Usability's Importance In Combination Products: The Mylan Citizen Petition Case Study

By David Amor, MSBE, CQA, Medgineering

The recent pricing controversy surrounding Mylan may be new to the public, but medtech industry experts have long known that the EpiPen manufacturer has employed various tactics in protecting and maintaining its 90 percent market share of the lucrative epinephrine auto-injector market. One of the most interesting methods that Mylan deployed was the filing of a “Citizen Petition” on Jan. 16, 2015.

Citizen Petitions – Notorious Tool Of The Branded Drug Manufacturer?

Citizen petitions – defined in 21 USC 355 and 21 CFR 10.30 – are requests to FDA, for or on behalf of an organization, to issue, amend, or revoke a regulation or order. Citizen petitions also may request that FDA take or refrain from taking any other form of administrative action – including submission approval. Citizen petitions often are submitted to question or persuade FDA to examine product safety issues, or any other prospective issue, that may have an adverse impact to public health.

However, a recent study¹ reveals a misuse of the citizen petition program by brand-name pharma manufacturers seeking to delay competitive generic approvals using “505(q)” citizen petitions, a sub-set aimed at FDA actions against pending generic approvals.  Of these requests, 92 percent are submitted by branded pharmaceutical companies in a thinly veiled attempt to block or delay 505(b)(2) and 505(j) submissions; both submission types are abbreviated applications for analogous or generic drugs. FDA ends up rejecting 92 percent of these 505(q) petitions due to poor scientific integrity or inadequate content. The petition abuse has become so commonplace that FDA requested congressional intervention to remove the requirement for responding within 150 days — a response time that the agency says is a burden exacerbated by the lack of integrity within the majority of the petitions².

The study authors note, “Citizen petitions represent a hidden tool in (the brand-name drug maker’s) toolkit of entry-delaying activity, all to the detriment of consumers forced to pay high drug prices… And in defiance of Congress’s attempt to limit abuse, citizen petitions play an increasingly important role in delaying generic competition.”¹

Mylan Uses the Citizen Petition Against Teva

In January 2015, Mylan submitted a citizen request “that the Commissioner refrain from approving the Teva [generic EpiPen] ANDA [abbreviated new drug application] unless, after conducting an appropriately rigorous review under the established standards for proposed generic emergency use auto-injectors, the agency concludes that the proposed product is the ‘same as’ the EpiPen auto-injector”³.

Teva Pharmaceuticals, a large drug manufacturer based in Israel, had settled in 2012 a patent infringement lawsuit that was filed by a Pfizer — who manufactured EpiPen for Mylan — a deal that allowed for a mid-2015 generic filing⁴.

One of the arguments within Mylan’s 2015 petition was that the differences in design and operating principles between EpiPen and Teva’s generic would render users trained in EpiPen use unable to comfortably substitute the Teva generic in a safe and effective manner. The crux of the design issues was a deviation from usability and human factors considerations of the “reference listed drug (RLD),” EpiPen, that could lead to user confusion and an inability to inject themselves in an emergency situation, compromising the lifesaving drug delivery.

In addition to using “study data” to support the usability concerns, Mylan cited statements by noted allergist Dr. Eli Meltzer, who wrote: “I do not believe that a user trained on the EpiPen … platform will be able to reliably use a different operational platform in an emergency situation as safely and effectively.”³ However, it should be noted that Dr. Meltzer was compensated by Mylan in the past and that the study had several potential flaws, including questionable study design and the use of a Teva prototype instead of the actual generic.⁴

In an article published by Stat Online, Mylan responded to the study deficiencies by stating that the studies “applied the fundamentals of human factor engineering and analysis to examine the proposed Teva product against FDA’s standards for approving a generic product like this.  The question FDA asks is whether, in an emergency, a patient or caregiver who is trained on the EpiPen could, without training on the proposed generic, successfully use the generic product in accordance with the EpiPen directions for use. Given the purpose of the study, we believe its design and implementation offered a valid examination of the human factor issues presented by Teva’s distinct design and operating steps.”

Ultimately, FDA denied the petition in June 2015. But, in a surprise boon for Mylan, FDA also rejected Teva’s application due to application deficiencies. As of this writing, the Teva generic still is not on the market, although rumblings continue within the industry that Teva will revisit the application with FDA at some point, especially in light of the Mylan price-gouging headlines.

A key takeaway in the Mylan citizen petition case study is the importance of usability in combination product design and development. EpiPen, other auto-injector drug delivery products, and other drug delivery combination products in general, are particularly sensitive to use errors, as poor interfaces may lead to compromised drug delivery and subsequent loss of efficacy or safety.

Usability and HFE: Combo Product “Musts”

The  practical importance of usability and HFE within combination products is further emphasized by FDA’s release of a draft guidance on the subject this year, entitled Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development. The guidance highlights some of the considerations that a company should evaluate when designing and developing a combination product.

Usability engineering may be considered a sub-set of design validation, a critical part of the design control requirements in 21 CFR 820.30, which requires that user needs are validated in simulated or actual use conditions. The goal of usability engineering practices is to reduce use errors that may compromise product safety and efficacy.

