Profieciency second test

. Research design models can be broadly categorized into how many categories?

4

Define Protocol design

a crucial component of a study's success the culmination of a rigorous review of previous experiemental results and literature

Which is true regarding the Declaration of Helsinki? (Select the best answer)

a: Developed by the World Medical Association b: Purpose was to develop and regulate ethical principles on a global scale c: The first significant effort by the medical community to regulate itself d: Translated the Nuremburg Code and provided the ethical principles for ICH GCP (International Conference on Harmonization, Good Clinical Practice)

The Belmont Report has four (4) ethical principles, meaning respect for persons, beneficence, justice and respect for society. Is this statement true or false?

f

Fraud or misconduct can be detected by anyone working with the trial data. Is this statement true or false

t

The Nuremberg Code (1949) states that during the course of an experiment, the human subjects should be at liberty to bring the experiment to an end if they have reached the physical or mental state where continuation seems to be impossible to them.

t

Unethical conduct in clinical trials can result in subject safety issues. Is this statement true or false?

t

What are the 4 basic types of research models

1. Population studies -OBSERVATIONAL -concerned with the collection of existing data from a defined population, which may be large -often the first approach in trying to identify a phenomenon in a population -involve the collection of existing data require few resources except for the actual data collection, and they can provide a degree of variety to a site's study portfolio 2. Case-control studies -OBSERVATIONAL - aka "retrospective studies" -Also involve collection of existing data -distinguished from population studies in terms of size, with case-control studies typically being smaller 3. cohort studies -OBSERVATIONAL -aka "perspective studies" -have more investigator involvement compared to population and case-control studies -they are most similar to case control studies in terms of observing those witha disease vs those without a disease, but in a prospective manner 4. randomized controlled trials -has the greatest level of interaction with the study participant -has the greatest involevmnet of the insetigator can be most complex in design --needs blinding --number of arms for the study (usually two, but can be more) --manner of randomization --regulatory and ethical requirements --eligibility criteria --required resources

Types of study models:

1. Randomized design 2. open label 3. observational - an observational study of standard treatments for a rare disease may be focused on the outcomes of those treatments, wherever they might be. 4. single-arm 5. multi-arm - two arm randomized study will be interested in directly comparing the two defined treatments described in the study 6. etc....

How to select a research design?

1. decide if quantitative or qualitative quantitative more common in clinical trials 2.

ethical codes

1900 prussion directive

During which year was the Declaration of Helsinki published?

1964

What is the appropriate definition of fraud?

A deception deliberately practiced in order to secure unfair or unlawful gain

What is the appropriate definition of misconduct?

A deviation from duty by one employed in a professional capacity; a transgression of an established rule

What is the appropriate definition of ethics in clinical research?

Actions or conduct that protect a subject's rights, safety and well-being at all times

Preventative measures for fraud or misconduct are: (Select all that apply)1) Adopting zero tolerance2) Protecting whistle blowers3) Calling your mother4) Being friends with your peers in the clinical research team5) Modeling ethical behavior6) Trusting the researchers will do a good job

Adopting zero tolerance, Protecting whistle blowers, modeling ethical behavior

Importance of Hypothesis

At the outset and as one becomes more accustomed to the function of the hypothesis and its wording, one can judge the scientific quality of the study via its hypothesis. Also, it points to the specific nature of the study, what is being investigated, and the possible outcome. These components of the hypothesis can be utilized by the investigator and study team to ascertain the scientific merit of the study and their interest in it.

6. Hypothesis testing involves which of the following?

Background, Purpose, Methods

case-Control Studies

Case-Control Studies are also called Retrospective Studies, and they too involve the collection of existing data. They are distinguished from Population Studies in terms of size, with Case-Control Studies typically being smaller. Also, investigators may have a more defined idea of the relationship than that of a Population Study. A suspected cause for a disease may be investigated to see if a relationship is present, which may warrant further investigation. This suspected cause may have been initially identified in the Population Study. From a study feasibility standpoint, Case-Control Studies may be of more interest to an investigator due to an increased level of involvement from a scientific standpoint, although no interaction with a patient occurs.

cohort studies

Cohort Studies are also termed called Prospective Studies and have a greater degree of investigator involvement. They are most similar to Case-Control studies in terms of observing those with a disease versus those without a disease. However, this study does so in a prospective manner. Participants are observed as their treatment progresses, and data is collected. The disadvantage of this approach is that a great amount of time may be needed to successfully complete the study, due to the need to follow participants. This is the same concern to consider when assessing a study. Does the site have the capability to invest time and resources for the long term?

