Package Inserts - Understanding What They Do (and Don't) Say

With the whole twitter tantrum over a supposed coverup revealed by an alleged whistleblower that really is much ado about nothing, a topic arose that I realized I hadn't written about before, other than in passing. It came up again last week when anti-vaccine activists tried to hijack the Twitter hashtag #vaccinesNOVA by astroturfing it with tons of copy-pasted tweets, rather than actually watching the excellent NOVA episode Vaccines - Calling the Shots and having a mature conversation about vaccines. It's the same tactic they used with the #CDCwhistleblower hashtag. They merely copied and pasted from a list of prepared tweets, rather than offering any original thoughts of their own, because they are convinced that they already know everything and have nothing to learn from a very informative program. If there's even a whiff of pro-vaccine message to a show or post, count on anti-vaxxers to rail and scream, rather than actually watching or reading, let alone understand.

At any rate, I engaged one of those tweeting easily disproved nonsense to #vaccinesNOVA. This individual brought up vaccine package inserts, pointing out that one vaccine insert actually mentions "autism" in the adverse events section. They linked to the insert for Tripedia, which protects against diphtheria, tetanus and pertussis (whooping cough). In their mind, this was ironclad proof that even vaccine manufacturers admit that vaccines cause autism. Of course, this person ignored the other bits in the paragraph that mentioned autism (emphasis added):

Adverse events reported during post-approval use of Tripedia vaccine include...autism...Events were included in this list because of the seriousness or frequency of reporting. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies or to establish a causal relationship to components of Tripedia vaccine.

In other words, autism was included because it was deemed either serious or was frequently reported, not because there was any causal relationship found between the vaccine and autism. It is far from being the slamdunk "gotcha!" that my interlocutor thought it was. But it prompted me to consider how many people probably do not understand just what the package insert for a vaccine (or any other drug) actually is or what its contents mean.

So here we go, a primer on drug package inserts and what they mean for a lay audience.

Let's get one thing straight before we even delve into the details. The package insert is not a scientific document or report, though it does discuss the results of studies. It is, first and foremost, a legal document. It provides information on how it is to be administered and to whom, insofar as the manufacturer has received FDA authorization for marketing. It does not include off-label uses. It does not include summaries of the entirety of scientific research. The package insert is the manufacturer complying with federal regulations. Period. Specifically, it is compliance with 21 CFR 201.57, which details what information each section must contain. All prescription drugs and biologics (e.g., vaccines) must have a package insert that follows these regulations. Each header below represents a required section, followed by a summary of what you will find there and what it means (or doesn't mean). Vaccines approved prior to 2001 may have a different format than what follows; regulations standardizing the layout and content have only been applied to more recently approved products.

Highlights of Prescribing Information

Each insert starts with a brief summary of the full prescribing information. It gives the very basic overview of how it's used, who the target population is, contraindications, warnings and precautions, and the more common/severe adverse reactions, as well as contact information.

Boxed Warning

Also known as a "Black Box Warning", this section is only on products for which FDA has required certain contraindications or serious warnings to be brought to the fore. It summarizes contraindications or precautions that may lead to death or serious injury. This is typically based on clinical evidence, but can sometimes be based on animal data. Further information on these warnings can be found in the Contraindications or Warnings and Precautions sections of the insert.

1. Indications and Usage

This section gives information on when the product should be used, such as what condition or disease it is meant to treat and what group of people it is meant to be used in. The insert can only include indications for which FDA has granted approval to the manufacturer. For example, if a product has been approved for treating a gastrointestinal disease, but is also used by doctors to treat migraines, if the manufacturer has not applied for and received approval for migraines as an indication, they cannot list migraines in this section, even if there is a lot of scientific evidence out there that it works.

2. Dosage and Administration

This details how the product is to be administered, in what amounts, over what period of time. It states the upper safe and effective limit on dosage, dose for each population or indication listed in section 1, timing between doses, how long treatment should continue, how dosing should be adjusted based on food or drug interactions and so on. It should also include information on how the product should be diluted/reconstituted and prepared, as well as how it should be administered to the patient (e.g., given by mouth, injected into a particular muscle, injected into a vein, etc.). As with the previous section, the information here is based on the studies that the manufacturer has done and reported to the FDA. It typically does not include information from studies done by other people or organizations.

3. Dosage Forms and Strengths

Just a brief description of what the product looks like and how it is supplied, as well as how much of the active drug/biologic is in it.

