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Understanding Drug Development - Why it Takes So Long & Costs So Much Money: A Four-Part Series

Updated: Nov 2, 2021

Part 2: The Journey Begins in a Lab

In Part 1, we covered the basics of drug development, the reasons why we need a process to do so, and the institutions leading the charge. Today let’s talk about the actual development of a treatment.

Drug Development Step by Step

So, what is that path, and what are those costs? Let’s break it down.

Step 1: Discovery, Development and Validation

Step 2: Preclinical Research & Testing

Step 3: Establishing a Natural History

Step 4: Industry Investment & Manufacturing

Step 5: Investigational New Drug (IND) Application Filing

Step 6: Phase 1, 2 and 3 Clinical Trials

Step 7: FDA Review (not the first, and not the last)

Step 8: Post-Marketing Surveillance

This post will cover the first three steps.

Step 1: Discovery, Development and Validation

The first step in the drug development process is to clearly define the pathology of a disease -- what causes it and what happens to the body as a result. In CMD, this is more than just identifying the gene responsible. Researchers must learn what impact a gene mutation has on the protein it provides instructions for creating, and what downstream effects happen as a result of that faulty gene and faulty protein. This type of investigation is often referred to as basic research -- research that fills in the knowledge we don't have to provide the foundation for applications and interventions. And while this research doesn’t always lead to actionable intel, nothing can come after without it. This process may cost several hundred thousand dollars, and take many years to complete, depending on the complexity of the underlying disease mechanism.

While all of that information on a molecular level is catalogued, analyzed and verified by researchers, clinicians are advancing a parallel line of inquiry. How does this disease manifest in affected individuals? What symptoms do they experience? Which symptoms impact quality of life more than others? What can we do to alleviate those symptoms while researchers work to find treatments? How do we recognize and diagnose others with the same disease, thereby building a “recipe” for the expected course of progression and best care practices? Answering these questions are just as important as the work being done in the lab. The processes are complementary and interdependent, and both are critical to the successful creation of a treatment.

Step 2: Preclinical Research & Testing

The dictionary says that efficacy is the ability to produce a desired or intended result. Relevant to this topic, efficacy means the development of an intervention that can suspend or reverse symptoms, or even the fundamental causes of a disease. This is no easy task! Once a disease has been well-characterized from both a scientific and a clinical perspective, researchers then begin the work of identifying ways in which that disease could possibly be treated through a variety of well-established practices. This type of research is referred to as preclinical or applied research, and falls into two basic categories: in vitro and in vivo.

In vitro (from the Latin term "in glass") refers to studies of microorganisms, cells, or biological molecules within a test tube. Sometimes those cells might be derived from blood or tissue samples donated by affected individuals. This process allows researchers to define the properties of potential drug compounds and get their first inclination about how cells react to that compound.

In vivo (from the Latin term “in life”) refers to studies that are conducted inside a live organism. In neuromuscular research, we use a variety of small animals, including zebrafish and mice. On rare occasion, we are fortunate to identify a larger animal that carries the same disease as its human counterpart. This process allows researchers to further investigate how a potential drug compound interacts within a living body, what previously unforeseen negative interactions or side effects occur, and whether or not the compound actually improves or reverses disease. While gaining a better understanding of efficacy is important in preclinical testing, establishing safety is paramount.

Preclinical testing is an important and necessary step in bringing treatments to market. The FDA will not authorize human trials without preclinical studies that provide extensive safety data. This stage of research narrows down the thousands of potential drug compound candidates to just a few, and takes many years and hundreds of thousands of dollars to complete.

Note: Cure CMD-funded projects that involve in vivo research adhere to established guidelines for the safe and ethical treatment of animals, and rigorous oversight by an IRB.

Step 3: Establishing a Natural History

While the preclinical work is happening in the research world, clinicians (and researchers!) are developing data about the expected course of a disease’s symptoms and the complications that often arise (otherwise known as adverse events). This catalogue of data is called a disease’s Natural History. Natural History studies are observational, non-interventional studies that can take a variety of forms, but generally fall into two categories: retrospective and prospective.

A Retrospective Natural History Study (rNHS) is an investigation of information collected in or about the past -- a review of historical data catalogued about an affected individual. This may include medical records (including examination notes, diagnostic testing, blood tests, biopsies, hospitalizations, and surgeries) or patient and family-reported surveys. This gives clinicians a better understanding of the typical symptoms and adverse events that happen over the course of the affected individual’s life, how diagnoses are successfully made, and what interventions have been useful in alleviating symptoms. Compared to prospective studies, rNHS are relatively inexpensive to conduct, costing somewhere in the range of 100-200K dollars, and can often be completed in just a couple of years, depending on how quickly study participants can be recruited, and how readily available medical records are.

rNHS also inform a critical aspect of a clinical trial design: outcome measures. Outcome measures are quantifiable changes in health or quality of life that result from an intervention. Identifying and characterizing outcome measures in a disease not only informs and improves standards of care, but also provides a way to see if a reaction or event observed during a clinical trial is the result of the treatment being tested, or simply a consequence of having the disease. “To get a treatment through the regulatory process, it is very important to choose the right outcome measure that is reliable, sensitive enough, changes enough over the course of a limited period of time, is valid and not volitional,” says Dr. Jodi Wolff, Head of Patient Advocacy for Santhera Pharmaceuticals and member of Cure CMD’s Board of Directors. “Many times, our understanding of this is changing over the course of the trial. It can hold up an entire development program or make an area really attractive to go into.”

A Prospective Natural History Study (pNHS) is an investigation of affected individuals, and sometimes even family members, conducted in the present. Physical examinations and tests are performed in accordance with a research protocol that defines the rationale, scope, and aims of the study. pNHS are usually conducted over several years; the same physical examinations and tests are repeated at each study visit in order to build an accurate picture of disease progression. This type of data is called longitudinal data. One of the primary aims of a pNHS is to further refine potential outcome measures identified in rNHS for use in clinical trials. pNHS can cost anywhere from a few hundred thousand to well over a million dollars, and typically take two to ten years to complete, depending the number of locations (study sites), the number of study participants, the difficulty in recruiting, and the frequency with which examinations are repeated.

Natural history studies are critical to the design of clinical trials and regulatory approval to conduct those trials. Says Jodi Wolff, “Natural history data helps regulators understand what is a fluke, what is natural progression, and whether those studied are representative of the general affected population.” The process of collecting natural history data doesn’t end here - it continues throughout the rest of the drug development journey, all the way to the end. What we learn in an early natural history study may change by the time we get to clinical trials. Understanding what a disease’s natural history looked like 10 years ago compared to today - how improvements in diagnostics and care standards, and implementations of new, symptom-alleviating treatments - make natural history studies never truly complete.


Cure CMD, in partnership with several patient advocacy organizations, researchers, clinicians and industry, operates the Congenital Muscle Disease International Registry (CMDIR) for the very purpose of assisting with the development of retrospective and prospective natural history data, the identification of adverse events and potential outcome measures, and the recruitment of clinical studies and trials. Are you registered?

In Part 3, we’ll cover the remaining steps of drug development.

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