Introduction to Clinical Study Design: Introduction to Observational & Interventional Studies Part 2

Summary

The video script discusses two primary types of research: observational and experimental. It covers various study designs like case reports, case series, cross-sectional surveys, case-control studies, cohort studies, natural history studies, ecological studies, and quasi-experimental studies. It also touches on clinical trials, phases of drug testing, and the challenges of randomized controlled trials.

Takeaways

• 🔬 There are two primary types of research: observational and experimental interventional. Observational research involves collecting data without influencing the subject, while experimental research involves deliberately influencing events to study the effects.
• 👨‍🔬 In observational studies, researchers aim to observe and document characteristics of interest without intervention, allowing for a natural progression of events to be studied.
• 🧪 Experimental studies, often referred to as clinical trials or clinical studies in humans, involve deliberate intervention by researchers to investigate the effects on a selected population.
• 📚 Observational studies can include case reports, where a doctor documents unusual findings in a structured manner, and case series, which compile multiple case reports.
• 📈 Cross-sectional prevalence surveys provide a snapshot of a population's health status at a specific point in time, such as the National Health Interview Survey in the United States.
• 🔍 Case-control studies compare disease cases with control subjects to identify differences that might explain the disease, useful for studying rare diseases.
• 👨‍⚕️ Cohort studies follow groups over time to observe changes, such as the impact of disasters on healthcare workers' health.
• 🌐 Natural history studies track the progression of diseases in patients over time, often conducted by institutions like the NIH Clinical Center.
• 🌳 Ecological studies analyze data at the population level rather than the individual level, providing insights into broader health trends.
• 🔄 Quasi-experimental studies, such as single-arm or nonrandomized interventional studies, lack control groups and are often used in early stages of research.
• 🏥 Phase 0 and phase 1 studies in clinical research focus on early safety and dose-finding, setting the stage for more comprehensive trials.
• 📊 Phase 3 studies, or pivotal trials, are large-scale efficacy studies that determine the effectiveness of a treatment or intervention.
• 🌐 Phase 4 studies in the FDA context involve post-market surveillance to assess safety and effectiveness in the general population.

Q & A

What are the two main types of research mentioned in the script?

The two main types of research mentioned are observational and experimental interventional research.

What is the primary goal of observational research?

The primary goal of observational research is to observe and collect data on characteristics of interest without influencing the participant, the environment, or the disease course.

What is the difference between observational and experimental research?

Observational research involves simply observing without intervention, while experimental research involves deliberately influencing the course of events to investigate the effects of an intervention.

What are case reports and case series in the context of observational studies?

Case reports are when a doctor writes down a structured set of information about a patient with unusual symptoms. Several case reports make a case series, which is a collection of such reports.

How did the CDC's Morbidity and Mortality Weekly Report contribute to the discovery of AIDS?

The CDC's Morbidity and Mortality Weekly Report contributed to the discovery of AIDS by publishing case series and case reports that highlighted unusual symptoms, leading to further investigation.

What is a cross-sectional prevalence survey?

A cross-sectional prevalence survey is a snapshot picture of the health status of a population at a specific point in time, such as the National Health Interview Survey in the United States.

What is the purpose of a case-control study?

The purpose of a case-control study is to identify factors that may be associated with a disease by comparing a group of people with the disease (cases) to a similar group without the disease (controls).

What is a cohort study and how does it differ from a case-control study?

A cohort study is a longitudinal study that follows a group of people over time to observe the natural history of a disease or the effects of an intervention. It differs from a case-control study in that it follows people forward in time rather than looking back from a disease outcome.

What is an ecological study and how does it differ from other types of studies?

An ecological study analyzes data at the population level rather than at the individual level. It differs from other studies in that it does not focus on individual subjects but rather on groups or populations.

What are quasi-experimental studies and how do they differ from experimental studies?

Quasi-experimental studies are interventional studies that lack a control group or randomization. They differ from experimental studies, which are designed with a control group and often involve randomization to test the effects of an intervention.

What is the significance of randomized controlled trials in clinical research?