4. Contraindications

This part lists the known situations in which the product should not be used because the risks of using it outweigh the benefits that it provides. For example, if some ingredient causes a severe, life-threatening allergic reaction in people with that allergy, this section would state that those people should not get the product. That said, this section can only list known, proven risks. If it is just a theoretical risk, it should not be listed here. So, if it's thought that it might cause an allergic reaction, but there hasn't been any proof that it does, the allergic reaction should not be listed as a contraindication.

5. Warnings and Precautions

Any clinically significant adverse reactions that impact how the product is used are listed here. Whereas the Contraindications section notes where the product should not be used at all, this section makes not of those situations where the product can be used, but extra caution should be taken. For instance, if a patient is suffering from an acute viral illness, it might state the the product should not be given until one week after their symptoms go away. This section may also include information on how the product might interfere with lab testing. For example, it might cause a false positive reading if the patient is tested for a particular disease within three months of receiving the product. This is one section where evidence from outside of the manufacturer can come into play. As soon as there is enough reasonable evidence to support a causal connection between a risk and the product, it must be listed in this section. A causal connection does not have to be definitively proven, however, to be listed.

6. Adverse Reactions

This is perhaps the most misunderstood section of the package insert. Often, people will think that if an adverse reaction is listed here, that means that there is definitive proof that the product causes that reaction. What they miss or don't understand is that this section breaks adverse reactions out into different categories.

Clinical Trials Experience - Adverse reactions listed in this section were observed during clinical trials conducted by the manufacturer, generally in the course of seeking FDA approval. This information includes how many people were exposed, how many suffered the reaction, and how that compares to a placebo or other comparator. Any adverse reaction listed in this section has good evidence for a causal connection.

Postmarketing Experience - Unlike the Clinical Trials Experience section, adverse events listed here are those that have been reported to the manufacturer, rather than from robust clinical trials. The manufacturer must list adverse events for which there is some plausibility of a causal relationship. For example, if someone reported that their car caught on fire after they received the product, the manufacturer would not list "car fires" as an adverse reaction because it is entirely implausible. However, if someone reports that they had a heart attack after receiving the product, that would be listed, even if it is later found that the heart attack was caused by their lifetime of eating nothing but fast food and getting no exercise. This section will also include adverse events for which the manufacturer gets a lot of reports. Again, this doesn't mean the product actually caused that reaction. If someone with an axe to grind got a whole bunch of people to report the same reaction to the company, it would probably get listed. A company will typically err on the side of caution and list something here if there's even the slightest chance of the product causing the event, no matter how unlikely, simply to cover their butts. If they receive reports of an adverse event and fail to list it, that leaves them open to a law suit for failure to warn if someone else suffers that same issue. When I talk about the insert being a legal document, this is where it can most come into play. The bottom line is that inclusion here does not mean the product really does cause the event, but rather that the manufacturer has received reports of that event. Whether those reports are true or not is irrelevant.

7. Drug Interactions

If the product interacts in any way with some other drug, biologic, supplement or food, the interaction must be detailed here. This includes more detail on anything mentioned in the Contraindications or Warnings and Precautions sections. If use of the product will increase the likelihood of adverse reactions when used with some other product, or if using it with some other drug will reduce its efficacy or the other drug's efficacy, that must be listed here. For example, taking the product with acetaminophen might increase the risk of liver damage. Or using the product while taking antibiotics might make it less effective.

8. Use in Specific Populations

As with the Adverse Reactions section, this part of the insert is also prone to misunderstanding, especially the section on use in pregnant women. Typically, clinical trials are done in adults who are either healthy or have the target disease or condition, but no other significant health issues. But there may be other categories of patients who are especially susceptible to altered safety or efficacy of the product. These include: pregnant or nursing women, children, the elderly and those with specific conditions (e.g., impaired liver or kidney function). Unless the product is likely to be used by pregnant women, manufacturers probably will not conduct studies in pregnant women prior to FDA approval. If they have not done such studies, this section will list the product as "Pregnancy Category C" and include the following mandated statement:

Animal reproduction studies have not been conducted with (name of drug). It is also not known whether (name of drug) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. (Name of drug) should be given to a pregnant woman only if clearly needed.

This means that the manufacturer has not conducted studies in pregnant women or animals. It does not mean that no one has conducted studies in pregnant women or done animal studies. Other researchers may have examined the effects of the drug on pregnant women and their fetuses and found the drug to have no effect, mild effects or severe effects. Manufacturers are likely to take a conservative approach to this section, again to avoid failure to warn law suits.

