You don’t have to be a drug labeling consultant to realize that a case series of serious events in the literature, FDA safety alert, FDA labeling change notification letter, or other new safety information should prompt a review of drug product labeling (aka package insert). That is not what this paper is about. This paper is meant to identify and addresses less obvious events that might trigger a critical review of drug labeling. The topics that follow do not constitute an exhaustive checklist, or a suggestion that each should always necessitate a complete labeling review.
Changing Your Label
The package insert is often considered the primary means of communicating safety information, the basis for prescribing decisions, and a guide for advertising and promotional labeling. Therefore, product labeling should convey all information possible for its safe and effective use as indicated. After a drug and labeling are approved for marketing, sponsors are provided with the regulatory mechanisms to revise their labeling to address new information.
Among those mechanisms to update a package insert are prior approval supplement (PAS), changes being effected (CBE), CBE-30, and the annual report. A prior approval supplement is most commonly used when a sponsor seeks to implement major changes. Using the CBE supplement, sponsors may immediately and independently update their product labeling to include new safety information. The CBE-30 is similar to the CBE. The CBE-30 can be utilized by a manufacturer when seeking approval from the FDA to make a moderate change to the label. When using this method to achieve a label change, the FDA is given a thirty (30) day period to respond to the manufacturer before the manufacturer can implement the change. If the FDA does not respond within the thirty (30) day window, the manufacturer can implement the requested change.  When the changes are relatively minor they may be effected independently and then included in annual reports. 
When considering the status of your drug product labeling, it is useful to think in terms of the five C’s of labeling compliance: current, complete, comprehensive, correct and consistent. The benchmarks that follow represent excellent opportunities to reconsider and reevaluate your package insert.
Has Your Labeling Become Static?
Has it been a significant period of time since the last change to your package insert? This is a sure sign that change may be needed. A useful exercise is to browse approval histories at FDA and benchmark against other drugs especially those in the same drug class or for similar indications. Many package inserts average a change per year or more frequently, while others don’t change for several years. According to the Guidance for Industry Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format Requirements “all express or implied claims in labeling must be supported by substantial evidence” and it is the manufacturer’s duty to “identify unsubstantiated claims or outdated information and revise it accordingly”. Another quick and effective test is to take a good look at your drug’s post-marketing adverse reactions section and compare to the same Guidance. Are all the events contained in the section still appropriate for inclusion? Besides considering new events for inclusion or movement of events to Warnings & Precautions, you may be surprised by those which should be deleted.
Do You Still Have Pre-PLR Labeling?
On January 24, 2006, FDA finalized the Physician Labeling Rule (PLR). Commonly known as the PLR, the rule ushered in today’s content and format requirements for drug product labeling. The idea was to provide for more standardized labeling that would be easier for prescribers to access, read and use when making decisions regarding patients and medications.
Applications submitted on or after June 30, 2006 (including NDAs, BLAs, and Efficacy Supplements), were required to conform to the new labeling requirements at the time of submission. The rest were required to implement the new format requirements on a sliding schedule based on the year the drug was approved. By June 30, 2013, all but those approved pre-June 30, 2001 were to have made the transition. Drug labeling approved pre-June 30, 2001 was permitted to transition to PLR voluntarily at any time. However, FDA has encouraged all applicants to revise their older drug product labeling to the PLR format.
It is important to note that “Requirements on content and format of labeling for human prescription drug and biological products” apply to all prescription drug labeling whether PLR or pre-PLR. However, for PLR labeling, the “Specific requirements on content and format of labeling for human prescription drug and biological products described in 201.56(b)(1)” are specified in 21 CFR 201.57. Meantime, for non-PLR prescription drug labeling, the “Specific requirements on content and format of labeling for human prescription drug and biological products; older drugs not described in 201.56(b)(1)” are specified at 21 CFR 201.80. In other words, 201.57 is to PLR what 201.80 is to non-PLR labeling. Oddly enough, 201.80 is located under C–Labeling Requirements for Over-the-Counter [emphasis added] Drugs.
