How We Go from Animal Model to Clinical Trial

Summary

SciShow explores the critical role of animal testing in medical research, emphasizing its necessity despite ethical concerns. Rodents, due to their genetic, behavioral, and biological similarities to humans, are often used to test treatments before human trials. The video highlights the complexity of translating animal results to humans, the importance of in vitro tests, and the implementation of safety measures in clinical trials. It also discusses the challenges and the evolution of safety protocols, including the use of computer models to predict drug interactions.

Takeaways

• 🐁 Animal studies are crucial for testing new treatments in living organisms before human trials.
• 🔬 Results from animal studies, like those in mice or rats, may not directly translate to humans due to biological differences.
• 🧪 In vitro tests are conducted before animal testing to ensure potential efficacy and minimize animal use.
• 🌐 Many countries have regulations to ensure the humane treatment of animals used in research.
• 🐀 Rodents are commonly used in medical research due to their genetic, behavioral, and biological similarities to humans, and their ease of breeding.
• 🧬 Scientists can create genetically identical or 'knockout' rodents to enhance the reliability of research results.
• 🐒 While primates are closer relatives, ethical and logistical concerns limit their use in research, making rodents suitable substitutes.
• 💊 Drug trials in animals are conducted with safety measures, starting with the minimum effective dose (MABEL) to minimize risks.
• 📊 Researchers define primary and secondary outcomes to avoid false positives and ensure the drug's effectiveness is accurately measured.
• ⚠️ Adverse event guidelines are established to determine when to stop a trial based on the severity and prevalence of side effects.
• 🛑 Despite precautions, unpredictable reactions can occur, as seen in the 2006 TeGenero trial, highlighting the challenges in drug testing.
• 🛠️ Modern trials incorporate more safety measures and technologies, like computer models, to improve the prediction of drug interactions with human proteins.

Q & A

Why are animal studies important in scientific research?

Animal studies are crucial as they allow scientists to test new treatments in living organisms before trying them in humans, which helps identify potential complications or issues.

Why can't findings from animal studies be directly applied to humans?

Animals are not mini humans, and their biological responses to treatments can differ significantly from humans, meaning that a treatment effective in mice may not necessarily be effective in humans.

What are in vitro tests, and how do they relate to animal studies?

In vitro tests are experiments conducted in dishes and tubes rather than in living organisms. They are performed before animal studies to establish potential efficacy, as the use of animals in research is limited and regulated.

Why are rodents commonly used in medical research?

Rodents are used because they are small, easy to breed, relatively cheap to maintain, and share enough genetic, behavioral, and biological similarities with humans to be useful for research.

What is a 'knockout specimen' in the context of animal research?

A 'knockout specimen' refers to animals, like rodents, that have been genetically manipulated to lack specific genes, allowing researchers to study the effects of treatments more precisely.

Why are other primates not always used for drug testing despite being closer relatives to humans?

While primates are used in some cases, ethical and logistical concerns limit their use. Rodents are often sufficient substitutes, and testing in primates does not guarantee a smooth transition to human trials.

What is the minimum anticipated biological effect level (MABEL) in drug testing?

MABEL refers to the smallest dose of a drug that showed effectiveness in animal studies, which is used as a starting point for human trials to minimize potential adverse effects.

What are primary and secondary outcomes in clinical trials?

Primary and secondary outcomes are predefined measures of effectiveness for a drug in a clinical trial. They help researchers determine whether the drug is working as intended and avoid false positives or missed benefits.

How do researchers handle unexpected adverse reactions during clinical trials?

Researchers establish guidelines for adverse event outcomes, detailing what reactions necessitate stopping the trial and which are tolerable. They also plan for unexpected reactions using data from preclinical animal experiments.

What safety measures have been implemented in recent years to improve clinical trials?

Recent safety measures include more time between dosing participants, use of computer models to predict drug interactions, and enhanced protocols for working with animals to ensure the clinical testing process is as safe as possible.

Why is animal testing still necessary despite advancements in computer modeling?

Animal testing remains necessary because bodies are complex, and real living organisms are needed to observe how treatments interact within a biological system, something that computer models cannot fully replicate.

Outlines

00:00

🐁 Animal Studies in Medical Research

This paragraph discusses the significance of animal studies in the development of new medical treatments. It explains that while animal models, particularly rodents, are used to test potential treatments before human trials due to their genetic, behavioral, and biological similarities to humans, it's important to note that animals are not perfect substitutes for humans. This is because the results from animal studies may not always translate directly to humans. The paragraph also touches on the ethical considerations and regulations in place to ensure humane treatment of animals used in research, and the limitations of animal models, emphasizing the need for caution when transitioning from animal to human trials.

05:00

🔬 The Complexities of Transitioning from Animal to Human Trials

The second paragraph delves into the complexities of moving from successful animal trials to human trials. It highlights the safety measures put in place to minimize risks, such as starting with the smallest effective dose (MABEL) and defining clear primary and secondary outcomes to avoid false positives. The paragraph also discusses the challenges of predicting adverse reactions, the importance of setting guidelines for adverse event outcomes, and the need for contingency plans. It mentions the 2006 TeGenero trial as an example of an unexpected severe reaction in human participants, despite successful primate trials. The paragraph concludes by acknowledging ongoing efforts to enhance safety measures in clinical trials and the continued reliance on animal testing due to the limitations of computer models in fully replicating human biology.

