Updated and revised article originally published on 24 April, 2013.
One of the cherished strategies of the vaccine deniers is to use the package insert (called a Patient Information Leaflet in EU countries and Instructions for Use in the case of medical devices) to “prove” that vaccines are dangerous. Spend anything more than a couple of minutes in discussion with an anti-vaccinationist, and you’ll get a reference to a particular vaccine’s package insert (PI) as “proof” that it is dangerous, contains dangerous stuff, or is just plain scary.
There are a lot of myths about what PI’s are and aren’t, and what information in them may or may not be useful. It’s time to look at what a PI is and what it really says.
What is a Package Insert?
All of you have probably seen a package insert–it’s a multiple page document that is included with all real medications (as opposed to unregulated alternative medicine), whether prescription or over-the-counter (OTC). Depending on the type of drug, the PI can be 30-40 pages long, although most are printed on one huge sheet of very thin paper, so that it can be folded tightly and placed in each box that over-packages the drugs container (vial, bottle, etc).
In general, package inserts are part of what is called the “labeling” of the drug, which means all the verbiage that pharmaceutical company may say about the drug. It is not just the printing on the vial or box, the word encompasses almost everything said about the drug, including advertising, PI’s, and yes, the box and printing on vial.
You will hear FDA regulators and individuals in pharmaceutical companies refer to “labeling” all of the time. Labeling is strictly regulated, because it establishes the claims made about the drug or device, how it is to be used, and other pertinent information. Even what sales reps say to physicians in a sales call is covered by the drug’s labeling.
In the USA, the Food and Drug Administration has established very strict rules in the Code of Federal Regulations (CFR) on what can be and cannot be stated in the package insert. There is very little variance in format or quality of information from one PI to another one even for very different classes of drugs. Amusingly, the regulations even state the type and size of font used in the PI.
Before we discuss what is actually contained in a PI, it’s important to understand how it is written by the pharmaceutical company’s medical staff, and subsequently reviewed (and hopefully cleared) by the FDA. During the Phase 1, 2 and 3 clinical trials for a new drug, scientific information is collected about the drug–everything from the pharmacology to shelf life to results of the trials. The Medical or Regulatory Departments (both or individually) of the pharmaceutical company then writes the PI, using the boilerplate language established by the FDA (or other regulatory agencies such as those from Japan or Europe). Note that there is a lot of consistency between all drug regulatory agencies for what is in the PI, so that it is similar across the world. You are not going to find better information in a European PI, though you’ll get to see the Latvian translation of the PI if that thrills you. In today’s world, part of the purpose of a PI is to protect the pharmaceutical company from legal issues. If the PI says “do not prescribe this drug to someone who abuses alcohol”, and a physician prescribes it to that type of patient, then the company has some protection from litigation.
After the Medical and/or Regulatory departments complete the initial draft of the PI, it is usually passed through different departments of the company for further review, correction and approval. For example, the manufacturing department may not agree with a statement about how the drug or device is manufactured, and it is corrected. Depending on the company up to 10-12 departments may review a single PI, and it could take a few weeks before this process is completed to everyone’s satisfaction.
The draft PI is then included with the New Drug Application (NDA) which is the system in the United States through which drug company formally propose to the Food and Drug Administration (FDA) that they review and approve a new pharmaceutical for sale and marketing. The FDA reviews the whole application, including all labeling (in addition to the PI), before determining if it will be approved. The FDA often requests changes to all labeling depending if they agree or disagree on statements. Many times a pharmaceutical company will attempt to add indications, that is the valid reason to use a medication, but the FDA will reject it until more data is accumulated.
PI’s are not static documents. Pharmaceutical companies may add more information, warnings, indications (or contraindications, meaning uses that may harm the patient if used in particular situations), and other information that can be supported by evidence from scientific investigations. Of course, the pharmaceutical company must resubmit its labeling (including the PI) to the FDA for approval of the changes. The FDA spends a lot of time reviewing pharmaceutical labeling, because it has the most direct impact on patients’ health–although not a critical issue with vaccines, contraindications and drug interactions are very important to pharmacists and physicians.
What does a Package Insert actually say?
Again, the FDA (and other regulatory agencies) have established regulations on what must be written in the PI. Essentially, every PI must include the following:
- Highlights–summarizes the most important information about benefits and risks.
- Table of contents–because there’s a lot of information there.