While a transition to the PLR format may at first seem irrelevant because of the time that has passed since final implementation, it is of particular importance to anyone who seeks to repurpose discontinued drug products or resurrect DESI/Grandfathered drug products. Additionally, any sponsor with a pre-6/30/01, non-PLR label is subject to the PLR transition with multiple regulatory events, such as adding or modifying an indication or claim; revising dose or dose regimen; providing a new route of administration; making a comparative efficacy claim vs. another product.
Do You Still Have Pregnancy Categories?
On June 30, 2015, the new pregnancy labeling rules for prescription drug labeling took effect. The new rule merged the previous Pregnancy and Labor and Delivery subsections into a single “Pregnancy” subsection and required the removal of the pregnancy categories (A, B, C, D, and X) from all drug product labeling. The subsection must also include a narrative “Risk Summary”. The new Lactation subsection requires a summary of the risks of using a drug during lactation as well as information about the data forming the basis for the information. Because there has been no consistent labeling of pregnancy testing, contraception, or infertility information, the “Females and Males of Reproductive Potential” subsection will now be required to include such data. Revised pregnancy labeling represents a clear opportunity for overall labeling review, plus it is currently an urgent requirement. The timetables for compliance are described in the table that follows:
Implementation of the 2015 Pregnancy Labeling Rule
Applications required to conform to new pregnancy/lactation content requirements
Time by which labeling with new Pregnancy/lactation content must be submitted to FDA for approval.
New or Pending Applications
Applications submitted on or after the effective date of the pregnancy final rule.
Time of submission
Applications pending on the effective date of the pregnancy final rule.
4 years after the effective date of pregnancy final rule or at time of approval, whichever is later.
Approved Applications Subject to the Physician Labeling Rule
Applications approved any time from June 30, 2001, up to and including June 29, 2002, and from June 30, 2005, up to and including June 29, 2007.
3 years after the effective date of pregnancy final rule.
Applications approved any time from June 30, 2007, up to and including the effective date of the pregnancy final rule.
4 years after the effective date of pregnancy final rule.
Applications approved from June 30, 2002, up to and including June 29, 2005.
5 years after the effective date of pregnancy final rule.
The new Pregnancy Labeling Rule poses the relatively immediate challenge of reformatting, correcting or deleting obsolete information, writing new material, and ensuring compliant information. In summary, any drug product required to comply with the Physician Labeling Rule, approved after June 30, 2001, must be in compliance with the Pregnancy Labeling Rule no later than June 30, 2018.
Have You Learned of Off-Label Use of Your Drug Product?
While a sponsor may not promote a drug for an off label use (for the latest on off label promotion see the news on Amarin Corporation Plc./Vascepa) , FDA does not regulate the practice of medicine. Therefore, off-label prescribing is legal, common, and in some cases may represent the standard of care. However, the efficacy and safety of drug products used off label have not generally been determined in clinical trials reviewed by FDA. Wittich et al have observed that off-label prescribing “occurs in every specialty of medicine, but it may be more common in areas of medicine in which the patient population is less likely to be included in clinical trials (eg, pediatric, pregnant, or psychiatric patients).”
According to the American Society of Health-System Pharmacists (ASHP) “before considering off-label use, supporting safety and efficacy evidence must be carefully evaluated and a risk–benefit determination made, especially when alternatives with FDA-approved labeling are available for the intended off-label use.” It is for these reasons that, when a sponsor becomes aware of off-label use, they are well advised to examine the associated labeling and potential/realized risks in a critical and deliberate manner.
Does Your Labeling Include a References Section?
Dating back over 35 years, “Clinical Studies” and “References” sections may appear in labeling in the place of a detailed discussion of a subject that is of limited interest but nonetheless important. In other words, references can add a disproportionately significant amount of information to a package insert using a miniscule amount of space.
A reference to a specific important clinical study may be made in any section of the format required under 201.56 and 201.57 (201.80 for Pre-PLR labeling) if the study is essential to an understandable presentation of the available information. A clinical study or reference may be cited in prescription drug labeling under the following conditions:
(1) If the clinical study or reference is cited in the labeling in the place of a detailed discussion of data and information concerning an indication for use of the drug, the reference shall be based upon, or the clinical study shall constitute, an adequate and well controlled clinical investigation under section 314.11(a)(5)(ii) of this chapter.
