Clinical Trials - PT01: Landscape: Purpose, People, and Challenges

E Pluribus Unum.

America's unofficial motto means "Out of many, one." It's how I remember the path of a single life-saving medicine through its drug development journey. This simple yet bold adage (and the image below) helps me visualize the concepts we will explore across the clinical trials [space] in this 6-part series. Over the course of the next several weeks, we'll get to know the landscape, planning, execution, data collection, market, and future of the trials space.

Signals From [Clinical Trials]

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Mapping Our Journey

Here's what you will learn over the course of this multi-part Signals series:

• Part 01: The Landscape: Purpose, People, and Challenges
• Part 02: The Plan: Protocols, Design, and Discovery
• Part 03: The Trial: Recruitment, Operations, and Activation
• Part 04: The Data: Biomarkers, Monitoring, and Analysis
• Part 05: The Market: Trends, Tailwinds, and Key Players
• Part 06: The Future: Drugs, Devices, and Digital Endpoints

Introduction

In a world of rapidly advancing medical technology, clinical trials serve as the proving ground for innovations that will shape the future of patient care. They bridge the gap between scientific discovery and standard of care, paving the way for groundbreaking treatments and therapies.

Clinical trials are among humanity's most profound discoveries and powerful tools for progress. They've helped us unravel countless mysteries of medicine and health. They serve as the place where scientific innovation meets compassionate frontline care, sparking hope for researchers and patients alike.

These historic roots run deep, from the 16th-century Siege of Turin to the high seas aboard the HMS Salisbury over 200 years later, culminating in landmark legislation that brought clinical trials oversight to the FDA in 1962 . Throughout the centuries, we've steadily marched toward a singular purpose: bringing new therapies to those in need.

Purpose

Clinical trials help us unlock the insights and answers we need about the safety and effectiveness of novel drugs, devices and therapies.

For patients, participation in these trials can produce both immediate and long-term health benefits and lead to greater care plan adherence.

For healthcare organizations, clinical research studies and the development of novel therapeutics have the potential to drive some of the greatest shifts in healthcare cost structure and outcomes.

However, it's important to note that clinical trials are not about discovering new treatments. As clinical trials pioneer Dr. William T. Beaver pointed out in 2007 , "The function of the controlled clinical trial is not the 'discovery' of a new drug or therapy. Discoveries are made in the animal laboratory, by chance observation, or at the bedside by an acute clinician."

The path to unlocking new, safe, and effective treatments demands rigor, collaboration, patience, and resilience. Equally vital are tangible things like funding, patient volunteers, and physicians willing to lead these studies.

But before we delve into trials and tribulations, let's first meet the people who make these studies possible.

People

The intricate fabric of clinical trials thrives on the collaborative efforts of a diverse tapestry of six major stakeholders.

A blog published by the NEXT VENTūRES team last year provides a clear and insightful glimpse into this space, shedding light on stakeholders, challenges, and opportunities:

? Study Participants are patient volunteers selected to participate in a trial.

? Principal Investigator leads the conduct of a study (usually a MD).

? Sponsors are the entities that fund the study (e.g. pharma, AMCs, VA).

? Regulators oversee clinical trials to ensure they are designed, conducted, analyzed and reported according to federal law (e.g. FDA in the US).

? Independent Review Boards (IRB) / IEC Ethics organizations are responsible for ensuring the trial is ethical and that participants' rights and welfare are protected.

? Contract Research Organizations (CRO) are hired by Sponsors to plan, coordinate, execute, and supervise trial operations. CROs function as the central contact point between the Sponsor and other trial actors (e.g. ethics, regulator, vendor, sites).

Phases

The drug/device development journey typically unfolds in three major stages: discovery, preclinical development, and clinical trials. While the transition from discovery to preclinical development is a continuum , the boundary between preclinical and clinical trial is clearly defined by the filing of an Investigational New Drug (IND) application .

For the purposes of brevity, we'll zero in on the clinical trial stage— everything that unfolds after the approval of the IND application.

Clinical trials are divided into distinct "Phases". Following the green light for human testing, there are three phases before a sponsor can submit their treatments to the FDA for approval. Each phase has a different purpose and helps researchers answer different questions related to that purpose.

Phase I

In Phase 1 clinical trials, the safety, tolerability and toxicity of the drug at different doses is tested in a small number of healthy volunteers.

Phase II

In Phase 2, the drug's efficacy and optimal dosing regimen are established. After Phase 2, the drug enters the most vital stage of its development.

Phase III

In Phase 3, the drug faces its defining test. Efficacy is meticulously evaluated across various populations and dosages, comparing it against existing treatments and established standards of care. This phase holds significant weight— it's the final hurdle the drug must clear before its information and clinical trial outcomes journey to the regulatory authorities for the coveted stamp of approval. It's no wonder that Phase 3 trials are often dubbed "Pivotal" trials, as they truly determine the future of the drug's fate.

Phase IV

Once the drug steps onto the market stage, its journey is far from over. Enter Phase 4, also known as Post Marketing Surveillance. Here, the drug's performance unfolds in real-world scenarios, mirroring the diverse experiences of the general public. This phase delves into the long-term tapestry of risks and benefits associated with the drug's usage, unveiling any rare side effects that might emerge after widespread use.

The Turning Point

Now, you may be thinking: "This sounds fairly straightforward. We know who we need to help, what we need to do, which questions to ask, and how long it should take, right?" Well, the hard truth is: clinical trials are hard, and that reality sets in when you consider that only 9.6% of Phase I drugs receive FDA approval .

