Not all studies are created equal

We’ve all heard that clinical trials are the gold standards of research. They have such favorable reputations, many consumers, media and healthcare professionals readily believe their findings are gold, too. But clinical trials are not all created equal. They come in different flavors and most being conducted today don’t merit us personally acting upon.

A recently released investigative report revealed that some companies are using our naivete about clinical trials as a loop-hole to sell therapies and drugs while avoiding the expense of the phase III trials required for FDA approvals. Especially tragic, countless numbers of people are bravely volunteering to participate in phase II trials believing they’re helping others suffering from their same disease and contributing towards the benefit of science, when, in fact, many times the researchers already know the trials will never go anywhere towards developing a credible therapy, but doing the study will bring themselves and their universities money and notoriety.

Phases 1-2-3

Before we delve into this story and its powerful significance, it’s imperative that we understand the different types of clinical trials because each has very different purposes, holds different levels of risks for the study participants, and answers different scientific questions.

Carol Rados wrote a good introductory overview for FDA Consumer Magazine a few years ago titled “Inside Clinical Trials — Testing medical products in people.” As she explained:

Clinical trials...test potential treatments in human volunteers to see if they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine, blood product, or gene therapy... Although "new" may imply “better," it is not known whether the potential medical treatment offers benefit to patients until clinical research on that treatment is complete. Clinical trials are an integral part of new product discovery and development, and are required by the FDA before a new product can be brought to the market.

She went on to discuss who can participate and what happens in a clinical trial, including the different types of trials and what they do, the risks and how people are protected. For some patients, participating in clinical trials can also offer them the best quality of care for their disease, said Rados. And for those with serious, life-threatening conditions, there are investigational drug trial provisions to give access to investigative treatments that may offer them the best chances. Rest assured, there are a number of safeguards in place to help protect people from undue risks for harm, look out for their rights and welfare, verify the quality and integrity of study data, and monitor for adverse effects that would not be in the best interests of the participants to continue.

The National Institutes of Health goes into more detail about clinical trials at clinicaltrials.gov and the FDA/Center for Drug Evaluation and Research describes the drug development, review and approval processes in their CDER Handbook.

Basically, clinical trials can be testing treatments (new drugs or drug combinations, new approaches to surgery or radiation therapy), preventions (testing medicines, vaccines, or interventions to prevent diseases), diagnostics (tests or procedures to diagnose a disease or condition), screenings (detect for certain diseases or conditions), or supportive care (improve comfort and quality of life for ill patients).

The development of a new medical treatment happens in phases.

A Phase I clinical trial is the very first introduction of an investigational new drug or treatment in humans. These studies are done on a small group of people (20-80) to determine a drug’s metabolic and pharmacologic actions in people, the active dose, initial risks and side effects, and gather enough evidence to justify the design of a scientifically valid phase II trial.

A Phase II trial is the initial study to gain preliminary data on the possible effectiveness of a drug or treatment for a particular indication or to see if it acts on a specific disease or condition. It also looks for common short-term side effects to help evaluate a drug’s initial degree of safety. It is conducted on a slightly larger group of people (50-300).

A Phase III trial is done after a phase II suggests some effectiveness for a particular condition. A phase III trial is conducted on a larger group of people (1,000-3,000) more representative of end users, to evaluate if a drug is effective and works better than current standard treatment over a period of time, and also that it has an overall favorable benefit-risk ratio. These findings are submitted to the FDA to get approval for marketing and labeling requirements.

A Phase IV trial is a study occasionally done after a drug has been on the market to learn more about its longer-term risks, benefits, and optimal use.

So, you can already see that if you hear glowing reports of a phase II trial showing that a new drug “works” for a certain condition, that’s still years away from proving it is a safe and effective treatment for a condition, works better than current care, and most importantly, that any benefits appear to reasonably outweigh the risks.

