Trumenba: A Briefing for Litigating Attorneys

Trumenba: A Briefing for Litigating Attorneys by Abby Timmons February 22nd, 2015 This paper is intended to function as a succinct background for attorneys who may need to litigate (either defending or prosecuting) involving the drug Trumenba. Descriptions of the drug s creation, target disease, clinical trials, FDA-granted special designations, and side effects will be presented in order to create the fullest and most unbiased picture possible. TECHNICAL WRITING

Trumenba: A Briefing for Litigating Attorneys Introduction Trumenba is a recently developed vaccine affiliated with the pharmaceutical company Pfizer Inc. that was developed to fight a particular subgroup of meningococcal disease. This particular subgroup subgroup B previously did not have any form of drug available to either prevent or treat the spread of meningococcal disease, and, as luck would have it, meningococcal disease made Figure 1. Trumenba s logo. Source: www.trumenba.com headlines when subgroup B cases cropped up in freshman dorms at Princeton and University of California at Santa Barbara in the fall of 2013. Due to this pressing societal need, Trumenba s creation and approval were fairly rapid by pharmaceutical standards, leading to its availability and use today. The drug s logo can be seen above in Figure 1. The Food and Drug Administration approved Trumenba on October 30 th, 2014. The extreme recency of this approval, however, might give some would-be users pause, as the long-term effects and reliability of the drug cannot be known. The purpose of this report is to provide future potential litigating attorneys with a brief background of the drug, as well as to give a context that could help situate Trumenba within a legal case. Given the particular designations the Food and Drug Administration (FDA) afforded to Trumenba to release the drug swiftly, there is a risk of possible future backlash should serious long-term side effects or issues emerge. This report aims to provide all potentially relevant information about the vaccine in an impartial and unbiased fashion in order to prove useful regardless of whether the drug is being prosecuted against or defended. To accomplish these goals, a brief history of Trumenba will be discussed, outlining in detail the immediate need for its creation and approval. The basics of meningococcal disease will be explored, to situate the drug within its appropriate context, and the vaccine s clinical trials and subsequent results will be presented. The special designations granted to Trumenba will be discussed at length, namely: Accelerated approval, Breakthrough therapy, Priority review, and Fast track status. A definition of each will be provided, as well as an explanation stating why Trumenba was eligible for the title. A comparable case involving a competitor drug, Bexsero, and its special status ( Expanded access IND ) will be presented. Finally, all recorded side effects to date will be presented, along with the warnings and restrictions affiliated with the drug. An extensive references section will also be present at the close of this paper for further perusal. 2

The Need Trumenba Fills: The Circumstances Behind Its Creation & the Vaccine Trumenba is not the first drug released with an aim at preventing meningococcal disease, but it is the first drug released specifically to target meningococcal disease s subgroup B. Some universities, aiming to stop future outbreaks like those at UCSB or Princeton, require that freshmen be inoculated against meningococcal disease. Despite previously existing drugs, outbreaks did occur in 2013, thanks to the remaining subgroup without a vaccine. Public health concerns led to an increased focus on creating a suitable vaccine, and Trumenba was the first FDA approved result. Trumenba is a vaccine currently approved for persons ages 10-25. While this range seems oddly small, it encapsulates the group who made the push for the vaccine: college kids. Trumenba is given in three separate doses in the upper arm muscle, and should resemble a.5 ml homogenous white suspension (Pfizer). The three doses take place at time (t) = 0 months, t = 2 months, and t = 6 months. The Disease Trumenba Fights: Meningococcal Disease & Its Effects on Society As mentioned previously, Trumenba s purpose is to prevent the contraction of meningococcal disease subgroup B. Meningococcal disease is caused by the bacterium Neisseria meningitides, and can develop into meningitis or septicemia (Mullen). It spreads through the air or through direct contact with infected bodily fluids. Symptoms of meningococcal disease include high fever, chills, lethargy, and a rash (Mullen). Meningococcal disease should not be treated lightly. As Figure 2 depicts, according to the Connecticut Department of Public Health, 10-15% of people die after contracting meningococcal disease, and 10-15% of people are permanently affected by the disease. In a typical year, the United States of America sees from 2,000-3,000 cases of meningococcal disease per year, which could lead to 300-450 deaths (Mullen). Therefore, Effects of Meningococcal Disease 70% 15% 15% People permanently affected People who died People who made a full recovery Figure 2. Chart representing effects of meningococcal disease. Source: Data from http://www.ct.gov/dph/cwp/view.asp?a=31 36&q=388352 2

