Abstract
An increase in new drugs first launched in the U.S. and shorter lags between first global drug launch and U.S. approval indicate that the U.S. drug lag has declined. This paper examines the impact of these changes on drug safety using adverse drug reaction data for FDA-approved drugs in 1990 to 2004. Results show two different effects. First, drugs having longer U.S. launch lags (more foreign market experience) have fewer post approval drug risks compared to drugs with shorter launch lags. This result implies that foreign market experience prior to U.S. entry provides information to help alleviate drug-related risks for U.S. patients. Second, drugs that are first launched in the U.S. have fewer serious drug reactions compared to those that were first launched abroad. This result is surprising, and may suggest that first U.S. drug launch signals information about unobserved application quality, which translates into lower post approval drug risks.
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Notes
Grabowski and Wang report finding a negative and insignificant coefficient for a first foreign drug launch variable in a sensitivity test in their paper. However, their test did not include a variable for a drug’s U.S. launch lag so they did not simultaneously examine the relative effect of each factor on adverse drug reactions.
They found the greatest lags for respiratory (5.1 years), cardiovascular (3.2 years), central nervous system (3.2 years), and anticancer (2.9 years) drugs.
The agency has generally interpreted “substantial evidence” to mean evidence from two large-scale controlled clinical studies instead of one, although the FDA has relaxed this requirement in recent years.
Abraham and Davis (2005) found that the U.S. FDA regulation delayed or prevented the approval of risky drugs into the U.S. market compared to the United Kingdom.
Most new drug compounds are typically patented prior to the submission of an NDA.
The threat of lawsuits from harm caused by serious drug-related side effects can also raise firms’ expected costs of U.S. drug launches (Philipson and Sun 2008).
See Letter from David A. Kessler, M.D., Comm. of Food and Drugs, to Rep. John D. Dingell & Rep. Norman Lent (Sept. 14, 1992), 138 Cong. Rec. H9099-9100 (daily ed. Sept. 22, 1992).
For all PDUFA performance goals, see http://www.fda.gov/ope/pdufa/report95/appenda.html.
Meetings were used to resolve disputes with sponsors, respond to sponsor questions about study protocols, or develop agency guidances. PDUFA II also contained a provision to allow the FDA to accept a single well-controlled clinical study in some cases instead of two.
PDUFA III maintained the review deadlines and timetables for sponsor meetings, and it expanded FDA interactions with sponsors during the development and review phases.
Grabowski and Wang (2006) report that while first drug launches among NCEs in the U.S. increased from 44 in 1982–1992 to 156 in 1993–2003, they declined in the EU from 260 in 1982–1992 to 151 in 1993–2003.
The increase includes drugs that were first launched abroad and approved by FDA in the same year.
The analysis will also examine selected interactions of interest.
Approval actions taken by foreign regulators may signal information to FDA regulators to inform their approval decisions. Once a drug is approved somewhere, the political pressures on the FDA from U.S. patient groups and firms to approve that drug will increase.
This does not suggest that clinical trials reveal no useful safety information. It only suggests longer IND phases may not reveal the kind of risk information that emerges with widespread use after approval such as information about relatively rare side effects, side effects observed in under-studied populations (i.e. children, women of child-bearing age, the elderly), and side effects due to drug interactions. Post-marketing drug safety surveillance, not clinical studies, often detects such information.
Focusing on the first 2 years after approval also limits reporting bias arising from differences in the length of time that drugs have been on the market.
For drugs first approved and launched in the U.S., the launch lag is equal to zero.
This includes the time that regulators spend reviewing the application and the time that firms take to respond to regulator requests for information following NDA submission.
Orphan drug status is designated for diseases that affect fewer than 200,000 patients. Since some orphan diseases like ALS affect only 1–2 per 100,000, the use of such drugs may not be reflected in even large health surveys like the MEPS.
