concern for participant welfare and interests
* A balance towards benefit over risks
* Post-trial access to tested therapies that had been withheld during the trial
{{div col end}}

===Pregnant women and children===
{{See also|pregnant women in clinical research|Children in clinical research}}
Pregnant women and children are typically excluded from clinical trials as vulnerable populations, though the data to support excluding them is not robust. By excluding them from clinical trials, information about the safety and effectiveness of therapies for these populations is often lacking. During the early history of the [[HIV/AIDS]] epidemic, a scientist noted that by excluding these groups from potentially life-saving treatment, they were being "protected to death". Projects such as  Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) have advocated for the ethical inclusion of pregnant women in vaccine trials. Inclusion of children in clinical trials has additional moral considerations, as children lack decision-making autonomy. Trials in the past had been criticized for using hospitalized children or orphans; these ethical concerns effectively stopped future research. In efforts to maintain effective pediatric care, several European countries and the US have policies to entice or compel pharmaceutical companies to conduct pediatric trials. International guidance recommends ethical pediatric trials by limiting harm, considering varied risks, and taking into account the complexities of pediatric care.<ref name="Edwards"/>