The Drug Development Path

Clinical trials used in the development process for pharmaceutical products aim to provide the most information about a new investigational compound or therapeutic intervention’s safety and efficacy. Each phase is designed to ensure the safety of study subjects and to answer a particular research question with the end goal of improving patient care.

Clinical Trial Phases

There are 2 main types of clinical studies: clinical trials/ interventional trials and observational studies. In an interventional trial, voluntary participants receive specific interventions according to the protocol created by the investigators. Observational studies are designed to draw inferences about the effect of a treatment on subjects, and although participants may receive interventions, they are not assigned to specific interventions by the investigator as in a clinical trial. Clinical trials used in drug development are often described by phase. They generally consist of 3 premarketing clinical development phases and a fourth phase of trials that provide postmarketing information regarding the product’s quality, safety, or effectiveness.

Phase 1.

This clinical trial phase represents the first time an experimental drug or treatment is tested in humans. The goal of this phase is to determine the drug’s safety, identify the most frequent side effects and, often, explore the drug’s metabolism and pharmacokinetic and pharmacodynamic profile. Typically this is a single-ascending dose and/or a multiple-ascending dose open-label or placebo-controlled clinical trial. In multiple dose scenarios, dosing frequency is typically short and sufficient to begin to understand systemic pharmacokinetic differences between a single dose and after multiple doses.

Phase 1 trials are usually comprised of a small group of approximately 20 to 80 healthy subjects.1 It is important to note that healthy subjects are generally enrolled for drugs that are systemically administered. However, for ophthalmic studies investigating intravitreally administered drugs, the initial human study is typically a Phase 1b/2a study in patients. Although safety may still be the primary focus, initial efficacy can also be evaluated because patients with disease are enrolled.

Phase 2.
Phase 2 trials focus on the effectiveness of the drug and provide supplementary data on safety.1 Enrolling a larger group of patients (approximately 100 to 300), this phase aims to obtain preliminary data on whether the drug works in those who have a particular disease or condition. Generally, these studies follow patients out for 6 to 12 months, at which time the study sponsor can feel comfortable that there is a clear effect in change from baseline, as well as sustained efficacy. Most phase 2 trials are randomized, double-masked controlled trials in which the group receiving the investigational treatment is compared with similar patients receiving placebo, a different treatment, or, in the case of retinal clinical trials, the standard of care. These trials are sometimes divided into phase 2a and phase 2b, which are specifically designed to assess dosing and to determine efficacy, respectively. Dosing, the largest variable that is evaluated at this stage, includes the ideal concentration or amount of drug, proper frequency, and best route of administration.

If there are several successful formulations in phase 1 trials, phase 2 trials may also evaluate multiple formulations to determine the best drug candidate. Additionally, trials at this stage are useful for endpoint evaluation and selecting optimal endpoints for subsequent trials based on the mechanism of action of the drug. From a statistical perspective, sometimes phase 2 studies are powered with a higher alpha (.1 instead of .05) and may seek to look for trends of efficacy as opposed to studies that will reach statistical significance. The results obtained during this trial, however, would then be used to properly power a phase 3 study for statistical significance.

Phase 3. 

In phase 3 clinical trials, the intervention under investigation is tested on a very large group of subjects with disease to confirm the treatment’s efficacy, compare it to commonly used therapies, monitor side effects, and evaluate the overall benefit-risk relationship of the intervention to provide an adequate basis for physician labeling.1 The sample size required for phase 3 clinical studies may depend on a number of factors, including whether the drug was previously evaluated or approved systemically, the sample size required to show statistical significance, the amount of systemic absorption, and the overall safety profile of the drug understood to date. A broader study population is typically used to gather a more comprehensive view of the safety and efficacy. If the results from the phase 3 trials are successful and demonstrate that the drug is both safe and efficacious, a New Drug Application (NDA) may be submitted for review. The US Food and Drug Administration (FDA) will typically require 2 pivotal trials to support the approval of a product, both of which must be well controlled with repeatable results. If these points are not already accomplished through a phase 2 trial, 2 replicated phase 3 trials to support approval would be needed. Depending on the disease, the FDA may have a requirement for a longer-term endpoint in order to evaluate and confirm the sustainability of the response. For example, wet age-related macular degeneration typically requires a 2-year visual acuity efficacy endpoint.

Studies that are performed after an NDA submission are loosely termed phase 3b studies and typically run parallel with the regulatory process to further expand the knowledge of the product. These trials may be used to supplement earlier trials, for marketing claims against other approved products, or for additional label indications.

Phase 4.
Even after a drug has been approved by the FDA, research on the effects of the product continues through postmarketing surveillance. These trials are used to gain additional information such as long-term safety and efficacy data (additional benefits or risks), optimal dosing schedule, and impact on a patient’s quality of life, or to test the product in various populations. Phase 4 trials may be mandated by the FDA or pursued by the sponsor.The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective.


Accessed January, 2013.



The FDA has laid out a road map to product commercialization, with one of the most integral pieces being the clinical trial process. While the road to an FDA drug approval is long and winding, it is important to become familiar with the approval requirements of each stage of product development.

Aron Shapiro is Vice President of Retina at Ora, Inc., in Andover, MA.

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