Posted: April 30th, 2022

Discuss the considerations of a controlled clinical trial

Discuss the considerations of a controlled clinical trial
Considerations of a Controlled Clinical Trial
1. Introduction
Controlled clinical trials are an important part of medical research. The introduction section explains the purpose, research questions, and significance of the study. The aim should be clearly defined in the introduction. After defining the aim, the background and reason why a particular treatment is chosen over others should be presented. In addition, the objectives of the research should be emphasized in the introduction. The main research question and sub-questions of the study should be mentioned in the introduction, to show the need of the research and to create the research aims. As the clinical researcher is going to disclose some important diagnosis, it requires the researcher to conduct an in-depth examination on the findings. He needs to detail the possibilities and the prevailing information on the diagnosis in the research. This is important especially on the statistical data and the research results. The significance of the study is also a section that could be inserted in the introduction. It explains the benefits that are expected to be realized upon successful completion of the study. Most of the time, the hypothesis is self-evident and it may not be necessary to include a sub-section on hypothesis. The hypothesis forms the basis of the research and will help in the validation of the findings of the study. The hypothesis should be the last sentence in the introduction paragraph. Sometimes the definition of terms or a literature review is required to help situate the study in a meaningful context. As such, the sub-sections should be focused and logical. The definition of terms should be in alphabetical order and it should be labeled as “Definition of Terms.” The introduction should share what we do in the dissertation and why we are doing it, and it should guide the researcher’s research. The research is restated differently in the first research sentence, a literature review, and a hypothesis and a method for the hypothesis. The clear understanding of the topic helps in the preparation of the introduction. Anytime when the research is based on comparison, the researchers must acknowledge the comparative studies and they have to examine each one of them. All limitations of the study and the anticipated problems in the methods should be clearly mentioned. Most of the researchers tend to implement a draft study or just write a little bit about the literature review as the introduction. However, a complete view of the background of the research will help in drafting a successful introduction. The introduction shall guide the readers by explaining what the paper is about and what it will learn. The readers could be able to understand the research and the context in which the research was taken. Through the introduction, the researcher must be able to determine the significance of the research, its purpose, the research questions to be addressed, and the objectives of the research. Last but not least, the researcher should engage the readers fully through the use of the first person. It could help the readers in understanding the research steps and to have visualization on how each step has been taken. Occasionally, the introductory sections of most academic research become an extended literature review. The primary set of researchers and authors will be referenced in the literature review. The author of a controlled clinical trial may particularly rely on the early findings to form the basis of a diagnosis.
1.1 Purpose of the Study
A controlled clinical trial involves several important considerations. Firstly, the introduction section explains the purpose, research questions, and significance of the study. Secondly, the trial design involves the selection of participants, randomization process, blinding procedures, and determining the sample size. The implementation section discusses the intervention and control groups, data collection methods, ethical considerations, adherence to protocol, and monitoring and quality control. Finally, the analysis and interpretation of results involve creating a statistical analysis plan, handling missing data, and reporting and publishing the findings. The purpose of a clinical trial is to explore the safety and efficacy of a new medical intervention. Safety in this context refers to the assessment of the medical intervention in terms of its potential risk and side effects. Efficacy, on the other hand, considers the extent to which a specific medical intervention produces a beneficial effect when compared with a placebo, alternative intervention, or no intervention. The emphasis on the words “safety” and “efficacy” used in the purpose is a common feature in clinical trial study protocols. This is readable by any member of the public who is able to understand the English language. The study takes us to consideration of the latest evidence of the vaccine for phase 1 clinical trial when issue of the Clinical trial authorization from competent authority in the United Kingdom to the latest vaccine trials in 2019. The research questions should be thought up in consideration of the purpose. For example, if the main purpose of the study is to assess the efficacy of the intervention, then one of the secondary research questions can be what is the safety profile of the intervention. This is because after understanding the purpose of the study as well as the main research, readers will have a clear understanding of why several research questions are necessary to be developed and how each research question is going to help to achieve the ultimate aim of the study. Any justification must be supported by medical texts. These texts should be different sources. Also, bear in mind to make sure that the explanation is logically and sequentially explain how the purpose and research questions are interlinked and why this part of the section can be written in such a manner.