- Boxed Warning (pdf, page 11)–this is usually a large black box in bold print that describes a serious warning about the drug. For example, a drug that might kill someone if used incorrectly in specific situations. Usually, the FDA mandates this for very serious adverse events. Note that I have been unable to find a single Boxed Warning on a vaccine PI. None. When the FDA mandates a “black box warning,” it is done publicly. Physicians who prescribe the drug receive receive letters about the warning. The FDA and the pharmaceutical company publicly announce the warning and its contents.
- Date of US approval.
- Description–this section describes the drug in detail including all of its ingredients.
- Clinical pharmacology–this section describes how the medicine works in the body, how it is absorbed and eliminated, and what its effects are likely to be at various concentrations, critical dose-response relationships (that is, does more of the drug have more of an effect, a fundamental piece of information about how the drug works). This section may also contain results of various clinical trials (studies), explanations of the medication’s effect on various populations, such as children and pregnant women, and other scientific information.
- Indications and usage–this section describes the uses and indications for which the drug has been cleared by the FDA. Importantly, physicians are legally allowed to prescribe medicines for purposes not listed in this section (so-called “off-label usage“), as long as that use is not specifically contraindicated. However, the pharmaceutical company’s labeling may not discuss this off-label use, even if there is scientific evidence supporting it, until the FDA approves it. Recently, there have been major fines levied by the US Department of Justice against pharmaceutical companies that push off-label use through subtle advertising or sales rep conversations.
- Contraindications–this section probably contains the most important information within all of the verbiage of a package insert. It lists situations in which medication should not be used, for example in patients with certain medical conditions, in children, or other situations. A good example of contraindications for vaccines is that most flu vaccines are contraindicated for patients with egg-protein allergies.
- Warnings and precautions–this covers possible serious side effects that may occur with use of the drugs. If the warnings are particularly serious (risk of death, for example), they may be placed in the Boxed Warning section. This section also explains how to use the medication safely, for example stating that “Do not drink alcohol while taking this medication” or other common precautions. It also describes any laboratory tests that may be necessary prior to using the drug. Serious side effects with known, evidence-based causal associations are listed in this section. This section is much more important with powerful therapeutic drugs that often have critical side effects.
- Nonclinical toxicology–this section describes the potential of carcinogenesis (causing cancer), mutagenesis (causing mutation) or impairment of fertility from the drug. This section has little applicability to vaccines, since they have no carcinogenic, mutagenic, or fertility effect, given that the level of the vaccine’s ingredients’ dosage fall far below the lower threshold of the any dose-response test of these issues. The PI may state some innocuous verbiage such as “no known information” meaning that in the 10-15 years of research and study, no evidence that the vaccine is carcinogenic or mutagenic.
- Use in specific populations–this describes if and how the drug may be used in the following populations of patients: pregnancy, labor and delivery, nursing mothers, pediatrics or geriatrics.
- Adverse reactions–this sections lists all side effects observed in all studies of the drug (including post-marketing studies), whether or not it has been scientifically established that the drug causes the side effect. Almost all of these side effects are coincidental observations and are rare of much concern.
- Drug interactions–essentially, this section describes any interaction this drug may have with other drugs.
- Drug abuse and dependence–this section provides information regarding whether prolonged use of the medication can cause physical dependence, not something that is critical for a vaccine package insert.
- Overdosage–this section, critically important in lifesaving situations, gives the results of an overdose and provides recommended action in such cases.
- Dosage and administration–this part provides the recommended dosages with detail for different ages, medical conditions, and size of patients.
- Dosage forms and strengths–this section lists out the various dosages and strengths of the drug
- How supplied–this explains in detail the physical characteristics of the medication including color, shape, markings, etc., and storage information (usually with a range of temperatures).
- Patient counseling information–this details information useful for patients including who to contact in an emergency and how to report adverse reactions to the company or to the FDA.
- Clinical studies–this covers the clinical trials that were performed prior to approval. It does not include anything more current, and some PI’s can be over 10 years old.
- References–this includes all of the citations for clinical trials, pharmacology, and other information related to the drug. Again, it is only as current as the date of the package insert (which is listed at the bottom), so it can be way out of date.
So, that’s a lot of information, but is any of it useful? How does one interpret the information in the PI? Especially for vaccines, which are not truly a therapeutic drug (it doesn’t cure a disease state, but prevents it), and which has ingredients in levels that are below the level of detection in a dose response study.
