Enhancing Post-Marketing Vaccine Safety Surveillance

Vaccines have long been a key public health strategy against a variety of infectious diseases.[1] In many cases, vaccines are not only highly effective, but cost-saving.[2] This is particularly true when they prevent serious diseases and present a low risk of adverse health effects.[3]

In the United States, vaccine production is regulated by the Food and Drug Administration (“FDA”). Vaccination schedules are set by the Centers for Disease Control and Prevention (“CDC”) following recommendations from the Advisory Committee on Immunization Practices (“ACIP”).[4] A vaccine’s safety and efficacy are estimated through clinical trials prior to regulatory approval.[5]

In post-marketing surveillance, data on suspected vaccine-related injuries are observed and studied after the vaccine is approved and in use.[6] The goal of post-marketing surveillance is to identify risks of injury that may have been too small to observe in clinical trials, but large enough to warrant recalling or reformulating the vaccine or changing recommendations for its use.[7]

Passive Surveillance

Broadly speaking, post-marketing surveillance can be divided into passive and active approaches.[8] In passive surveillance, people who experience vaccine adverse events, or their physicians, can self-report their injuries.[9] The Vaccine Adverse Event Reporting System (“VAERS”) and the Vaccine Injury Compensation Program (“VICP”) are two passive surveillance programs enacted by the National Childhood Vaccine Injury Act (“NCVIA”) of 1986.[10]

VAERS, operated by the CDC and FDA, provides a mechanism for patients to report adverse events they believe resulted from vaccination.[11] Manufacturers are required to report all adverse events[12]; healthcare providers are required to report certain specified adverse events, which vary by vaccine, and encouraged to report any others.[13] VAERS data is publicly available.[14]

For example, in 1999, post-marketing surveillance of the RotaShield® vaccine for rotavirus in children suggested that it increased the risk of intussusception (a dangerous telescoping of the intestines) in infants by 1-2 per 10,000.[15] Although a similar effect was observed in the pre-licensing trials, which involved about 15,000 infants, the risk was too small to be statistically significant.[16] After receiving reports of intussusception through VAERS, the ACIP withdrew its recommendation and the manufacturer voluntarily took the vaccine off the market approximately 14 months after it was initially licensed.[17] However, the CDC could not determine how many infants actually received RotaShield®.[18]

VAERS is often criticized because the data are self-reported by patients, cannot establish the prevalence of reported events, and are limited in their ability to draw conclusions about whether the vaccine was the cause of the injury or whether the two simply co-occurred.[19] VAERS reporting is also associated with the visibility of litigation relating to vaccine injuries.[20] Finally, VAERS records each symptom of a vaccine reaction as a separate adverse event, resulting in a greater number of adverse events than vaccinations.[21]

VICP provides a no-fault adjudication mechanism for compensating those injured by vaccines who can establish their injury.[22] Because VICP publishes summaries of its adjudications,[23] VICP data yields some information about which vaccines have resulted in substantial vaccine-related injuries. However, VICP records only the number and size of compensable litigated judgments and negotiated settlements and the number of dismissed or non-compensable judgments. About 60% of VICP petitions are settled without evidence that the vaccine was the cause of injury.[24]

Active Surveillance

In active surveillance, everyone who is vaccinated is monitored to assess the effects they experience during a fixed period of time.[25] Active surveillance better estimates the incidence of adverse effects, because it includes data from those who receive the vaccine but do not have adverse events.[26] The primary disadvantages of active surveillance are the cost and difficulty of gathering the data, particularly from recipients who experience no ill effects.[27]

Outside the U.S., some countries have robust active surveillance programs based in national patient registry programs.[28] Population-based registries that record vaccination can be used for post-marketing vaccine surveillance.[29] For example, Denmark’s Danish Vaccination Register (“Register”) records all vaccinations administered since 2015 (and many prior). [30] Researchers have used the Register to demonstrate increased risk of deep vein thrombosis associated with the Oxford-AstraZeneca COVID-19 vaccine but not with the Pfizer-BioNTech vaccine.[31]

In the U.S., the patchwork of private care and public and private payment militates against a national registry in most contexts.[32] However, there is growing interest in other active surveillance approaches.