1.2 Research Questions
Research questions should be developed on the basis of the existing knowledge in the field. In other words, the research questions are put to address the gaps in the current knowledge. The question which is prevailing or for which the decision makers appear to be indifferent are often asked. In addition, a good research question should be clear, specific, focused and answerable. Good research questions also have the following characteristics: a question which is under current investigation or in need of investigation; a question which propose a solution to a problem, rather than an opinion; a question that is relevant to one or more academic disciplines; a question that has not already been sufficiently addressed in the literature; a question that could be put to the test of a hypothesis or a goal for the research. The research question should be clear, focused and concise. Moreover, the research question should be answerable. It means the question should not be so broad that some time could be spent to seek for the solution rather than focusing on the study. On the other hand, the research question should not be so narrow that the answer is obvious or the literature that is available related to the question is not relevant. If the answer to the research question is not already sweet study bay available in the existing literature, then the research methods should be identified and the appropriate researches should be planned. If there are many results and discussion about the literature is available, then the research question should be thought about as it may be raised. The research question could be coming out from the results. In most of the cases, the existing literature and the theories are used to generate the research question. Many scholars said that in various academic disciplines, a question have been raised and investigated.
1.3 Significance of the Study
The investigation includes a step-by-step progression of the symptoms of opiate withdrawal and causes and approaches in its management. According to historical perspective, the opiate withdrawal syndrome has been described for thousands of years. The earliest recorded examples of its description are found in the Ebers Papyrus of ancient Egypt which is about 1500-1700 BC, in which opium extract was used as remedy for insomnia, chronic coughs and an excessive crying caused by child teething. Nonetheless, major advances in understanding the pharmacology and neurobiology of the opiate withdrawal occurred over the past 50 years with discovery of opiate receptor subtypes and developmental of antagonist drugs for opiate and alcohol dependence. However, the first definition of the opiate abstinence was presented to the World Health Organization (WHO) in 1959 and it states ‘abstinence syndrome occurs when a dependant individual suddenly stop using the drug or reduces the regular dose’. Yet, it is important to clarify that this definition primarily draws on the physical symptoms of withdrawal which still forms the basis of the modern classifications. The Introduction also dives into the neuroscience of addiction and how opiate withdrawal fits into that. According to Uhl and Grow, the major effects of opiates in the human body include drug craving and dependence, but when the supply of opiates is reduced or stopped, the addicted individual will first develop tolerance and then show withdrawal syndrome. Therefore, opiate withdrawal can be very important in helping to understand the central nervous system effects of opiates since specific behavioural symptoms are likely to correspond to particular activities in the nervous system. Furthermore, the various theories on drug addiction are discussed in relation to opiate withdrawal. Uhl and Grow suggest that the belief that the repeated self-administration of opiates causes long-term adaptation in the nervous system and leads to the withdrawal symptoms and other aspects of drug dependence. In the book named ‘Opioids in pain control: basic and clinical aspects’, Schulz and Turnquist give a very detailed picture about drug abuse and dependence. The books says ‘neuronal consequences of chronic opiate administration, such as the downregulation of certain opioid receptors and the upregulation of cyclic adenosine monophosphate (cAMP) and Ca2+ transport, lead to increased excitability of certain neurons when the drug is withdrawn. These and similar phenomena probably produce in many areas of the CNS that when the abuser is not under the influence of the drug, withdrawal occurs regularly’. Another important point is that although acute withdrawal may not be life-threatening, something opiate dependant people experience several times a year due to relapse and fresh attempts to withdraw, home detoxification can be dangerous and serious complications are common. In an article called ‘A case of opiate withdrawal’ in the British Medical Journal, Griffiths and Thompson describe a 31-year old man who recently discharged himself from hospital and developed severe diarrhoea, vomiting and dehydration at home. However, a rapid reversal of withdrawal symptoms occurred once the patient was admitted back and given enough doses of methadone.