Keywords

💡Animal studies

Animal studies refer to the use of animals, such as rats and mice, as subjects in scientific research to test new treatments before they are tried in humans. This practice is crucial for identifying potential complications or side effects. In the video, it's mentioned that 'Animal studies allow scientists to test new treatments in living, breathing, organisms before they try them out in people,' highlighting the importance of these studies in the drug development process.

💡In vitro tests

In vitro tests are experiments conducted outside of a living organism, typically in a laboratory setting using dishes and tubes. These tests are preliminary to animal studies and are used to determine the potential of a treatment before it is tested on living organisms. The video script mentions, 'Before any animals even get involved, pharmaceutical researchers run a bunch of what are called in vitro tests,' emphasizing the initial step in the research process.

💡Rodents

Rodents, such as rats and mice, are commonly used in medical research due to their similarities to humans in genetics, behavior, and biology, as well as their ease of breeding and cost-effectiveness. The script points out that 'a lot of medical research is conducted in rodents' and explains that they 'have enough similarity to humans in a lot of areas' to be useful in research.

💡Genomes

The genome refers to the complete set of genetic information of an organism. In the context of the video, scientists can breed rats with almost identical genomes to ensure uniform and reliable research results. The script states, 'Large numbers of rats can have almost identical genomes,' which allows for more standardized experimental outcomes.

💡Knockout specimens

Knockout specimens are genetically modified organisms that have been engineered to lack a specific gene. This allows researchers to study the effects of a missing gene on the organism's biology and the potential impact of treatments. The video explains that scientists can breed rodents to be 'optimized for research' and mentions the use of 'knockout specimens: ones that lack specific genes' to delve deeper into treatment effects.

💡Primates

Primates are a group of mammals that include humans and are often considered closer relatives to humans than rodents. While they could provide more reliable information for human trials, the video points out ethical and logistical concerns with using primates for research. It mentions that 'while primates are the right choice in some cases, there are ethical and logistical concerns with conducting research on them.'

💡Minimum Anticipated Biological Effect Level (MABEL)

MABEL refers to the smallest amount of a drug that has shown an effect in animal studies and is used as a starting point for human trials. The video explains that researchers start with 'the smallest amount that seemed to work in animals, called the minimum anticipated biological effect level, or MABEL,' to minimize risks in human trials.

💡Primary and secondary outcomes

These are the predefined measures used to determine the success of a clinical trial. Primary outcomes are the main goals, while secondary outcomes are additional effects that are also considered. The script discusses the importance of clearly defining 'what their definition of “working” is ahead of time' and the potential issues with 'multiplicity in a trial,' which arises from the statistical margin of error.

💡Adverse event outcomes

Adverse event outcomes are the negative reactions or side effects that occur during a clinical trial. Researchers set guidelines to determine how to react if adverse events occur, which is crucial for ensuring safety. The video script mentions that researchers 'also set guidelines for adverse event outcomes,' which help in deciding when to stop a trial or when side effects are tolerable.

💡TeGenero trial

The TeGenero trial is a historical example of a clinical trial that went wrong. In 2006, healthy participants experienced severe inflammatory reactions after being given an antibody intended to treat autoimmune diseases. The video uses this case to illustrate the unpredictability of drug reactions in humans, even when animal trials are successful. It states that 'all experienced severe inflammatory reactions requiring hospitalization' despite the drug being tested at a much lower dose than used in primates.

💡Clinical testing process

The clinical testing process refers to the stages of testing a new drug or treatment on humans, starting with a small group and expanding if the drug proves safe and effective. The video discusses the evolution of safety measures in clinical trials and the ongoing efforts to improve the process. It mentions that 'trials build in a lot more safety measures than they did a couple decades ago' to enhance patient safety.

Highlights

Animal studies are crucial for testing new treatments before human trials.

Animals are not mini humans, so results from animal studies may not directly translate to humans.

In vitro tests are conducted before animal testing to ensure potential of treatments.

Rodents are commonly used in medical research due to their similarities with humans and ease of breeding.

Rodents can be bred with identical genomes for more uniform research results.

Knockout specimens, lacking specific genes, help researchers understand treatment effects.

Primates are used in some cases, but ethical and logistical concerns limit their use.

Human trials involve safety measures like starting with the minimum anticipated biological effect level (MABEL).

Primary and secondary outcomes are defined to avoid multiplicity issues in trials.

Researchers set guidelines for adverse event outcomes to determine when to stop a trial.

Preclinical animal experiments provide insights into potential adverse reactions.

Clinical trials have improved safety measures over the years, including more time between dosing.

Computer models are used to predict how human proteins interact with potential drugs.

Researchers continue to develop better protocols for working with animals in research.

Despite technological advancements, animal testing remains necessary for understanding complex biological systems.