producing drugs that could help prevent the spread of disease became a source of public health concern. Vaccines and treatment for the A, C, W, and Y subgroups of meningococcal disease have existed since 1981 33 years previous to the development and release of Trumenba (Mullen). This rather large disparity, coupled with the outbreaks in 2013, may have led to the FDA s sense of urgency when it came time to evaluate Trumenba for approval. The Trials Trumenba Faced: Studies & Results Regarding the Injection Sites Like any other FDA-approved drug, Trumenba was subject to clinical trials before it became available on the market. According to the Pfizer labeling website, Trumenba was tested in 4,282 subjects across the United States, Europe, and Australia. The trials appear to follow principles of good experimental design, using observerblinded methods to eliminate researcher bias and control groups to reduce the placebo effect. Figure 3 below shows a table charting any reaction to Trumenba at the injection site over a seven-day period. Trumenba Local Reaction Dose 1 N=1970 Dose 2 N=1826 Dose 3 N=1688 Pain Any 92.8 86.1 84.5 Mild 42.5 49.9 44.1 Moderate 42.1 31.6 34.7 Severe 8.2 4.6 5.7 Redness Any 20.4 14.9 15.8 Mild 9.0 6.6 7.3 Moderate 9.1 7.0 7.0 Severe 2.2 1.3 1.4 Swelling Any 21.6 18.2 20.1 Mild 12.5 10.8 11.7 Moderate 8.5 7.1 8.2 Severe 0.5 0.3 0.2 Figure 3. Clinical trial results for local adverse reactions. Source: http://labeling.pfizer.com/showlabeling.aspx?id=1796 3

While there were some adverse effects at the injection site for most participants, the data do not appear to be too unusually high. They do, however, show a correlation with the strength of the doses (N) that might suggest that each consequent administration of Trumenba (as it is a three-injection vaccine) would be less painful. At the current date, there does not appear to be any publicly available data regarding the overall effectiveness of Trumenba, or studies regarding decreased effectiveness if a dose is missed or given late. The Approval Trumenba Received: Special Designations & the FDA Release As stated in the introduction, Trumenba was awarded four special designations by the FDA that aided in its speedy approval. In the below subsections, I will outline and define all four designations, as well as discuss a comparable case: the competitor drug, Bexsero. Accelerated Approval Designation The accelerated approval designation allows the FDA to base approval of a drug on an intermediate endpoint if the drug fills a current serious void in the medical market (US Food and Drug Administration). Trumenba was eligible for this designation because there was no preexisting vaccine available to treat the subgroup B strain of meningococcal disease. What intermediate endpoint might have been used is unknown. An example given on the FDA s website: marked tumor shrinkage. Rather than waiting for a proven extended rate of survival of cancer patients, a new drug can be approved if it meets the intermediate endpoint of shrinking tumors. However, if the intermediate endpoint fails to eventually translate into the true end goals, the FDA can pull their approval of the drug a concern Pfizer Inc, as the manufacturing company of Trumenba, ought to be aware of. Breakthrough Therapy Designation The breakthrough therapy designation shares many of the above criteria with the above accelerated approval designation, but must be requested by the drug company itself. A drug that receives breakthrough therapy designation is privy to intensive guidance and all features of the Fast Track designation by the FDA (US Food and Drug Administration). 4