2. Designing the Trial
The next step in initiating a controlled clinical trial is for the researchers to plan the study. This phase of a new surgical trial involves defining the following details: the primary and secondary endpoints of the trial, the pivotal steps in the surgical procedure that will be watched and evaluated, the appropriate and acceptable comparator interventions, proper control of bias including randomization and blinding procedures, and the expected effect size. In the design of a new surgical study, similar to patient allocation to different treatment teams, appropriate patient randomization is the key so that every patient has an equal chance to receive any certain treatment under the trial, and biased treatment assignment or patient selection can be prevented. Randomization process in a surgical trial is simply like tossing a coin. Now most clinical trial teams use computer systems to perform the process, which are usually provided by national clinical trial units. Unpredictability, control and flexibility of the computerized randomizations are the main advantages over the use of random permuted blocks – a method of allocation to a treatment group which ensures that a balance is struck in the number of patients in each treatment arm after, for instance, every five patients have been entered – or of a pre-prepared randomization list. In a large, multicentre trial, a more efficient and responsive system from a central trial unit is usually used. The term blinding refers to keeping one or more key individuals in a clinical research trial unaware of which participants have been allocated to which treatment group. There are three main types of blinding which can be employed – patient, observer and treatment. Patient blinding refers to keeping trial subjects unaware of which treatment they are receiving. This type of blinding is used where the intervention involves minimal input from the patient, such as the taking of pills or a one-off vaccine. Observer blinding means keeping those assessing a particular outcome, such as a radiologist looking at trial images, unaware of which treatment each participant has received. Treatment blinding refers to keeping doctors and nurses unaware of the treatment allocation. This type of blinding is usually employed when patients may receive hands-on care by the direct study staff, such as in a surgical trial. This step is crucial. The sample size determination relies on the expected effect size and pre-trial data or other external information. It is often determined by ensuring that the study will have sufficient power to detect a clinically meaningful effect of the study across the range of treatments and patient case mix that the study might represent. However, designing a new surgical trial with an inappropriately small sample size runs the risk that the study results will remain inconclusive or fail to disprove the null hypothesis, that is, there is no real difference. On the other hand, designing a trial with an excessively large sample size will be both a waste of time and money and a great ethical concern if the trial needed to expose patients to potential risks of harm. Thus, a well-informed and carefully calculated sample size prior to the initiation of the trial is powerful and meaningful.
2.1 Selection of Participants
The section “2.1 Selection of Participants” will provide a brief description on how participants for the trial will be selected. Specifically, it will inform the reader that patients with the conditions of interest for the trial should become or it will be a waste of time. The section will also highlight that any exclusions to the trial should be justified and documented. Then, it should mention that many trials will separate patients into groups based on their condition or what they are testing such as in drug trials. So, the section should also include an explanation of the different types of trial design, such as parallel group, cross-over or factorial. Obviously, explanation of these different trial designs will come under another section of “Study designs” of this element of the track. However, since the current section is involved in the process of choosing patients, an explanation research essay pro papers of the significance of selecting certain trial designs will be relevant. Also, it is significant to mention in this section that patients’ details will be confidential and every patient should receive the best treatment. Then, it should go a bit further in-depth in the topic of how to stratify a trial. Stratifying a trial is making sure that patients who are similar get randomized to each group. This type of methodology is used in a trial which splits patients into strata.
2.2 Randomization Process
The process of randomization has been considered the most important element in generating comparable treatment groups for numerous decades. Its roots can be traced back to agriculture and irrigation. The idea was born from “Comparative Crop Experiments,” a paper published in 1923 by Sir Ronald A. Fisher, a giant figure in the history of statistics. In the paper, he demonstrated that a properly randomized experiment could make inferences about the whole population from what was observed in a limited piece of that population. Thanks to the development of stratified randomization and blocked randomization, the research community is nowadays able to apply randomization to studies that involve more complicated designs than the parallel 1:1 design described above. For triple-blinding, in addition to not telling the volunteers and the clinical team who is receiving the study treatment, the data analysts do not know either. This also helps in eliminating the risk of human bias in data analysis. Nowadays, there are researches focusing on the comparison between different randomization methods and further development of the theory of randomization, hoping to ensure the best evidence could be generated while sparing the participants from any potential harms. All of these ongoing efforts reflect a shared vision within the research community: to obtain better and clearer evidence, not just for the sake of advancing the academic fields, but more importantly, for the well-being of the human society. The ultimate goal of a randomization process is to produce treatment groups that are unbiased and exchangeable. Also, the assignment of volunteers to the study treatment is the only random element in the whole research process. The idea of randomization is not to create the best treatment group for the individual person, but rather to generate the best possible evidence that could suggest the guideline or the base of the decision making for that disease or that certain condition. The assumption behind is that, over time, the results from each randomization arm would be expected to yield an average result, and it is reasonable to expect such average results would apply to the wider population. However, if there is no randomization, a non-random sequence or process might be used instead. It could be anything from the day of the week to a medical record number. By doing so, this might introduce selection bias and confounders. For example, if the medical record number is applied and by coincidence, every even-numbered volunteer receives the study treatment, then it is later found from the data that the even-numbered group appears to have better outcomes, is it because of the treatment effect or simply due to the chance of the random number allocation? Such a question would cast doubt on the quality of the evidence generated from the study. On the other hand, if the medical record number is used but it distributes evenly throughout the data collection period, no doubt the selection would not be biased.