The characteristics of the 'Informed Consent' as per the Belmont Report are:

Comprehension, Voluntary, Information

The introduction of which ethical guideline states: It is the mission of the doctor to safeguard the health of the people. His knowledge and conscience are dedicated to the fulfilment of this mission.The Belmont ReportDeclaration of HelsinkiThe Nuremberg CodeNone of the above

Declaration of Helsinki

Why are ethics important in clinical research? (Select the correct answer)

Ensures respectful treatment of all trials

Other considerations for both study design and feasibility assessment include:

Ethics Funding Practicality

funding

Even an observational study will need to cover the costs of time and effort for the investigator and/or other study personnel engaged in data collection and analysis, not to mention the development of the study protocol and subsequent publications. The costs of equipment, drugs, and administration only add to the requirement for funding. Sources of funding are varied and may include: o The investigator's organization o Federal grants o Private foundation grants o Industry sponsorship o Philanthropy Each source requires a different approach, but generally an application process of some type is required. This may involve explaining the feasibility of the study, its scientific merit, risks, and benefits, and in some cases a business plan. Other components are also likely to be present, depending on the requirements of the funding agency. A component that some may forget to include in a study budget are the indirect costs. These are costs generally invisible and, as the name implies, they do not play a direct role in the study. Examples include the costs of facilities, office space and materials, administration, and 2 others. Such costs can be very significant, exceeding 70% of the budget. Moreover, funding sources may not cover all of these costs because they may expect the host organization to cover some or all of these indirect costs.

4. A consideration of a scientific study that is NOT found in the protocol is:

Exploratory data collection and analysis and hypothesis testing

Randomized Controlled Trials

For most of us, the Randomized Controlled Trial may be the most familiar model. It also has the greatest level of interaction with the study participant, particularly due to the assigning of specific treatments to the participant, along with any associated activities such as diagnostic testing. It also has the greatest involvement of the investigator, and often these types of studies can be the most complex in design. Several aspects must be considered in the Randomized Controlled Trial. These include the need and extent for blinding, the number of arms for the study, which is usually two 3 but can be more, and the manner of randomization. Regulatory and ethical requirements, eligibility criteria, and required resources are also a few areas to consider. In fact, such aspects are also important while selecting a study to open. Some points to keep in mind are: • Blinding: Is the study single or double blinded? How easily can the blind be broken in case of an emergency? • Number of Arms: A multi-arm study can become very complex, especially if the number exceeds two. • Randomization: Who performs this action, and how is it done? How are the results communicated to the site? • Regulatory and ethical considerations: Self-explanatory, but some studies may impose a greater burden in this area than others. • Eligibility criteria: Does the local patient population meet the criteria, at least generally? What are your chances of meeting enrollment targets? Are there any unusual or questionable eligibility criteria? • Required resources: Do you have the staff and expertise to conduct the study? Is there specific equipment needed and do you have access?

ethics review committees

IRB/IEC institutional review board US ethics review committee globally independent ethics committee (iec) independently charged with the protection of rights, safety, and wellbeing of human subjects they review and approve protocols, informed consent, methods governing bodies to ensure clinical trials are carried out ethically must ensure the laws and regulations

Which activity would you need to perform prior to actually starting protocol design?

Identification of a gap in the existing knowledge.

What do you do when you detect potential fraud or misconduct? (Select all that apply)1) Call the police or fire brigade2) Investigate3) Leave as it is, it will be resolved by itself4) Gather evidence in any matter (legal or illegal)5) Discuss with the person you suspect6) Believe hearsay7) Follow applicable regulations

Investigate, Follow applicable regulations

What is the appropriate definition of ethics?

Involves moral decision making processes and distinguishes right from wrong, good from bad and acceptable from unacceptable behaviors

Possible reasons for fraud or misconduct are (Select all that apply):1) Lack of resources2) Lack of knowledge and training3) Conducting clinical trials mainly for financial reasons4) Human nature, which is by default 'bad'5) The will to challenge inspectors to see if they can get 'caught'6) Time constraints

Lack of Resources, Lack of knowledge and training, conducting clinical trials mainly for financial reasons, time constraints

Funding for a study:

May be derived from internal or external sources

What is the appropriate definition of clinical equipoise?

No conflict between the ethics of clinical care (treating the patient) and those of research (collecting data)

Null hypothesis

Null hypothesis:the opposite of what you originally set out to study (H0) "there is no change" To understand this concept, it helps to have an appreciation of scientific rigor. In order to demonstrate that an observed event is indeed true, one needs to test it in an extreme fashion. Even when an effect is seen, it cannot be assumed to always be true. In a scientific study, the researcher addresses the predicted event by starting with the assumption that the event will not occur. In other words, you start out by stating that what you are testing will not occur. This is the null hypothesis, and it takes more rigor to disprove this statement then it would to prove that something would occur. Generally, if one is testing that if "A" happens then "B" will follow, the null hypothesis is written to reflect that "There is no relation between A and B". Then, you need to conduct the study to see if they will reject the null hypothesis and accept the alternate hypothesis that there is indeed a relationship present.