Phase III trials rarely materialize

Canadian researchers recently reported in the Journal of Clinical Oncology their review of 200 phase II clinical trials presented at American Society of Clinical Oncology (ASCO) meetings in 1995-1996. They found that ten years after 100 presented favorable results in phase II trials for five different cancers, only 13 treatments (13%) had ever gone on to be tested in phase III trials. Yet these larger, randomized trials are needed to get FDA approval to bring a new drug or treatment to patients.

Of 100 phase II trials presented last year, only 10 investigators said they’d planned to undertake a phase III trial and only 8 said they had the resources to do so. The reasons given for not planning phase III studies included lack of financial support and lack of support from the drug companies (drugs supplied), insufficient efficacy of the trial and not enough patients to enlist. “Many of these limitations are known when planning the phase II study,” wrote the authors, “implying that many phase II trials are not planned as precursors of phase III trials. Resources spent on such trials would be better applied to practice-changing phase III trials.”

This week, Health Day reported on the important implications of these findings:

Study Questions Dead-End Cancer Clinical Trials

...In many cases, the researchers conducting the phase II effort knew beforehand that, due to financial or other constraints, a phase III trial was unlikely....[raising] the troubling question of why the phase II study was done at all. “If all of this effort in supporting phase II trials doesn't go anywhere, it means that the patients included — and the efforts of their doctors — could have been spent in finishing potentially practice-changing phase III studies," said the study's lead author, Ian Tannock, professor of medical oncology at Princess Margaret Hospital and the University of Toronto, Canada.... Given the scarcity of both money and willing volunteers for cancer research, “a phase II trial shouldn't even be started unless there is an intention — if the phase II results look promising — to take it forward," said Tannock...

So, why the wasted time, money, and effort for research that the investigators suspect will go nowhere? Tannock believes that, in many cases, the researchers' career goals may have come first. “There's a lot of young oncologists out there, and they are encouraged to publish," he explained. “Their promotion at academic centers is dependent on publication. So, many of them may be encouraged to put together a protocol in which they take new drugs and treat a small number of patients with a certain disease in a phase II trial."

Because the teams that conduct phase II trials are smaller, a young researcher is more likely to be listed as the prestigious “lead researcher." This gains researchers more recognition than if their name is buried among the much-longer list of authors that typically accompanies phase III studies, Tannock explained.

University and research centers benefit from the recognition, as well. In contrast, most phase III trials (especially for rarer conditions), because they involve larger groups of subjects, are usually conducted at multiple centers and headed by leaders in the field.

“It is clearly impossible for a young investigator to run a large phase III study," Tannock noted. “And they just don't get the academic kudos for entering patients into a potentially practice-changing phase III study that they do from running a 20-patient phase II study." Tannock believes that most young researchers do not “consciously" seek to begin a dead-end phase II trial, “but I think the system encourages it."

Promises that may not deliver

The significant revenue generated by conducting trials for pharmaceutical and medical supply companies also proves an irresistible incentive. According to research by Dr. Bruce Hillner, professor of medicine at Virginia Commonwealth University, “the depth of financial entanglements with the pharmaceutical industry” is more rampant among American faculty and university research centers than in Europe.

But he revealed a troubling way some drug companies are using promising results from small phase II trials: “to encourage doctors to use an already FDA-approved drug 'off-label' for another purpose.” As Health Day reported:

In this way, the company boosts drug sales while sparing itself the expense of the multimillion-dollar phase III trial that's required for new agency approvals... In many cases, researchers simply label their results “encouraging" or “positive," but never compare them to outcomes seen with currently available drugs or treatments. “They compare it to a straw man, just saying ‘this looks great,’” Hillner said. “This failure to define a benchmark is a major reason why many of these reports are just short-term fireworks.”

The take-home message for all of us whenever we hear the results of a clinical trial, is to take care to learn if the study was a phase I, II or III trial and to especially not get caught up in “exciting” results reported from phase II trials. As Dr. Tannock said: “The literature is replete with things that looked very good in phase II but did not prove to be any better than standard treatment in phase III. You have to be careful.”