Package Inserts' Clinical Studies Section Is More Interesting Than You'd Think

When was the last time you looked closely at the Clinical Studies section of a prescription’s package insert?

All too often, you’re in a rush to open a newly filled prescription, and that pesky, folded piece of thin paper is more of a nuisance than a useful resource. The fact is, the package insert contains a wealth of practical information that might surprise you, and the Clinical Studies section is way more interesting than you might think.

What Information Is in the Clinical Studies Section?

As of 2006, all FDA-approved drugs must have a Clinical Studies section in the package insert.¹ Although it was previously an optional section, many drug manufacturers still provided it.

In most circumstances, it includes information regarding the phase 3 studies the FDA used to approve the medication for each indication. Specifically, it includes information regarding each study’s design, patient population, primary and secondary endpoint, comparators, and results.

To clarify, the studies mentioned within the package insert are usually published in peer-reviewed journals and searchable on PubMed. However, unlike a PubMed search of hundreds or thousands of potential articles, the package insert highlights the specific studies the FDA used to evaluate the drug for each of its indications.

How Can I Access the Package Insert?

Although Drugs@FDA is the official electronic resource for obtaining all documents related to a drug (package insert, approval letters, therapeutic equivalents), it’s neither user-friendly nor timely. Instead, the US National Library of Medicine provides a website called DailyMed, an official provider of FDA package inserts and label information in an electronic, standardized, up-to-date way that makes it easy to review.

What’s So Interesting About the Clinical Studies Section?

Pharmacists can refer to this section to quickly understand key points of the phase 3 trials, including how the efficacy of the drug was measured, what drug it was compared against, and the amount of benefit the drug offered versus its comparator.

Consider the following 3 medications:

1. Diclegis (doxylamine /pyridoxine)

This combination of doxylamine (a first-generation antihistamine) and pyridoxine (vitamin B6) was approved for the treatment of nausea and vomiting of pregnancy (also known as morning sickness).² Because morning sickness is so common, there’s always been considerable interest in identifying medications that are both effective and safe for use in the first trimester of pregnancy.

In examining the Clinical Studies section of the labeling information, the phase 3 trial used for FDA approval was a randomized, controlled (RCT) trial versus placebo. The primary endpoint of the trial was an improvement in the Pregnancy Unique-Quantification of Emesis (PUQE—yes, someone had a sense of humor) score. On the 12-point PUQE scale, Diclegis dramatically improved the score by…0.7 points compared with placebo.

Although the reduction in PUQE score was statistically significant, many would argue that improving a meager 0.7 points out of 12 is unlikely to warrant the cost, pill burden, and adverse effects of a medication. From the perspective of a pharmacist, having this knowledge (especially so readily accessible) could be useful during the patient counseling process to discuss the risks and benefits of the medication.

2. Ranexa (ranolazine)

Used for chest pain (chronic stable angina), this is unique compared to other antianginal medications in that it minimally affects heart rate or blood pressure.³ The package insert highlights 2 studies regarding its angina indication. Compared with placebo, ranolazine increases the amount of time on a treadmill test by about 30 seconds and decreases the number of angina attacks per week by about 1 attack per week.

After examining this drug’s Clinical Studies section, a pharmacist could describe these 2 endpoints to a patient during a counseling session or explain the benefit of the medication for a typical patient to a provider. Some patients or providers may find that 30 additional seconds isn’t particularly meaningful, but having one fewer anginal attack per week could provide a significant change in quality of life for a patient.

3. Uloric (febuxostat)

This xanthine oxidase inhibitor was approved for the chronic management of hyperuricemia in patients with gout.⁴ Its mechanism is similar to allopurinol, but it’s a more potent inhibitor of the xanthine oxidase enzyme.

Its Clinical Studies section describes 3 RCTs comparing the medication with allopurinol. In all 3 studies, patients receiving febuxostat were 25% to 38% more likely to have a uric acid level below 6 mg/dL at the final visit of the study—an endpoint that would suggest superior efficacy over allopurinol.

Interestingly, this section fails to describe the efficacy of febuxostat in reducing acute gout attacks or flares compared to allopurinol. The endpoint regarding uric acid levels is a “surrogate” endpoint for gout attacks—that is, patients with lower uric acid levels should experience fever gout attacks. In reality, though, there was no difference in gout attacks in the febuxostat studies versus allopurinol.

The febuxostat example is particularly relevant because it highlights the fact that the drug manufacturer is responsible for preparing the package insert (and the Clinical Studies section). Although the label information is peer-reviewed by the FDA for approval, the information is at risk for bias, just like phase 3 trials published in medical journals.

For all these examples, the phase 3 trials and other RCTs are usually available in peer-reviewed journals (searchable in PubMed). Although the package insert isn’t a comprehensive view of all clinical data regarding the medication, it does provide a brief snapshot or overview to help clinicians quickly review the trials that the FDA evaluated when deciding whether or not to approve the medication.

When to Supplement with PubMed for More Information

Because the Clinical Studies section in PubMed typically only contains selected phase 3 trials used to evaluate efficacy and safety, you should do PubMed literature search for:

• A comprehensive list of all studies involving the drug;
• Most phase 4 (postmarketing) studies of the medication;
• Most observational or uncontrolled trials of the medication; or
• Full-text articles (not just a summary) of the studies mentioned within the package insert.

As drug experts, pharmacists rely on different tools for drug information. Each tool has strengths and limitations, and the package insert’s Clinical Studies section is no exception. By succinctly highlighting the studies used for FDA approval within a single document, the pharmacist can quickly appreciate the study design, endpoints, comparators, and results that a medication (or drug maker) used to obtain FDA approval.

References

• FDA. Title 21—food and drugs. Chapter 1—FDA Department of Health and Human Services, Subchapter C—Drugs: general. Food and Drugs. Part 201, Labeling. 21 CFR 201.56(b). accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=201.56.
• Diclegis [package insert]. Bryn Mawr, PA: Duchesnay USA, Inc.; 2013.
• Ranexa [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.
• Uloric [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2013.