In general, population based, case control and cohort studies are what types of studies?

Observational

population studies

Population Studies are concerned with the collection of existing data from a defined population, which may be large. It is often the first approach in trying to identify a phenomenon in a population. An aspect to notice is that this design involves the collection of existing data. An example could be a disease registry, which is concerned with collecting data on the standard treatments for a disease or group of diseases. Such studies will collect data from existing patient records, and as no direct interaction with the patient occurs, might not involve informed consent or full board approval by an IRB/IEC, though one must verify this with their respective IRB/IEC. In terms of study assessment, population studies may provide a great introduction to those new to

Population studies differ from case-control studies in what way?

Population studies are often larger in the sample size than case control studies

Randomized Controlled Trials (RCTs) differ from other study type categories in what way?

RCTs often have the greatest level of interaction with study participants The RCT often has the greatest involvement of the investigator RCTs can be the most complex in design and structure

Development of hypothesis

Research step that emphasizes an understanding about the concepts and variables in the research problem. the formulation of a hypothesis is an aspect of quantitative resarch. it is a research category predominant in most clinical trials Derived from the research questions and can defined as a tentative statement - subject to empirical testing - to explain a possible relationship between variables ~more than a statement, or "rewording" of the research questions Every hypothesis is tentative and temporary. Empirical testing, which means testing based on evidence, focuses on negating the hypothesis, in order to subject the hypothesis to the highest level of scrutiny. Even if the hypothesis is supported by the study data, all this leads to is a new hypothesis! You'll notice that the words "accepted," "disproved," and "supported" are being used to describe how a hypothesis is handled. One does not "prove" a hypothesis. Absolute proof that a scientific phenomenon always occurs transcends beyond hypotheses and even theories into the realm of scientific laws, which is beyond the scope of this course. The specifics of a hypothesis and how it can be worded can be a course in and of itself. That said, a few factors can be explored. Remember that the hypothesis describes the relationship you are investigating, and as such will name the variables and the relationship (for example, one treatment is better than another). Also, statistics typically play a role in a hypothesis, and as statistics usually deal in probability rather than absolutes, a factor termed as "significance", point to the transient nature of the hypothesis. To this end, one may not word a hypothesis as "Treatment A is better than Treatment B at ..." Rather, one may phrase it as "Treatment A is significantly better than Treatment B at ..."

What are the three key principals of the Belmont Report?

Respect for Persons, Justice, Beneficence

Risk related to a study can involve what aspect?

Risk is only a concern in terms of study participants Risk is a factor in study integrity

According to the Nuremberg Code, experiments can be conducted by:

Scientifically qualified persons

Statistics is a consideration of risk in both study design and feasibility assessment for what reason?

Statistics can be used to ensure adequate sample size, so that participants are not placed at unnecessary risk

What is the appropriate definition of therapeutic misconception?

Tensions between the ethical obligations of the physician-patient relationship and those of the researcher-subject relationship

5. An activity present in scientific research is:

The determination if a possible relationship among variables is indeed true

What is the appropriate definition of ethics committees?

The governing bodies established to oversee research conducted in human subjects

7. The hypothesis can be used for assessing opening a study at a site in which way?

The hypothesis can be used to judge the scientific merit and site interest in the study

When selecting a trial site for a clinical trial, which does the selector need to be vigilant about with regards to 'ethics'?

The investigator and the site staff have the potential subjects and the resources to be able to conduct the trial according to the protocol

What is the appropriate definition of ethical codes?

The rules that govern how ethics are to be handled

Who can detect fraud or misconduct? (Select all that apply)

The site staff The trial subject Auditors/Inspectors The monitor (CRA) conducting Quality control (QC) Data entry personnel or data manager Whistle-blower Writer of the final trial report Next Question