2.3 Blinding Procedures
Blinding is an important method to reduce bias in a clinical trial. If a study is described as “open-label”, both the participant and the investigator know which treatment the participant is receiving. This type of study is the most vulnerable to biased results because the participant’s and the investigator’s expectations can influence the results. On the other hand, in a “double-blind” study, neither the participant nor the investigator knows which treatment the participant is receiving. All the bottles of investigational product and the labels for the bottles are coded so that the investigator can break the code only in emergent situations and the participant can be identified only in medical emergencies where knowledge of the treatment is absolutely essential for the medical personnel to provide appropriate care. In the context of a clinical trial, “blinding” specifically refers to maintaining the study’s scientific integrity by preventing any one person’s knowledge, such as the participant, investigator, statistician, or anyone directly involved in the trial, from influencing the conduct or the results of the trial. Although blinding is the most common way to reduce bias, it’s not feasible in all clinical trials. For example, it is not possible to blind some surgical trials, where some of the participants will receive real surgeries and some others will receive sham surgeries. However, in order to maintain the scientific rigor of a clinical trial, a blinded clinical trial should be implemented whenever it is scientifically and ethically feasible. There are two categories of bias that can be reduced by blinding: performance bias and detection bias. Performance bias refers to the situations where the knowledge of the intervention by either the participant or the care provider influences the care that is provided. For example, if the patient knows he is receiving the new drug being studied, he might pay more attention to any discomfort he is having or any improvement he perceives, thus potentially biasing his own assessment of the treatment’s effect. Detection bias, on the other hand, refers to the situations in which the knowledge of the intervention by either the assessor or investigator influences the measurement of the outcome. For example, if the investigator knows which treatment a participant is receiving, he might record the participant’s positive findings more frequently or the negative findings less frequently, thus potentially biasing the outcome measurement. Both of these biases can be reduced by blinding.
2.4 Sample Size Determination
Sample size plays a very significant role in research study. The rule of thumb in determining sample size in a research study is to use at least 100 subjects and the larger of 10% of the population. The major challenges in determining the adequate sample size are that it has to be sufficiently large to produce a reliable outcome and interpreting statistical significance. In reality, sample size is depending on the statistical analysis planned and the need of the study, bearing in mind that there are clinical and statistical significance. Creative and scientific justification on the choice of sample size is necessary. There are several approaches in determining the ideal sample size in research study. First, using a previous study on the same research area; researcher can calculate the sample size by employing a confidence interval or by using a pilot study. A pilot study is a practice run in which procedures are tested and all the kinks are expected to be ironed out. However, all the steps of using a pilot study have to be developed with a thoughtful and detailed research and trial plan. Nevertheless, it is an essential approach to determine the sample size. By using a pilot study, the credibility of the research can be established. Another method to determine the ideal sample size is by using power analysis, using effect size and the confidence level chosen. Power is actually the probability that the test will correctly reject a false null hypothesis. Effect size, a measure of difference between two levels, is the expected averaged level value in the numerator. Using a power of 80%, the conventional level of 0.05 and a medium effect size of 0.25, we will get the sample size of 98. InputGroup creative new research ideas while at the same time respecting the current knowledge is very important. With the current knowledge, researchers are clever enough to perform a thorough and valid research using the previous study’s results and sample size calculations. Respect the current knowledge means that the research work and the selected sample size should be beneficial and scientifically acceptable, not to harm the subject under investigation. Well, no clinician or investigator wants to waste their time doing a study that is overpowered.
3. Implementation of the Trial
In carrying out a controlled clinical trial, one has to adhere to a particular designed protocol so as to arrive at an answer to the research question. It is important that the trial design and guidelines to the research is followed to the letter. Any deviation from the protocol may result in a systematic error or a biased conclusion. In fact, most scientific journals and health authorities go by the ICH-GCP rules which enunciate that for any research to be acceptable, it must have been conducted in strict compliance with the research and trial protocol.
