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necessary for participation in the trial (e.g. s/he may have other health problems). In such cases and if the person has a life-threatening or serious condition for which there is no effective treatment, s/he may benefit from “expanded access” use of the drug. There must, however, be evidence that the |
drug under investigation has some likelihood of being effective for that patient and that taking it would not constitute an unreasonable risk. The use of placebo and other forms of comparison The main purpose of clinical drug studies is to distinguish the effect of the trial drug from other influences |
such as spontaneous change in the course of the disease, placebo effect, or biased observation. A valid comparison must be made with a control. The American Food and Drugs Administration recognises different types of control namely, - active treatment with a known effective therapy or - no treatment, - historical |
treatment (which could be an adequately documented natural history of the disease or condition, or the results of active treatment in comparable patients or populations). The EMA considers three-armed trials (including the experimental medicine, a placebo and an active control) as a scientific gold standard and that there are multiple |
reasons to support their use in drug development . Participants in clinical trials are usually divided into two or more groups. One group receives the active treatment with the experimental substance and the other group receives a placebo, a different drug or another intervention. The active treatment is expected to |
have a positive curative effect whereas the placebo is expected to have zero effect. With regard to the aim to develop more effective treatments, there are two possibilities: 1. the experimental substance is more effective than the current treatment or 2. it is more effective than no treatment at all. |
According to article 11 of the International Ethical Guidelines for Biomedical Research (IEGBR) of 2002, participants allocated to the control group in a trial for a diagnostic, therapeutic or preventive intervention should receive an established effective intervention but it may in some circumstances be considered ethically acceptable to use a |
placebo (i.e. no treatment). In article 11 of the IEGBR, reasons for the use of placebo are: 1. that there is no established intervention 2. that withholding an established effective intervention would expose subjects to, at most, temporary discomfort or delay in relief of symptoms 3. that use of an |
established effective intervention as comparator would not yield scientifically reliable results and use of placebo would not add any risk of serious or irreversible harm to the subjects. November 2010, EMA/759784/2010 Committee for Medicinal Products for Human Use The use of placebo and the issue of irreversible harm It has |
been suggested that clinical trials are only acceptable in ethical terms if there is uncertainty within the medical community as to which treatment is most suitable to cure or treat a disease (National Bioethics Commission of Greece, 2005). In the case of dementia, whilst there is no cure, there are |
a few drugs for the symptomatic treatment of dementia. Consequently, one could ask whether it is ethical to deprive a group of participants of treatment which would have most likely improved their condition for the purpose of testing a potentially better drug (National Bioethics Commission of Greece, 2005). Can they |
be expected to sacrifice their own best interests for those of other people in the future? It is also important to ask whether not taking an established effective intervention is likely to result in serious or irreversible harm. In the 2008 amended version of the Helsinki Declaration (World Medical Association, |
1964), the possible legitimate use of placebo and the need to protect subjects from harm are addressed. “32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances: The use of placebo, or no |
treatment, is acceptable in studies where no current proven intervention exists; or Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any |
risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.” (WMA, 1964 with amendments up to 2008) The above is also quite similar to the position supported by the Presidential Commission for the Study of Bioethical Issues (PCSBI) (2011). In its recently published |
report entitled “Moral science: protecting participants in human subjects research ”, the Presidential Commission argues largely in favour of a “middle ground” for ethical research, citing the work of Emanuel and Miller (2001) who state: “A placebo-controlled trial can sometimes be considered ethical if certain methodological and ethical standards are |
met. It these standards cannot be met, then the use of placebos in a clinical trial is unethical.” (Emanuel and Miller, 2001 cited in PCSBI, 2011, p. 89). One of the standards mentioned is the condition that withholding proven effective treatment will not cause more than minimal harm. The importance |
of placebo groups for drug development The ethical necessity to include a placebo arm in a clinical trial may differ depending on the type of drug being developed and whether other comparable drugs exist. For example, a placebo arm would be absolutely necessary in the testing of a new compound |
for which no drug has yet been developed. This would be combined with comparative arms involving other alternative drugs which have already been proven effective. For studies involving the development of a drug based on an existing compound, a comparative trial would be necessary but not necessarily with a placebo |
arm, or at least with a smaller placebo arm Nevertheless, the EMA emphasises the value of placebo-controlled trials in the development of new medicinal products even in cases where a proven effective drug exists: “forbiddingplacebo-controlled trials in therapeutic areas where there are proven, therapeutic methods would preclude obtaining reliable scientific |
