Talking with Issam Zineh, PharmD, MPH, FCP, FCCP, who is the director of the Office of Clinical Pharmacology, Office of Translational Sciences, CDER.
All drugs inherently carry risks. During development, drug makers test their investigational drugs to identify risks and benefits, and work to minimize the risks – including those posed by drug-drug interactions. Still, major adverse drug interactions are preventable causes of morbidity and mortality. Issam Zineh, director of CDER’s Office of Clinical Pharmacology, further highlights how drug interactions affect patients, and how FDA addresses the issue.
What is a drug-drug interaction? Does this apply to supplements, vitamins, or certain foods, as well?
First, it is important to consider how most drugs work. A medication is taken by a patient, gets absorbed into the bloodstream, and is distributed into different tissues or target organs where the drug exerts its pharmacological effect. The drug is also metabolized and excreted as part of bodily processes that clear it.
A drug-drug interaction occurs when the co-administration of two or more drugs alters any of these processes. Taking interacting drugs together can potentially delay, decrease, or enhance absorption, affect a drug’s pharmacology at the target, or influence drug metabolism or excretion. As a result, this can decrease or increase the action of either drug or both drugs, or cause adverse effects and unintended consequences.
Certain foods, vitamins and supplements can also interact with medications. The potential effect of food on a drug product is routinely evaluated in drug development, and we are currently in the process of revising a guidance on that topic. Supplement-drug interactions are increasingly being scrutinized in the research setting because supplement use is fairly widespread.
Who is at risk for drug-drug interactions?
Anyone who is taking more than one drug is at risk. Some populations are at higher risk, such as older adults who typically take more than one medication for chronic conditions, and people who take multiple drugs as part of standard treatment regimens for certain diseases. People who take supplements along with prescription drugs are potentially at risk, depending on the supplement being taken.
Why is it important to assess drug-drug interactions? What happens when drugs interact?
When we take medications, we expect them to work in a predictable way. If drugs are interacting, there are a few potential consequences. First, the risk-benefit balance can be altered. If a drug interaction results in an increase of the concentration of a drug, the risk of side effects could be higher. If the interaction triggers faster clearance of the drug from the body, then you may not be getting the appropriate therapeutic benefit.
How many people are taking more than one drug? Who should be most concerned about drug-drug interactions?
Data from the Centers for Disease Control and Prevention’s (CDC’s) National Health and Nutrition Examination Survey tell us that about 20 percent of U.S. adults are taking three or more drugs, and likely, the prevalence is higher when we consider the number of patients taking two or more drugs. Among adults age 65 and older, 40 percent are taking five or more medications. These older adults, who are typically taking multiple medications for multiple conditions, are among those at highest risk for drug interactions, though it is important to note that serious drug interactions can happen to anyone.
There is extensive effort to try to understand how many people are taking supplements. We know from work conducted by the National Institutes of Health, the CDC and others that a significant portion of the population has used complementary and alternative medicine (CAM) at some point, and that women are more likely than men to use CAM. In research published about 10 years ago, we found that even among fairly healthy volunteers, about half were taking CAM, and that there was potential for interactions with prescription and over-the-counter medications. We also learned that few people were asked by their physicians if they were taking any supplements or vitamins.
When and how do drug makers evaluate a new drug’s potential for drug-drug interactions? What types of studies are conducted?
In vitro studies are conducted early in the process to assess the investigational drug’s metabolism pathways. This knowledge helps inform whether a clinical drug-drug interaction study is needed. Many companies consider drug interaction liability when making a decision to move forward with an investigational drug. For example, if a compound is known to be susceptible to major drug interactions, the company might decide to de-prioritize that compound.
Ideally, clinical drug interaction studies are completed before phase 3 clinical studies, but not always. For instance, if there is a high unmet medical need among a certain population and a push to make a promising new drug available, some drug interaction data may not be collected until after drug approval. This is more common if the drug has Breakthrough designation, which expedites the development and review of the drug. In these situations, a drug company may be required to conduct post-marketing studies to identify drug interactions and other serious risks.
What types of drugs have been pulled from the market after post-approval data showed problems related to drug-drug interactions?
A wide range of drug classes have been pulled from the market or withdrawn post-approval due to drug interactions that increased risk for some serious adverse drug event. For instance, the antihistamines terfenadine and asteminzole, the gastrointestinal drug cisapride, and the cardiovascular drugs cerivastatin and mibefradil, were all pulled after post-approval data revealed serious interaction problems that led to potential life-threatening adverse reactions. In the post-approval setting, the risk became amplified and eclipsed the potential benefits.
How does the agency communicate information about drug-drug interactions?
FDA communicates drug interaction information in a variety of ways. Drug labels include several sections that address this issue. First, the “drug interactions” section lists clinically relevant drug interactions and how to manage them to minimize the risk. Second, the “clinical pharmacology” section describes the nature of the in vitro and clinical studies that served as the basis for the clinical recommendations. Other high visibility sections, such as “contraindications” and “warnings and precautions,” may include important drug interaction information if they are serious enough.
For drugs with interaction issues that are of high consequence, we can communicate directly to prescribers with targeted “dear healthcare provider” letters. We can also distribute information through drug safety communications, and via the subscription-based Clinical Pharmacology Corner, an e-newsletter.
New draft guidances for drug makers on how to best evaluate drug-drug interactions are now available for comment. What do the guidances provide?
FDA has issued two draft guidances that replace one older guidance from 2012. These complementary guidances have been updated to reflect our current thinking and create some alignment among international regulatory agencies, in particular with the European Medicines Agency and Japan’s Pharmaceutical and Medical Devices Agency. The first guidance provides drug developers with a framework for assessing drug interaction potential using in vitro data. The guidance describes the thresholds at which in vitro results may trigger a need for clinical studies to further understand potential drug interactions. The second guidance speaks to the importance of clinical studies from a public health perspective. It describes the necessary timing of the studies, and provides advice on study design, interpretation of data, and communication of the results.
The guidances are available for comment until January 28, 2018.