Study Protocol Anatomy

There is NO SUCH THING as a "typical protocol" (see 5 listed above) there are a few compoentns that can be seen across the spectrum of study types No one section of a protocol is more important than another all sections are needed to provide thinkking and planning to assess a research problem STUDY PROTOCOL SECTIONS 1. Background -defining why it is important to devote scarce resources and time to research the problem at hand -"the introduction", "justification", "existing knowledge" -starting with a broad overview of t he field --> then briefly describing previous and ongoing work in the area of interest --> then focusing on a gap of knowledge of that field -because the background of a study is important for defining the study, it also plays a valuable role in assessing the study from a feasibility and review standpoint. when deciding to undertake a study, review its backgrounf and then question whether the reasoning makes any sense -can elucidate the prupose of the study 2. Method -applies the design to the research questions -provides the instructions for conducting the study -Addresses aspects such as *eligibility criteria, *randomization, *blinding, *treatment cycles and adjustments, *data collection, *statistical analysis, *participant safety measures -it is difficult to pinpoint the methods section in a course, as it varies with study design -the key is the need for clear instruction as well as contact info for the PI and othe rkey personnel -An unclear methods section presents an increased risk for adversely affecting study integrity and participant safety -individuals seeking to undertake a study need to carefully review the methods section for two reasons. 1)the first is to ensure that the instructions are clear, complete, and can be easily followed. 2)the second is to detemrine if one's site can indeed manage the requirements of the methods section 3. Purpose - the defining statement of a study - the research question anad hypotheses are derived from this statement -Note: all studies may not have these compoenents - these components are primarily seen in experimental design Some questions to ask when thinking about a study protocol: -is the purpose clearly defined? -does it relate well to the background? -does it make sense?

practicality

This includes considering if the needs and requirements of the proposed study can reasonably be accommodated. The study may have addressed ethical aspects and a funding source may have been identified, but these alone do not mean the study will be successful. Some aspects to consider include: o Availability of research participants and data: A study that is well-designed and has funding will not succeed if the data cannot be accessed and collected. Many clinical trials have failed due to the inability to enroll at a reasonable rate. o Equipment and Techniques: Are specific types of equipment and/or techniques needed and can they be accessed or purchased? For example, a study involving genetics may require sequencing, for which specific knowledge and equipment is needed. o Expertise: Investigators may be very knowledgeable and perhaps even well-known in their field. However, they may not be as knowledgeable in fields such as statistics. Specialized expertise may be needed, which often comes with an associated cost. o Time: This above all else is an essential factor. Research studies often take longer than originally planned. The increase in time needed may translate into additional reviews by the IRB, the need to prioritize other current and future projects, retaining the interest of co-investigators and staff, research staff turnover factors, and the additional costs that can accompany the need for more tim

How to choose the correct study model:

Use and function In scientific research there are two activities: 1. Exploratory data collection and analysis - primary concern is the identification of variables and identifying potential relationships among those variables -this phase of research is typically done in the early stages of overall research endevour. however, it may run parallel to the second phase of hypotheiss testing, particularyl if this phase reveals variables not previously thought as important to investigate 2. Hypothesis testing - usually the phase when considering scientific research -helps determine possible relationship, which was observed during the exploratory phase between or among variables, is indeed real

Approaches

adaptive design -includes clinical trials that are capable of changes in design or features in response to accumulated data to make the study more efficeint. this design is more likely to demonstrate an effect, if the effect exists, or be more informative patient-centered outcomes research -type of research that takes into account the voice and input of patients and their caregivers comparative effectiveness -type of research intended to inform health care by providing and examining data, from existing or new studies, on the effectiveness, benefits, and risks of different existing treatment options translational research - research involving a "bench-to-bedisde" approach to expedite the discovery and availability of new treatments and facilitate the relationship between the basic and clinical sciences computer modeling and simulation -includes the utilization of data and existing experiences in the designing and operating of computer simulations of clinical trials prior to the actual study, to help facilitate efficiency and safety and/or expand on results of collected data

Adhering to ethical practices: (Select all that apply)1) Establishes sound principles for evaluating clinical studies on a global scale2) Reduces the risks for the sponsor3)Protects the reputation of the clinical researcher4) Protects the subject and thereby human life

all

ethics

all individuals participating in resaerching humans, even if observational only, should engage in some degree of research ethics training Aspects of ethics were addressed earlier, but in the end the focus will be on weighing risk with benefit. Due to the intent of research, this is the risk incurred by participants versus the benefit of improving generalizable knowledge. So, the intent of research does not necessarily include direct benefit to the participant. The benefit to the participant is often assessed by IRB/IEC, but as an investigator it is your responsibility to adhere to the ethical requirements of the study. Ethics are also an important consideration for those assessing the study. Again, the measure of risk versus benefit comes into play: Is there more than minimal risk and how can it be managed?

minimizing risk of study

enrollment of otherwise ineligible participants failure to collect data an inadequate sample size loss of data technological error presence of bias **no study can be completely safegaurded against all risks. however, steps can be taken to ensure that those that could be expected are minimized or at least addressed in some fashion ^^aka limitations in the study --> indicate the epxected issues that could affect the study and how are they being addressed

