Do Not Fear the Humans; Common Misconceptions About Moving from Preclinical to Clinical Development

Brad Wyman

What are some challenges in taking a drug from the preclinical stage to the first clinical study in humans?

The biggest challenge is that, often, investigators who discover the ideas or do the initial research are comfortable in the laboratory and with the preclinical research, yet they're unfamiliar with what has to be accomplished to meet FDA regulations in order to have the drug approved. They may be intimidated by or have misconceptions about obtaining institutional review board (IRB) approval and completing an investigational new drug (IND) application so they can translate their research clinically in humans.

The hesitation may come from the fear about what has to be done to take their research into the clinic. However, creating a formal study protocol for approval is similar to what they probably already do in the lab with their research plans.

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Preparing an IND application and going before a federal agency seems very daunting. The sheer number of sections can be intimidating. However, starting with a standard template or table of contents helps guide the writing. Plus, some of the sections are essentially boilerplate and are similar across studies.

An IRB submission can seem equally daunting, but again, there are templates available for the various required items: background, clinical protocols, safety, medical monitoring, and so on. Investigators who do clinical studies are familiar with the paperwork and, in some cases, it's just a matter of putting your study specific details into the document.

Translating into the clinic is necessary if we want to achieve advances in human medicine. It does not benefit humans to cure cancer in mice or Alzheimer disease in rats; we have to use these results to justify moving the research into the clinic and study humans. One should not be intimidated by either the required documentation or the regulatory process.

What kinds of resources do you suggest for potential investigators who don’t know how to take their research from the lab into the clinic?

There's a lot of information available from the FDA, and documents are fairly straightforward to download and follow. Many of these documents have a formal outline that you can use, and it's always easier to write a document when you're given the table of contents at the onset. Then, it just becomes a matter of filling in each section.

Some of the resources available include, an overview of the drug development process published by the FDA, a library of FDA guidance documents covering a range of topics from specific to more general. Additional info worth reviewing include information on what preclinical work is needed before human studies can be conducted; clinical trials guidance documents; info on how to generate a clinical protocol; an IRB written procedures checklist; information for sponsor-investigators submitting INDs; and investigator-initiated IND applications, among many others. Beyond the guidance documents, examples of protocols and INDs can always be found by searching the internet and can help in the generation of your first set of documents.

What are some common misconceptions about the transition from preclinical to clinical research?

Drug development is not just another clinical experiment. A common misnomer for clinicians is they think that running a clinical trial is the same as running their clinical practice. A clinical trial is very different, and the requirements are different; researchers who approach a trial like a clinical practice generally end up making mistakes and getting into trouble, in that they've either run afoul of the IRB or they don't collect sufficiently robust data to support the study claims or objectives.

So, when making that transition — It is important to involve someone who is experienced in running clinical studies, whose expertise can be added to the clinical and research laboratory expertise and assist in running the study in a way that's appropriate for gaining approval by regulatory agencies.

Tell me more about the trouble teams can get into that you've seen, and how they might have avoided that.

When you collect study data, you want to make sure to minimize any sources of variability. Take something simple, like blood pressure. In clinical practice, you might just place the cuff on a patient, take the blood pressure, write down the numbers, and think all is fine. But for a clinical trial, researchers must ensure consistent positioning of the patient. Details such as: ensuring that no patient crosses their legs, that before each measurement the patient has rested for a couple of minutes, and that data is recorded in an electronic database to eliminate errors. The blood pressure measuring device needs to be calibrated for accuracy throughout the study to ensure accuracy. All of this helps to ensure the blood pressure numbers best reflect the biological state of the patient and are not artefacts of inconsistent methodology.

This is one small example of how conducting a trial is different from what clinicians might do on a day-to-day basis. A trial requires more control and care in order to ensure good consistent data at the end of the day — It is important that you don't introduce operational variations, which might obscure a clinical or safety effect. 

Thinking about teams who have made the transition to clinical trials extremely well, can you tell us about characteristics of those teams, or what they did successfully?

Running a clinical trial is extremely complicated, and the truth is, it's not something that can be done by a single person. Everyone involved has some relevant knowledge that comes into play—whether it's statistics, clinical care, the oversight and monitoring, data acquisition and storage, or the final analysis of the results. It really does take a coordinated team effort; that's one of the reasons that documents like a protocol are required in order to coordinate all aspects of the clinical trial

Creating a well-written protocol is a process that integrates everyone's perspective and expertise, and documents everything accurately, so that the trial is executed consistently and in a repeatable fashion. Doing the planning at the onset, during the creation of the design document, which we call the protocol, is critical for a successful trial. The protocol in essence provides a roadmap for the conduct of the clinical study.

For pharmaceutical and medical device companies that need help getting a clinical trial going, what consulting services do you provide?

Whoever is helping a company launch a clinical trial, it's important that they represent the team's scientific and technical interests. It's also important to ensure that they're aligned with the company’s business goals and that the company is not paying for additional data that may be unnecessary.

One of the things that I enjoy doing as a consultant is leveraging my extensive experience in the device/biotech/pharma industry, listening to the many perspectives and interests in a given program and then assessing what critically needs to be done.  Keeping a company's interests in mind, I've reviewed many proposals from contract research organizations (CROs) and have reduced costs tens to even several hundred thousand dollars.  This is because the CROs were offering services that the company didn't need and, in many cases, the company didn't recognize that these things weren’t needed.

It always makes me feel good when I can reduce a client’s bill by a hundred thousand dollars, because then I know I've earned my keep for that day. That’s just one of the more exciting and rewarding services that I can provide as a consultant.  I also endeavour to make certain that the key attributes of the drug from a business perspective are being measured and captured in the clinical study to support the company’s business strategy.

You mentioned that coordination and leveraging expertise is a huge part of making a preclinical to clinical transition smooth and successful. What is it that you enjoy doing to improve that overall team coordination?

It's exciting to figure out how to coordinate a diverse array of experts— to work on the trial design with the goal of maintaining the integrity of each of these experts and their interests. Sometimes it requires a compromise; I determine what's of most value to the team, and when I am working with everyone and it all comes together — it's a beautiful thing.

Is there anything else you’d like to add to this topic of the preclinical to clinical transition?

Yes, although it's a sensitive subject. Very often, pharmaceutical and medical device companies will work with key opinion leaders, who are the foremost authorities in their field. As such, they deserve and receive a lot of respect.  Sometimes too much deference is given to them, because they represent only one viewpoint. That viewpoint might be scientific or medical, which is certainly valid, but oftentimes, their viewpoint is not aligned with the business needs of a company or runs counter to some other things, like running a clinical trial with consistency. Oftentimes, people in the pharmaceutical and medical device companies are hesitant to challenge the key opinion leaders, and this sometimes leads to a trial design that may be untenable.

Here’s a good example: The key opinion leader may think the trial is a great opportunity to collect an expanded set of data and endpoints, and may propose a trial complexity that's very expensive, especially when trying to implement a multicenter trial. The trial can often become unworkable because of the complexity.

Before that happens, it helps to have someone step in and say, “Hey, I’ve analyzed your proposals. Here are the best pieces of those ideas; here are the key endpoints we need to collect; and unfortunately — given the budget, the timeline, the trial complexity, and the burden to patients — maybe we can't do all of the original plan. So, let's just focus on those key endpoints.”

As I said, nobody likes to challenge the experts, but employing the help of an outside consultant advocate, who has a company’s business goals in mind, is a really important takeaway.

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