Adherence to scientific standards and strictly prescribed research guidelines are key ethical considerations in controlled clinical trials. Every collected piece of data stipulated by the research method and procedure must be recorded and accounted for. Raw data collected are later subjected to a rigorous statistical analysis to check its authenticity and the reliability of the evidence. I feel I am capable of coordinating the trials with a high degree of acceptance and compliance. During trial implementations, it is subjected to constant period review by the ethics and scientific committees. This is to ensure that participants are well protected from any likely harm resultant from the trial. Also, as ailments do change over time, introduction of new scientific findings or withdrawal of any intervention is communicated fast to the participants in the trial with a view of either modifying the protocol for the better or taking an informed decision. This is in line with the strict operational requirement for any well-designed research.
3.1 Intervention and Control Groups
The process of randomization to create the intervention and control groups was explained in the section “Designing the Trial”. In this section, we are going to look at what actually happens after the randomization, which led to the assignment of the participants into either the intervention or the control group. Once the randomization process has been completed, the researchers will start to recruit and include participants into the study. The recruitment process was usually explained in the methods section with details such as the settings of the recruitment and the eligibility criteria. After the potential participants are identified based on the initial assessment of the eligibility, the researchers will start to obtain the informed consents from the participants. The informed consent process was also an essential part in research involving human subjects and it was usually explained in a separate section in the research proposal. Both the participants and the researchers who obtained the consent will receive a copy of the signed informed consent form and the participants will be given sufficient time to consider about the research. However, the participants who have been assigned to a given intervention in the clinical trial can choose to continue their participation or to withdraw from the study at any time. This concept was referred to the term of “Subject Withdrawal of Consent”, which means the participants can decide to leave the study at any point. This is to protect the interest and the willingness of the participants to continue the treatment in any studies. By allowing and ensuring the withdrawal of consent can be obtained at any time during the study, it can encourage more people to participate in clinical trials, as the participants’ legal right was being respected. Oh! I almost forgot to tell you the actual differences between the control and the intervention group. Well, in fact, typically the researchers will not tell the participants which group they are being assigned to until the very end of the study. This is important because if the participants know which group they are in, this knowledge may affect the outcome of that treatment comparison. This concept that the knowledge of the patients may alter the treatment’s effect was referred to as the “Placebo Effect”. On the other hand, members of the intervention group will receive the new treatment that the researchers are studying in the clinical trial. The intervention can be a new therapy, a new diagnostic tool, or a new preventive measure. In contrast, the control group will receive either the standard of the therapy or a placebo.
3.2 Data Collection Methods
Data in a clinical trial must be collected or recorded in a way that is accurate and reproducible. There are different forms of data and methods of data collection that apply across the various stages of a clinical trial. All data collection, whether involving clinical laboratory tests or patient self-assessment, must be conducted in accordance with the trial’s data collection plan. This plan must be clear, well-structured and imposed in such a way that all members of the trial team know how and when to use and complete the required case report forms. The first and most important consideration when establishing a data collection method is to ensure that the condition (if clinical trial is involving its treatment) is being investigated properly. It is vital that the data collected is relevant to the end points of the trial. Information may be collected in various different forms including: scientific laboratory data – this involves the collection of bodily materials such as blood, urine, tissue, etc. for analysis; medical imaging data such as X-rays, CAT scans and MRI scans; and patient data which involves information that is provided and recorded during the patient’s participation in the trial. This can take the form of diaries, online data collection or patient medical records. It is also important that the data collection method is scientifically valid and most appropriately answers the objectives of the trial. It is good practice to put in place measures that ensure the security and quality of the data and the right resources should be made available to support the method; for example, training for personnel, maintenance of equipment, quality assurance processes. The method must include arrangements for the resolution of discrepancies and audits and inspections, as well as stipulating the retention times of records and the final custodian of the data.
