Pivotal Clinical Trials: Frequently Asked Questions (Sofpromed).

What is a pivotal clinical trial?

A pivotal clinical trial is a clinical study seeking to demonstrate the efficacy of a new drug in order to obtain its marketing approval by regulatory authorities (e.g. FDA in the United States and EMA in Europe).

Why are pivotal clinical trials important?

Pivotal clinical trials (also known as “registration studies”) are very important because their results will be evaluated by regulatory authorities to decide whether or not a drug shows the safety and efficacy required to be approved and commercialized.

What is the main general goal of a pivotal clinical trial?

Normally, the main goal of a pivotal clinical trial is to demonstrate that a new experimental drug has better efficacy than another drug currently used as standard of care. 

For this reason, pivotal studies are “randomized”, meaning that patients are randomly assigned to an experimental arm (new drug) or to a control arm (current standard drug), to compare both treatments.

Is a pivotal clinical trial the same as a phase 3 study?

Pivotal clinical trials are normally phase 3 studies. However, a pivotal trial may not always be phase 3, since (exceptionally) phase 2 studies could also be utilized as pivotal trials.

What are the main challenges of pivotal clinical trials and what errors should be avoided?

Pivotal clinical trials imply various challenges. Adequate endpoints, well-defined populations, patient recruitment potential, and operational efficiency are particularly critical aspects.

Adequate endpoints

Endpoints are the variables used to measure the safety and efficacy of a drug tested in a clinical trial. For example, a typical endpoint in oncology studies is progression-free survival (PFS); essentially the time during which the tumor has not worsened.

Trial sponsors must be very careful when selecting the main endpoint of the trial, which conditions the entire study design (i.e. the sample size is calculated using the primary endpoint).

The primary endpoint of a trial must be relevant for the patient, clinically meaningful, and objectively measured without bias.

Defining irrelevant, inadequate main endpoints in the study protocol may mean that the trial results will not be suitable to rightly assess the efficacy of the drug, which is of course a big problem for drug approval.

In order to ensure appropriate and meaningful endpoints, sponsors planning pivotal trials should obtain advice from clinical experts in the specific disease they are targeting.

The reader is encouraged to check the article “Improving the Design of Pivotal Clinical Trials” for further information on pivotal trial design considerations.

Well-defined populations

The correct definition of the eligible patient population is another key element when designing a pivotal trial.

An excessively heterogeneous patient population should be avoided, since heterogeneity (patient with too different characteristics) will decrease the robustness and consistency of the results.

This is particularly important in cancer trials with different tumor subtypes. Sponsors should target specific histologies with very specific inclusion criteria, in order to ensure consistent outcomes and conclusions.

Patient recruitment potential

Patient recruitment can be a major challenge in pivotal trials, since these types of studies may enroll a very large number of subjects.

Without doubt, guaranteeing sufficient enrollment potential is particularly crucial in trials testing drugs in rare diseases.

The rarity of a disease (few eligible patients) forces the sponsor to involve several countries in order to reach the sample size in the planned recruitment period.

How can sponsors ensure enrollment potential in infrequent diseases? 

Enrollment feasibility questionnaires should be carefully designed and reviewed in depth before study initiation, asking sites to be realistic about their recruitment forecasts.

In addition, if the study has to involve many countries due to the rareness of the disease, sponsors should select expert hospitals centralizing eligible patients in the country.

Not paying enough attention to patient recruitment viability in the early stages of the study can have costly consequences. 

Operational efficiency

Pivotal trials will require a large number of patients, sites, and countries, which increases operational complexity.

Dealing with different hospitals and countries with different regulatory rules and policies poses a challenge for overall clinical trial management efficiency.

In order to cope with the administrative, regulatory, and technical complexities of large international pivotal studies, sponsors should select appropriate Contract Research Organizations (CROs) able to manage such demanding projects.

Principles for optimizing operational efficiency in trial management include using as less vendors as possible, hiring CROs with proven expertise in the specific disease under study and able to cover multiple countries, and setting up cost-efficient web-based systems (e.g. eCRF, eTMF, imaging platforms for central CT scan/MRI reviews), among others.

What protocol design considerations are critical in pivotal clinical trials?

Some of the most critical aspects of a pivotal clinical trial protocol are the primary clinical objective/endpoint, the statistical design (sample size calculation), the inclusion/exclusion criteria, and the treatment scheme.

The primary objective/endpoint determines the main variable to assess whether the study result is positive or negative.

In connection with the primary endpoint, the sample size calculation specifies the number of patients needed to evaluate such main endpoint.

The inclusion/exclusion criteria defines the characteristics of the subjects to be treated in the trial.

Finally, the treatment scheme describes how the study drugs are administered, proposing the experimental drug administration dose and sequence with the best chances of success. 

How many sites are normally required in a pivotal clinical trial?

The number of clinical sites required to conduct a pivotal trial will greatly depend on the number of patients needed and the level of difficulty to find such patients. 

In oncology, pivotal trials may involve anywhere between 30-90 sites (even more).

How many patients are normally recruited in a pivotal clinical trial?

The number of patients (sample size) to be recruited in a pivotal trial may vary a lot across different therapeutic areas. In sarcoma clinical trials, for instance, typical sample sizes of pivotal studies may be in the range of 350-500 participants. In other diseases, a pivotal trial can include more than 1,000 patients.

What is the duration of a pivotal clinical trial?

The duration of a pivotal clinical trial is highly dependent on the number of patients to be enrolled and the accrual rate of the study. In average, pivotal trials in cancer may have enrollment periods of 2-3 years.

Can a drug be approved by the FDA based on the results of one single pivotal clinical trial?

Yes, a drug could be approved by the FDA only based on the results of one single pivotal study.

The following article provides an interesting discussion about drugs approved with one single trial: “Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies”.

How much does a pivotal clinical trial cost?

Please refer to the article “How Much Does a Clinical Trial Cost?” to learn about clinical trial costs.

Which clinical research organization (CRO) should I choose for my pivotal clinical trial?

Please refer to the article “How to Select a Clinical Research Organization (CRO)” to get advice on CRO selection.

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