The main differences between this designation and the fast track/accelerated approval status is that Pfizer was responsible for submitting a request to the FDA in order to receive this title, as well as the intensive guidance of the agency as a whole. Breakthrough therapy status can be granted through either the Center for Biologics Evaluation and Research or through the Center for Drug Evaluation and Research. Figures 4 and 5 show statistics about the number of submitted requests vs. assigned designations and eventual approvals between the two Centers. CBER Breakthrough Therapy Submissions CDER Breakthrough Therapy Submissions 3% Denied 8% Denied 21% 76% Granted status Granted status and approved 29% 63% Granted status Granted status and approved Figure 4. Statistics on CBER Breakthrough Therapy Submissions. Source: http://www.focr.org/news/pinksheet-pfizer s-meningitis-b-vaccinetrumenba-cber s-first- breakthrough - approval Figure 5. Statistics on CDER Breakthrough Therapy Submissions. Source: http://www.focr.org/news/pinksheet-pfizer s-meningitis-b-vaccinetrumenba-cber s-first- breakthrough - approval Trumenba is the first and current only drug afforded breakthrough therapy status via the Center for Biologics Evaluation and Research to be approved (Mullen). Fast Track Designation The fast track designation also must be requested by the drug company, and again shares several overlaps with the two previously defined designations. Fast Track designations may be received if the drug fills a currently unmet medical needs as it does with the case of Trumenba or if the drug stands a chance of outperforming current medical therapy (US Food and Drug Administration). 5

The Fast Track Designation also entitles the drug company to yet more guidance from the FDA, in the form of frequent meetings and communication with the agency. It also entitles the company to rolling review, so that the New Drug Application filed with the FDA can be reviewed as it is written, rather than waiting to submit it as a completed document. Priority Review Designation The simplest of all Trumenba s designations, priority review entitled the drug to receiving action either a denial or an approval within six months. A typical, non-priority review is completed in ten months (US Food and Drug Administration). The FDA may award this designation to drugs, or the parent company may ask for it. Trumenba was awarded this designation because of the implications for public health again falling under the umbrella of an unmet medical need. A Comparable Case: Bexsero s Expanded Access IND Designation In the fall of 2013, when meningococcal disease subgroup B outbreaks were occurring on university campuses, the FDA granted Bexsero a vaccine also designed to prevent subgroup B infections an expanded access investigational new drug designation, allowing administration of the drug (US Food and Drug Administration). The general use of this designation is only in emergency situations, where the potential public health benefits outstrip the potential risks. To date, Bexsero has not come under legal fire for its use as an Expanded Access IND drug, but also has not been formally approved by the FDA. In an interview with the CDC, the Princeton Public Health Review discovered that Bexsero was used during the outbreaks rather than Trumenba because it was licensed in other countries (Princeton Public Health Review). The CDC suggests in that same interview that Trumenba was licensed first simply because its application was completed more quickly. The Side Effects Trumenba Creates: Cautions & Warnings for Users Like any other drug, Trumenba comes with its own set of warnings and side effects, one of which (pain at the injection site) was examined in Figure 3 (Page 3) due to its affiliation with clinical trials. Aside from pain at the injection site, the side effects fatigue, headache, muscle pain, and chills were also documented in Figure 6 (see full next page): 6

Group 2: Trumenba + Saline Dose 1 Dose 2 N=985 N=907 Dose 3 N=846 Systemic Reactions Fever ( 38.0 C) 38.0 C 6.4 1.3 1.1 38.0 to <38.5 C 3.7 1.1 0.8 38.5 to <39.0 C 1.5 0.1 0.1 39.0 to 40.0 C 1.0 0.1 0.1 Vomiting Any, 7.4 2.4 2.5 Mild 5.3 1.4 1.8 Moderate 1.7 0.9 0.5 Severe 0.0 0.0 0.0 Diarrhea# Any 15.2 9.3 8.9 Mild 13.3 7.5 7.3 Moderate 1.7 1.8 1.2 Severe 0.2 0.0 0.4 HeadacheÞ Any 54.8 40.8 34.8 Mild 36.1 28.3 24.0 Moderate 16.5 10.7 10.2 Severe 2.1 1.8 0.6 FatigueÞ Any 62.4 44.8 42.9 Mild 39.1 30.8 30.9 Moderate 19.7 12.3 10.9 Severe 3.7 1.7 1.2 ChillsÞ Any 29.0 17.4 15.6 Mild 22.0 13.6 12.5 Moderate 5.6 2.9 3.0 Severe 1.4 1.0 0.1 Muscle pain (other than muscle pain at the injection site)þ Any 42.4 30.5 30.9 Mild 25.7 19.8 21.3 Moderate 13.9 9.3 8.5 Severe 2.8 1.4 1.1 Joint painþ Any 21.6 15.4 17.0 Mild 14.7 11.8 13.7 Moderate 5.9 3.0 3.1 Severe 1.0 0.7 0.2 Figure 6. Percentage of Subjects 11 to <18 years of age reporting systemic adverse reactions affiliated with Trumenba. Source: http://labeling.pfizer.com/showlabeling.aspx?id=1796 7