But what can we learn from a package insert?
The information in a package insert can be used in a manner to help treat a patient. Vaccine deniers idolize vaccine PI’s as some biblical statement about the dangers of vaccines. Once again, it’s easy to cherry pick information out of a PI if one doesn’t fully comprehend how the information in the PI is included.
To a real evidence-based (or science-based) physician, the only useful information in PI for vaccines are (in no particular order of importance):
- Clinical pharmacology. Knowing this information helps the scientific minded (not a skill set well known in vaccine deniers) how the drugs work. By understanding this section, you begin to comprehend how a drug may treat a disease, but also how it probably isn’t related to a mythical adverse event. For example, knowing how immunizations work, you will realize that intramuscular injections are a perfectly scientific method of inducing an immune response, that there is no logical reason to believe an injection would cause a neurological disorder, and other silly myths. But pharmacology is very hard to understand, so most people ignore it. I wouldn’t.
- Contraindications. There are very few contraindications in vaccines. But the ones that do exist are quite serious. For example, the aforementioned sensitivity to egg proteins in flu vaccines. Or yeast sensitivity for Gardasil. Physicians are very aware of these issues, as are most places, like pharmacies, that do vaccinations.
- Warnings. These are adverse events that have evidence supporting their causal association with the drug or vaccine. As opposed to the adverse reactions section, which tends to be abused by vaccine deniers, this section is where solid, repeatable scientific data is located. The FDA, by regulation, can mandate a change in the PI to include new warnings as evidence arises. Not a single PI for vaccines mentions autism as a “warning.” Not one.
The most misinterpreted misused section of the PI insert is “Adverse Reactions.” The FDA states that the section should include events “for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.” The key word is “believe”, instead of based on evidence. And frankly, anything with serious evidence would be in the Warnings section, so the Adverse Reactions section is a laundry list of observed events that probably have nothing to do with the drug (or vaccine) but remain there so that the pharmaceutical company is covered in case of a lawsuit. Yes, pharmaceutical companies are constantly frightened of litigation, and the package insert is often the first line of defense against those frequent lawsuits. But we digress.
The Adverse Reactions section, taken by itself, is the pseudoscientific way of reviewing the data. Here’s what is important:
The chance of death is 1000X higher than the chance of proven causal adverse events. This is real science, where the benefit, saving lives, vastly outweighs any risks, even the nonsense “laundry list” risks that may not have anything to do with the vaccine. If you fall for the Nirvana Fallacy, that is if it’s not perfect, then it’s worthless, then sure, vaccines aren’t perfect so they must be useless. But the fact is that they save lives, and until such time the vaccine deniers can actually spend the time in getting their Ph.D. or MD, then do research in a world-class laboratory and then publish data that shows either the adverse events are all real and are much higher than stated in the PI, and shows that vaccines have no benefit, the vaccine deniers just have no basis for their claims. They are misinforming and misusing information to support their beliefs, rather than using real science and determine whether all of the evidence supports or nullifies their hypothesis. Of course, that takes real work, and vaccine deniers are just too lazy to do real research. It’s just better to spout off a belief rather than actually accumulate real evidence.
A fellow skeptic, and thorn in the side of vaccine deniers everywhere, wrote a hysterically funny article about a mythical airline package insert. The adverse events are, of course, death, massive body damage, and more death. But the risk of dying on a flight across the country is 10,000X lower than driving across the country. So if you focus on the adverse events, without understanding the frequency of the risk (let alone the causality), it is absolutely useless. Context matters. Take a single data point out of the context of all other information, and you could “prove” anything. But being a real critical thinker, and using that information along with all other available data, especially data of a higher quality, then you might reach a rational decision.
Package inserts have excellent and useful information, important for physicians and other healthcare workers in treating patients. However, package inserts must be read fully, without cherry picking data that supports your point of view. Taking information out of context, without spending the effort to understand it completely, just shows the level of denialism. The anti-vaccinationists are focused on finding any data, no matter the quality, that supports what they want to believe. But if you are truly on the fence about vaccinations, then the adverse events information in a package insert is not the place to start. There is so much information out there, but if you read that information with an open, critical mind, you will find that the scientific consensus strongly supports the safety and effectiveness of vaccines.
One young woman did just that, despite initially being antivaccine. Her open mind lead her to eventually vaccinate her two children. Good for her.
Vaccines save lives, and we have evidence that supports it.