Prior to 1992, the FDA used the A, B, C, AA, system. Drugs rated A, B, and AA (for AIDS drugs) were defined as having some therapeutic advance over existing remedies. For this reason, drugs having an A, B, and AA rating are assumed to have a priority designation. Drugs given a C rating were defined as offering no therapeutic gain over existing remedies, which is how S rated drugs are defined.
Drugs receiving standard ratings offer little gain over existing remedies, and hence are not considered as urgent.
Subpart E consists of procedures to help facilitate the development and submission of NDAs for life-threatening or debilitating illnesses. Accelerated approvals, which target the same patient populations, are permitted to use surrogate endpoints other than survival or morbidity in some clinical studies.
Accelerated approvals are also given priority or standard ratings, which determine their drug review deadlines.
This analysis includes the seventeen disease classifications in Olson (2008) plus new classifications for: erectile dysfunction, overactive bladder, kidney disease, and insomnia. Additional drug approvals in these four classes in 2002 to 2004 increased cell sizes for the condition effect. Disease classifications were made based on the information from a drug’s label and approved indication and then confirmed by online medical sources (i.e. WebMD). The omitted case is an ‘other’ category, which consists of drugs that had small cells and didn’t fit into existing classifications. Other includes 15 drugs representing enzyme deficiency (1), poisoning remedies (2), weight loss (2), stimulant for excessive sleepiness (2), psoriasis (1), a metabolic disorder (1), hypodermoclysis (2), urea cycle disorder (1), a drug to reduce pupil size (1), Sjogren’s Syndrome (1), and a drug for intravenous use in MRI (1).
These variables provide ex post control for heterogeneity in the age and gender mix of patients reflected in the ADR counts.
The FDA’s adverse event reporting system was designed as an alert system for serious unanticipated drug risks or new risks not detected in clinical trials and regulators especially encourage the reporting of such risks through this system.
Olson (2008) finds that once review time and the other explanatory variables are controlled for, a PDUFA regime variable is not associated with post approval ADRs.
The frequency distributions for other counts are similar. Since 2 year cumulative counts are used in the analysis, most drugs have positive counts. Only 7.6% of the drugs have zero serious ADR counts, 10% of the drugs have zero ADR hospitalization counts, and 20% have zero ADR death counts.
The FDA does not make information available about drugs that were not approved in the U.S. so those drugs are not included in the analysis.
The FDA changed the name in October 1997 from the SRS to AERS. Both contain similar information although in AERS, both primary and secondary suspect drugs are included in each report. In the SRS the FDA only requested the name of the drug suspected of causing the adverse event, and did not list any secondary suspect drugs.
ADRs that cite the generic name can be attributed to the branded drug since generic versions of these drugs are not available until after patent expiration.
I thank Margaret Kyle for sharing this data with me. The PharmaProjects database is maintained by the UK consulting firm PJB Publications. Data from IMS R&D focus has the month and year of first launch. When data on first drug launch were missing in these sources, first launch country and/or first launch year were obtained from Tufts Center for the Study of Drug Development for the 1993-1998 approvals or the FDA for other years.
For the 1999 to 2004 approvals, monthly launch lags are also calculated and used in sensitivity tests.
The analysis does not consider supplemental NDAs, which may represent a different formulation of an NCE.
I thank Ernst Berndt for sharing his data on IND submission dates for NCEs approved from 1990 to April 2004. I thank Roy Castle at the FDA for providing the IND submission dates for the remaining drugs, May to December 2004 approvals.
National Cancer Institute’s SEER database, 1985–1989 data, was used to code fatal for different cancers. These determinations were similar using the 1993–1997 SEER data. Fatal determinations for the remaining diseases were based on major journal articles prior to a drug’s approval (i.e. 1990 data were used for AIDS). National Center for Health Statistics at the Centers for Disease Control was used for AIDs opportunistic infections. Information from an ALS organization was used to code ALS as fatal.
Results are not sensitive to the exclusion of these six drugs. The signs and significance of the key results were the same as in Table 3 when the drugs with the truncated ADR counts were included.