evidence for the evaluation of new medicinal products, and be contrary to public health interest as there is a need for both new products and alternatives to existing medicinal products.” (EMA, 2001). In 2001, concerns were raised about the interpretation of paragraph 29 of the 2000 version of the Helsinki |
Declaration in which prudence was called for in the use of placebo in research trials and it was advised that placebo should only be used in cases where there was no proven therapy for the condition under investigation. A document clarifying the position of the WMA regarding the use of |
placebo was issued by the WMA in 2001 in which it was made clear that the use of placebo might be ethically acceptable even if proven therapy was available. The current version of this statement is article 32 of the 2008 revised Helsinki Declaration (quoted in sub-section 7.2.1). The PCSBI |
(2011) highlight the importance of ensuring that the design of clinical trials enables the researchers to resolve controversy and uncertainty over the merits of the trial drug and whether the trial drug is better than an existing drug if there is one. They suggest that studies which cannot resolve such |
questions or uncertainty are likely to be ignored by the scientific community and this would be unethical as it would mean that people had been unnecessarily exposed to risk without there being any social benefit. Reasons for participation People with dementia who take part in clinical trials may do so |
for a variety of reasons. One possible reason is that they hope to receive some form of treatment that will improve their condition or even result in a cure. This is sometimes called the “therapeutic misconception”. In such cases, clinical trials may seem unethical in that advantage is being taken |
of the vulnerability of some of the participants. On the other hand, the possibility of participating in such a trial may help foster hope which may even enable a person to maintain their morale. A review of 61 studies on attitudes to trials has shed some light on why people |
participate in clinical trials (Edwards, Lilford and Hewison, 1998). In this review, it was found that over 60% of participants in seven studies stated that they did or would participate in clinical trials for altruistic reasons. However, in 4 studies, over 70% of people stated that they participated out of |
self-interest and in two studies over 50% of people stated that they would participate in such a study out of self-interest. As far as informed consent is concerned, in two studies (which were also part of this review) 47% of responding doctors thought that few patients were actually aware that |
they were taking part in a clinical trial. On the other hand, an audit of four further studies revealed that at least 80% of participants felt that they had made an autonomous decision. There is no proof whether such perceptions were accurate or not. The authors conclude that self-interest was |
more common than altruism amongst the reasons given for participating in clinical trials but draw attention to the poor quality of some of the studies reviewed thereby suggesting the need for further research. It should not be necessary for people to justify why they are willing to participate in clinical |
trials. Reasons for participating in research are further discussed in section 3.2.4 insofar as they relate to end-of-life research. In a series of focus groups organised in 8 European countries plus Israel and covering six conditions including dementia, helping others was seen as the main reason why people wanted to |
take part in clinical trials (Bartlam et al., 2010). In a US trial of anti-inflammatory medication in Alzheimer’s disease in which 402 people were considered eligible, of the 359 who accepted, their main reasons for wanting to participate were altruism, personal benefit and family history of Alzheimer’s disease. Random assignment |
to study groups As people are randomly assigned to the placebo or the active treatment group, everyone has an equal chance of receiving the active ingredient or whichever other control groups are included in the study. There are possible advantages and drawbacks to being in each group and people are |
likely to have preferences for being a particular study group but randomization means that allocation is not in any way linked to the best interests of each participant from a medical perspective. This is not an ethical issue provided that each participant fully understands that the purpose of research is |
not to provide a tailor-made response to an individual’s medical condition and that while some participants benefit from participation, others do not. There are, however, medical issues to consider. In the case in double-blind studies, neither the participant nor the investigator knows to which groups a participant has been allocated. |
Consequently, if a participant encounters medical problems during the study, it is not immediately known whether this is linked to the trial drug or another unrelated factor, but the problems must be addressed and possible contraindications avoided, which may necessitate “de-blinding” (DuBois, 2008). Although many people would perhaps like to |
benefit from a new drug which is more effective than existing drugs, people have different ideas about what is an acceptable risk and different reasons for taking part in clinical trials. People who receive the placebo are not exposed to the same potential risks as those given the experimental drug. |
On the other hand, they have no possibility to benefit from the advantages the drug may offer. Those receiving a drug commonly considered as the standard therapy are not necessarily better off than those receiving a placebo as some participants may already know that they do not respond well to |
the accepted treatment (DuBois, 2008). If people who participate in a clinical trial are not informed which arm of the trial they were in, valuable information is lost which might have otherwise contributed towards to treatment decisions made after the clinical trial. Taylor and Wainwright (2005) suggest that “unblinding” should |