A trial coordinator told an investigator that unethical conduct almost never occurs anymore since there are accepted guidelines for ethical conduct in clinical trials, so she/he doesn't need to review and cross-check the data for its accuracy for each enrolled subject. Is this statement true or false in view of what you learned in this course?

f

A trial site is behind on its enrollment of trial subjects - only two subjects enrolled and two enrollment failures while the average enrollment on a global scale is 15 subjects per trial site. The site has limited resources (no study coordinator) to conduct the trial and it is the first Phase II trial the investigator undertakes. It takes an average of five (5) days to screen a patient for enrollment. The investigator is promised by a monitor (CRA) a city trip to New York if he/she enrolls another ten (10) patients in the trial in the next couple of weeks. The investigator really appreciates the offer and promised to have at least five (5) more subjects enrolled this week and ten (10) more next week. The CRA claims this is ethical behavior and the enrollment expectations are feasible, because the enrollments will occur according the protocol and the investigator knows what he/she is doing as the investigator did a Phase III trial before. They just now need to prioritize the trial over their other duties. Is this a true or false statement, in view of what you have learned in this course?

f

The Nuremberg Code is considered the first actual "law" on ethical conduct in clinical trials. Is this statement true or false?

f

When you suspect fraud it is ok to speak of 'fraud' in any communication related to the issue. Is this statement true or false?

f

functionality for protocol review

focus on assessing the: -functionality --refers to both the functionality of study and/or site --does the study fit into the research of interested of the site? if not, does it represent a new area of interest or would it be met with barriers? --are the resources required for the study readily avaible at the site or easily acquired? --is the targeted patient population amenable to the study in terms of patient volume and attitude towards research --what funding sources are availbale --what is the history of research at your site --what is the organizational support for research? does research play a central role or is it a sideline, or even a new endevour, for an organization whose primary focus is patient care? -study design --learn form literture, collaboration, textbooks, etc. -meeting sites -subject needs --all sites are not emndable to all studies and vise versa

amending an existing protocol

minor clarificaitons to changes that completly change the study points to the conviction that prtocol developemnt is an ongoing process that continues beyond the launch of the study

misconduct vs fraud

misconduct is not illegal but is unacceptable usually done unknowingly

A data manager detects an inconsistency in trial data. He/she immediately calls the investigator of the trial at the trial site and asks for clarifications and starts the conversation by saying fraud has been committed. The data manager then sets up an appointment to visit the site and to check all data. Based upon what you learned in this course, did the data manager act as he/she should?

no

In the case of a randomized study - two or more investigational products (medicines) are being used - an investigator keeps on randomizing the same patient until this patient gets the investigational product or medication he/she wants the patient to get to ensure the patient's health. Is this ethical conduct in view of what you learned in this course?

no

Minimizing risk

risk may be to the health of the participants, their information, or both the key, specifically for studies involving greater than minimal risk, is to minimize the risk to participants as much as possible

Developing a research question

sometimes the hardest part of the design needs to be incredibly specific

statistical considerations

statistical considerations are important not only for the study integrity and sisgnificance but also to mitigate participant risk, as a study deemed to have an inadequate sample size wastes resources and places those who did participate at unnecessary risk 1. the size of the study population the smaller the effect, the harder it is to detect requires large number of patients statistical considerations: - descriptive statistics only describes charateristics. the total number of participant, the perecentage of male or female, ages, and other general aspects are provided, some degree of calculation may be included, but these are often limited to range, minimum and maximum values, means, and other simple mathematics -inferential statistics, test for significance. conclusions are subsequently drawn from these results. it is here where one may encounter statistical tests pertinent to the study design. in short, one is assessing a sample population, and attempting to make inferences about the general population - if one is adept at statistics, even in general terms, these aspects can be useful in the assessment of a protocol. a determination of teh appropriate statistical tests and the sample size can be made. as a result, one can determine if the study is sound enough to warrant conducting at a site

Bioethics vs ethics

the study of ethical issues resulting from advances in biology and medicine includes law, politics, science, religion

Evaluating your needs

what stage is the research at are you at the exploratory stage, where a population study may be appropriarte, or are you looking to compare treatments what resources are avialable what is you instituional support? are you applying for external funding what is your long-term commitment to see the study through, especially if it takes years do you plane to publish and/or perform addiitonal studies after the current one iss complete

An investigator conducting a trial in your institute or for your organization keeps on postponing the dates for organizing a quality control (QC) monitoring visit by the monitor (CRA) because he/she is too busy. Can you consider this 'unethical' behavior based on what you learned in this course?

y