CDC Vaccine Safety Datalink and FDA PRISM/BEST

The CDC’s Vaccine Safety Datalink (“VSD”) project employs active surveillance in collaboration with nine managed care organizations across the United States.[33] The health care organizations provide weekly electronic updates to VSD on vaccinations and any adverse events.[34] Since 2001, data is only available through collaboration with one of the managed healthcare organizations.[35]

In response to the 2009 H1N1 pandemic, the FDA created a similar active surveillance system, the Post-Licensure Rapid Immunization Safety Monitoring (“PRISM”) program.[36] PRISM used the FDA’s Sentinel data system, which obtains data from thirteen partnering health systems and health plans, and is the largest U.S. general population cohort data for vaccine surveillance.[37] Although (and because) Sentinel is larger than VSD, its data are updated only quarterly, rather than weekly.[38] PRISM conducted five vaccine safety analyses between 2014 – 2018.[39] In October 2017, the FDA launched a new component of Sentinel, the Biologics Effectiveness and Safety (“BEST”), that is now the primary mechanism for active surveillance of vaccines.[40]

v-safe

The introduction of vaccines against SARS-CoV-2 during the COVID-19 pandemic prompted the CDC to create and offer a novel opt-in active surveillance system called v-safe.[41] Patients enroll in v-safe using their cell phones and receive periodic text messages asking them to respond to surveys assessing post-vaccine outcomes.[42] If a patient reports a serious health impact, the CDC may follow up directly by phone.[43] The CDC also utilized v-safe enrollment to recruit women who identify themselves as pregnant for its COVID-19 Vaccine Pregnancy Registry to study the safety and effectiveness of vaccination during pregnancy.[44] V-safe was employed again by CDC between 2022 and March 2023 to monitor safety of mpox vaccines.[45]

A study comparing v-safe to VAERS data on COVID-19 vaccination demonstrates the value of the v-safe system. From December 2020 to June 2021, approximately 299 million doses of mRNA (Pfizer or Moderna) COVID-19 vaccines were administered in the US.[46] VAERS included about 341,000 reports of adverse events, 7.9% of which were serious; v-safe included 4.6 million reports of injection-site reactions and 3.6 million reports of systemic reactions among its 7.9 million registered participants, with 1% of participants seeking medical care.[47] That is, opt-in active surveillance identified far more common adverse events, allowed for estimates of incidence, and suggested a lower incidence of serious adverse events than passive surveillance.

Increasing Active Surveillance

Although passive surveillance is important and cost-effective, increased use of active surveillance is likely to benefit vaccine regulators, vaccine researchers, and the public. In an ideal world, near-real-time active surveillance systems would provide regulators with signals of vaccine risk, and also propagate VICP-specified adverse event data to VAERS to support passive surveillance and VICP claims. More recently-designed systems, such as BEST, have the greatest potential for future improvement in these regards, but are limited by the resources required of partnering health care organization to connect their electronic health record systems with BEST’s database.

Federal legislation has increasingly provided mandates and incentives for the rapid adoption of electronic health records and the standardization of electronic health information.[48] Future legislation in this arena could ensure that data specifications are aligned with the needs of BEST’s data model, supporting widespread rapid data transfer. For example, Congress could require health insurance plans subject to the Affordable Care Act to participate in projects to provide data to BEST, or the Centers for Medicare & Medicaid Services could issue regulations to require or incentivize participation of hospitals that receive Medicare reimbursement in similar projects. Funding to support adoption of suitable data standards and participation in BEST could be obtained by employing some of the surplus in the Vaccine Injury Trust Fund.[49]

Vaccine manufacturers may have other important roles to play beyond contributing to the Injury Trust Fund. Professor Efthimios Parasidis suggests that Congress should require manufacturers to engage in rigorous and routine post-marketing collection and analysis of vaccine safety data.[50] These practices could be further encouraged by predicating vaccine manufacturer legal immunity from design-defect suits on compliance with post-marketing safety surveillance.[51]

The capacity to rapidly create and authorize new vaccine products in response to public health needs, as exemplified most recently in the COVID-19 pandemic, emphasizes the importance of equally rapid post-marketing safety surveillance. Despite the fragmented nature of U.S. health care, federal capabilities for active surveillance are developing and represent a promising approach for understanding and limiting risks associated with future vaccines.