(2) If the clinical study or reference is cited in the labeling in the place of a detailed discussion of data and information concerning a risk or risks from the use of the drug, the risk or risks shall also be identified or discussed in the appropriate section of the labeling for the drug”.
A well maintained reference section is an excellent complement to a communications strategy designed to point prescribers to critical information in the literature or to alert them of data on file. In either case, the section can be a valuable support in facilitating interchange between detailers, medical departments and prescribers. If your product’s labeling does contain a reference section, the guidance recommends review and removal of outdated references annually. This may be effected through the annual report.
Are You Working on a Supplement Anyway?
One of the ultimate goals of drug product labeling is to ensure that prescribers and patients have access to an accurate representation of the complete safety profile associated with a drug so that an appropriate risk-benefit decision may be made for each individual patient. Therefore, if you are planning to submit a sNDA for any reason at all, there exists a natural opportunity to take inventory of all evidence in support of any labeling change and consider presenting the data/proposal to FDA. Clearly there is a wide gap between subject matter and user fee between a CMC supplement for an ANDA ($38,020 as of FY 2016) and a NDA supplement requiring clinical data ($1,187,100 as of FY 2016).
Utilization of a pharmaceutical consultant/regulatory strategist, formal meetings with FDA, and the Guidance on Changes to an Approved NDA or ANDA will be tremendously helpful in maximizing the effect of sNDAs and ensuring that no opportunity is missed. For example, the guidance actually addresses postapproval changes in (1) components and composition, (2) manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system, and (6) labeling, as well as (7) miscellaneous changes and (8) multiple related changes” (emphasis added).
Has Your Safety Committee Made a Labeling Recommendation That Has Not Been Implemented?
Typically, a sponsors drug safety committee or variation thereof will be accountable for safety-related decisions such as changes in the core data sheets, risk mitigation activities to include additional labeling, and other package insert-related communications (Dear Healthcare Professional, Dear Pharmacist, etc.). Your responsibility spans all products from first in human studies through launch and the balance of the product life cycle. The purpose of the sponsor-appointed committee should be the minimization of risks for both study volunteers and patients taking marketed medications. Continual monitoring of marketplace products and changing benefit risk profiles, especially in actual use environments and populations is critical and should be actionable by communication of safety and efficacy information to protect patients and fully inform prescribers.
Not all drug sponsors have formal safety committees. If you are one of them, consider a pharmacovigilance consultant to assist in setting up the necessary safety surveillance infrastructure. If you do have such a committee and have received recommendations with regard to labeling changes, it is time to take action. This also applies to concerns expressed by outside clinical and scientific experts, professional organizations, consultants, etc. The action to take? The amount of new safety information necessary to justify a labeling change will vary according to many factors e.g. the seriousness of the adverse events, labeled indications, and populations affected. However, it is critical that whatever action is taken prescribers must understand all risks associated with a drug such that appropriate risk-benefit decisions are made for each individual patient.
Have Other Drugs in the Class Described Safety Concerns That Are Not in the Labeling of Your Product?
What is a drug class? FDA defines two types in the Guidance; a “pharmacologic class” and an “established pharmacologic class” (EPC). The first is more loosely defined and can be based on any of the following three characteristics: mechanism of action, physiologic effect, or chemical structure.
An established pharmacologic class on the other hand “is represented by a term or phrase that is scientifically valid and clinically meaningful” according to the following definitions:
- A scientifically valid pharmacologic class is supported by documented and submitted empiric evidence showing that the drug’s pharmacologic class is known, not theoretical, and relevant and specific to the indication.
- A clinically meaningful pharmacologic class term or phrase enhances the ability of professionals to understand physiologic effects related to the indication or to anticipate undesirable effects that may be associated with the drug or pharmacologic class.