Randomized controlled trials are significant in clinical research because they provide strong evidence of causation by controlling for confounding variables through randomization, which helps to ensure that the observed effects are due to the intervention rather than other factors.

Why might a researcher choose to conduct a non-randomized study?

A researcher might choose to conduct a non-randomized study when randomization is not feasible, such as in the case of rare diseases, or when the study design requires observing natural progressions without intervention.

What is the difference between phase 1 and phase 3 clinical trials?

Phase 1 trials are the initial studies to determine the safety, dosage, and side effects of a new drug in a small group of people. Phase 3 trials are large-scale studies that confirm the efficacy and monitor side effects in a larger population, often referred to as pivotal trials.

What is the role of phase 4 studies in the FDA world?

Phase 4 studies, or post-market studies, are conducted after a drug has been approved and released to the general population. They monitor the drug's safety and effectiveness in real-world conditions and among diverse populations.

What are dissemination and implementation studies, and why are they important?

Dissemination and implementation studies focus on how to effectively spread and apply the results of research findings, interventions, or therapies in different settings. They are important to ensure that evidence-based practices work in various real-world scenarios and are accessible to diverse populations.

Why is it important to distinguish between observational and randomized studies when analyzing data?

It is important to distinguish between observational and randomized studies because observational studies can only show associations due to potential confounding factors, while randomized studies can demonstrate both association and causation, assuming proper randomization has been conducted.

What are the limitations of nonadaptive randomization in the context of unknown confounders?

In nonadaptive randomization, unknown confounders should not create problems, as the randomization process is designed to evenly distribute known and unknown confounders across treatment groups. However, in adaptive trials, where the randomization process may change based on accumulating data, unknown confounders can introduce bias.

Outlines

00:00

🔬 Types of Research and Observational Studies

The first paragraph introduces two fundamental types of research: observational and experimental. Observational research involves collecting data on subjects without influencing them, aiming to capture natural occurrences. In contrast, experimental research involves deliberate interventions to study their effects on a selected population. The paragraph also discusses the application of these methods in clinical trials and case reports, which are crucial for understanding disease patterns and progression. It mentions the significance of case reports in the discovery of AIDS and the role of the CDC's Morbidity and Mortality Weekly Report in monitoring public health. The paragraph concludes with an overview of various observational study designs, including case series, cross-sectional surveys, case-control studies, cohort studies, natural history studies, and ecological studies, emphasizing their importance in early-stage research.

05:00

💊 Phases of Clinical Trials and Research Expectations

The second paragraph delves into the different phases of clinical trials, starting with Phase 1 for dose-finding and tolerability, followed by Phase 2 for safety and efficacy assessments. Phase 3 is highlighted as pivotal trials for major efficacy evaluations, while Phase 4 focuses on post-market surveillance to ensure ongoing safety and effectiveness. The paragraph also touches on dissemination and implementation studies, which explore the practical application of interventions in various healthcare settings. Comparative and cost-effectiveness studies are mentioned, comparing different therapies for major depressive disorder as an example. The paragraph addresses common expectations in study design, such as control arms, randomized assignments, and double-blinding, and acknowledges the challenges and limitations in meeting these ideals in certain research contexts.

10:00

📊 Distinguishing Research Types and Analyzing Data

The third paragraph discusses the importance of distinguishing between observational and randomized studies, especially when analyzing data. It emphasizes that observational studies can only demonstrate associations due to the potential for unknown confounders, whereas randomized studies can establish causation. The paragraph also differentiates between nonadaptive and adaptive trials, noting that the latter can be more susceptible to confounding factors. The importance of asking the right questions and ensuring that research methods align with the fundamental questions of interest is stressed. The paragraph concludes with examples from the BMJ, illustrating the variety of meaningful research methods beyond the traditional randomized, double-blind, controlled trial.

Keywords

💡Observational Research

Observational research is a method where researchers collect data on characteristics of interest without influencing the participants or the environment. It is crucial in understanding natural occurrences and behaviors. In the script, observational research is contrasted with experimental research, highlighting its role in capturing real-world data without intervention. Examples include case reports and case series, which are foundational in epidemiology and can lead to significant medical discoveries, such as the identification of AIDS.