[1] Harold M. Schmeck, The New Age of Vaccines, N.Y. Times, April 29, 1984 (§ 6), at 58.

[2] Jane J. Kim, The Role of Cost-Effectiveness in U.S. Vaccination Policy, 365 New Eng. J. Med. 1760, 1760 (2011).

[3] See Mondher Toumi & Walter Ricciardi, The Economic Value of Vaccination: Why Prevention is Wealth, 3 J. Mkt. Access & Health Pol’y 29204, 1 (2015) (introducing special issue reviewing economic impacts of vaccination).

[4] Larry K. Pickering et al., FDA Licensure of and ACIP Recommendations for Vaccines, 35 Vaccine 5027, 5027-29 (2017).

[5] Vaccine Development – 101, U.S. Food & Drug Admin. (12/14/2020), www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101.

[6] Id.

[7] See Nikhil Raj et al., Postmarket Surveillance: A Review on Key Aspects and Measures on the Effective Functioning in the Context of the United Kingdom and Canada, 10 Therapeutic Advances in Drug Safety 2042098619865413, 1 (July 29, 2019), journals.sagepub.com/doi/10.1177/2042098619865413 (describing purposes of post-marketing surveillance). For example, events that are too rare to observe in a clinical trial of 30,000 patients may emerge during routine use in 500,000 patients.

[8] See COVID-19 Vaccine Safety Surveillance, U.S. Food & Drug Admin., www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/covid-19-vaccine-safety-surveillance (last visited April 14, 2022) (describing surveillance approaches in the context of COVID-19 vaccines).

[9] Id.

[10] Pub.L. 99–660, Title III, Nov. 14, 1986, 100 Stat. 3755, codified at 42 USC § 300aa-1 through -33 (West).

[11] U.S. Dep’t of Health & Hum. Serv., About VAERS, Vaccine Adverse Event Reporting System, vaers.hhs.gov/about.html (last visited April 8, 2022).

[12] 21 C.F.R. § 600.80 (2022).

[13] U.S. Dep’t of Health & Hum. Serv., Frequently Asked Questions (FAQs), Vaccine Adverse Event Reporting System, vaers.hhs.gov/faq.html; 42 U.S.C.A. § 300aa-25 (West) (mandating reporting by health care providers) (last visited April 8, 2022).

[14] See, U.S. Dep’t of Health & Hum. Serv., Guide to Interpreting VAERS Data, Vaccine Adverse Event Reporting System,  https://vaers.hhs.gov/data/dataguide.html (last visited April 8, 2022).

[15]Rotavirus Vaccine (RotaShield®) and Intussusception, Ctrs. for Disease Control and Prevention, www.cdc.gov/vaccines/vpd-vac/rotavirus/vac-rotashield-historical.htm (last visited April 8, 2022).

[16] Id.

[17] Id.; Cf. Jason L. Schwartz, The First Rotavirus Vaccine and The Politics of Acceptable Risk, 90 Milbank Q. 278, 281-91 (2012) (detailing the approval and withdrawal process for RotaShield®).

[18] Ctrs. for Disease Control and Prevention, supra note 15.

[19] See, e.g., Weigong Zhou et al., Surveillance for Safety After Immunization: Vaccine Adverse Event Reporting System (VAERS) — United States, 1991–2001, 52/SS-1 Morbidity & Mortality Wkly. Rep. 1, 7-8 (2003) (reviewing limitations of VAERS and noting that “differentiating causal from coincidental conditions by using VAERS data alone usually is not possible”).

