Introduction
The aim of this learning activity is to identify and understand some of the key decisions that occur throughout clinical drug development.
We’ll follow the clinical drug development of rofecoxib and imatinib. The development of these drugs will be used to illustrate the key phases of drug development and outline the regulatory framework. We’ll also discuss the challenges of drug development in more general terms.
Resources
Turner (2010b): New Drug Development is an online textbook on drug development that may be of use. Chapter 5 gives a good overview of the terminology and purpose of the key stages of clinical drug development.
Sheiner (1997) is a classic article that provides a good way to understand clinical drug development. It also introduces informative drug development.
Objectives
Understand the key phases of clinical drug development: the focus of each phase, the types of participants involved, and kinds of analysis used.
Appreciate the challenges of clinical drug development.
Understand the role of informative drug development.
Overview
This section provides an overview of clinical drug development and discusses some of the key terms. There is considerable overlap here with other work you have completed within the course. This section can be skipped if you are familiar with the process of clinical drug development and the key terms.
History
Before going further it is worth keeping in mind that regulatory frameworks exist to protect the public. The regulation of pharmaceuticals is no different.
| Date | History |
|---|---|
| 1937 | Pharmacist kills 107 people with manufactured anaesthetic |
| 1938 | US Food and Drug Administration (FDA) requires manufacturers to demonstrate safety |
| 1960 | FDA rejects new drug submission for Thalidomide |
| 1962 | FDA requires safety and efficacy |
| 2004 | Rofecoxib voluntarily withdrawn |
There has been a range of regulatory responses to rofexocib and similar cases in which postmarketing evidence has identified additional risks, such as rosiglitazone. Rosiglitazone is a diabetes drug which caused considerable controversy regarding whether it increases the risk of myocardial infarction. In response to cases like rosiglitazone, the US FDA issued additional guidance to industry regarding the need for more rigourous evidence regarding long term cardiovascular outcomes throughout the approval process for new diabetes medicines.(US Food and Drug Administration 2018) The conduct of these additional trials has, arguably, been very successful, but the guidance is currently under review (Regier, Venkat, and Close 2016; Kieffer and Robertson 2019).
Process
Clinical drug development is an international process. Most drugs are first lodged with the US Food and Drug Administration. The regulatory approach in other places such as Australia and Europe are similar, and provide channels for drugs to be approved following FDA approval.
| Phases | Population | Purpose | Success Rate |
|---|---|---|---|
| Pre-clinical | Animal studies | Assess safety/activity | 5000 |
| Phase I | 20–80 volunteers | Safety and dose | |
| Phase II | 100-300 patients | Proof of concept | 5 |
| Phase III | 1000–3000 patients | Confirm efficacy | |
| FDA | Review process | 1 | |
| Phase IV | Routine use | Post-marketing surveillance |
Phases of clinical drug development
The “phases” are heuristics more than definitions—different studies with similar aims may be classified as being in different phases, and studies with different aims might be classified in the same phase.
Alternative classifications have been provided, but are yet to become standard. See Turner (2010a) for a helpful classification.
In addition to the three key phases (Phase I–III) are:
- Phase 0
studies with very limited human exposure (“microdose”) and no therapeutic intent, they are used to gain important pharmacokinetic and imagining information prior to traditional Phase I studies
- Phase IV
post-marketing studies, include large studies similar to Phase III studies, pharmacoeconomic analyses, and comparative effectiveness studies.
Terminology and important concepts
Important terminology (and acronyms):
FDA terminology
- NME
New molecular entity
- IND
Investigational new drug application (to undergo clinical testing)
- NDA
New drug application to market drug following clinical drug development
Internal v External Validity
- Internal Validity
the degree to which the results of the study are accurate for the participants in the study
- External Validity
the degree to which the results of the study are accurate for patients undergoing routine care
The focus of studies in clinical drug development is on internal validity. Regulators, such as the FDA, provide guidance to ensure each study conducted within a clinical drug development program has sufficient internal validity.
Once the drug is on the market, the focus of clinicians and other decision-makers is on external validity.
Endpoints: biomarker and surrogate marker/endpoint
- Endpoint
a measured outcome of a trial
- Biomarker
an indicator of change in a biological system (e.g. rheumatoid factor)
- Surrogate endpoint
a biomarker that can be justified to provide a measure for a clinical outcome (e.g. blood pressure, cholesterol)
Intervening on a surrogate marker is expected to influence the clinical outcome. Not all biomarkers are surrogates for a clinical endpoint. Lowering blood pressure (within a certain range) reduces the patient’s risk of cardiovascular disease; intervening on rheumatoid factor does not reduce rheumatoid arthritis. Rheumatoid factor is a marker of disease, but does not change in response to treatment or symptom resolution.
FDA Table of surrogate endpoints lists the endpoints that have been accepted by the FDA within clinical drug development.
This does not mean that a drug that influences a surrogate marker is a useful drug—in addition to influencing the surrogate marker it might produce adverse effects that outweigh the benefit. There are many examples of drugs that influence a surrogate marker that are not marketed, or are marketed and then withdrawn (cerivastatin, troglitazone, and—of course—rofecoxib)
Proof of concept
“Proof of concept” is the earliest point in the drug development process at which the weight of evidence suggests that it is “reasonably likely” that the key attributes for success are present and the key causes of failure are absent. (Cartwright et al. 2010)
Proof of concept
Usually at the end of Phase II
Takes many factors into consideration: safety, efficacy, drug-ability, competitors, market, …
Ideally proof of concept decisions use best science to manage uncertainty
References
Cartwright, M E, S Cohen, J C Fleishaker, S Madani, J F Mcleod, B Musser, and S A Williams. 2010. “Proof of Concept: A PhRMA Position Paper With Recommendations for Best Practice.” Clinical Pharmacology {&} Therapeutics 87 (3): 278–85. https://doi.org/doi:10.1038/clpt.2009.286.
Kieffer, Cameron M., and Andrew S. Robertson. 2019. “Impact of FDA-Required Cardiovascular Outcome Trials on Type 2 Diabetes Clinical Study Initiation From 2008 to 2017.” Therapeutic Innovation and Regulatory Science, 1–5. https://doi.org/10.1177/2168479019860122.
Regier, Emily E., Manu V. Venkat, and Kelly L. Close. 2016. “More than 7 years of hindsight: Revisiting the FDA’s 2008 guidance on cardiovascular outcomes trials for type 2 diabetes medications.” Clinical Diabetes 34 (4): 173–80. https://doi.org/10.2337/cd16-0005.
Sheiner, L B. 1997. “Learning versus confirming in clinical drug development.” Clinical Pharmacology {&} Therapeutics 61 (3): 275–91. https://doi.org/10.1016/S0009-9236(97)90160-0.
Turner, J Rick. 2010a. “Designing Clinical Trials.” In New Drug Development, 47–67. New York, NY: Springer New York. https://doi.org/10.1007/978-1-4419-6418-2_5.
———. 2010b. New Drug Development. New York, NY: Springer New York. https://doi.org/10.1007/978-1-4419-6418-2_1.
US Food and Drug Administration. 2018. “FDA Background Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting.” https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM623913.pdf.