Pharmacovigilance activities in the United States, European Union and Japan: Harmonic convergence or convergent evolution?

Food and Drug Law Journal

Volumn 63, Issue 3, 2008, Pages

  Faden, Laura B ^a   Milne, Christopher Paul ^b  

^a HARVARD UNIVERSITY   (United States)

^b TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG APPROVAL; DRUG COST; DRUG EFFICACY; DRUG INDUSTRY; DRUG MARKETING; DRUG MONITORING; DRUG QUALITY; DRUG RESEARCH; DRUG SAFETY; DRUG SURVEILLANCE PROGRAM; EUROPEAN UNION; FOOD AND DRUG ADMINISTRATION; JAPAN; PATIENT SAFETY; REVIEW; RISK ASSESSMENT; RISK BENEFIT ANALYSIS; RISK MANAGEMENT; RISK REDUCTION; UNITED STATES; WORLD HEALTH ORGANIZATION;

DRUG MONITORING; EUROPEAN UNION; GOVERNMENT REGULATION; HUMANS; INTERNATIONAL COOPERATION; INTERNATIONALITY; JAPAN; PHARMACOEPIDEMIOLOGY; PRODUCT SURVEILLANCE, POSTMARKETING; RISK MANAGEMENT; SAFETY; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 51149113736     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (84)

