You will often hear the phrase “learn and confirm” related to clinical trials. Phase II clinical trials are where you “learn” about your treatment and phase III clinical trials are where you “confirm” what you know for regulatory agencies.  One important part of the learning that takes place in phase II is looking at various efficacy outcomes to determine which primary end point you will use for phase III and what specific label claims you will be able to make following an approved NDA.

Biological Mechanism

These outcomes measure some component of the biological mechanism the treatment is targeting.  An example an endpoint of a biological mechanism would be measuring hemoglobin levels for a treatment of anemia.  An advantage of this type of outcome is that they are clear and objective.  This type of endpoint may not be an option in the case where the mechanism of action is not well understood or easily measured, such as in many psychiatric drugs.

Physical Manifestation

Measuring some aspect of the physical manifestation of the disease can serve as an outcome.  For example, cystic fibrosis impacts lung function.  To demonstrate efficacy of a treatment for cystic fibrosis you can use spirometry to assess lung function.  This is especially useful when your therapy doesn’t attack the disease state itself, but ameliorates the symptoms of the disease.  It’s also good in the situation where the disease progresses slowly, but the symptoms have a much earlier onset.

Qualitative Improvement

You can also look at qualitative aspects of subject improvement.  Sometimes these are qualitative assessments by the physician or patient, like rating their pain on a scale of 1 to 10.  It can also be a more objective measurement like looking for a decrease in the number of hospitalizations during a period of time.  These can be important endpoints because there is an opportunity to clearly demonstrate the impact on a patient.  Since these types of outcomes are more subjective, it is important to provide as much structure as possible to the assessment to limit the potential for bias in the results.

Disease Progression

Often, the outcome of most interest is a direct measure of disease progression, as when you measure death or cancer progression in an oncology study. This sometimes overlaps with the physical manifestation or symptom endpoints, but is more focused on the direct consequences of the disease instead of the early symptoms of progression or opportunistic events.

A few other considerations when considering the types of outcomes you will measure in your phase II trials:

• Collect any measurement you might consider using as an endpoint in your phase III trials.  You don’t want any surprises in phase III when mistakes are much more expensive because of the scale of the trial.
• If there is a “typical” endpoint for the indication you are studying, you should collect it, even if you don’t plan to use it as your primary endpoint.  This makes comparing your results to prior results in other studies easier to do.
• The types of outcomes described above are all about demonstrating efficacy.  Safety is important in all stages of development, including phase II, so consider if there are specific safety endpoints that you should also be measuring.

Each investigational product and indication is unique, and it would be impossible to provide one set of rules or guidelines for picking endpoints, but hopefully you find the information provided here useful.

Dr. Karen Kesler, Senior Statistical Scientist and Dr. Andrea Mospan, Program Manager contributed to this article.  Check out the video below where Dr. Kesler discusses the basics of adaptive design.