💡Experimental Research

Experimental research involves deliberately influencing the course of events to investigate the effects of an intervention. It is a proactive approach where researchers manipulate variables to observe outcomes, aiming to establish cause-and-effect relationships. The script mentions clinical trials and clinical studies as examples of experimental research on humans, emphasizing the importance of this method in advancing medical knowledge and treatment efficacy.

💡Case Reports

Case reports are detailed accounts of individual patients' medical cases, often used to highlight unusual or significant findings. They are a fundamental part of observational research, as mentioned in the script. Case reports can lead to the identification of new diseases or treatment approaches, as was the case with AIDS, where a pharmacist noticed something odd and initiated a series of case reports.

💡Case Series

A case series is a collection of case reports that provide a broader perspective on a particular disease or condition. It is a step up from individual case reports in terms of observational research, allowing for patterns and trends to be identified. The script uses the discovery of AIDS as an example of how case series can lead to significant medical insights.

💡Cross-Sectional Prevalence Surveys

Cross-sectional prevalence surveys provide a snapshot of the prevalence of a disease or condition within a population at a specific point in time. An example given in the script is the National Health Interview Survey in the United States. These surveys are essential for understanding the distribution of health issues in a population and can inform public health policies.

💡Case-Control Studies

Case-control studies are a type of observational study where researchers compare individuals with a disease (cases) to those without (controls) to identify risk factors. The script mentions that these studies are particularly useful for rare diseases, as they help in understanding the factors that contribute to the disease.

💡Cohort Studies

Cohort studies are longitudinal observational studies that follow a group of individuals over time to observe outcomes related to exposure to a particular factor. The script references following healthcare workers or disaster cleanup personnel to study long-term health effects, illustrating how cohort studies can provide insights into the natural progression of diseases or the effects of interventions.

💡Natural History Studies

Natural history studies involve tracking the progression of a disease in a group of patients over time without intervention. The script mentions that these studies can help understand how diseases evolve and how patients age with their conditions, which is crucial for developing treatment strategies.

💡Ecological Studies

Ecological studies analyze data at the population level rather than at the individual level. The script suggests that these studies can provide insights into health patterns and behaviors within communities, which can be used to inform public health strategies and interventions.

💡Quasi-Experimental Studies

Quasi-experimental studies are non-randomized interventional studies that lack a control group. The script explains that these studies are often early in the research process and can involve non-random allocation of interventions, such as comparing different wards in a hospital without random assignment.

💡Phase Studies

Phase studies refer to the stages of clinical trials, from early safety and dose-finding studies (Phase 1) to large-scale efficacy studies (Phase 3) and post-market surveillance (Phase 4). The script discusses the progression from early exploratory studies to pivotal trials and post-market studies, highlighting the importance of each phase in establishing the safety and efficacy of medical interventions.

Highlights

Two types of research: observational and experimental interventional.

Observational research aims to collect data without influencing participants or the environment.

Experimental research involves deliberate influence on the course of events to investigate the effect of an intervention.

Clinical trials or clinical studies are used for experimental subjects on humans.

Case reports and case series are fundamental to epidemiology.

Morbidity and Mortality Weekly Report is a resource for tracking new and unusual health trends.

Cross-sectional prevalence surveys provide a snapshot of health data.

Case control studies compare disease cases with controls to identify differences.

Cohort studies follow individuals over time to observe health outcomes.

Natural history studies track the progression of disease in patients.

Ecological studies analyze data at the population level rather than the individual level.

Quasi-experimental studies lack a control group and are often early in the investigation process.

Historically controlled studies use past patient data as a control group.

Phase 0 and pre-clinical studies are early in the research spectrum, setting the foundation for phase 1 studies.

Phase 1 studies focus on dose finding and tolerability.

Phase 2 studies examine safety, dose, and delivery methods.

Phase 3 studies, or pivotal trials, are major large efficacy studies.

Phase 4 studies involve post-market surveillance to assess safety and effectiveness in the general population.

Dissemination and implementation studies test whether interventions effective in one setting can be replicated in others.

