HOW STUDY DESIGN Impacts FDA Approvals

‘Enrichment strategies’ can help applicants conduct better clinical trials.

By Jerry Helzner, Senior Editor

As part of a new initiative to help facilitate the process for developing new drugs and devices, the FDA recently published a preliminary draft document offering what it called “enrichment strategies” for the conduct of drug-related clinical trials. The goal of the FDA is to assist companies in all areas of medicine conducting clinical trials to create study designs that have the best chance of supporting an approval.

This initiative does not mean the FDA is lowering its standards for approvals. However, the agency is now providing tips on study design for clinical trials that give investigational drugs their best chance of success. The FDA notes it is now inviting comments on the draft document and the agency does not consider the draft a final or complete set of recommendations. The complete draft document is now available at: www.fda.gov/downloads/Drugs/Guidance Compliance RegulatoryInformation/Guidances/UCM332181.pdf.

Why Study Design Matters

Companies and individuals that conduct clinical trials know that study design is critical and can sometimes mean the difference between a successful trial and a problematic one. Many ophthalmologists who have been involved in the invention of new drugs and devices tend to be somewhat secretive, as if they are talking “inside baseball” and don’t want to give too much away to potential rivals.

One ophthalmologist who was co-inventor of a promising retinal drug maintains the drug was on a positive path in early-stage trials until the company that purchased the drug decided to run its own pivotal phase 3 trial without any input from the inventors. The drug showed unimpressive results in the late-stage trial. Eventually the company shelved the drug.

For a more specific example of how study design can make a difference, Regeneron’s pivotal phase 3 VIEW trial for Eylea (aflibercept) wound up comparing a 2-mg dose of Eylea to an 0.5-mg dose of Lucentis (ranibizumab). Given that a larger dose was likely to be more efficacious and with a more durable response, Regeneron had somewhat of an advantage in the head-to-head comparison. A later trial (HARBOR) conducted by Genentech/Roche, the developer of ranibizumab, found that a 2 mg dose of ranibizumab did not have any advantages over the standard 0.5 mg dose.

However, the shoe was on the other foot in the second year of the VIEW trial, when the study design mandated that patients have Eylea retreatment at least every 12 weeks. In this instance, some patients may have been injected more times than they actually needed, and the data may have shown a less durable response from Eylea than a different study design could have demonstrated.

Tips From the FDA

In what may be viewed as a new direction in the FDA’s interactions with industry, the agency is now providing recommendations on specific areas of the clinical trials process. These include encouraging compliance, refining patient selection to reduce non-drug-related variability, and identifying likely responders — all with an eye toward enabling clinical trials to optimize the quality of the data in regard to demonstrating safety and efficacy.

The FDA cautions the guidance it provides describes the agency’s “current thinking” on a topic and should be viewed “only as recommendations,” unless it cites specific regulatory or statutory requirements. The use of the word “should” in FDA guidance “means that something is suggested or recommended, but not required.”

Advice on Compliance

One of the best — and easiest — ways to obtain accurate data from a clinical trial is to ensure the participants are good compliers. The FDA notes that practices such as making patients aware of the conditions and demands of the trial, avoiding too-rapid titration of drugs that could cause intolerable early side effects, using adherence prompts and alert systems, and monitoring drug use have all become standard in clinical trials. However, the agency also cites other innovative methods that can encourage compliance.

For example, in one study prospective trial participants initially received placebo tablets containing riboflavin that caused their urine to fluoresce. When the urine was examined, those patients whose urine did not fluoresce were considered non-compliers and were eliminated from the actual clinical trial. In another long-term study, patients who self-reported poor compliance during an 18-week pre-randomization placebo run-up were dropped. Compliance during the clinical trial was reported at 90% over the five years of the study, greatly increasing its power and justifying the wisdom of dropping those individuals who demonstrated non-compliance during the run-up period.

Refining Patient Selection

The FDA notes the goal of clinical trial patient selection is to create a patient base highly likely to be responsive to the actual treatment undergoing study. This means eliminating other outside factors, such as placebo effect, that might lead to improved results for reasons other than a true response to the test treatment. The FDA suggests that one way to enrich the patient base is to begin with a placebo lead-in period and exclude from the actual trial those patients who show a marked effect from the placebo.

