Choosing the Disease

Imagine you want to study a new investigational cancer medicine. Data from an early (Phase I) trial showed it could shrink tumors in certain types of advanced stage cancers. The percentage of people whose tumors shrank is known as the response rate.

Here's the breakdown of these hypothetical Phase I data:

• In Cancer A, 50% of people responded. For this type of cancer, there are a number of other targeted and immunotherapy medicines already approved with similar response rates, and survival rates have been steadily increasing
• In Cancer B, 40% of people responded. For this type of cancer, the only approved medicine is a chemotherapy that was approved 20 years ago (and only about 20% of people experience any benefit from this chemotherapy).
• In Cancer C, 30% of people responded. For this type of cancer, the only approved medicine is chemotherapy, however approval of another medicine that has been shown to be more effective is anticipated soon.

Based on this information, you must decide which area to prioritize for further study.

Your colleagues are skeptical. Given that people with this type of cancer have numerous treatment options and the prognosis is improving, they feel the resources should be put towards a different area of medical need. Try again!

Your colleagues agree. Given that people with this type of cancer have limited treatment options and the early data look promising, it seems like the right area to prioritize.

Your colleagues are hesitant. Given that people with this type of cancer may have a new treatment option very soon, they feel this shouldn't be the first area to invest resources. Try again!

Planning The Phase II Trial

Now it's time to build upon the results from your Phase I study, with a Phase II trial. This will be a larger, double-blind study.

First, you'll need to decide who will be eligible to participate. Your Phase I trial allowed anyone with Cancer Type B to enroll (an "all comers" approach). However, the presence of a certain protein may potentially indicate who is most likely to respond to treatment (i.e., a biomarker). Your Phase I study assessed this biomarker from the outset (a "pre-specified analysis"). The results confirmed this biomarker was associated with greater efficacy, although several people without the biomarker experienced benefit as well.

You've chosen a path that has the potential to help the most people with Cancer Type B. It may also be easier to recruit trial participants and get the trial started as soon as possible. The disadvantage is that the magnitude of benefit may appear smaller than if you'd used a biomarker to enroll only the people most likely to respond to treatment.

You've chosen a selective path by requiring participants to test positive for a biomarker – and this approach may show the strongest efficacy possible. However, you may be excluding some people who could experience benefit. In addition, if for example only three out of five people have the biomarker, you'll need to screen nearly twice as many people and it may take longer to enroll enough trial participants. On the other hand, if the magnitude of benefit is large, you may not need as many participants to show a statistically significant result.

Next, choose the treatment comparison you want to evaluate. For our hypothetical example of Cancer Type B, the current standard of care is chemotherapy. Let's also imagine that based on the disease biology, you suspect your investigational medicine may enhance the efficacy of this chemotherapy.

One option for your clinical trial is to directly compare your investigational medicine to the standard of care. Or, you can add your investigational medicine to the standard of care and compare the combination to the standard of care alone.

With this choice, your investigational medicine not only has to be effective, it has to be more effective than the best available treatment – which might be difficult to demonstrate. However, if the results are positive, you have very compelling evidence for establishing a new standard of care. In this case, it could mean an effective chemotherapy-free option.

Once your trial begins, you won't be able to change the design. You'll have to stick with your choices and see how the data look when the results are first revealed (this is known as the "unblinding").

With this choice, your investigational medicine needs to add significant benefit on top of the standard of care. This may be relatively easier to show than going head-to-head versus the standard of care. It may even be the case that the efficacy of these treatments combined is greater than the sum of their individual effects (synergistic efficacy). On the other hand, people may experience more side effects than with either treatment alone.

Once your trial begins, you won't be able to change the design. You'll have to stick with your choices and see how the data look when the results are first revealed (this is known as the "unblinding").

Phase II Unblinding

Time has passed and now your study results are ready. Great news: the data look very good! Next, you and your team plan to conduct a large, randomized, late-stage (Phase III) trial to better understand the potential of this investigational medicine – and potentially submit a new drug application to the U.S. Food and Drug Administration (FDA) for approval.

Planning the Phase III Trial

In your Phase III trial, you can focus on the same patient population as in Phase II, or you can expand your inclusion criteria – and hope that more people could potentially benefit from this investigational medicine.

Moving into Phase III, there's always a chance that earlier results won't hold up in a bigger patient population. Keeping factors like inclusion criteria consistent improves your odds. On the other hand, you're missing an opportunity to see whether your investigational medicine could help a wider range of people... but that's something you could explore later on.

Moving into Phase III, there's always a chance that earlier results won't hold up in a bigger patient population. Changing the inclusion criteria increases these odds by introducing new variations. If the overall study results are negative, it can be difficult to interpret – but positive results may provide a path to helping more people with the disease being treated.

Another important decision to consider is what primary endpoint to use. You can choose to measure the length of time that people live (overall survival), or a surrogate endpoint (a measurement that predicts clinical benefit but can be measured sooner).

You've chosen the "gold standard" endpoint of cancer clinical trials. If your trial is positive, it means your treatment helps people live longer – the ultimate goal when developing potential new cancer medicines. However, in some cancer types, it can take years to measure differences in survival, especially as treatments improve and people with cancer live longer overall. As a result, the FDA has been increasingly open to validated endpoints that can be assessed months or even years earlier. These can include tumor shrinkage (response rates) or progression-free survival (PFS, a measure of how long people live without their cancer getting worse).

Your chosen approach of overall survival may take longer, but a positive result will provide a strong case to support full regulatory approval of your investigational medicine.

The choices you made above represent only a fraction of the complex decisions involved when designing clinical trials. To learn more about clinical trials, check out the related links below.

As treatments continue to improve and people with cancer live longer overall, the FDA has been increasingly open to endpoints that can be assessed months or even years earlier than overall survival. These can include tumor shrinkage (response rates) or progression-free survival (PFS, a measure of how long people live without their cancer getting worse).

Importantly, surrogate endpoints must be validated in each cancer type. Some endpoints like PFS can be considered surrogates in certain contexts but standard endpoints in others.

Your selection of a surrogate endpoint could mean you first receive accelerated (conditional) approval, and you'll be required to confirm clinical benefit in further studies to convert to a full regulatory approval. However, if accelerated approval is granted, people will have access to this new treatment option sooner.

The choices you made above represent only a fraction of the complex decisions involved when designing clinical trials. To learn more about clinical trials, check out the related links below.