3.3 Ethical Considerations
Ethically, researchers must fulfill a number of criteria in order to carry out the trial. First of all, the research and the specific research plan and protocol for the trial must be approved by an independent research ethics committee. The research must also be registered in a public registry in order to promote transparency and improve access to information about clinical trials. Any ‘risks’ or ‘burdens’ of the trial that go beyond normal medical treatment must be justified and minimized. In this case, where a patient may receive a placebo or where there may be additional interventions or extra procedures carried out, the patient must give ‘informed consent’ after having been provided with all the necessary information about the trial to be able to make a meaningful decision. It is important to note that for some serious medical conditions, a placebo-controlled trial may not be ethically acceptable. In these cases, it may be more appropriate to compare the new treatment with the best existing treatment, or sometimes, if there is no standard treatment, the new treatment on its own may be compared. Also, as previously stated, the use of randomization, where the patient is allocated to either the intervention or control group randomly in order to reduce bias, is considered a fundamental aspect of a controlled clinical trial. However, there are ethical implications in any approach to randomization since a participant, on giving informed consent to join the trial, should then have an equal chance of receiving any of the treatments being compared. Finally, it is a very important ethical requirement that the management of the trial as well as the collection, analysis, and publication of results should be completely independent from the funder or the sponsor of the trial and from the manufacturer of the medical product under investigation. This is because conflicts of interest could potentially lead to bias and this would seriously impact the reliability and validity of the findings of the trial.
3.4 Adherence to Protocol
rate. This includes ensuring that the protocol is followed accurately and any deviations are properly documented and justified. The protocol serves as a guide for the conduct of the trial and helps to ensure that the trial is conducted in a consistent and standardized manner. It also helps to protect the rights and well-being of the trial participants. Therefore, it is essential that the protocol is carefully developed, reviewed, and approved before the trial begins. The protocol should be clear, concise, and comprehensive, providing all necessary information for the conduct of the trial. It should also be flexible enough to allow for any necessary amendments or modifications during the course of the trial. Overall, the protocol plays a crucial role in the successful implementation and completion of a clinical trial.
3.5 Monitoring and Quality Control
In virtually all studies, and certainly in all studies conducted under Good Clinical Practice (GCP), it is vital that appropriate and effective systems are in place to ensure that the study is progressing as it should and that the safety and the well-being of subjects are not compromised. This is the role of monitoring and quality control. The International Conference on Harmonisation (ICH) defines clinical trials as “a systematic study or investigation in human subjects, intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to such investigational product(s), and/or to study absorption, distribution, metabolism, and excretion”. It should be appreciated that the term “clinical trial” is not confined to just trials where an investigational medicinal product is used. It includes investigations involving, for example, medicinal products other than investigational medicinal products (e.g., where a product is used outside its authorized indication), the use of a medical device or surgery to investigate their effects in diagnosis or therapy, and studies to investigate the safety and efficacy of physical therapies, nursing care or other methods of caring for patients. These other clinical investigations are, however, governed by the same principles as Clinical Trials of Investigational Medicinal Products (CTIMPs) under the Medicines for Human Use (Clinical Trials) Regulations 2004 as amended from time to time (and parallel legislation in Scotland).
Monitoring and Quality Control
4. Analysis and Interpretation of Results
The statistical analysis plan should be finalised before the code is unblinded. The plan should include details of the statistical methods to be used and the procedures for their actual implementation. It is good practice for the statistical analysis plan to be written, reviewed and signed off by relevant members of the trial team before the analysis starts. Any deviations from the pre-specified statistical analysis methods should be explained and well justified. Often, it will be appropriate to include these deviations when reporting and publishing the findings of the trial. A key principle of the analysis of clinical trials is the intention to treat analysis. In such an analysis, patients are analysed in the groups to which they were randomised, regardless of whether they completed or adhered to their allocated treatment. This preserves the benefits of randomisation and provides a more unbiased comparison of the treatment groups. However, the findings from an intention to treat analysis may be conservative, especially if there are a substantial number of patients with missing outcome data and the missing data are not missing completely at random. In practice, everything should be done to minimise the amount of missing outcome data. For example, good trial conduct, including an appropriate consenting process and good data collection standards, will help to minimise the amount of missing data. However, it is recognised that it is not always possible to avoid all missing data. It is a regulatory requirement that the clinical study report is prepared by or under the immediate direction of the sponsor.
