Making a New Medicine Part 2: Introducing Clinical Trials

The discovery and development of new medicines is a complex and lengthy process. Many founders begin their search for a new therapy without an understanding of these details. In my experience, most of the public views drug development as “the news reports that scientists show it works in a mouse, so my doctor will be able to write a prescription next week.” In an educational effort for summer break, I offer this four-part series describing the different stages of drug development, which are applicable in all regulatory jurisdictions.

Clinical studies, frequently referred to as trials, are performed to determine whether the proposed drug can be safely administered to patients and that safe doses will produce a meaningful benefit for most patients. The primary challenge is to design and conduct a study that has enough control to demonstrate the validity of the study hypothesis and still be able to generalize the results to a wider patient population. Ethical issues increase because human subjects are involved, and the risks and benefits of the drug are not yet fully understood (since they are the purpose of the study). All clinical studies are guided by a protocol that specifies the goals of the trial, its design, measures, and treatment success targets or endpoints, and how the data will be managed and used to determine the trial results. The protocol will be approved by an Institution Review Board (IRB) to ensure it meets the legal and ethical standards of the countries in which the study will be conducted. Investigators and study teams receive responsible conduct of research training as well as any specialized training needed for study activities, and the study database and data tools are set up.

Once these steps are completed, study recruitment can begin. Study staff contact patients who meet the criteria specified in the protocol to discuss the risks and benefits of the trial and ask for their participation. All patients (or their guardians) are required to read and sign consent documents before enrollment and at regular points throughout the trial since the actual risks and benefits of the treatment only become clearer as the trial proceeds. Following patient enrollment, the study proceeds for each individual with treatment, follow-up, and data collection, cleaning, and entry into the database. During treatment, study teams pay close attention to the type and frequency of adverse events to determine which are treatment related as soon as possible. At pre-scheduled points during the trial period, data is retrieved for interim statistical analysis and preliminary results. At the close of the study, the database is locked, and the final study analysis is completed. Patient records are retained for post-study follow-up including access to the results of the study. There are generally three phases of clinical trials conducted to support a New Drug Application (NDA), and all phases follow this general outline.

The clinical assessment of a new medicine starts with a Phase 1 trial. Because clinical trials are expensive, each is followed by an assessment of the lead candidate’s continuing potential as a safe and effective treatment. While the trials and their data generally receive the most attention in the press, considerable work is simultaneously underway to verify and validate the methods for producing the lead compound at a commercial scale and manufacturing the final dose form (often referred to as the drug product). The Phase 1 trial assesses the disposition and behavior of the drug when administered to a small number of healthy human subjects. Safety is the key area of focus for this phase. During Phase 1, investigators administer increasing doses of the lead compound and evaluate the maximum tolerated dose, pharmacokinetics (how the drug circulates in and is eliminated from the body), and any human-specific safety signals. Phase 1 trials are not blinded, as the investigators are specifically studying the effect of the lead compound. Should the trial meet the prespecified acceptance criteria, the candidate can proceed to a Phase 2 trial (assuming it meets it’s other development milestones).

The Phase 2 trials provide the first data on the efficacy of the proposed drug in subjects diagnosed with the target disease. They may be independent of the Phase 1 trial, but may also be combined with Phase 1 studies in a single protocol with multiple arms (this is more common in “fast-track” development programs). A Phase 2 trial is performed using the lead compound and a placebo or already approved treatment approach (called the standard of care). The study is likely to be blinded (the patients and/or investigators do not know which treatment is administered) and the number of subjects is still small (often less than 100). Data is collected using standard laboratory and clinical tests, imaging scans, and patient surveys. Blood and sometimes tissue samples are analyzed to provide data on the level of the compound in the body over time. The Phase 2 data, when unblinded and analyzed to produce the trial results, give the first indication that a drug will work in the human disease state and are often referred to as ‘proof of concept’ studies. This is a key development and financial milestone for a new drug as well as for the sponsor company, especially if the drug is first in their pipeline.

Learn More

For readers interested in more details on clinical trials, I recommend an accessible narrative review of clinical trial concepts published by Umscheid, Margolis, and Grossman in 2011. [1]

Part 3 of this series looks at the phase 3 pivotal safety and efficacy trial, production of the new medicine, and the NDA, or New Drug Application. You can catch up on Part 1 of this series, Discovery and Preclinical Development, here .

References

[1] Umscheid, C. A., Margolis, D. J., & Grossman, C. E. (2011). Key concepts of clinical trials: a narrative review. Postgraduate medicine, 123(5), 194–204. https://doi.org/10.3810/pgm.2011.09.2475