The most common misunderstanding among anti-vaccine activists for this section is if it has that "It is not known..." statement. To reiterate, the insert will have that language if the manufacturer has not conducted studies in pregnant women (or other special population). An example of this is found with flu vaccines. Several different versions have some variation of the "has not been studied" text, yet there are a lot of studies listed in PubMed examining the safety of influenza vaccination in pregnant women, such as this one or this one. So while independent researchers may have found the vaccine to be safe, the company is unlikely to list that unless they have conducted their own study showing it is safe.

9. Drug Abuse and Dependence and 10. Overdosage

These sections generally do not apply to vaccines. Section 9. is for drugs that are controlled by the Drug Enforcement Administration and describes the type of abuse that can occur with the drug, types of adverse reactions, patient populations particularly at risk of abuse and the effects of dependence. Section 10 documents symptoms of an overdose, what complications occur, how much of the product causes an overdose, how an overdose should be treated and whether the drug can be eliminated with dialysis.

11. Description

Pretty straight forward, this section describes the product, including the names used to describe it, dosage forms and routes of administration, ingredient information (including those used during manufacture that are either not present or only in trace amounts in the final product), statement that the product is sterile, class of drug and any other important chemical or physical properties.

12. Clinical Pharmacology

The Clinical Pharmacology section describes what is known about how the product works, what effects it has on the body (pharmacodynamics) and what effects the body has on it (pharmacokinetics).

13. Nonclinical Toxicology

If any animal studies have been done to determine whether the product causes (or is likely to cause) cancer, mutations or impaired fertility, those results will be discussed in this section. If the manufacturer has not conducted such studies, they will include something like "(Product name) has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility." However, that does not mean that no studies have been done. As with the note about use in pregnant women, above, studies may have been done by other researchers not affiliated with the manufacturer.

14. Clinical Studies

The manufacturer uses this section to detail the clinical studies they conducted for the product in order to get it approved by FDA. The studies show the safety and efficacy profiles, as well as discuss the adverse events listed in section 6 under "Clinical Trials Experience". It summarizes the studies performed, their populations, design, endpoints and results. While the information is extensive, this section is not the same as a published, peer-reviewed journal article. It also does not include all of the studies performed on the product. The regulations explicit note that this section "must not include an encyclopedic listing of all, or even most, studies performed as part of the product's clinical development program".

15. References

Any other scientific references that are important to the prescribing of the product will be listed in this section.

16. How Supplied/Storage and Handling

This is a basic explanation of how the product is provided by the manufacturer and how the product should be stored and handled. For vaccines, this has important information on the temperature range for storing the vaccine. If the temperature goes outside the range indicated, the vaccine will be less effective or even ineffective.

17. Patient Counseling Information

Any information needed for the patient to use the product safely must be listed in this section. It should highlight any discussions that the healthcare provider should have with the patient, instructions that the provider should discuss the adverse events associated with the product and instructions for the patient if they experience any adverse reactions. For vaccines, this section also notes that the patient should receive the Vaccine Information Statement.

Conclusion

The package insert contains a lot of information. A lot of work goes into it to make sure that healthcare providers have enough information for them to safely prescribe and use the product. Yet while there is a wealth of information in the insert, it's important to remember that it is first and foremost a company complying with federal regulations and buffering them against litigation. The most commonly misunderstood and misused sections are the Adverse Reactions and the Use in Specific Populations sections. For Adverse Reactions, people can easily assume that anything listed has been proven to be cause by the product. But that is not the case. The manufacturer will list any adverse reactions that are reported to them that are plausibly caused by the product, even if the chance of that is so close to zero that we can safely conclude there's no connection. The Use in Specific Populations section might state that the product has not been studied in, for example, pregnant women. Yet that only means that the manufacturer has not conducted studies in that population. Other researchers may have examined the safety of the product in those special populations. Figuring that out often requires searching the published scientific literature, which frequently turns up a number of studies that have been done.

When someone pulls up a package insert to support their argument, it's important to understand what it says and what it doesn't say, not to mention the purpose of the insert. This understanding would prevent a lot of misunderstanding around vaccines.

A list of approved vaccines and their supporting documents, including package inserts, can be found on the FDA's web site. Regulations governing labeling can be found at 21 CFR 201. Requirements for the content of the inserts for prescriptions drugs and biologics can be found in 21 CFR 201.57.