The FDA suggests that study power can also be increased by “defining entry criteria carefully to ensure that entered patients actually have the disease that is being studied and training investigators to adhere to protocol-specified entry definitions and criteria.”

The FDA also recommends decreasing individual-patient variability by enrolling only patients who give consistent baseline values, such as blood pressure measurements and pulmonary function tests. The agency also suggests excluding patients taking drugs that are pharmacologically similar to, or that could interact with, the study drug. Trials should also exclude patients who may not be able to tolerate the drug.

Finally, the FDA recommends excluding from trials patients likely to drop out for non-medical reasons, such as lack of transportation to the study site.

In some trials, the study design may also exclude patients who are elderly, seriously ill with a concomitant disease or already on concomitant therapies. However, the FDA says these exclusions raise concerns that the resulting data could provide too little information about the full range of people who will receive the drug in clinical practice, such as the elderly, people with multiple illnesses and those taking multiple drug therapies.

“The implications of using these (exclusionary) strategies should be carefully considered before they are used,” the FDA cautions.

Identifying Responder Populations

This aspect of clinical trial study design dovetails with the strategies used in patient selection. Here, the aim is to increase the chances of producing study results that demonstrate the actual effect of the drug upon the disease while eliminating outside factors that could make the trial data inconclusive.

The FDA advises using what it calls “predictive enrichment strategies” to achieve this goal. For example, a smaller study population can be used if initial screening techniques identify both likely responder and non-responder populations. The FDA says this approach is “of particular value when responders constitute only a small fraction of the overall population” that may need to be treated.

“Identification of a high treatment-response population greatly increases the chance that a study of an effective drug will be able to detect a treatment effect and allows a study to succeed with a smaller sample size than a study of an unselected population,” the FDA notes in its guidance.

Such a strategy can be useful in early-stage effectiveness studies, the FDA notes, because it can provide clinical proof of concept and contribute to selection of appropriate doses for later studies.

“When the treatment responder population constitutes only a small fraction of all patients, say 20%, (which is common in some diseases), enrichment can permit a drug to show effectiveness when a study of the overall patient population may have difficulty showing any effect,” the FDA states. Clearly, pre-screening potential responders increases the chances of a drug being identified as effective.

A side benefit of this type of pre-screening for responders means that potential non-responders can be eliminated from the trial and be spared any side effects, such as toxicity, that would do them harm.

“For drugs with significant toxicity and a low overall response in a general population — factors that could deter further development — identifying a responder population could make a risk more acceptable and facilitate continued development and approval,” the FDA document concludes.

FDA Focus on Cooperation

Critics of the FDA have long noted that the conditions for the approval of drugs and devices in the United States tend to be much stricter than the criteria used in Europe and Canada. An often-heard criticism is that European regulators tend to approve drugs and devices based on safety alone, while the FDA insists on proof of both safety and efficacy.

Critics contend that as long as a drug or device is safe, it should be up to the practitioner’s discretion as to whether to use it or not. Alan Aker, MD, advocated this type of FDA approval process for ophthalmic technology in a guest editorial in in the April 2012 issue of Ophthalmology Management. “Why can’t products being safely used by our colleagues in Europe also be used by US ophthalmic surgeons?” wrote Dr. Aker. Critics of the FDA approval process, including Dr. Aker, have also predicted that industry-discouraging FDA policies may cause the medical device industry to move overseas, with patients having to go abroad to receive cutting-edge treatments.

Other critics, including Fred Hassan when he was CEO of Schering-Plough, have in the past criticized the FDA for being generally slow to approve drugs while causing delays by requesting additional data. They contend that the FDA became more cautious after the painkiller Vioxx recall.

The willingness of the FDA to now publish suggested guidance for the conduct of clinical trials goes along with its recent establishment of a public/private partnership to exchange ideas on creating “best practices” for facilitating drug and device development. These two breakthroughs in FDA thinking are likely to be welcomed by both practitioners and industry once they become more aware of the existence of these new initiatives. OM