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1、H E A L T H C A R E Drug Approval Trends at the FDA and EMEA Process improvements, heightened scrutiny and industry response By Alison Sahoo Alison Sahoo Alison Sahoo is a pharmaceutical industry analyst with more than 10 years of experience researching the development of medicines and medical devic
2、es. She holds a B.S. in Physics from McGill University and an M.B.A. in International Business from Rutgers University. Copyright 2008 Business Insights Ltd This Management Report is published by Business Insights Ltd. All rights reserved. Reproduction or redistribution of this Management Report in
3、any form for any purpose is expressly prohibited without the prior consent of Business Insights Ltd. The views expressed in this Management Report are those of the publisher, not of Business Insights. Business Insights Ltd accepts no liability for the accuracy or completeness of the information, adv
4、ice or comment contained in this Management Report nor for any actions taken in reliance thereon. While information, advice or comment is believed to be correct at the time of publication, no responsibility can be accepted by Business Insights Ltd for its completeness or accuracy. ii Table of Conten
5、ts Drug Approval Trends at the FDA, EMEA Executive Summary 10 The shifting regulatory landscape 10 Drug approval trends at FDA 11 Drug approval trends at EMEA 12 Industry response 13 Global drug approval trends through 2012 14 Chapter 1 The shifting regulatory landscape 18 Summary 18 Drug usage in t
6、he U.S. and Europe 19 New molecular entities 20 Generic drugs 21 Rising usage of generics 21 Generic drug application trends 22 Indication expansions 23 Drug approval issues 26 Ensuring drug safety 27 Safety shortfalls: rising adverse drug reactions 29 Safety failures: drug withdrawals 30 The import
7、ance of time to market 31 Impact of cost constraints 34 Conclusion 35 Chapter 2 Drug approval trends at the FDA 38 Summary 38 Drug approval process 39 Pressure to approve drug candidates 42 iii Future directions in the FDA drug approval process 43 Ensuring drug safety 44 Evolution of drug safety tes
8、ting 44 Pediatric safety testing 48 Future directions in drug safety reviews 49 Reducing time to market 50 Fast track approvals 52 Orphan drug approvals 53 Decreasing FDA drug approvals 54 Future directions in speeding drug approvals 56 Delaying risky applications 58 Rising data requirements 58 Case
9、 study: hormone replacement therapy 59 Case study: Galvus 60 The future for risky drug applications 62 Biosimilars 62 The future of biosimilar approvals 62 Canadian biosimilars legislation 63 Rx-to-OTC switches 64 New OTC drug categories 66 Antihistamines 67 Emergency contraceptives 69 Hyperosmotic
10、laxatives 71 Ophthalmic allergy medications 72 Proton pump inhibitors 73 Weight loss medications 75 Switch rejections 76 Statins 77 Future directions in nonprescription drug approvals 78 Creation of a pharmacist dispensed class 79 Marketing withdrawals 80 Application withdrawals 81 Future directions
11、 in marketing and application withdrawals 82 Conclusion 82 Chapter 3 Drug approval trends at the EMEA 86 Summary 86 Drug approval process 87 History of European drug regulation 87 The formation of the EMEA and the MRP 88 The EMEA 89 iv The Mutual Recognition Procedure (MRP) 91 The National Competent
12、 Authorities 93 The Common Technical Document 93 Ensuring drug safety 96 Creation of Scientific Advisory Groups 97 Future directions in drug safety testing 98 Reducing time to market 98 Accelerated opinions 100 Pediatric testing exemptions 101 Decreasing EMEA approvals vs. FDA approvals 101 Current
13、EMEA approval levels 104 Future directions in speeding drug approvals 104 Delaying risky applications 105 The future for risky drug applications 106 Biosimilars 107 New biosimilar guidelines 107 Future directions in biosimilar approvals 108 Rx-to-OTC switches 109 Future directions in nonprescription
14、 drug approvals 110 Marketing withdrawals 110 Application withdrawals 110 Future directions in marketing and application withdrawals 112 Conclusion 112 Chapter 4 Industry response 114 Summary 114 Background 115 Improving safety testing 115 Genomics 116 Stem cell approaches 117 Future drug safety tes
15、ting improvements 118 Raising investment in R ? generic drugs, which are based bioequivalent to previously approved products; ? previously approved drugs seeking expansions of their original indications. 19 As discussed in the subsections below, each of these drug candidates poses different types of
16、 challenges and is therefore subject to different approval trends. Because the greatest gains are to be earned from new molecular entities, and therefore most drug spending is focused on novel compounds, this report will center on approval trends for these products with only a peripheral discussion
17、of generic approvals and indication expansions. New molecular entities New molecular entities represent novel compounds that are submitted to regulators for the first time. In the U.S., drug makers file a New Drug Application (NDA) with the FDA, while in Europe, applicants file similar documents eit