Comparative or cost-effectiveness studies compare different therapies head-to-head.

Randomized, double-blind, control trials are the gold standard but not always feasible.

Nonrandomized studies can only show associations, not causation.

Adaptive trials can be affected by unknown confounders.

Transcripts

But remember kind of this basic, that first bullet.

Kind of two types of research.

It's observational versus this kind of experimental interventional.

So the observational,

my goal is to observe and collect data on characteristics of interest

without influencing the participant, the environment, or the disease course.

I literally observing.

I do not want to intervene in any way.

I want to see natural.

Experimental is when you are

-- the researcher, are deliberately influencing the course of events,

at least you're hoping to, and investigating the effect of the intervention

on some carefully selected population of subjects.

I'll say observational is usually a carefully selected set of subjects, too.

When we do experimental subjects on humans, we call them clinical trials

or clinal studies.

Similarly, though, you know, a lot of this work, all of this

applies to animals, it applies to a lot of different projects.

So we're going to cover observational studies in detail next week,

but the general idea here is that you may have case reports,

which is literally the doctor writing down

a set of information, like something looks weird, but I'm going to

write it up in a structured manner so I can share it with other folks.

Several case reports make a case series.

This kind of fundamental epidemiology 101.

It's also because a pharmacist noticed something looked odd and started

working on a set of case series and case reports that we discovered AIDS.

So you used to get -- CDC actually now publishes

it more electronically, but you had Morbidity and Mortality Weekly Report.

So when I was in school, every Friday we went to read this report,

to see kind of what looked new and weird around the country.

What we should have our eyes open for.

Those are usually case series.

You still see them published today in a lot of journals.

Cross-sectional prevalence surveys. This is a snapshot picture.

So this might be the National Health Interview Survey in the United States.

Case control studies.

We'll talk a little bit about this, but usually you get a series of disease

cases, and try to find some match controls, and figure out what's different between them.

If you have a really rare disease, this is a very useful type of study to do,

to try to figure out a list of reasons that you might have disease.

Cohort studies that are longitudinal.

A lot of times -- so when we had major disasters,

we will follow the healthcare workers, or the people that are cleaning up

those disaster sites long-term to see if they have psychological issues,

if they have respiratory-related issues, other problems that come up.

Natural history studies.

You may have a group of patients,

and you're going to follow them, and see how they actually age.

You may see how their disease progresses.

The NIH at the Clinical Center does quite a few of these.

And then the ecological studies.

This is data that's on a population rather than an individual level.

So like I said, we'll talk more about these next week.

Then we

have these kind of -- some groups call them quasi-experimental studies.

These are those one or single arm, nonrandomized, interventional studies. Dr.

Gallin talked about several of these actually if you think about his historical lecture.

You don't have a control group.

They tend to be early in the investigation.

Sometimes you may have a concurrent control group, so I may decide I'm going to bathe

one side of the hall in my hospital, but not bathe the other side of the hall.

I can do some weird, interesting things, but I'm not randomly choosing it.

I just kind of allocate it.

Then you sometimes have things called historically controlled studies.

So pediatric oncology we used to do these where patients that -- you know,

we basically only had enough patients to put everybody on the therapy.

So we said, well, we'll use old patient information as kind of our control group.

So that's kind of that early intervention-based research spectrum.

So I talk about the sometimes it's interventional, sometimes not.

But that quasi-experimental,

those pre-clinical studies, phase 0, those are early studies.

But all of this is setting the foundation for trying to do

what's a phase 1 study or those dose finding studies many times.

You know, in this patient population, what's tolerable?

You know, and what might be sometimes we also look to see early efficacy there,

or at least some change that says we might think we'll have efficacy down the line.

Dig into these early and late phase 2 studies, again, we're looking a lot at safety

like we are in phase 1, but we're starting to get a better idea of the dose.

We're starting to get a better idea

of how we should deliver a medication, or some type of medical product, or therapy.

We're trying to get an idea of who should be in these studies and not.

Phase 3, or what we typically call pivotal trials.

These are your major, large efficacy studies.

