How Can Small Biotechs Use CROs to Apply the 5R’s Concept?

HEADER Charles River  Zolnierek

Although the exact percentage of drugs failing clinical trials is still widely disputed, the fact remains that the number of compounds successfully passing clinical trials is persistently slim. The reasons for this are varied and are often based on numerous challenges biotech and pharma companies face during drug discovery and development.

The two main reasons for high failure rates in clinical trials are issues with safety and efficacy. So what can biotech and pharma companies do to mitigate these risks and work towards increasing their drugs’ success rates? In 2014, the large pharma company AstraZeneca decided to take a closer look at why their drugs failed and, as a result, published a concept that other companies have followed since.

What is the 5R’s concept?

Omar Aziz, Charles River
Omar Aziz, Senior Director of Integrated Biology at Charles River Laboratories

When AstraZeneca started reviewing all the small molecule drug projects they had conducted between 2005 and 2010, the goal was to understand the factors impacting the progression of these projects. “The company was looking at which of their programs had progressed, how many had failed and why they had failed,” says Omar Aziz, Senior Director of Integrated Biology at Charles River Laboratories.

As a result of their internal research, AstraZeneca came up with the so-called 5R’s concept or 5R’s framework, which – once adopted – would help them change their approach toward research and development processes.

“The five R’s are the right target, the right tissue, the right safety, the right patients, and the right commercial potential,” Aziz explains. “AstraZeneca discovered that many of their projects were failing down the line because of safety and efficacy issues. The 5R’s concept was focused on getting a stronger link between target diseases and biomarkers to measure whether their compound and target engagement markers would be efficacious in the proposed model.”

The right target and the right tissue

tissue exposure, 5R's concept, drug development
Following the identification of the right target, the drug’s exposure in the right tissue needs to be demonstrated

Identifying the right target for the disease of interest is an important factor of a successful drug discovery program, especially when it comes to efficacy. AstraZeneca’s analysis showed that successful projects were more likely to have identified the biological role a target played in disease progression. “A good understanding of effective biomarkers that could be measured from blood or the target organ, be it the brain, the liver or the lung, was also associated with more successful projects,” Aziz adds.

The probability of success is also increased, says the report, if pharmacokinetic and pharmacodynamic (PK/PD) modeling reveals that the drug candidate gained exposure in the target organ with sufficient pharmacological activity. “The PK/PD relationship tells us what the correlation of the exposure of the drug in a system and the efficaciousness of that drug is,” says Aziz. “So how much of the drug does it take to cause an effect of a beneficial nature?”

Following the identification of the right target, the drug’s exposure in the right tissue needs to be demonstrated. In most tissues, the exposure is fairly well known. However, in a few niche areas, the exposure of a drug candidate can be associated with a number of issues. “In central nervous system therapeutics, for example, understanding exposure can be a struggle because it is harder to gain an overview of your actual target coverage in the patient population,” Aziz explains. “Unlike measuring the exposure of your drug candidate in the bloodstream, there is no easy, direct way to measure it in the brain.”

The right safety, the right patients, and the right commercial potential

patient population, 5R's framework, CRO, drug development
Researchers need to understand the patient population to get an idea of how a specific target can affect a certain disease

AstraZeneca’s report revealed that the most common reason for project failure was safety. Safety issues were related to over half of the failures in preclinical and phase I studies. In phase II, safety was responsible for 30% of project failures.

“Getting a good understanding of the safety profile and understanding the concerns related to it, is important for a molecule’s success,” Aziz explains. “AstraZeneca reported that they had identified and known about a number of flagged safety issues, but had not acted on them, which led to more failures. On the other hand, projects that had very few safety issues seemed to be doing remarkably well. Now, this seems like an obvious thing to say, but a lot of our learnings about compounds moving into the clinic are about where the boundaries are drawn in regards to safety.”