Besides the listed side effects and their respective severities, Trumenba is also only for use with pregnant women if clearly needed (Pfizer). As the drug has only been approved for four months, it s likely there s not much data if any at all regarding effects on pregnancies. Trumenba is also not suggested for use with children under ten years of age. As time passes, the FDA and Pfizer will certainly gather and aggregate much more data involving this newly released drug, Trumenba. Pfizer also remains responsible for meeting the end goals of Trumenba s usage as delineated in the section on accelerated approval. Whatever litigation may arise over Trumenba and its approval, the United States can rest in the knowledge that there is now a meningococcal subgroup B vaccine available for its citizens. 8

References FDA. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. US Food and Drug Administration, 18 September 2014. http://www.fda.gov/forpatients/approvals/fast/default.htm. Web. 29 January 2015. FDA. Trumenba (Serogroup B Meningococcal Vaccine) Questions and Answers. US Food and Drug Administration. 30 October 2014. http://www.fda.gov/biologicsbloodvaccines/vaccines/questionsaboutva ccines/ucm421128.htm. Web. 04 February 2015. Medina, Genevieve. EXCLUSIVE: Interview with the CDC on the Approval of New Meningitis Vaccine. The Princeton Public Health Review. 4 November 2014. https://pphr.princeton.edu/2014/11/04/exclusiveinterview-with-the-cdc-on-the-approval-of-new-meningitis-vaccine/. Web. 21 February 2015. Mullen, Jewel. Meningococcal disease (bacterial meningitis) - Fact Sheet. Connecticut Department of Public Health, 29 January 2009. http://www.ct.gov/dph/cwp/view.asp?a=3136&q=388352. Web. 04 February 2015. Pfizer. Pfizer Receives FDA Accelerated Approval for TRUMENBA (Meningococcal Group B Vaccine) for the Prevention of Invasive Meningococcal B Disease in Adolescents and Young Adults. Pfizer. http://www.pfizer.com/news/press-release/press-releasedetail/pfizer_receives_fda_accelerated_approval_for_trumenba_meningoc occal_group_b_vaccine_for_the_prevention_of_invasive_meningococcal_b _disease_in_adolescents_and_young_adults. Web. 29 January 2015. Pfizer. Trumenba Labeling. Pfizer. http://labeling.pfizer.com/showlabeling.aspx?id=1796. Web. 26 January 2015. Pfizer. Meningitis B Trumenba (Meningococcal Group B Vaccine) Safety Info. Pfizer. http://www.trumenba.com. Web. 21 February 2015. Schnirring, Lisa. CDC urges vigilance over college meningitis outbreaks. Center for Infectious Disease Research and Policy, 25 November 2013. http://www.cidrap.umn.edu/news-perspective/2013/11/cdc-urgesvigilance-over-college-meningitis-outbreaks. Web. 21 February 2015. 9

Sutter, Sue. Pink Sheet - Pfizer s Meningitis B Vaccine Trumenba Is CBER s First Breakthrough Approval. Friends of Cancer Research, 30 October 2014. http://www.focr.org/news/pink-sheet-pfizer s-meningitis-b-vaccinetrumenba-cber s-first- breakthrough -approval. Web. 29 January 2015. 10