18、her with individual national regulators or centrally through the mutual recognition procedure (MRP). In all cases, the goal of the review process is to provide sufficient information to establish that: ? The drug is safe and effective for its proposed usage, with benefits outweighing risk; ? the dru
19、gs proposed labeling is appropriate; ? the methods used to manufacture the drug and maintain quality are adequate. This process is particularly important since new molecular entities increasingly address complicated conditions with highly sophisticated science. Applications typically contain tens, a
20、nd sometimes hundreds, of thousands of pages and detail the results of animal studies, human clinical trials, drug formulation, human drug metabolism, manufacturing, processing and packaging. Biologic products, such as vaccines and many recombinant proteins, are approved by FDA via a Biologic Licens
21、e Application (BLA), rather than an NDA. Manufacture of biologics is considered to differ fundamentally from that of less complicated chemicals, requiring a different approval process. 20 Generic drugs Generic drugs are essentially copies of products that have previously been approved. They are gene
22、rally introduced when the patent on the original drug expires or is found to be invalid. Generics may be introduced by the developer of the original drug, but are more often launched by specialty generics manufacturers as a means to enter a new market. Rising usage of generics Because generic drug m
23、akers need not reproduce safety studies when seeking approval for product that is bioequivalent to an approved medicine, their R ? extension of the drugs original usage to new patient populations, like children and/or adolescents; ? extension of the drugs usage to related indications, such as the ap
24、proval of an antibiotic for specific types of infections; ? addition of entirely new therapeutic indications, such as treatment of additional diseases or conditions. While all of these extensions serve to increase the size of the potential patient population for the drug, pediatric expansion and par
25、ticularly the addition of large new therapeutic indications generally have the most significant effect upon the drugs usage. They can also serve as an effective means of delaying generic competition, since regulations in both the U.S. and the E.U. provide some additional protection for drugs whose u
26、sage is extended. In the U.S., innovator companies are awarded three years of data exclusivity for a change to a products label that requires clinical trials to be conducted, although changes to the Medicare Modernization Act of 2003 have limited the opportunity to generate multiple 30-month stays.
27、Originator companies had historically relied upon listing patents covering new indications in the Orange Book, thereby forcing generics manufacturers to make a paragraph IV certification in its Abbreviated New Drug Application (ANDA), and generating an automatic 30-month stay of approval. In Europe,
28、 manufacturers have long taken advantage of the requirement for generics companies to use the Mutual Recognition Procedure (MRP) process but also have the same Summary of Product Characteristics (SmPC) as the listed drug in each market, to 23 24 extend patent protection by filing different indicatio
29、ns in different markets. This results in SmPCs for the listed drug differing between regions and makes it impossible for a generic to gain approval for the full range of indications in each market via the MRP. A related action that can delay generic competition, even if SmPCs are harmonized across m
30、arkets, is the filing of patents for new indications, which may expire at different times in different countries. Thus the generic company would be prevented from marketing the product for a particular indication. This can prevent launch of the product even for patent expired indications. The mentio
31、n of a patented indication in the generics companys marketing authorization (MA) amounts to patent infringement, but excluding the patented indication can result in difficulties in gaining approval since the generic SmPC would differ from that of the originator product. Because of these benefits, in
32、dication expansion is a common lifecycle management strategy, with more than four fifths of the 50 top selling brands in 2007 having had additional indications approved since their initial U.S launch. Developers of blockbuster drugs often investigate additional indications particularly usage expansi
33、on to younger patients as a means to extend the products patent life and delay generic competition. This can give rise to multiple new indications for a single drug, as shown in Table 1.1. Often, a manufacturer will obtain information from external sources suggesting a potential new indication. This
