The U.S. Food and Drug Administration (FDA) recently issued a revised Pregnancy Lactation Labeling Rule (PLLR) after 35 years of rating medication safety for pregnant and breast-feeding women with the traditional lettering scale: A, B, C, D, and X. The new PLLR eliminates the letter categories, and now requires more detail about pregnancy registries, risks, clinical considerations, and supporting evidence.
Anything new requires a little time to adjust to change. And many healthcare professionals still aren’t clear on how the new labels will work. Here, Drs. Michael Schatz, Christina Chambers, and Allen Mitchell – three stakeholders from the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) program – answer some of your questions:
Q: The new PLLR is only being applied to drugs approved since June 30, 2001. But what about medicines approved before 2001? Will there be nothing on their labels once the letters go away?
A: It is hoped that the bully pulpit of FDA and the needs of the rest of the field will motivate those manufacturers with older products to populate labels with what data are available once the letters have completely gone away. Older products, unfortunately, may not be more likely to have huge amounts of data available than some of the newer products, so they're in the same sort of dilemma. And it's critically important, as they may be some of the most commonly used products, for those data to be developed. So, the hope is that, with encouragement, products approved prior to that cutoff date will move in the direction of changing the label format to be consistent and harmonized with the newer format.
If providers and patients demand this kind of information from the manufacturers, they will feel there's a real need out there for conducting studies or gathering the data needed to populate the label.
Q: Is there a requirement for regular updates to the labels?
A: Yes. However, it's going to be interesting to see how it’s carried out. It's very encouraging that new data will be included in the label if it will change what the general direction of the risk summary would be. We just don’t yet know how it will be done.
Q: How does the new PLLR take into consideration gestational age of pregnancy?
A: The fact that risk may vary with gestational age of pregnancy is one of the major reasons for getting rid of the letter categories. The letter categories tended to be applied as if that designation were relevant whether or not the drug was taken in the first trimester or only in the third trimester, etc. But under the new PLLR, the risk summary and supporting data categories will indicate timing of exposure and the outcomes that are relevant to that timing of exposure. That will be one of the major improvements in going to this new label format – that it actually can and should address the timing of exposure during specific periods of pregnancy.
Q: Is any of this updated information available now?
A: Some currently labeled drugs are already in the new label format. Some manufacturers have voluntarily gone to the new label format, knowing that it was coming.
Certainly data have existed that aren't included in the current letter-category labels. So, the new labels will include more of those existing data and how they relate to supporting the risk summary. But it still doesn't take away the critical issue that more data need to be generated and that the commitment of the VAMPSS organization to be able to do that is critical and going to become even more glaringly apparent when the old label categories are not there anymore.
Q: What about the ethical issues of conducting clinical research on pregnant women? Are there ways to obtain some of the missing information, such as studying the relative safety of patients who have already been exposed, so that the researchers are not responsible for their exposure?
A: The only time that pregnant women are deliberately included in pre-marketing randomized clinical trials, or, for that matter, post-marketing trials, is when there's a drug that's specifically indicated for use in pregnancy. And even in those studies, the trial sizes range from 200-300 or fewer, really just large enough to identify efficacy, but they couldn't possibly be large enough to identify safety. So, it's not just the ethical constraint, which is enough, but there's also a limitation in statistical power that requires that we do observational studies for these outcomes. Since observational studies are based on actual practice, researchers are not responsible for the exposures.
Even though there are some people who are pushing to have more clinical trials done, that's probably not going to be the primary source of information. Because observational studies are both ethical and can be statistically powerful (and therefore highly informative), they are going to continue to be the primary source of information, and it's our ethical responsibility to actually do those studies.
Q: Will there be pregnancy/lactation label-style information that can be obtained regarding illicit drug exposures or for marijuana in the increasing number of states with legal marijuana?
A: Although there are no pregnancy labels for non-FDA regulated drugs, there is information available and ongoing research related to the risks of illicit drugs and marijuana in pregnancy and lactation. This is also an incredibly important group of exposures to consider as confounding factors when studying the safety of prescription drugs – and this information is largely absent in many sources of data that are used to study the safety of prescription medications. Clearly, this is not information one would likely get from the medical record. Women may be reluctant, even under circumstances where marijuana is legal, to volunteer that they've smoked or ingested marijuana, let alone opioids and other illegal drugs. But, as is done in VAMPSS studies, if you talk to the mother in a way she feels confident that the information can be provided confidentially and you get a volunteered response, it's reasonable to conclude that it’s an accurate response. We also need to consider use of ADHD drugs, which are often shared with others than the person to whom they were prescribed.
VAMPPS data systems are capable of capturing uses irrespective of the source of the medication. So, for some drugs that are sort of in the gray zone in terms of reporting, we find that mothers are quite willing to share the fact that they've taken methylphenidate, for example, or Adderall, where they might not reveal that information to their physician.
Q: What reference materials will be available for pharmacists to provide information to physicians?
A: The physician can get the summary information from the new label, of course. Pharmacists might also use references like Briggs’ Drugs in Pregnancy and Lactation and the Lexicomp Pregnancy & Lactation Database, which have been using this risk summary format with a weighted evidence approach to looking at the data since their inception. It's the label now that's going to have to conform to that way of looking at pregnancy safety information. Pharmacists and other clinicians will now likely find more consistency and harmonization between their other resources or references and the new labels. Where that information is slow in coming, pharmacists can play an important role in encouraging manufacturers to provide the data that can be used to make the label more clinically relevant and helpful.
Michael Schatz, MD, MS, has been a staff allergist at Kaiser-Permanente Medical Center in San Diego since 1977 and served as Chief of the Allergy Department from 2000-2011. Christina Chambers, PhD, MPH, is a perinatal epidemiologist and teratologist whose research is focused on environmental causes of birth defects and other adverse pregnancy and child health outcomes. Allen A. Mitchell, MD, is professor of epidemiology and pediatrics at the Boston University Schools of Public Health and Medicine and Director of the Slone Epidemiology Center at Boston University. All three hold leadership positions with the American Academy of Allergy, Asthma, and Immunology's Vaccines and Medication in Pregnancy Safety Surveillance (VAMPSS) initiative.