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8. Ray Hill, The Japanese Pharmaceutical Industry - On the Road to Change, Excerpts from Think On magazine, Altana AG (on file at Tufts CSDD), at 17-20.
9. Center for Drug Evaluation and Research (CDER) CDER Report to the Nation 2003, available at: http://www.fda.gov/cder/reports/rtn/2003/rtn2003- 3.HTML;
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12. Ebr Despriya & Iwase Nobutada, Stigma of mental illness in Japan (Correspondence), 359 THE LANCET 1866 (May 25, 2002).
13. See for example: The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of pharmaceutical product registration and produce guidelines in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines;
14. See also as another example, WHO Programme for International Drug Monitoring, which collects and assesses reports of adverse drug reactions and alerts regulatory authorities in member countries (84 official member and 24 associate member countries).
15. WHO Policy Perspectives on Medicines: Pharmacovigilance: Ensuring the Safe Use of Medicines, WHO (Oct. 2004), available at: http://www.who-umc.org/graphics/7128.pdf.
16. Harmonic Convergence was a new age spiritual event that occurred in the late 1980s when groups of people gathered at various mystical places all over the world to usher in a new age of co-operation, the coming of which was ascertained by consulting sources from three regions - the Maya Calendar from the Americas as well as European and Asian astrology. Convergent Evolution is a concept from evolutionary biology that describes a process whereby organisms that are not closely related evolve similar traits as a result of having to adapt to a similar environment. (Source: Wikipedia).
17. P.L. 107-188 (Public Health Security and Bioterrorism Preparedness Response Act of 2002), commonly referred to as PDUFA III. The Prescription Drug User Fee Act (PDUFA I) was originally enacted in 1992 (Pub. L. No. 102-571) and has been reauthorized every five years as the Food and Drug Administration Modernization Act of 1997 (FDAMA/PDUFA II) (Pub. L. No. 105-115), the Public Health Security and Bioterrorism Preparedness of 2002 and Response Act (PDUFA III)(Public Law 107-188), and the Food and Drug Administration Amendments Act of 2007 (FDAAA/PDUFA IV) (Pub. L. No 110-185).
18. See FDA Guidance for Industry: Premarketing Risk Assessment, (Mar. 2005), http://www.fda.gov/CDER/guidance/6357fnl.htm;
19. FDA Guidance for Industry: Development and Use of Risk Minimization Action Plans, (Mar. 2005), http://www.fda.gov/cder/Guidance/6358fnl.htm;
20. FDA Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment, (Mar. 2005), http://www.fda.gov/Cder/ Guidance/63590CC.htm.
21. See id., the Premarketing Risk Assessment (Premarketing Guidance) and the Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment (Pharmacovigilance Guidance) address pre- and postmarketing risk assessment, respectively, and the Development and Use of Risk Minimization Actions Plans (RiskMAP Guidance) addresses postmarketing risk minimization.
22. P.L. 110-185.
23. P.L. 105-115 and P.L. 107-188, respectively.
24. FDA Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment (Mar. 2005), http://www.fda.gov/Cder/ Guidance/63590CC.htm.
25. 21 CRF 314.80.
26. See P.L. 110-185, Title IX, Subtitle B, § 921 (121 STAT. 962), amending 21USC 355.
27. FDA Guidance for Industry: Development and Use of Risk Minimization Action Plans, (Mar. 2005), http://www.fda.gov/cder/Guidance/6358fhl.htm.
28. Id.
29. Id.
30. See P.L. 110-185, Title IX, Subtitle A, § 901 (121 STAT. 926), amending FDA Act by adding § 505-1.
31. 21 U.S.C. 356.
32. See 21 CFR § 314.510 and 21 CFR § 314.53021 U.S.C. 356 in which FDA approves drugs based on a surrogate clinical endpoint and then requires PMCs to verify safety and efficacy once the drug is on market.
33. See 21 CFR § 314.55 in which FDA requires applicants of all new drugs likely to be used in pediatric patients to demonstrate safety and efficacy in pediatric populations prior to approval. In some cases, FDA will grant deferral of this requirement and require the sponsor to conduct PMCs.
34. See 21 CFR § 314.610 and 21 CFR § 314.620 stating that if clinical studies in humans cannot be conducted ethically, FDA may approve a drug solely on animal studies and require the sponsor to conduct PMCs to verify safety and efficacy in humans.
35. FDA's Monitoring of Postmarketing Study Commitments, Office of Inspector General (OIG), Department of Health and Human Services (HHS), (June 2006), http://www.oig.hhs.gov/oei/reports/oei-01-04-00390.pdf.
36. 21 U.S.C. § 356b.
37. Marc-Andre Gagnon and Joel Lexchin, The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States. 5 PLOS MEDICINE 1-5 (Jan. 2008), available at www.plosmedicine.org.
38. 21 U.S.C. §§ 355(e) and 355(k).
39. See P.L. 110-185, Title IX, Subtitle A, § 902 (121 STAT. 943).
40. Directive 2001/83/EC Article 8(3)(ia).
41. EC No. 726/2004 (30).
42. Regulation EC No. 726/2004 Article 9(4).
43. Regulation EC No. 726/2004 Article 127.
44. Directive 2001/83/EC Title IX; Regulation EC No. 726/2004 Title II, Chapter 3.
45. Directive 2001/83/EC, Article 103.
46. All human medicine product applications are reviewed by the Committee for Medicinal Products for Human Use (CHMP) within the EMEA. The CHMP is responsible for preparing the agency's opinions on all questions concerning medicinal products for human use, in accordance with Regulation (EC) No 726/2004. For the remainder of the article, although the EMEA is referred to in general, all pharmacovigilance decisions are made by the CHMP.
47. Regulation EC No. 726/2004 Title II, Chapter 3, Article 23(3).
48. CHMP, EMEA, Post-Authorization Guidance:Human Medicinal Products (June 2007). The EMEA itself has very few scientific resources of its own. Therefore it must regularly make use of the experts of the national regulatory agencies of its member states. It appoints so-called rapporteurs and co-rapporteurs from the members of the CHMP to provide expert evaluations. Rapporteurs and co-rapporteurs draw up expert scientific opinions on the medicinal products in question, which are then used as the basis for deciding whether marketing authorization should be granted by the European Commission (EC). See also note 42.
49. Regulation EC No. 726/2004 Title II, Chapter 3, Article 23(3).
50. Directive 2001/83/EC Article 8(3)(ia).