[20] Michael J. Goodman & James Nordin, Vaccine Adverse Event Reporting System Reporting Source: A Possible Source of Bias in Longitudinal Studies, 117 Pediatrics 387, 389 (2006) (demonstrating increased reporting in VAERS for vaccines following litigation, including reports submitted by attorneys).

[21] Inst. of Med. (U.S.) Comm. To Study New Rsch. On Vaccines, Case Reports and Passive Surveillance, in Research Strategies for Assessing Adverse Events Associated with Vaccines: A Workshop Summary (KR Stratton, CJ Howe, & RB Johnston Jr. eds., 1994), https://www.ncbi.nlm.nih.gov/books/NBK231536/.

[22] 42 U.S.C.A. § 300aa-15 (West). When VICP is liable, it is secondarily liable, after any state programs or health insurance coverage.

[23] Vaccine Injury Compensation Data, Health Res. & Servs. Admin., www.hrsa.gov/vaccine-compensation/data/index.html (last visited April 8, 2022).

[24] Id.

[25] U.S. Food & Drug Admin., supra note 5.

[26] See Zhike Lui et al., Active Vaccine Safety Surveillance: Global Trends and Challenges in China, 2021 Health Data Sci. 9851067, 1 (2021) (explaining the value of active surveillance in drawing causal conclusions about vaccine safety).

[27] See Gaël Dos Santos, Challenges in implementing yearly enhanced safety surveillance of influenza vaccination in Europe: lessons learned and future perspectives, 15 Human Vaccines & Immunotherapeutics 2624, 2634 (2019) (describing logistical challenges in active surveillance for seasonal flu vaccines).

[28] See Patient Registries, in ENCePP Guide on Methodological Standards in Pharmacoepidemiology (July 2021), Eur. Network of Ctrs. For Pharmacoepidemiology & Pharmacoviligance, www.encepp.eu/standards_and_guidances/methodologicalGuide4_3.shtml (describing different types of registries).

[29] See Alexandra Pacuraiu et al., Imposed Registries within the European Postmarketing Surveillance system: Extended Analysis and Lessons Learned for Regulators, 27 Pharmacoepidemiology and Drug Safety 823, 825 (2018) (noting that registries do not always routinely collect information needed for post-marketing research studies, particularly with respect to specific diseases).

[30] The Danish Vaccination Register, Copenhagen Healthtech Cluster, www.danishhealthdata.com/find-health-data/Det-Danske-Vaccinationsregister (last visited April 8, 2022); see T. Grove Krause et al., The Danish Vaccination Register, 17 Eurosurveillance 20155 (2012) (describing history of the register).

[31] Anders Hviid et al., Association of AZD1222 and BNT162b2 COVID-19 Vaccination with Thromboembolic and Thrombocytopenic Events in Frontline Personnel: A Retrospective Cohort Study, Annals of Internal Med. (Feb 1, 2022), doi.org/10.7326/M21-2452.

[32] One exception is the Veterans Health Administration, where military veterans can receive government-provided care through a national network of hospitals and clinics that share a common medical record and registry of veterans who apply to receive care. See generally Veterans Health Administration, U.S. Dep’t of Veterans Affs., www.va.gov/health/ (last visited April 14, 2022) (introducing the VA health care system). However, the VA does not require reporting of adverse drug events, although it encourages its providers to do so; when a vaccine adverse event is reported to the VA, the report is forwarded to VAERS. U.S. Dep’t of Veterans Affs., VHA Directive 1070: Adverse Drug Event Reporting and Monitoring (May 15, 2020).

[33] Vaccine Safety Monitoring – VSD, Ctrs. For Disease Control & Prevention, www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html (last visited April 8, 2022).

[34] Id.

[35] How to Access Data from the Vaccine Safety Datalink, Ctrs. For Disease Control & Prevention, www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/accessing-data.html (last visited April 8, 2022).