First drug launches in the EU account for 149 of the NCEs first launched abroad while non EU countries including Japan account for the remaining 79 NCEs first launched abroad.
The sensitivity of the above results to the use of monthly lags will be examined in the next section.
These results are less precisely measured than those using the actual launch lag.
Companies could be launching a greater number of less novel (and less risky) drugs (me too drugs) first in the U.S., which could provide an alternative explanation for why first U.S. launches are associated with fewer ADRs. The coefficient for the first U.S. launch variable in each regression will reveal the extent to which novel and non novel first U.S. drug launches are associated with fewer ADRs.
In the analyses of less novel (standard) drugs only, the coefficients (standard errors) for first U.S. launch are −.54 (.22) and −.59 (.21) in the serious ADR and ADR hospitalization regressions, respectively. Both are significant at the .01 level. In the analyses of novel drugs only, the coefficients for first U.S. launch are −.53 (.25) and −.49 (.25) in the serious ADR and ADR hospitalization regressions, respectively. Both are significant at the .05 level.
44 In the alternative regression for ADR deaths, FDA review time is negative and weakly significant at the .1 level.
The coefficients for black box are significant in the expressions for serious ADRs and ADR hospitalizations, but not ADR deaths.
Eleven drugs, Fosamax, Lipitor, Taxotere, Aricept, Celebrex, Viagra, Vioxx, Exelon, Reminyl, Namenda, and Lyrica had predicted counts greater than two standard deviations above the mean predicted count.
Data show that more novel drugs were first launched in the U.S. than less novel drugs.
Among those missing month of launch, fifteen had annual launch lags over 5 years.
Philipson et al. (2008) estimate large welfare gains for consumers from faster FDA drug reviews, but they do not account for the effects of third party insurance on drug prices. Estimated consumer welfare is likely to be overstated with insurance because consumer demand does not reflect the marginal benefit to consumers.
PDUFA V also contained new provisions to accelerate the development and approval of new antibiotics and drugs serving unmet medical needs for life threatening or rare diseases.
References
Abraham, & J., Davis C. (2005). A comparative analysis of drug safety withdrawals in the UK and U.S. (1971–1992): Implications for current regulatory thinking and policy. Social Science and Medicine, 61, 881–892.
Carson, J., Strom B., Maislin G. (1994). Pharmacoepidemiology, 2nd ed. (B. Strom, Ed.) New York: Wiley.
Center for Drug Evaluation and Research, Food and Drug Administration (1996). The clinical impact of adverse event reporting. A MedWatch continuing education article.
Danzon, P., & Epstein A. (2009). Effects of regulation on drug launch and pricing in interdependent markets. NBER working Paper # 14041.
David, G, Markowitz S., Richards-Shubik S. (2010). The effects of pharmaceutical marketing and promotion on adverse drug events and regulation. American Economic Journal: Economic Policy, 2(4), 1–25.
DiMasi, J., Hansen R., Grabowski H. (2003). The price of innovation: new estimates of drug development costs. Journal of Health Economics 22(2), 151–185.
Grabowski, H., & Wang Y. (2006). The quantity and quality of worldwide new drug introductions, 1982–2003. Health Affairs 25(2), 452–460.
Grabowski, H., & Wang Y. (2008). Do faster Food and Drug Administration drug reviews adversely affect patient safety? An analysis of the 1992 prescription drug user fee act. Journal of Law and Economics 51(2), 377–406.
Grabowski, H., Vernon J., Thomas L. (1978). Estimating the effects of regulation on innovation: an international comparative analysis of the pharmaceutical industry. Journal of Law & Economics 21(1), 133–163.
Institute of Medicine Committee on the Assessment of the U.S. Drug Safety System. 2007. The future of drug safety: Promoting and protecting the health of the public. Washington, DC: National Academy Press.
Kaitin, K., & Brown J. (1995) A drug lag update. Drug Information Journal 29(2), 361–73.