occur at the end of all studies and so as not to interfere with the analysis of data, this could be done by a person who is totally independent of the analysis. This would, however, have implications for open label extended trials as in that case participants, whilst better equipped |
to give informed consent would have more information than the researchers and this might be conveyed to researchers in anad hocmanner. Open label extension trails Open label extension studies (mentioned in sub-section 7.1.8) seem quite fair as they give each participant the opportunity to freely consent to continuing with the |
study in the full knowledge that s/he will receive the experimental drug. However, Taylor and Wainwright (2005) have highlighted a couple of ethical concerns linked to the consent process, the scientific value of such studies and issues linked to access to drugs at the end of the prior study. With |
regard to consent, they argue that people may have had a positive or negative experience of the trial but do not know whether this was due to the experimental drug, another drug or a placebo. They may nevertheless base their decision whether to continue on their experience so far. For |
those who were not taking the experimental drug, their experience in the follow-up trial may turn out to be very different. Also, if they are told about the possibility of the open label extension trial when deciding whether or not to take part in the initial trial (i.e. with the |
implication that whatever group they are ascribed to, in the follow-up study they will be guaranteed the experimental drug), this might induce them to participate in the initial study which could be considered as a form of subtle coercion. Finally, researchers may be under pressure to recruit as they can |
only recruit people in an open label extended trial who took part in the initial study. This may lead them in turn to put pressure (even inadvertently) on participants to continue with the study. The scientific validity of open label extension trials is questioned by Taylor and Wainwright (2005) on |
the grounds that people from the experimental arm of the first study who did not tolerate the drug would be unlikely to participate in the extension trial and this would lead to bias in the results. In addition, open-label trials often lack a precise duration other than “until the drug |
is licensed” which casts doubt on there being a valid research purpose. The above authors suggest that open label extension studies are dressed up marketing activities which lack the ethical justification for biomedical research which is the prospect of finding new ways of benefiting people’s health. However, it could be |
argued that the aim of assessing long-term tolerability of a new drug is a worthwhile pursuit and if conducted in a scientific manner could be considered as research. Moreover, not all open label extension trials are open-ended with regard to their duration. The main problem in interpreting open label extension |
studies is that little is known about the natural course of the disease. Protecting participants’ well-being at the end of the clinical trial Some people who participate in a clinical trial and who receive the experimental drug experience an improvement in their condition. This is to be hoped even if |
benefit to the health of individuals is not the aim of the study. However, at the end of the study, the drug is not yet licenced and there is no legal right to continue taking it. This could be psychologically disturbing to the participants in the trial and also to |
their families who may have seen a marked improvement in their condition. Taylor and Wainwright (2005) suggest that the open label trials may serve the purpose of prescribing an unlicensed drug on compassionate grounds, which whilst laudable, should not be camouflaged as scientific research. Rather governments should take responsibility and |
set up the appropriate legal mechanisms to make it possible for participants whose medical condition merits prolonged treatment with the experimental drug to have access to it. Minimising pain and discomfort Certain procedures to which people with dementia or their representatives consent may by burdensome or painful or simply worrying |
but in accordance with the principles of autonomy or justice/equity, people with dementia have the right to participate. The fact that they have made an informed decision to participate and are willing to tolerate such pain or burden does not release researchers from the obligation to try to minimise it. |
For example, if repeated blood samples are going to be necessary, an indwelling catheter could be inserted under local anaesthetic to make it easier or medical staff should provide reassurance about the use of various scanning equipment which might be worrying or enable the person’s carer to be present. In |
order to minimize fear, trained personnel are needed who have experience dealing with people with dementia. The advice of the carer, if there is one, could also be sought. Drug trials in countries with less developed safeguards Clinical trials are sometimes carried out in countries where safeguards are not well |
developed and where the participants and even the general population are likely to have less possibility to benefit from the results of successful trials. For example, some countries have not signed the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application |
of Biology and Medicine (1997) (referred to in section 188.8.131.52). The participants in those countries may be exposed to possible risks but have little chance of future medical benefit if the trial is successful. Yet people in countries with stricter safeguards for participants (which are often richer countries) stand to |
benefit from their efforts and from the risks they take, as they are more likely to be able to afford the drugs once developed. This raises ethical issues linked to voluntariness because there may be, in addition to the less developed safeguards, factors which make participation in such trials more |