The key to usability engineering for drug-device combo products lies in examination of a few specific activities detailed in the FDA guidance:

Ensure that the intended use is well-understood — One of the most critical components of an outstanding usability engineering file is deep definition and understanding of the intended use. Some drug applications, such as ANDAs and/ or 505(b)(2)s,  depend on the intended use being the same or materially analogous. A branded pharmaceutical or related data is used as the basis for submission.

For combination products in particular, understanding the use environment is key. Many injectors, for example, are home health products intended for operation by the end-user, often with no healthcare professional supervision, in a stressful situation. During formative and summative usability evaluations, ensure that simulated use testing represents actual use conditions, including varying lighting, noise, activity levels, speed of use, and situational use conditions for the most accurate and useful results.

The same can be said of user groups. For example, for injector usability studies, a company should cross-test the product with experienced users and lay users, as well as various sub-groups.

Identify and assess use-related risk — In the Mylan petition, the authors describe a situation where differences between EpiPen and the generic could lead to “use errors likely to occur including potential delayed therapy, partial or complete failure to delivery therapy, and possible injury due to unintentional or inverted injection.” This description highlights the significance of understanding how hazards and hazardous situations from use failures may lead to harms. Using a risk assessment tool — per EN ISO 14971:2012 or ICH Q9 — to organize how hazards may lead to harms allows a manufacturer to better design the device constituent of a combination drug-delivery product.

Critical task identification — Critical tasks are steps that may cause harm to the patient or user if not performed, or if performed inadequately. Combination product critical tasks are fairly similar. For example, within auto-injectors, critical tasks may include:

• Preparing the product for use by removing a needle guard or activating the product. This includes cross-labeled or co-packaged products, where placing the two constituents together is one of the preliminary steps (ex: placing a dose cartridge into an inhaler device). Failure may result in a needle-stick injury or failure to inject.
• Distinguishing two different, but similar, models of injectors. Many injectors have an adult and a pediatric version. Thus, differentiating the products is critical to avoid overdose or underdose situations.
• Actuation of the injection mechanism. If the plunger or actuation is too easy to push/ pull, or if it provides too much resistance, a user may stick themselves or be unable to provide the dose delivery.
• Syringe or injector disposal. Inadequate disposal may harm the environment or nearby healthcare providers who come across the product while working nearby.

Usability testing — The end result of usability testing is ensuring that a device design incorporates all of the human factors considerations we’ve discussed so far, leading to a product that prevents use errors and doesn’t impact safety or efficacy. Design features and additional tasks incorporated into the process to help achieve those goals should be validated through usability testing.

Iterative formative testing early in the combination product development process helps a company find out whether the pro-usability design decisions made during development truly do prevent use errors from occurring. Once a final design is determined, summative usability evaluations are performed to demonstrate to the company and to regulators that the product is free from unacceptable use errors. Through simulated and actual use testing, proof emerges that the combination product should deliver drug reliably, safely and effectively.

Conclusion

Despite FDA’s protests of abuse of the Citizen Petition program, the Mylan petition against Teva’s generic EAI presents an opportune case study for us to evaluate the role of usability in a product development program. When developing a drug delivery device, the key role of usability engineering is to determine whether any user tasks or actions may lead to compromised drug delivery (i.e., compromised intended use).

About The Author

David Amor, MSBE, CQA is a medtech/ biotech consultant and mobile health entrepreneur who founded Medgineering, a company focused on remote compliance, regulatory & quality systems consulting for larger companies and start-ups alike. A graduate of the prestigious Innovation Fellows program at the University of Minnesota’s Medical Device Center, Amor was named a Top 40 Under 40 Medical Device Innovator in 2012 and a 35 Under 35 Entrepreneur in 2015 by MN Biz Magazine. He co-founded and helped launch Remind Technologies, a Texas-based mobile health company developing a smartphone-based remote medication management system. He is also co-inventor on several issued utility patents and co-pioneered a disruptive e-consulting platform for the medtech and pharma industries called QuickConsult. Amor serves as an adjunct professor at St. Cloud State University (Maple Grove, MN) where he teaches courses on risk management and design control. The current focal points of his consulting practice are specializing in risk management, design controls, combination products and mHealth. He can be reached at david@medgineering.com or at 786-546-1806.

REFERENCES

1. Carrier and Minniti, 2016. “Citizen Petitions: Long, Late-Filed, and At-Last Denied”. (http://freepdfhosting.com/f6a4423f7c.pdf)
2. FDA Report to Congress: Eighth Annual Report on Delays in Approvals of Applications Related to Citizen Petitions and Petitions for Stay of Agency Action for Fiscal Year 2015. (http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ReportsBudgets/UCM517279.pdf )
3. Mylan Citizen Petition, 2015. (https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%20Sheet%20DAILY/2015/January/Citizen_Petition_Mylan_Specialty_epinephrine%20autoinjector%20ANDA.pdf )
4. Silverman, 2016. “How Mylan tried to keep Teva from selling a generic EpiPen.” (https://www.statnews.com/pharmalot/2016/08/31/mylan-teva-generic-epipen/)