[36] Michael Nguyen et al., The Food and Drug Administration’s Post-Licensure Rapid Immunization Safety Monitoring Program: Strengthening the Federal Vaccine Safety Enterprise, 21 Pharmacoepidemiology & Drug Safety 291, 291-92 (2012).

[37] See generally R. Ball et al., The FDA's Sentinel Initiative—A Comprehensive Approach to Medical Product Surveillance, 99 Clinical Pharmacology & Therapeutics 265 (2016) (providing history and overview of Sentinel). Sentinel contains 360 million unique patient identifiers as of 2021 (although identifiers are health plan-based, thus the same individual may have multiple identifiers in Sentinel if they change insurance plans). Sentinel Initiative, Key Database Statistics, Sentinel, www.sentinelinitiative.org/about/key-database-statistics (last visited April 9, 2022). Sentinel’s authorizing legislation is the FDA Amendments Act of 2007, with the relevant provisions codified at 21 U.S.C.A. § 355(k) (West).

[38] Id.

[39] See Sentinel Initiative, Vaccines, Blood, & Biologics Studies, Sentinel, www.sentinelinitiative.org/studies/vaccines-blood-biologics (last visited April 8, 2022) (providing a searchable table of available reports). PRISM’s reports include three on flu vaccine (examining pregnancy outcomes, febrile seizures, and general surveillance methods), one on HPV vaccine and venous thromboembolism, and one on rotavirus vaccines and intussusception.

[40] Background, BEST, www.bestinitiative.org/best/about/background (last visited April 9, 2022).

[41] v-safe After Vaccination Health Checker, Ctrs. For Disease Control & Prevention (Jan 20, 2022), www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html.

[42] Id.

[43] Note, however, that a voluntary system like v-safe that relies on vaccine recipient surveys will not capture the most serious of adverse events, such as death or disability that prevents the user from responding to the survey.

[44] v-safe COVID-19 Vaccine Pregnancy Registry, Ctrs. for Disease Control & Prevention (April 12, 2022), www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafepregnancyregistry.html.

[45] See Smallpox/Monkeypox VIS, Ctrs. For Disease Control & Prevention (Nov. 14, 2022), www.cdc.gov/vaccines/hcp/vis/vis-statements/smallpox-monkeypox.html (need parenthetical here); see also Frequently Asked Questions and Troubleshooting, Ctrs. For Disease Control & Prevention (last updated Mar. 22, 2023), www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/v-safe/faqs.html (noting that v-safe for mpox enrollment closed March 21, 2023).

[46] See Hannah G. Rosenblum et al., Safety of mRNA Vaccines Administered During the Initial 6 Months of the US COVID-19 Vaccination Programme: An Observational Study of Reports to the Vaccine Adverse Event Reporting System and v-safe, Lancet Infectious Disease 1, 2-3, 9 (March 7, 2022), https://doi.org/10.1016/S1473-3099(22)00054-8 (noting that COVID-19 vaccination was unusual in the U.S. in that the Federal government tracked doses administered rather than distributed).

[47] Id. at 3-6.

[48] E.g., Health Information Technology for Economic and Clinical Health (HITECH) Act, Title XIII of Division A and Title IV of Division B of the American Recovery and Reinvestment Act of 2009 (ARRA), Pub. L. No. 111-5, 123 Stat. 226 (Feb. 17, 2009) (codified at 42 U.S.C. §§300jj-31 to -38) (incentivizing meaningful use of electronic health records and directing the Office of the National Coordinator for Health Information Technology to promulgate standards).

[49] See Efthimios Parasidis, RECALIBRATING VACCINATION LAWS, 97 B.U. L. Rev. 2153, 2239 (2017) (noting the surplus in the trust fund and suggesting using a portion for vaccine research and development).

[50] Id. at 2227.

[51] Id. at 2228-30. This would require legislation replacing the Supreme Court’s broad immunity interpretation in Bruesewitz v. Wyeth LLC, 562 U.S. 223 (2011) with a statutory framework for pre-empting state tort claims for compliant manufacturers.