attractive to potential participants. Such practices also represent a lack of equity in the distribution of risk, burden and possible benefit within society and could be interpreted as using people as a means to an end. Parallels can also be drawn to the situation whereby people in countries where stem |
cell research is banned profit from the results of studies carried out in countries where it is permitted or to the results of studies carried out in countries where research ethics are slack or inexistent. For a detailed discussion of the ethical issues linked to the involvement in research of |
people in other countries, particularly lower and middle income countries where standards of protection may by lower, please refer to the afore-mentioned report by the Presidential Commission for the Study of Bioethical Issues. - Researchers should consider including a placebo arm in clinical trials when there are compelling and sound |
methodological reasons for doing so. - Researchers should ensure that patients are aware that the aim of a randomised controlled trial is to test a hypothesis and provide generalizable knowledge leading to the development of a medical drug or procedure. They should explain how this differs from medical treatment and |
care which are aimed at enhancing the health and wellbeing of individual patients and where there is a reasonable expectation that this will be successful. - Researchers should ensure that potential participants understand that they may be allocated to the placebo group. - It should not be presumed that the |
treating doctor or contact person having proposed the participant for a trial has been successful in communicating the above information. - Researchers conducting clinical trials may need training in how to ensure effective communication with people with dementia. - Appropriate measures should be taken by researchers to minimize fear, pain |
and discomfort of participants. - All participants should, when possible, preferably have the option of receiving the experimental drug (if proven safe) after completion of the study. - Pharmaceutical companies should not be discouraged from carrying out open-label extension studies but this should not be the sole possibility for participants |
to access the trial drug after the end of the study if it is proving beneficial to them. - In multi-centre clinical trials, where data is transferred to another country in which data protection laws are perhaps less severe, the data should be treated as stated in the consent form |
United Kingdom - Scotland Restrictions of freedom Mental Health (Care and Treatment) (Scotland) Act 2003 The Act was designed to modernise and improve the use of compulsory measures in mental health care. It reflects the general move over the last two decades towards care and treatment in the community rather |
than in hospitals or other residential settings. The title reflects the philosophy of the legislation with the focus on ‘care’ and ‘treatment’. In basic terms, the Act provides for the protection of people with a mental disorder in a hospital or community setting. It contains mechanisms for dealing with offenders |
who have a mental disorder and so interacts with the criminal justice system. The Act covers individuals who are defined as having a ‘mental disorder’. The term includes mental illness, personality disorder and learning disability. The majority of cases involving compulsory measures have been in relation to people diagnosed with |
a mental illness. However, the Mental Welfare Commission for Scotland monitors the use of compulsory measures and has found increasing use of emergency or short term measures being used for people aged over 75 years with a diagnosis of dementia. Detention (Involuntary internment) The Act deals with several forms of |
compulsion in relation to a person with mental disorder where: There is a significant risk to the person’s health, safety or welfare or the safety of any other person (what is a significant risk is a question of judgement for health and social care professionals. The tribunal will test this |
assessment during an appeal or on an application for a compulsory treatment order). Treatment is available to prevent the person’s condition from deteriorating or to relieve its symptoms or effects Compulsory admission is necessary because the person will not agree to admission and/or treatment; and The person’s ability to make |
decisions about the provision of medical treatment is significantly impaired because of mental disorder. Types of order Emergency Detention (72 hours) Short Term Detention (28 days and can be extended) Compulsory Treatment Order (6 months – can be extended) Mental Health Tribunals The Act introduced a new system of mental |
health tribunals with a number of functions, including considering applications for orders and appeals against orders. This is detention in a psychiatric hospital for up to 72 hours if necessary. It does not authorise any medical treatment. In an emergency, common law powers might be used. A registered medical practitioner |
can sign an emergency detention certificate if s/he believes that a person’s ability to make decisions about medical treatment is significantly impaired because of mental disorder. This authorises the removal of the individual to a specific hospital. Before signing the certificate the medical practitioner must be satisfied that: There is |
an urgent need to detain the person in hospital to access the medical treatment s/he needs If the person was not detained, there would be a significant risk to his or her health, safety, or welfare or the safety of another person, and Any delay caused by starting the short |
term detention procedure is undesirable. If any treatment is needed the short-term detention procedure must generally be used. Short term detention This may be used where it is necessary to detain an individual with mental disorder who cannot be treated voluntarily and without the treatment the person would be at |
risk of significant harm. To obtain a certificate the approved medical practitioner must consult and gain the approval of a Mental Health Officer whatever the circumstances. Compulsory Treatment Order Compulsory Treatment Orders (CTOs) are granted by the Mental Health Tribunal. They last for 6 months, can be extended by the |