Animals, particularly rats, play a vital role in ensuring the safety of treatments for humans.

Transcripts

[♩INTRO]

When we talk about cool new research here on SciShow, you might hear us say

something like: “This study was done on rats.

And rats aren’t people.”

It’s nothing against them personally.

Animal studies allow scientists to test new treatments in living, breathing

organisms before they try them out in people,

which helps spot complications or potential pitfalls.

But animals aren’t mini humans,

so what happens in a mouse may not happen the same way in a person.

And that means two things.

For one, it means we can’t always assume a cure in mice

will be effective in human patients.

But it also means that safely going from animal to human trials

is a lot more complicated than you might think.

Before any animals even get involved, pharmaceutical researchers run a bunch

of what are called in vitro tests,

basically anything done in dishes and tubes rather than animals.

What they’re doing has to have a lot of potential since, as you can imagine,

the use of animals in research can be unsettling for a lot of people.

Many countries have formal institutions in place which try to limit the use

of animals for cases where they’re really needed, and they have regulations

which specifically ensure these animals are treated in a humane way.

Now, a lot of medical research is conducted in rodents.

That’s because rodents are small, easy to breed,

and relatively cheap to care for in large numbers.

And rodents have enough similarity to humans in a lot of areas,

including genetics, behavior, and biology, that they can help scientists suss out

whether a drug has real potential.

Also, we can breed them to be optimized for research.

Large numbers of rats can have almost identical genomes, for example,

allowing for more uniform and reliable results.

And scientists know how to manipulate their genomes to get what we call

knockout specimens: ones that lack specific genes.

This lets them dig deeper into what a treatment is actually doing to the body,

which helps minimize any surprises that might happen when a drug is given to

humans instead.

You might think it’s strange that so many trials are done in mice or rats

when we’d get the most reliable information from animals

that are closer relatives, especially other primates.

But while primates are the right choice in some cases, there are ethical and

logistical concerns with conducting research on them, and for the most part,

rodents are pretty good substitutes.

Besides, testing a drug in primates doesn’t guarantee a smooth transition to

human trials, because the only animals with all the right cells and proteins to

perfectly predict what happens in a human body are, well, humans.

That’s why, even when a drug has passed animal tests with flying colors,

researchers build in a number of safety measures to minimize the risk of adverse

reactions in people.

It’s considered important to use as little of the drug as possible, for example.

That usually means starting with the smallest amount that seemed to work in animals,

called the minimum anticipated biological effect level, or MABEL.

If that doesn’t cause any problems, but doesn’t work, either,

then researchers can dial up the dosage.

They also lay out exactly what their definition of “working” is ahead of time.

These are what are called primary and secondary outcomes.

If they’re too lofty or unfocused,

like if there are dozens of things the drug could do,

then you’re likely to perceive a benefit that isn’t really there.

This is what’s called multiplicity in a trial, and it arises because the statistics used

to determine whether something has made an impact or not

have a certain margin of error.

On the flip side, if your trial outcomes are too narrow or impossible to obtain,

you might not realize a drug is actually doing something good.

And at the same time as they’re determining primary and secondary outcomes,

researchers also set guidelines for adverse event outcomes,

basically, what reactions mean it’s time to call it quits, and what reactions,

though perhaps unpleasant to experience, aren’t really that big a deal.

The good news is that they already have an idea what might happen

from those preclinical animal experiments.

But they also have to make plans for things that come out of left field.

So, they make guidelines to determine how to react if things go wrong,

which take into account everything from the number of participants

affected to the severity of their reactions.

Of course, it doesn’t help matters if companies are overzealous

about their hopeful cures.

In many cases, when a failed clinical trial makes headlines,

investigators later discover corners that were cut along the way.

But sometimes, researchers do everything right and the worst still happens.

Take the 2006 trial for TeGenero,

an antibody that researchers hoped would be the next cure

for a set of autoimmune diseases.

For the first human test, 6 of the otherwise healthy participants

were given 1/500th the dose used during primate trials, but within an hour,

all experienced severe inflammatory reactions requiring hospitalization.

The drug was supposed to activate certain cells in the immune system,

so in a sense, it was doing its job, it just did it a little too well.

The human cells the drug targeted turned out to be way more sensitive

than any of the animals tried.

And that kind of uniquely human reaction to a drug is really hard to predict.

Nowadays, trials build in a lot more safety measures than they did a couple

decades ago, like taking more time between dosing each participant

to see if something bad happens.

And they can take advantage of newer technologies like computer models

that can better predict how human proteins interact with potential drugs.

But researchers and regulators are still working on ways to make the clinical

testing process even safer.

And a big part of that is making better protocols for working with animals.

That’s because, despite all the amazing things we can do with computers,

bodies are really complicated.

So we still need animal testing to see how things work in real living things.

So even though rats aren’t people, we still need their help to keep people safe.

Thanks for watching this episode of SciShow!

If you enjoyed learning more about the importance of animals in research,

you might like our episode about 5 times researchers gave animals drugs

and what we learned from those experiments.

[♩OUTRO]