34、 may arise from physicians, researchers and others who notice additional therapeutic benefits from a particular product, as well as similar competing products that obtain approval for additional indications. When this latter event occurs, it is not unusual for all the drugs within a particular class
35、 to one by one undergo an indication expansion. This occurred, for example, with Abbotts, Amgens and Johnson patients to age 16 Patients to age 12 December 2003 Shire Adderall ADHD; pediatric patients ADHD; adults October 2003 Novartis Lescol Cholesterol reduction Risk reduction in coronary May 2003
36、 revascularization in patients with coronary heart disease Merck Singulair Asthma Allergies January 2003 Pfizer Zyrtec Allergies; patients to age 2 Allergies; patients to age 6 mos. November 2002 GlaxoSmithKline Flonase Allergies Non-allergic nasal symptoms May 2002 Allergan Botox Various medical in
37、dications Cosmetic/aesthetic use April 2002 TAP Pharmaceuticals Prevacid Ulcers and heartburn; to age 11 Patients to age 1 March 2002 Source: Company news releases and public filings Business Insights Ltd Expansion of a drugs usage to pediatric patients is not appropriate for all products, however,
38、since many of the most widely-used drugs address conditions that are most prevalent among older persons. These include medications that lower cholesterol, control hypertension, address various cardiovascular conditions, mitigate depression, etc. Some developers employ extensive indication expansion
39、strategies, particularly for products whose usage can be leveraged to address closely related conditions. For example, through the end of 2007, Johnson manufacturer may recommend monitoring Manufacturer discontinues testing or drug not approved or drug recalled Increasing safety Generally unsafe und
40、er any circumstances Safe under certain conditions Generally safe for a wide population Few restrictions Labeling restricts usage; manufacturer may recommend monitoring Manufacturer discontinues testing or drug not approved or drug recalled Increasing safety Source: Authors analysis Business Insight
41、s Ltd These safety risks run the gamut from minor discomforts such as the nausea and headaches associated with many classes of medications to life-threatening conditions like increased risk of liver toxicity caused by cholesterol-reducing statins. Although in most cases, the likelihood of serious si
42、de effects is quite small, for some groups of drugs, the risk is higher. These include some very broadly used classes of medications, such as those that address pain relief, asthma, migraine, osteoporosis, hypertension and other widespread conditions. Table 1.2 lists some widely used groups of medic
43、ations and side effects that have been reported in clinical and post-marketing experience. 28 Table 1.2: Potential safety risks of popular drug classes Drug Class Indication Potential Reactions Safeguard COX-2 inhibitors Pain relief Risk of stroke, heart attack Expanded labeling, recalls Statins Cho
44、lesterol Liver toxicity Liver tests reduction NSAIDs Pain relief Ulcers Expanded labeling, contraindications Bisphosphonates Osteoporosis Gastrointestinal effects Expanded labeling, contraindications Hormone replacement Symptoms of Cardiovascular effects Expanded labeling, therapy menopause contrain
45、dications Leukotriene receptor Asthma Liver toxicity Expanded labeling, antagonists contraindications, liver tests Triptans Migraine Cardiovascular effects Expanded labeling, contraindications ACE inhibitors Hypertension Renal impairment Expanded labeling, physician supervision Source: Authors analy
46、sis Business Insights Ltd Safety shortfalls: rising adverse drug reactions In 2007, the estimated number of adverse drug reactions reported to the FDA from manufacturers and health care professionals exceeded 500,000, compared with approximately 150,000 in 1995. As shown in Figure 1.2, this 10.4% an
47、nual growth demonstrates a trend of increasing incidence of dangerous drug side effects. Although prescription volume has risen over the same period of time, growing from 2.2b prescriptions in 1995 to 3.8b in 2007, adverse reactions are occurring in an 29 increasingly larger portion. While 0.007% of
48、 all prescriptions produced an adverse reaction in 1995, by 2007 this proportion had almost doubled to an estimated 0.013%. Affected populations increasingly include vulnerable groups such as seniors, which are expanding with the aging of the Baby Boomers. Figure 1.2: Growth in U.S. reported adverse
49、 drug reactions, 1995 - 2007 0 100,000 200,000 300,000 400,000 500,000 600,000 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Reported Adverse Drug Event Source: FDA Business Insights Ltd Safety failures: drug withdrawals Drug recalls are intended to prevent unsafe drugs from use and may be either temporary or permanent. Temporary recalls may involve one or a small number of batches of a particular drug that experience problems in distribution or manufacturing. These may include a variety of issues such as subpotency, stability data that does n