4.1 Statistical Analysis Plan
The statistical analysis plan is a key aspect of the proposals that will be reviewed. One of the first elements of the statistical analysis plan is a description of the data that are going to be collected in the trial. This should include both the primary outcome measures and any secondary outcome measures as well as details of the timing of these measurements. Also, if any intermediate analyses are planned, these should be carried out in accordance with the statistical analysis plan. Any factors that are going to be taken into account in the analysis of the data should also be stated; for example any stratification or minimization parameters used at randomization. This might include a statement about the assessment of interactions and/or any subgroup analysis. Also, if any stopping rules are going to be used in the trial, the statistical basis for these should be fully explained in the statistical analysis plan. This includes details of any methods that are used to adjust for the fact that multiple interim analyses represent an inflation of the overall significance level for a stopping rule based on a single analysis at the end of the trial. The statistical analysis plan should also provide details of the methods that are going to be used to handle missing and unexpected data. This could include for instance a statement of whether completer or intention-to-treat analysis will be used or both. Completer analysis involves only those patients who have a complete set of measurements at all time points whereas intention-to-treat analysis includes all patients on a random basis according to the treatment they have been allocated regardless of whether they have completed the study or whether they have adhered to the protocol in any way. Any other adju
4.2 Handling of Missing Data
When subject is missing data, the first decision involves choosing a missing data handling strategy. This is done at the time the study is designed, that is, before the study starts and before anyone knows who is going to have missing data and who is not. The data analyst also has a key decision to make about missing data in the analysis data set. The options are as follows: Analyze all of the data available. This is called a complete case analysis. The principle of ‘complete case analysis’ is that only subjects who have no missing data for any of the variables involved are used in the analysis. Clearly if this option is chosen then the sample size for analysis will be smaller than the total sample size as some subjects may have missing data for at least one variable. Use all of the available data and create imputed or modeled values for the missing data. This is called a multiple imputation analysis. This uses ‘data creation’ methods in that they calculate values for the missing data based on the other observed data. Multiple imputation works by replacing each missing data value with a set of a number of imputations (which could for example be 5 or 10 imputations per missing value yielding 5 or 10 complete data sets). What was originally one incomplete data set becomes five or ten complete data sets. Each of these ‘new’ complete data sets is then analyzed using the method or analysis of interest. The results from these analyses are then combined to produce a single result. Such an analysis takes into account the overall uncertainty about what the missing values should be. If imputation is performed, the method of imputation and the rationale for the choice made should be presented. It may be that a number of different missing data handling strategies are of interest and sensible in any given situation. As a result, findings from different methods can and should always be compared. However, this document outlines three scenarios which are felt to represent typical examples where missing data could occur and how applicable approaches to dealing with the missing data in the analysis might be chosen.
4.3 Reporting and Publication of Findings
When a clinical trial has been completed, the next important step is to ensure that the findings are made available to the wider scientific community through the process of publication. If the trial was well designed and properly conducted, it should be possible to write up the results for publication in a scientific journal. However, it is important to note that not all trials should be published. The International Committee of Medical Journal Editors has provided a set of criteria that all trials should be expected to meet in order to justify their publication. These criteria are known as the ‘uniform requirements’ and they specify that in general, the methods and results of all clinical trials should be submitted to a journal before the trial has started. Even if the research is not accepted for publication, the fact that the results were submitted for consideration for publication is often seen as an acceptable way of meeting the ethical requirement to make the results of the trial publicly available. Once the manuscript has been prepared by the research team and submitted to a journal, responsibility for overseeing the process of revision and resubmission following peer review often falls to the lead investigator or the first named author of the paper. It is important to engage properly with the peer review process, even if the feedback received from reviewers is critical or challenging. By taking these comments on board and working to improve the submitted manuscript, the research team can help to ensure that the final published paper is clear, accurate, and accessible to its intended audience. An essential part of the manuscript is the abstract, which summarizes the entire paper in a concise form. All authors are expected to be able to critically assess the entire manuscript and to approve the submission, which should include a statement to confirm their involvement and compliance with authorship guidance issued by a relevant professional body. However, it is important to emphasize that the final decision on the content of the paper, the choice of the journal for submission, and the sign-off for the submission itself should always rest with the lead author or the person who has taken on the role of corresponding author for the publication process. A copy of the final accepted manuscript and published paper should always be sent to the relevant research governance and ethics committee, as this is an important part of meeting the obligation to make the results of a clinical trial publicly available. It also helps to ensure that the research output of a particular institution or team is accurately recorded and that the personnel records and CVs of all those involved in the research can be properly maintained.

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