0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letter |

Drug Manufacturers’ Delayed Disclosure of Serious and Unexpected Adverse Events to the US Food and Drug Administration FREE

Paul Ma, PhD1; Iván Marinovic, PhD2; Pinar Karaca-Mandic, PhD3,4
[+] Author Affiliations
1Carlson School of Management, University of Minnesota, Minneapolis
2Graduate School of Business, Stanford University, Palo Alto, California
3Division of Health Policy and Management, University of Minnesota School of Public Health, Minneapolis
4National Bureau of Economic Research, Cambridge, Massachusetts
JAMA Intern Med. 2015;175(9):1565-1566. doi:10.1001/jamainternmed.2015.3565.
Text Size: A A A
Published online

Federal regulations define adverse drug events as those “associated with the use of a drug in humans whether or not considered drug related”.1 Health care professionals and consumers can voluntarily report adverse drug events directly to the US Food and Drug Administration (FDA) or the drug manufacturer. Serious adverse events (AEs) are defined by the regulation as those involving “death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.”1 Unexpected AEs are defined as those involving “any adverse drug experience that is not listed in the current labeling for the drug product.”1 Serious and unexpected events are classified as expedited, and manufacturers receiving any such reports are mandated to forward them to the FDA “as soon as possible but in no case later than 15 calendar days of the initial receipt of the information.”1 The regulation also requests that the manufacturer conduct an investigation and forward findings as follow-up reports to the FDA. Previous studies highlighted that reports by manufacturers to the FDA of serious adverse drug events have increased steadily during the past decade.2,3 Manufacturer compliance with the regulation to report serious and unexpected AEs to the FDA within 15 calendar days is unknown, although some media coverage has offered anecdotal examples of delays.4,5 As the FDA uses this information to update drug warnings, delays in reporting can have important public health consequences, particularly if manufacturers selectively delay reporting based on relevant patient outcomes. We investigated patient and event characteristics associated with manufacturers’ delayed submission of the expedited reports to the FDA.

We extracted the quarterly FDA Adverse Event Reporting System data files of AE reports received between January 1, 2004, and June 30, 2014. We excluded direct reports to the FDA (about 5%) in which drug manufacturers are not involved. Our final sample included only the initial reports (excluding follow-ups) characterized by the FDA as expedited, and therefore subject to the regulation requiring the reports to be submitted within 15 calendar days. Analysis was conducted from May 2014 to May 2015. The University of Minnesota Institutional Review Board determined that this study does not meet the regulatory definition of human subjects research.

Our categorical outcome variable indicated whether the number of calendar days between the date the manufacturer received the report and the date the FDA received the same report from the manufacturer (“days to FDA”) was: 15 days or fewer, 16 to 90 days, 91 to 180 days, or more than 180 days. We estimated a multivariable ordered logit model to examine the association between the categorical outcome variable and whether the AE involved patient death, adjusting for the number of unique drugs the patient was taking, the source of the report to the manufacturer (ie, consumer, physician, pharmacist, lawyer, or other), whether the report was electronically submitted, and patient age, sex, and weight. We included an indicator for the missing values of patient age, sex, and weight. To account for time trends, we included quarter and year indicators, and to account for systematic differences across manufacturers, we included indicators for manufacturers. We clustered standard errors at the drug level to account for correlation within drugs.

The study included 1 613 079 AE reports. Kaplan-Meier estimates show that 9.94% of reports (N = 160 383; 40 464 with patient death and 119 919 without patient death) were not received by the FDA by the 15-day threshold (Figure). Results of the log-rank test rejected the equality of the survivor functions by patient death (P < .001). In multivariable analyses, patient death was associated with delayed reporting (Table). A larger adjusted rate of events without patient death was reported to the FDA within the 15-day threshold relative to those without patient death: 88.25% (95% CI, 86.49% to 90.02%) for events involving patient death vs 90.71% (95% CI, 89.48% to 91.94%) for events without patient death, representing a difference of –2.46% (95% CI, –4.46% to –0.46%). Adjusted rates of reports taking between 16 and 90 days to reach the FDA were 6.42% (95% CI, 5.38% to 7.46%) for events with patient death and 5.19% (95% CI, 4.72% to 5.65%) for events without patient death, representing a difference of 1.23% (95% CI, 0.18% to 2.27%). Similarly, adjusted rates for 91 to 180 days were higher for reports with patient death (2.53% [95% CI, 0.04% to 5.01%] for events with patient death and 1.98% [95% CI, –0.14% to 4.11%] for events without patient death, representing a difference of 0.55% [95% CI, 0.02% to 1.08%]).