Kaitin, K., & Manocchia M. (1997). The new drug approvals of 1993, 1994, and 1995: Trends in drug development. American Journal of Therapeutics 4(1), 46–54.
Kaitin, K., & Healy E. (2000). The new drug approvals of 1996, 1997, and 1998: drug development trends in the user fee era. Drug Information Journa l34, 1–14.
Kaitin, K., & Cairns C. (2003). The new drug approvals of 1999, 2000, and 2001: drug development trends after the passage of the prescription drug user fee act of 1992. Drug Information Journal 37, 357–371.
Kaitin, K., Mattison N., Northington F., Lasagna L. (1989). The drug lag: an update of new drug introductions in the United States and in the United Kingdom, 1977 through 1987. Clinical Pharmacology & Therapeutics 46(2), 121–38.
Kaitin, K., Manocchia M., Seibring M., Lasagna L. (1994). The new drug approvals of 1990, 1991, and 1992: Trends in drug development. The Journal of Clinical Pharmacology 34, 120–127.
Kyle, M. K. (2006). The role of firm characteristics in pharmaceutical product launches. RAND Journal of Economics 37(3), 602–618.
Kyle, M. K. (2007). Pharmaceutical price controls and entry strategies. Review of Economics and Statistics 89(1), 88–99.
Lanjouw, J. O. (2005). Patents, price controls and access to new drugs: how policy affects global market entry. NBER working paper #11321.
Olson, M. K. (1997). Firm characteristics and the speed of new drug approval. Journal of Economics and Management Strategy 6(2), 377–401.
Olson, M. K. (2004a). Managing delegation with user fees: Reducing delay in new drug review. Journal of Health Politics, Policy, and Law 29(3), 397–430.
Olson, M. K. (2004b). Are novel drugs more risky for patients than less novel drugs? Journal of Health Economics 23(6), 1135–1158.
Olson, M. K. (2008). The risk we bear: The effects of review speed and industry user fees on drug safety. Journal of Health Economics 27(2), 175–200.
Olson, M. K. (2009) PDUFA and initial U.S. drug launches. Michigan Telecommunications and Technology Law Review 15(2), 393–414.
Peltzman, S. (1973). An evaluation of consumer protection legislation: 1962 drug amendments. Journal of Political Economy 81, 1049–1091.
Philipson, T., & Sun E. (2008). Is the Food and Drug Administration safe and effective? Journal of Economic Perspectives 22, 85–102.
Philipson, T., Berndt E., Gottschalk A., Strobeck M. (2008). Cost-benefit analysis of the FDA: the case of the prescription drug user fee acts. Journal of Public Economics 92(5–6), 1306–1325.
Wardell, W. M. (1978) The drug lag revisited: Comparison by therapeutic area of patterns of drugs marketed in the United States and Great Britain from 1972 through 1976. Clinical Pharmacology & Therapeutics 24, 499–524.
Wooldridge, J. (2002). Econometric analysis of cross section and panel data. Cambridge: MIT Press.
Yamada, T., Kusama M., Hirai Y., Arnold F., Sugiyama Y., Ono S. (2010). Analysis of pharmaceutical safety-related regulatory actions in Japan: Do tradeoffs exist between safer drugs and launch delay? The Annals of Pharmacotherapy 44: 1976–1985.
Acknowledgments
I thank Margaret Kyle and Ernst Berndt for generously sharing their data with me, Roy Castle at the FDA for providing additional data, and Emily Karwat for assisting in the collection of firm data. I gratefully acknowledge helpful comments from seminar participants from Tulane, the Legal and Regulatory Issues in Pharmaceutical Research conference at Harvard, Sara Markowitz, the editor, and an anonymous referee. This project also benefited from valuable research support from the Murphy Institute of Political Economy at Tulane.
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Olson, M.K. Eliminating the U.S. drug lag: Implications for drug safety. J Risk Uncertain 47, 1–30 (2013). https://doi.org/10.1007/s11166-013-9169-5
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DOI: https://doi.org/10.1007/s11166-013-9169-5