Phase 4, for me in the FDA world, is post market.

So we've kind of decided there's efficacy, but if I put this out

in the general population, do I still see safety and effectiveness?

You also get into these dissemination and implementation studies.

Great.

You think that if you make this change your hospital process that you will improve,

you know, let's say it's rates of some type of hospital-acquired infection.

You've done this at your very rigorous, focused hospital.

Is that going to work at the middle of nowhere hospital?

Is it going to work in a really busy public hospital?

Dissemination implementation is can I take all of the information

about how to deliver a therapy, and how deliver an intervention,

and actually do it everywhere in the real world.

You also then see comparative or cost effectiveness studies.

So there's a large study done many years ago by the National Institute of Mental Health

where they took several different therapies for people who had major depressive disorder.

And they said, okay, we're putting them head to head.

That's a comparative study.

But your ideal study, the problem that comes up, is that we have these ideals, right.

Whenever anybody looks at your study design, they are going to say, "I expect

to have a treatment and a control arm." What about all those studies

that don't have a control arms?

They expect

you to have parallel groups, that you're going to have randomized people,

to two different arms of a study, and you're going to watch these folks simultaneously.

Well, sometimes that's not feasible.

They expect you to look for superiority.

You know, drug A is better than drug B.

Well, maybe, you know, drug A costs $30,000 a year and drug B costs 30 cents.

Maybe it's more accessible to use that or maybe there're

a lot fewer side effects with drug B than drug A.

Prospective.

They expect you to be following people into the future.

If there are only 34 people in the world with your disease, you may not be able

to follow them all prospectively in a randomized, parallel arm study.

They expect to be double blinded and masked.

Well, what if you're doing surgery versus non-surgical intervention.

We used to actually blind those studies, but you may not be able to blind them.

Although, sometimes you may say, well, kind of what am I trying to look at?

Do I want to control for all the risks of opening somebody up

and the extra infections they may get from opening and closing them?

Or do I not?

What is your exact question you want to answer?

But if you're looking at a pill versus an IV in a pediatric population,

you're probably not going to be able to give a fake IV.

And they expect a randomized study.

A lot of studies can be randomized if you get inventive, and you're

working in the right population, but not all studies can be randomized.

If I want to look at long-term antiretroviral therapy in HIV patients, it's

going to be really hard for me to run a randomized trial.

So we have these gold standards but sometimes we have to explain

why we need to be a little bit bronze.

Now the next two slides are a handful of studies from BMJ

back in 2013 because it was actually easy to lift the information.

You'll see actually I give a lot of examples from BMJ.

That's because you can access it publicly.

It's open for anybody in the world so what I show you is something

I want you all to be able to access.

If there are articles that are not publicly available,

we will put them up as part of the course information along with my slides.

So in BMJ, they had four articles in their research section this one week.

Noninvasive versus evasive respiratory support, a systematic review meta-analysis.

Another one was a multicenter randomized control trial that was blinded.

At least the researchers were blinded.

You had a population-based cohort study and a large-scale survey.

A lot of different research there.

Only one of those projects was actually randomized, double-blind, control trial.

There's a lot of different types of research you can do that's meaningful.

But as you're doing it, you still have to

distinguish the observational studies from your randomized studies.

A lot of times we start doing these analyses of observational studies

thinking that they were a controlled,

randomized trial, but that tacit assumption of randomness

is what makes a lot of other assumptions work in statistics land.

So, you really have to do a lot of extra work when you're analyzing

observational trial data.

The idea is in a nonrandomized study you can only show associations.

You're never going to know all possible confounders.

In a randomized studies, you can show association and causation.

Now in a well-done nonadaptive randomization, so we'll get to that

in a few weeks, the unknown confounder should not create problems.

If you are doing an adaptive trial, unknown confounders can cause a lot of problems.

But in nonadaptive studies, nonadaptive randomizations,

the general idea is that unknown confounders should not create problems.

But again, always remember that your questions are going to come first.

So, as you're making all these changes, all these things that you're thinking about

with your patients, and what's going to work, are you still answering the fundamental

question of interest?