Closely related to safety are, of course, the patients. Here, the most important point for researchers is to understand the patient population to get an idea of how a specific target can affect a certain disease. “Being able to identify those groups that are most likely to benefit from engaging a particular target in a disease is crucial,” says Aziz. “If only 50% of your patients are dependent on that target, you are far less likely to hit the endpoints for a successful clinical trial. But if 100% of your patients are dependent on the target, success is much more likely.”

The last point of the five R’s concept is the right commercial potential. The basis of this concept is the question of whether the drug can make a difference. “Is your drug going to have sufficient benefits against the current standard of care?” says Aziz. “Is it going to be efficacious enough that it has an advantage not only from a clinical perspective but also for the quality of life of the patients? Will the drug be relevant to the disease and modulate it in the long term?”

The importance of the 5R’s concept and the help of CROs

researchers, collaboration, CROs, partner
“When we start with integrated programs, which include biology, chemistry, and drug metabolism and pharmacokinetics, we involve safety as early as we can” Omar Aziz

For a company the size of AstraZeneca, the failure of four or five molecules in the clinic may be seen as a setback, but at the same time, many other programs will still be running. “Failures in the clinic are not the life or death of a large company,” says Aziz. “A small biotech, on the other hand, might only have one or two drugs in clinical development. If one or both of these fail, the company’s existence may be at stake.”

For a small biotech company, the costs of drug discovery and development are enormous. This automatically increases the risks associated with these programs. Therefore, using the 5R’s concept as a guide can help small biotechs to progress their molecules to the clinic successfully.

With the help of expert CROs, these chances for success and the consequent survival of the company can be achieved. At Charles River Laboratories, for instance, the experts in-house are well aware of the risks that small biotechs face in advance of reaching the clinic; they know what key areas to focus on to ensure that a clinical trial remains as low-risk as possible.

“When we start what we call integrated programs, which include biology, chemistry, and drug metabolism and pharmacokinetics (DMPK), we involve safety as early as we can,” Aziz explains. “That way, we can get an indication of the risks facing us and mitigate these as soon as possible. At the start of any program, we therefore build drug discovery screening cascades. Like a funnel, with each progression step, the number of promising compounds is reduced so in the end we are left with the most relevant and most clinically attractive molecules.”

Tips for small biotechs directly from the expert

The different stages of Charles River’s drug discovery screening cascade match AstraZeneca’s 5R’s concept. Their goal is to understand the target and disease relationship, as well as use measurable biomarkers to study the target engagement, get an idea of a molecule’s efficacy, and determine what level it could be dosed at.

“Every time we embark on a drug discovery program, we absolutely want to succeed,” says Aziz. “We will go the extra mile to understand what questions we need to ask and what information can guide us to success. That is the main focus for small biotechs: understand the unknowns and learn how to accommodate these as best you can when progressing to the clinic.”

Aziz explains that the only way to differentiate and anticipate the success of a molecule is to form in-depth knowledge around it. For instance, the Charles River chemistry team analyses as many different types of chemical structures that target the molecule as possible. “The main idea is that each of these chemotypes have differing strengths and weaknesses,” Aziz explains. “Understanding the off-target environment when you are binding your molecule to your target can really help you to move your program along.”

The key advice to follow during drug discovery and development is the importance of collecting as much information as possible and knowing how to apply this information to give your molecule the best chance of survival in the clinic. “Ask yourself, do you have a backup plan? Have you learned from any setbacks and can now make a better molecule?” Aziz explains. “Ultimately, we want to help the patient population and if we can’t understand which patient group will benefit most from our novel therapeutics, then we will struggle to get the answers we are looking for from clinical trials.”

Are you interested in learning more about the 5R’s concept and how best to apply it to your drug development process? Get in touch with the experts at Charles River Laboratories for more information!

Images via

Author: Larissa Warneck, Science Journalist at

Newsletter Signup - Under Article

"*" indicates required fields

Subscribe to our newsletter to get the latest biotech news!

This field is for validation purposes and should be left unchanged.

Suggested Articles

Show More