Sometimes it seems like new drugs suddenly appear like magic. Have you ever wondered if there was something special going on behind the scenes? Earlier in Clinical Trials for Beginners, we looked briefly at why drug studies came into being, then at how a drug is developed, from test tube to your tissues. Let's take a look behind the hype and the hoopla, at the hard work and the drudgery that create the magic.

Whether a drug is being developed by a pharmaceutical company, a small government grant, or an individual physician or institution, all studies have traditionally followed a basic "recipe" of a protocol. This is akin to Atul Gawande’s checklist, to make sure that all essential elements are present and that nothing is overlooked.

One recent development is the rise of "citizen science" groups. There is often some tension between traditional scientists and these advocacy groups, nicely summarized by Kent Bottles. On the one hand, the scientists tend to view the citizen groups as lacking rigor. On the other, advocates provide the perspective and sense of urgency that can be an impetus to overcoming bureaucratic obstacles. The importance of advocacy groups in translational research—making the link between basic science and useful applications for patients—is well-illustrated by the PXE International organization.

The ingredients for a typical research protocol include:

An introduction: What is the illness you are targeting? Why do we need this drug?

Objectives: Why bother conducting this trial? Are you looking at understanding basic disease processes and mechanisms of action or studying the effect of specific interventions? As explained earlier in “Phases of Drug Development,” basic clinical research elements are most likely to be addressed in phase 1 (safety and pharmacokinetics) and phase 2 (safety and efficacy) trials. Phase 3 trials are intended to be the definitive efficacy trials. By phase 4, the objective is more likely to show that “My drug is better than your drug.”

Trial plan: How large is this trial? What type of population is targeted (e.g., diabetics, patients with a specific kind of cancer)? How many arms, or treatment groups, will the study include?

Inclusion and exclusion criteria: What is your definition for the group of people who have the disease you want to study? This definition should clearly eliminate those groups that may confuse the outcome and hurt your chance of a successful trial. Careful diagnostic criteria are critical to successful study design.

Study design and methodology: What exactly are you going to do with the volunteer patients, and when?

The Power of Numbers

Some studies even have a built in “circuit breakers.” These safety features are designed to catch unintended adverse effects early on by having a Data Safety Monitoring Board (DSMB) monitoring the study. On May 31, 2002, the Women’s Health Initiative, a federal hormone replacement trial with 16,000 participants, was unexpectedly stopped when the DSMB analyzing the response of the participants found a small but significant—8 more women per 10,000 participants per year— increase in the risk of breast cancer. This was seen among the women who had received estrogen and progesterone hormone replacement therapy for more than 5 years. There were also small increases in the incidences of heart attacks, strokes, and blood clots. However, the DSMB found a similarly reduced number of colorectal cancers and hip fractures during this period.

An estimated 6 million women take estrogen-progesterone either for menopausal symptoms or to prevent osteoporosis. Although they have taken these hormones for decades, this was the first study to examine the outcome of that therapy in a careful, controlled, scientific manner. The findings would not have been possible without this being a huge multicenter trial with oversight by DSMB.

Treatment termination criteria: What end points, or outcome, will you establish for ending the study, based on both safety and efficacy? A statistician often determines the end points.

Adverse events: How will you define and report adverse events?

Laboratory procedures.

Administrative section: How will you delineate the responsibilities of the site, the sponsor, the CRO, the regulatory agencies, and so on?

Statistical plan: What is the trial’s rationale in terms of mathematical justification or validation? The statistical plan also helps determine how many patients are needed (how large the trial itself must be) to show any differences in outcomes between treatment groups. (See Darryl Huff’s How to Lie with Statistics for a good introduction to this topic.) For a more sophisticated introduction to medical statistics, take a peek at Marya Zilberberg’s Between the Lines; it’s a well-done primer.

Study personnel list.

Informed consent template.

Now that we have the framework of the protocol, we need to add the patients. Having the right mix of patients is essential to the success of any protocol. In the inclusion criteria, you need to define the illness being studied carefully to make sure that you are selecting a population that can provide the answer to the central question asked by the study.

The exclusion criteria, in addition to excluding patients who do not have the illness in question, further refine the patient pool. Exclusion criteria generally include protection for patients:

Who are allergic to the study drug.

Who are at risk for serious adverse events due to the study drug interacting with their other medications.

Exclusion criteria also serve to protect the protocol integrity by excluding patients:

Who are too ill to demonstrate a benefit from the study drug.

Who have other underlying diseases or need treatments that would seriously interfere with evaluation of the study drug’s efficacy or safety.

Who have received medication for the same condition without an adequate washout period, which is a period of time that a patient does not take a drug for the condition being studied. This is to ensure that all of the first drug’s effects are eliminated before the patient begins the new treatment, so any changes from the newly introduced study medication can be clearly attributable to it.

A more detailed example of a protocol's elements and templates are available through the NIH, for those who like immersing themselves in extremely obsessive detail.

Seals of approval

As the elements of a protocol are being finalized by the sponsor, before implementing a study, the sponsor may turn to the FDA for assurances that its plan is sound and to improve the likelihood that a study’s results will later be accepted by the agency and that the study will not have to be repeated due to a design flaw. Then the protocols are sent to each site that will be conducting the trial, as each protocol requires approval at the local level from the Principal Investigator and from a number of different departments at the sites. For example, contracts will need to be reviewed by the grants office and legal departments, particularly if the site is a large hospital or university. The nursing department and pharmacy will want to be sure that the protocol requirements won’t strain their staff excessively.

Additionally, an approval is required for each site conducting the study by an institutional review board. The IRB is a committee that must review and approve each protocol for safety and ethical considerations and each volunteer informed consent form for clarity, accuracy, and completeness. The IRB must include at least five members of diverse backgrounds, including a layperson and someone not associated with the institution (organization). There are extensive requirements for IRBs that we’ll address later.

The IRB is unlikely to be allowed to modify a pharmaceutical company’s protocol as this would affect every other study site; instead, the IRB may reject a protocol’s application for its own site. This is more likely to happen on investigator-initiated studies, especially if the IRB has any concern about the scientific validity of the proposal. The IRB can, however, insist on wording changes to the sponsor’s volunteer informed consent agreement, as the IRB’s primary responsibility is to ensure patient safety.

We’ve talked a bit about the elements needed for a successful protocol and the considerations in selecting participants. Next, we’ll talk about how the ingredients are mixed, or study design.



Dr. Alex Fleming and 240 vol NDA from FDA

Clinical Trial Participants image from NIH

“Molecules to Medicine” banner © Michele Banks

This post is adapted from my book, Conducting Clinical Research: A Practical Guide for Physicians, Nurses, Study Coordinators, and Investigators.