Place holder to copy figure label and caption
Figure.
Kaplan-Meier Survival Estimates

Survival estimates of the number of days between the date the manufacturer received the adverse event (AE) report and the date the US Food and Drug Administration (FDA) received the same report from the manufacturer. Log-rank, P < .001. A, Kaplan-Meier estimates from day 1 onward. B, Kaplan-Meier estimates from day 15 onward.

Graphic Jump Location
Table Graphic Jump LocationTable.  Rates of Manufacturers’ Delayed Reporting of Serious and Unexpected Adverse Drug Events to the FDAa

Our analysis provided evidence that drug manufacturers delay reporting of serious AEs to the FDA. Strikingly, AEs with patient death were more likely to be delayed. It is possible that manufacturers spend additional time in verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.

Our findings are likely an underestimate of overall underreporting or misreporting, given the anecdotal evidence of FDA warning letters to manufacturers alleging downward misclassification of serious AEs. While increased enforcement may decrease violations, a simple alternative would be to recommend direct submission of reports to the FDA rather than via the manufacturer. Further research is needed to better understand the mechanisms behind the manufacturers’ delayed reporting and the optimal regulatory policy toward mandatory disclosures of AEs.

Corresponding Author: Pinar Karaca-Mandic, PhD, Division of Health Policy and Management, University of Minnesota School of Public Health, 420 Delaware St SE, Minneapolis, MN 55455 (pkmandic@umn.edu).

Published Online: July 27, 2015. doi:10.1001/jamainternmed.2015.3565.

Author Contributions: Dr Ma had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Obtained funding: Karaca-Mandic.

Administrative, technical, or material support: Ma, Karaca-Mandic.

Study supervision: Ma, Karaca-Mandic.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by research funding from the University of Minnesota Accounting Research Center (Dr. Ma) and grant K01AG036740 from the National Institute of Aging (Dr Karaca-Mandic).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

US Food and Drug Administration. CFR—Code of Federal Regulations, Title 21, Volume 5 (21CFR314.80).http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=314.80. Accessed May 6, 2015.
Moore  TJ, Cohen  MR, Furberg  CD.  Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med. 2007;167(16):1752-1759.
PubMed   |  Link to Article
Weiss-Smith  S, Deshpande  G, Chung  S, Gogolak  V.  The FDA drug safety surveillance program. Arch Intern Med. 2011;171(6):591-593.
PubMed   |  Link to Article
Morgenson  G. Questcor reveals adverse events data for Achtar for first time.New York Times. July 10, 2014.http://www.nytimes.com/2014/07/11/business/questcor-reveals-adverse-events-data-for-acthar-for-first-time.html. Accessed February 26, 2015.
Heavey  S. FDA warns Pfizer for not reporting side effects. June 10, 2010. http://www.reuters.com/article/2010/06/10/us-pfizer-fda-idUSTRE6586PE20100610. Accessed February 26, 2015.

Figures

Place holder to copy figure label and caption
Figure.
Kaplan-Meier Survival Estimates

Survival estimates of the number of days between the date the manufacturer received the adverse event (AE) report and the date the US Food and Drug Administration (FDA) received the same report from the manufacturer. Log-rank, P < .001. A, Kaplan-Meier estimates from day 1 onward. B, Kaplan-Meier estimates from day 15 onward.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Rates of Manufacturers’ Delayed Reporting of Serious and Unexpected Adverse Drug Events to the FDAa

References

US Food and Drug Administration. CFR—Code of Federal Regulations, Title 21, Volume 5 (21CFR314.80).http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=314.80. Accessed May 6, 2015.
Moore  TJ, Cohen  MR, Furberg  CD.  Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med. 2007;167(16):1752-1759.
PubMed   |  Link to Article
Weiss-Smith  S, Deshpande  G, Chung  S, Gogolak  V.  The FDA drug safety surveillance program. Arch Intern Med. 2011;171(6):591-593.
PubMed   |  Link to Article
Morgenson  G. Questcor reveals adverse events data for Achtar for first time.New York Times. July 10, 2014.http://www.nytimes.com/2014/07/11/business/questcor-reveals-adverse-events-data-for-acthar-for-first-time.html. Accessed February 26, 2015.
Heavey  S. FDA warns Pfizer for not reporting side effects. June 10, 2010. http://www.reuters.com/article/2010/06/10/us-pfizer-fda-idUSTRE6586PE20100610. Accessed February 26, 2015.

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

1,901 Views
3 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Jobs