The image above shows the average approval rates for different indications, from infectious diseases on the high end (19.1%) to oncology on the low end (5.1%). We will get into more detail on 'why trials fail' later in this series.

Challenges

Clinical studies are time-consuming, expensive, and face constant challenges for participants and sponsors alike.

Sponsors spend billions of dollars to bring a single drug to market over a 10 to 15-year period. And yet, most trials still fail or fall short. A staggering 80% miss their enrollment timelines, leading to delays that can cost upwards of $8 million per day . Up to half of research sites enroll one or no patients.

The high failure rates of clinical trials across drugs and devices reflect the complex and uncertain nature of medical research and the difficulty of developing new treatments that are both effective and safe.

In this final section of Part I, let's take a closer look at what we know about a few of these barriers, including recruitment, study design, and funding.

1. Recruitment

One of the significant hurdles in clinical trials is the challenge of recruitment. Many studies struggle to meet their timelines due to low patient participation and slow recruitment. Challenges with recruitment and retention are influenced by several factors, such as the type of study being conducted and the local context:

• Low Awareness: Several studies indicate that awareness changes attitudes toward clinical trials, enrollment, and the benefits of participation. A 2001 Harris Interactive Survey showed 85% of patients were either unaware or unsure that participation in a clinical trial was an option at the time of diagnosis ; 75% of these patients said they would have been willing to enroll had they known it was possible.
• Access to Treatment: Prospective participants who already have access to treatment within their community might be less motivated to join a clinical trial. (data: community access , existing care options )
• Perceived Risks: The potential risks associated with the study, both known and unknown, can influence a person's decision to participate. (data: risk perception , patient preferences )
• Logistical Considerations: Factors such as the frequency of follow-up visits, travel distance, and invasiveness of testing can significantly impact participation. (data: location , travel distance , visit frequency )
• Distrust: Distrust among minority populations may be a persistent barrier to minority research participation. Distrust is the most frequently cited disincentive for research participation among minority populations. As one example, the legacy of the Tuskegee Study continues to cast a lingering shadow of mistrust over medical research in minority communities, with reverberations still visible in the COVID-era . (data: pharma , race , legacy , equity , diversity )

2. Study Design

The design of a clinical trial lays the groundwork for its success, yet it introduces its own unique set of obstacles that can influence the accuracy and reliability of research findings. A well-designed study ensures that results are credible and applicable to the intended population. However, challenges in study design can arise from various factors:

• Complexity of Protocols: Elaborate trial protocols, including intricate eligibility criteria and extensive testing procedures, might discourage potential participants from enrolling. (data: protocol complexity , patient selection )
• Selection Bias: Inherent biases in selecting participants can affect the universality of study results. For instance, if a trial predominantly includes participants from a specific demographic, the conclusions may not represent the wider population. This is why high quality RCTs conceal randomization — it limits selection bias. (data: diversity in clinical trials )
• Inadequate Controls: Studies lacking proper control or comparison groups may yield inconclusive results. Proper control groups are pivotal in demonstrating the efficacy of a new treatment or intervention. (data: control group importance , treatment efficacy )
• Endpoint Selection: The choice of primary and secondary endpoints can impact the relevance and clinical significance of study results. Picking appropriate endpoints that mirror patient outcomes and treatment effectiveness is vital for the trial's credibility.?(data: endpoint selection importance , patient-relevant outcomes )
• Adherence and Compliance: Ensuring participant adherence to study protocols and interventions can be difficult. Inadequate adherence can introduce variability and compromise the integrity of trial results. Strategies to enhance participant compliance are essential for the success of a study. (data: participant adherence , intervention compliance )

3. Funding

Combined, the Top 20 Pharmaceutical companies spend approximately $60 billion on drug development each year , and the estimated average cost of bringing a drug to market (including drug failures) is now $2.6 billion—a 140 percent increase in the past ten years. For medical devices, the path to market costs around $54 million per device . Despite the massive uptick in spending, we have not seen a meaningful increase in new drugs on the market in that time.

• Economic Viability: The amount of money that drug companies devote to R&D is determined by the amount of revenue they expect to earn from a new drug, the expected cost of developing that drug, and policies that influence the supply of and demand for drugs. The cost of developing a new drug encompasses capital expenses and outlays on drugs that fail to reach the market. (e.g. Pivotal studies for new FDA-approved drugs average $41,117 per patient )
• Limited Resources: While private sector investment (e.g. pharmaceutical companies) is often considered the primary driver of innovation in R&D, the federal government — and particularly the National Institutes of Health (NIH) — plays a leading role in fueling that effort. NIH funding contributed to 354 of 356 drugs approved from 2010 to 2019, with a total of $187 billion invested .

Conclusion

Remember: E Pluribus Unum. Out of many, one. While the journey to bring a life-saving drug or device to market is lengthy, challenging, and resource-intensive, it represents a beacon of hope and limitless potential within the medical community. Yes, we have come a long way since the Drug Amendments Act of 1962 and even since the launch of ClinicalTrials.gov in 2000 — 450,000 registered trials and counting! — but there are still significant hurdles to overcome. Costs, time-to-market, failure rates, physician enablement, diversity and patient access are the challenges of our time. My hope is to shed some light on the people answering that call as we continue exploring this space.

Part 2: The Plan

Having gained insights into the Landscape of clinical trials, we're now poised to delve into the Plan. In Part 2, we'll explore how a trial takes shape during the pre-clinical phase. Protocols, design, and meticulous planning are the cornerstones of a successful study. It's time to find out why.

If you're working on something in this space, let us know in the comments below. And if you haven't already, join 4K+ clinical and business leaders as we explore a new [space] each month.?? Subscribe today .

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