5 Tips for Developing a Successful Research Protocol

Jan 30, 2015

Perspective from the ASCO/AACR Methods in Clinical Cancer Research Workshop

By Kathleen Mahoney, MD, PhD, Beth Israel Deaconess Medical Center

When invited to write about my perspectiveon the ASCO/American Association of Cancer Research (AACR) Methods in Clinical Cancer Research Workshop (often called the “Vail workshop” due to its location in Vail, CO), I was a bit hesitant to accept, having completed the workshop less than 3 months before. However, as a participant, I believe this workshop was an excellent program and an intensive means of improving my skill in the process of protocol development. I took away some valuable lessons that can benefit any researcher developing a protocol.

1. Think Big
At the workshop’s opening presentation, we were encouraged to “think big.” Cancer clearly is a big problem. In a field where a few months of benefit can result in U.S. Food and Drug Administration (FDA) approval for medicines that cost thousands to tens of thousands of dollars for treatment, we need to do better for our patients. Developing cures and finding clinically meaningful benefits takes collaboration, it takes thinking outside the box, and it takes thinking big.

My field of interest is immune therapy for genitourinary cancers. Over 20 years ago, interleukin-2 was FDA-approved for the treatment of renal cell carcinoma, and a few years later for melanoma, because of its ability to produce complete and durable remissions for a small subset of patients. Over the course of my clinical training, I have witnessed a paradigm shift in the acceptance of immunotherapy across the field of oncology with the development and success of the immune checkpoint inhibitors, starting with anti-CTLA-4 blocking antibody (ipilimumab, FDA approval in 2011) and continuing with the anti-PD-1 blocking antibodies (including pembrolizumab, FDA accelerated approval in 2014). Hopefully, future research will lead to complete and durable remission not only for more patients with melanoma and renal cell carcinoma, but with many other cancers as well.

It is important to realize that “big” does not have to mean “new.” For example, the CHAARTED trial presented at the 2014 ASCO Annual Meeting was practice-changing, and used an FDA-approved therapy for prostate cancer in a new context. This trial compared 6 cycles of the standard chemotherapy initiated “up front” with androgen deprivation therapy (ADT) to the standard-of-care ADT alone in men with a high volume of metastatic castration-sensitive prostate cancer. The trial was amended to include patients with low volume of disease because of low accrual. However, the interim analysis revealed a 17-month difference in overall survival with early cytoreductive chemotherapy in men with extensive metastatic prostate cancer (median overall survival: 49.2 vs. 32.2 months; hazard ratio 0.60, 95% CI 0.45, 0.81; p = 0.0006).1

We are at the start of our careers in oncology. Despite upcoming changes in the practice of medicine and dwindling research funding, this is an amazing time to build on the biologic advances made over recent decades in the fight against cancer.


Kathleen Mahoney, MD, PhD
Institution: Instructor of Medicine, Hematology Oncology, Beth Israel Deaconess Medical Center
Member since: 2012


2. Be Specific
Even when thinking big, you cannot lose sight of the importance of hypothesis-driven research.

Just two days after we were encouraged to think big, Dr. Brian Rini’s take-home message was, “You get one good and realistic question to ask and answer in a phase II trial.” Your primary endpoint is the answer to the one question you are asking. While you can pursue additional questions with your secondary endpoints, they should be realistic, focused, and limited in number. Across our small group’s faculty, there was agreement that it is easy to kill a protocol by trying to answer too many questions in a single study.

3. Do Your Homework
Whether you are defending your idea in the setting of this workshop or writing the background for your protocol or the consent form, know the literature and be able to clearly explain the rationale for your proposal.

A cohesive background should lay the foundation for your well-organized aims and endpoints. This facilitates the review process for your institution’s Scientific Review Committee (SRC) and Institutional Review Board (IRB). While the core responsibility of obtaining patient consent lies in the hands of the consenting physician, this recommendation extends to the patient consent form as well. When reading a consent form, it should be clear to the patient what they are volunteering to be a part of and why they should want to be involved in the clinical research study.

4. Take Criticism Constructively
This workshop was an excellent opportunity to get many opinions and receive constructive criticism on how to strengthen my protocol. Whether you reach outside of your institution or within your institution, even the harshest of criticism often can be constructive. Redefining the target population can speed accrual, minimize competition with ongoing trials, or expedite FDA approval for a subset of patients with an unmet clinical need. Narrowing the primary objective or changing the endpoints of a study may better define the most relevant clinical outcome for patients. Be open to incorporating criticism constructively, particularly as it can often strengthen the final result.

5. Pick a Good Mentor(s)
This is arguably the most essential step in the process of developing a successful protocol.

Selecting a good mentor is important for facilitating the entire process of trial development, from defining your investigator-initiated hypothesis, to gaining access to pertinent pharmaceuticals, to determining what other clinical trial may compete with your study, to assessing whether your site has sufficient patients for accrual or whether other sites will need to be included to complete the trial. I found that having an experienced and available mentor was extremely practical in being able to incorporate constructive criticism into my protocol during the Vail workshop and to move the protocol forward after the workshop was over.

1. Sweeney C, Chen Y, Carducci MA, et al. J Clin Oncol. 2014;32:5s (suppl; abstr LBA2).

In addition to my clinical research mentor, David F. McDermott, MD, I would like to thank the wonderful physician and statistician faculty at Vail, who were so generous with their time and energy. I am particularly grateful to the faculty within my small group: Brian I. Rini, MD, Michael T. Lotze, MD, Tatiana M. Prowell, MD, and Vivian K. Weinberg, PhD.


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