51. Guideline on Risk Management Systems for Medicinal Products for Human Use, EMEA/CHMP/96268/2005.
52. Pharmacovigilance Planning E2E, ICH Harmonized Tripartite Guideline.
53. See Guideline on Similar Biological Medicinal Products, EMEA/CHMP/43704/2005. Biosimilars are biologies similar in molecular and biological terms to an original reference medicinal product, which has been granted a marketing authorization in the EU.
54. EMEA Risk Management Guideline, supra note 47.
55. The Scientific Advice Working Group (SAWP) is composed of professionals with both wide-ranging and specific expertise such as preclinical safety, pharmacokinetics, as well as knowledge of therapeutic areas, who advise product sponsors during the development phase and serve under the auspices of the CHMP. See also note 42.
56. Directive 2001/83/EC, Article 1(15).
57. Directive 2001/83/EC, Article 8(3)(ia).
58. Volume 9A of The Rules Governing Medicinal Products in the EU, Guidelines on Pharmacovigilance for Medicinal Products for Human Use (Part 1, Section 7)
59. EMEA Post-Authorization Guidance, supra note 44
60. EC No 726/2004, Article 14 (7).
61. Approval under Exceptional Circumstances is granted when comprehensive data cannot be provided (and sponsor is unlikely to ever be able to assemble full data package necessary for "normal" marketing authorization) because of specific circumstances such as rarity, medical ethics and the state of scientific knowledge. See Francesco Pignatti, EMEA Current Thinking on Conditional Marketing Authorization (Presentation), (8 Nov. 2005).
62. EC No 726/2004, Article 14 (7).
63. Conditional Marketing Authorizations are granted when a sponsor can demonstrate a positive risk-benefit balance based on preliminary evidence from an ultimately comprehensive development program that will provide the missing data necessary for "normal" marketing authorization See Francesco Pignatti, EMEA Current Thinking on Conditional Marketing Authorization (Presentation), (8 Nov. 2005).
64. EC No 726/2004, Article 14 (2).
65. EC No 726/2004, Article 14 (3).
66. EMEA Post-Authorization Guidance, supra note 44.
67. EC No 658/2007.
68. 2008.3 Information in English on Japan Regulatory Affairs: Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association: English Regulatory Information Task Force, (March 2008), available at: http://www.jpma.or.ip/english/.
69. Id.
70. Id. at 120.
71. ICH Pharmacovigilance Guideline, supra note 48.
72. MedDRA website, available at http://www.meddramsso.com/MSSOWeb/ index.htm.
73. Information in English on Japan Regulatory Affairs, supra note 64, at 119.
74. Positive Benefit-Risk Is EMEA's Post-Market Drug Safety Watchword, [THE PINK SHEET] DAILY, (June 27, 2008), (Volume 20, Issue 125, Number 001).
75. Managing the Risks from Medical Product Use: Creating a Risk Management Framework: Report to the FDA Commissioner from the Task Force on Risk Management, (May 1999), available at http://www.fda.gov/oc/tfrm/ riskmanagement.pdf.
76. This study only looked at commitments made at the time of initial approval (i.e., approval was contingent on the agreement) and did not include subsequent commitments made throughout the products' lifecycle.
77. The majority of these companies had responded to the 2007 FDA PMC survey, reported in: Kenneth Kaitin (ed.), Challenges Loom for Postmarketing Study Commitment; Benefits Unclear (May/June 2007), Tufts Center for the Study of Drug Development Impact Report.
78. On average, endocrine system products had the highest number of PMCs per approval (13.3, 14.7, 1.0), followed by anti-infective (9.2, 13.3, 2.2) and anti-neoplastic (8.3, 7.7, 1.0) in U.S., E.U. and Japan, respectively. (Note: 80 percent of products in the sample fell into these three therapeutic areas). In the U.S., the average number of PMCs for a product with accelerated approval was 9.5 (median=8.0; n=10) and non-accelerated was 8.6 (median=7.0, n=19); the average number of PMCs for a product with orphan approval was 8.8 (median=7.5; n=10) and non-orphan was 9.0 (median=7.0, n=19); and, the average number of PMCs for a product with fast track was 8.6 (median=7.0; n=16) and non-fast track was 9.31 (median=9.0; n=13). In the EU, the average number of PMCs for a product with exceptional circumstances was 9.4 (median=5; n=7) and non-exceptional was 11.4 (median=10, n=18); the average number of PMCs for a product with orphan status was 8.2 (median=4.5; n=10) and non-orphan was 12.7 (median=12, n=15). In Japan, the average number of PMCs for a product with orphan status was 2.0 (median=2, n=10) and non-orphan is 1.1 (median=1, n=7); and, the average number of PMCs for a product with priority status was 1.0 (median=1, n=4) and standard status was 2 (median=2, n=13).
79. The percentage of approvals (among approvals with commitments) that had efficacy commitments was 76 percent, 56 percent and 89 percent, for U.S., E.U. and Japan, respectively. The percentage of approvals (among approvals with commitments) that had safety commitments was 55 percent, 72 percent and 89 percent, for U.S., E.U. and Japan, respectively.
80. A few sponsors reported that the actual agreements came 1 to 3 months prior to approval.
81. In Japan, 100 percent of products had agreements reached at the time of approval. In the U.S., the percentage of products that had agreements reached before, at the time of, and after approval was 38 percent, 52 percent and 28 percent, respectively. In the E.U., the percentage of products that had agreements reached before, at the time of, and after approval was 44 percent, 52 percent and 20 percent, respectively. (Note: These percentages equal over 100 percent since a few drugs in the U.S. and E.U. are double counted due to two separate agreements at different times.)
82. See New drug development periods and postmarketing commitments in Japan, Office of Pharmaceutical Industry Research, JPMA, (Aug., 2006), on file at Tufts CSDD. This data was based on a cohort of drugs approved from 2003-2005. During this time period 100 percent of orphan approvals had postapproval commitments for drug use-result surveys.
83. Survey 2007 on the performance of EMEA scientific procedures for medicinal products for human use, (Mar. 2008), EMEA/15887/2008.
84. Another part of the answer could be that the European system is a floor upon which member states can layer additional measures as they deem necessary or commensurate with available resources, but again this is beyond the scope of this article.