It is important to monitor the labeling of other drugs within the same class in order to ensure currency, completeness, comprehensiveness, correctness and consistency. Consider this: when investigating a safety signal, it is well known that biologic plausibility, consistency with the mechanism of action, comparison with data previously collected in preclinical/clinical studies, “and with data on other drugs in the same class” are standard avenues of investigation. Indeed, evaluation of data from such sources could result in continued monitoring, label changes, epidemiological evaluation or even regulatory action.
It stands to reason that this concept works in reverse: what is in the labels of other drugs in the same class that is not in the labeling for our drug product? Have we investigated? Can the difference be scientifically justified? While boxed warnings are generally the same or similar across all drugs in a class, even these may differ among members of an EPC such as in cases where “drugs within the same class may have similar pharmacodynamic properties and chemical structures, but different pharmacokinetic properties”. No similarity or difference in drug products within a class should be ignored.
Does your Drug Have Different Labeling in Other Nations Than in the U.S.?
Clearly and justifiably certain drug labeling differs between nations. Regulations, formulations, indications, populations etc., differ between countries. However, differences that are not known to the sponsor, or are not scientifically justified can pose embarrassing problems, or worse, expose patients to preventable risks. As with differences between drugs of the same class, these differences need to be known, understood and addressed as appropriate. Examples of inattention to this concern abound. Following is an excerpt of an article appearing in thestar.com on April 19, 2013 which is illustrative of the potential concerns:
More than 500 Canadian men feel they weren’t warned properly about a prescription baldness medication they say has left them impotent, even years after they stopped taking it. Two class-action lawsuits, one in Ontario and one in British Columbia, have been filed against Merck Frosst Canada, makers of finasteride — the key ingredient used in Propecia, a hair loss drug, and Proscar, a prostate drug also used to treat baldness. The B.C. case was approved by the province’s supreme court this month.
Merck denies the claims and says it acted responsibly in all aspects of producing and marketing the drugs. The plaintiffs argue Merck failed to warn them of lasting sexual dysfunction after stopping treatment, despite the product’s labels in Europe indicating a risk of “persistent erectile dysfunction after discontinuation of treatment” as far back as 2008.
Are You an ANDA Holder?
You have nothing to be concerned with when it comes to updating your drug product labeling. Simply conform to the labeling of the reference listed drug (RLD). If that seems to be good to be true, it is. On November 13, 2013, FDA issued notice of a proposed rule entitled “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products”. If finalized as originally proposed, the rule will allow for ANDA holders to update safety related product labeling by submitting a CBE. The result will be temporary differences between the labels of RLDs and their generic counterparts. However, in November 2014 GPhA and PhRMA put forth an alternative proposal. Known as the Expedited Agency Review (EAR), EAR would require NDA/ANDA holders to submit new safety information to FDA. FDA would then review the information in light of information in its Sentinel System and require changes based on the review. Quite a departure from the CBE, the proposal described the EAR as replacing the CBE process for safety related labeling changes now permitted under 21 CFR. Section 314.70(c)(6). The final rule was due at the end of July 2016 at the time this paper was drafted. However, by the time of publication of this paper, the date was pushed back another year (well after the 2016 elections).
Do You Wish to Avoid Product Failure Litigation?
A recent estimate of adverse reactions caused by prescription medications in the U.S. each year stood at nearly 50 million events per year resulting in over two million hospitalizations and 100,000 plus deaths. It is the obligation of the sponsor to ensure the safety of marketed drugs by conducting appropriate studies and engaging in active pharmacovigilance. The obligation includes the duty to communicate new safety information to prescribers, patients and other stakeholders through compliant labeling (current, complete, comprehensive, correct and consistent).
Look for more papers to come this year on labeling. Planned is a discussion confined to safety concerns, a primer on the various forms of U.S. drug labeling (FDA approved patient labeling, medication guides, voluntary labeling, etc.), and a summary of the “Generic CBE Rule” when finalized (now next year if ever finalized:Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products). If you have concerns with the adequacy of your drug product’s labeling, feel free to click here to contact us.
Charles Jaap is Vice-President of Operations and Business Development for PDG, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices. Please feel free to contact us for more information.
The opinions and statements in this paper are solely those of Charles Jaap and do not necessarily reflect those of PDG.