responsible medical officer for a further six months and then extended annually. The Tribunal reviews them at least every two years. Therefore, they can restrict or deprive liberty for long periods of time. The Mental Welfare Commission for Scotland looks at how these orders are used for people of different |
ages and genders to see if there are any trends. Over recent years, the number of new orders has come down. The use of CTOs for people aged 65 and over has increased for people with dementia in recent years. ‘De facto detention’ Practitioners must be careful that they are |
not using excessive coercion to prevent people from leaving hospital when they wish to. They must take care to document situations where they have concerns if an informal patient wishes to leave. The Tribunal can, under section 291 of the 2003 Act, order that an informal patient is being unlawfully |
detained. People with dementia pose a difficult problem. The Tribunal has ruled that a person with dementia is unlawfully detained in a general hospital when prevented from leaving. It can be appropriate to redirect someone and dissuade him/her from leaving but repeatedly thwarting a determined effort to leave is likely |
to a significant deprivation of liberty, and the patient should be formally detained. Adults with Incapacity (Scotland) Act 2000 Scottish incapacity laws were reformed with the introduction of the Adults with Incapacity (Scotland) Act in 2000. This Act covers people with a mental disorder who lack some or all capacity |
to make decisions or act in their own interests. It recognises that capacity is not all or nothing but is ‘decision specific’. The Act introduced a number of measures to authorise someone else to make decisions on behalf of the person with incapacity, on the basis of a set of |
principles on the face of the Act. These are fundamental. Any action or decision - Must benefit the person - Must be the least restrictive of the person’s liberty in order to gain that benefit - Must take account of the person’s past and present wishes (s/he must be given |
assisted to communicate by whatever means is appropriate to the individual) - Must follow consultation with relevant others as far as practicable - Must encourage and support the person to maintain existing skills and develop new skills. The individual may, whilst competent, appoint one or more persons to act their |
financial (continuing) and or welfare attorney. This must be registered with the Office of the Public Guardian. It does not allow the attorney to detain the grantor in a psychiatric hospital. If the person refuses to comply with the attorney the attorney has no compulsory powers to detain. Where there |
is concern for the person’s safety the attorney can apply to the court for a welfare guardianship order. Powers can be granted to allow the guardian to decide on the accommodation of the person and other powers such as who they can consort with. Where the welfare guardian has powers |
over accommodation s/he is able to restrict the freedom of the person by placing them in a care home against their will. However, whether this amounts to deprivation of liberty under the European Court of Human Rights ruling will depend on a number of other circumstances and the accumulative impact |
of which would need to be considered (Patrick and Smith, 2009; Mental Welfare Commission for Scotland, 2011). With regard to the issue of non-compliance, if the person on guardianship, for example, runs away, the guardian can apply to the Court under s70 for an order to require the person to |
return. Because there is no automatic review of welfare guardianship orders there is concern that the Adults with Incapacity (Scotland) Act 2000 may not be compliant with the European Convention on Human Rights. The Act states that the order should be for a standard 3 years but can be more |
or less at the discretion of the Court. However, there has been a practice of orders being granted for indefinite periods and this has given rise to concern in relation to certain groups. However, for people with dementia, who have a progressive brain disorder, an indefinite order may be deemed |
appropriate. The Scottish Law Commission is currently undertaking a review of the Adults with Incapacity (Scotland) Act 2000 in relation to deprivation of liberty issues. It has established an advisory group of key stakeholders, including Alzheimer Scotland, and will be reporting in due course. The Road Traffic Act of 1991 |
contains a few articles relating to offences involving driving when unfit to do so, e.g.: - A person who causes the death of another person by driving a mechanically propelled vehicle dangerously on a road or other public place is guilty of an offence. - A person who drives a |
mechanically propelled vehicle dangerously on a road or other public place is guilty of an offence. - If a person drives a mechanically propelled vehicle on a road or other public place without due care and attention, or without reasonable consideration for other persons using the road or place, he |
(or she) is guilty of an offence. - According to the provisions of this act, a person is regarded as driving dangerously if the way s/he drives falls far below what would be expected of a competent and careful driver and it would be obvious to a competent and careful |
driver that driving in that way would be dangerous. A person who has been diagnosed with dementia must inform the Driver and Vehicle Licensing Authority (DVLA). Failure to do could lead to a fine of up to £1,000. Moreover, a person who had an accident but did not previously inform |
the DVLA of his/her dementia might not be covered by his/her insurance company. Once the DVLA has been informed of that someone has dementia, they send a questionnaire to the person and request a medical report. A driving assessment may also be required. The Medical Advisers at the DVLA then |
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