Expired CME Article

An Overview of Drug Development in the United States and Current Challenges

Authors: Sharon Wyatt Moore, MD, MBA, MPH

Abstract

Drug development in the United States has undergone many changes in the past 25 years, but relatively few fully realize the complexities involved in developing a new drug. Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development.


Drug development in the United States has undergone many changes in the past 25 years. Many entirely new classes of compounds are now available, and the scientific advances, including those in genomics and proteomics, indicate a promising future. Although it is well recognized that multiple stakeholders are affected by drug development, relatively few fully realize the complexities involved in developing a new drug and bringing it to market. This is especially important for physicians when using new medications 1 and when discussing medications with patients, who have increasing opportunities to gain health information through television, radio, newspapers, magazines, and the Internet.


In the current environment, many types of pressures—including scientific, socioeconomic, ethical, regulatory, and legal—continue to mount on both publicly and privately sponsored research. Each set of stakeholders has distinct expectations on necessary data whether they are academic and/or practicing physicians, formulary managers, patients and their families, government regulators from around the world, or scientists/managers from the companies developing the new products. This has led one pharmaceutical executive to conclude, “Satisfying the multiplicities of the demands for information that these varied ‘customers’ place on industry for information is a key force that drives today’s large development programs.”2 This information usually involves such questions as these: Is the drug safe and does it work? What are the most appropriate endpoints for determining efficacy? How does it compare with currently available alternative therapies? Are there differences in population subgroups (eg, pediatrics, geriatrics, male/female patients, ethnic groups, renal insufficiency)? Is it cost-effective? Are there significant drug interactions? Does the drug prolong the QT interval? This article reviews general information regarding drug development processes, including the major regulatory requirements in the United States, and then assesses some of the current challenges in drug development.

This content is limited to qualifying members.

Existing members, please login first

If you have an existing account please login now to access this article or view purchase options.

Purchase only this article ($25)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. Lipsky MS, Sharp LK. From idea to market: The drug approval process. J Am Board Fam Pract 2001; 14: 362–367.
 
2. Niblack JF. Why are drug development programs growing in size and cost? A view from industry. Food Drug Law J 1997; 52: 151–154.
 
3. U.S. Food and Drug Administration. FDA Backgrounder: Milestones in U.S. food and drug law history. Available at: http://www.fda.gov/opacom/backgrounders/miles.html. Accessed October 9, 2003.
 
4. 21 U.S. Code § 321(g).
 
5. 42 U.S. Code § 262(i).
 
6. 21 U.S. Code § 321(h).
 
7. 21 U.S. Code § 353(g).
 
8. 68 Fed. Reg. 38,067 (2003).
 
9. Center for Biologics Evaluation and Review, U.S. Food and Drug Administration. Transfer of therapeutic products to the Center for Drug Evaluation and Research. Available at:http://www.fda.gov/cber/transfer/transfer.htm. Accessed October 9, 2003.
 
10. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Number of active INDs at the close of the calendar year: Calendar years 1986–2002. Available at:http://www.fda.gov/cder/rdmt/cyactind.htm. Accessed October 9, 2003.
 
11. CenterWatch Clinical Trials Listing Service. Clinical grants market decelerates. CenterWatch Monthly 2003; 10( 4): 1, 4–8.
 
12. CenterWatch Clinical Trials Listing Service. AHCs (academic health centers) face a tightening NIH funding supply. CenterWatch Monthly 2003; 10( 8): 1, 9–14.
 
13. Pharmaceutical Research and Manufacturers of America (PhRMA). Pharmaceutical Industry Profile 2003. Washington, DC: PhRMA, 2003.
 
14. Attarchi F. Preclinical regulatory requirements. Regulatory Aff Focus 2003Apr;9.
 
15. Olejniczak K, Günzel P, Bass R. Preclinical testing strategies. Drug Inf J 2001; 35: 321–336.
 
16. 21 CFR § 312.2(b).
 
17. Chow SC, Pong A. An overview of the regulatory approval process in drug development. Drug Inf J 1998; 32: 1175S–1185S.
 
18. Center for Drug Evaluation and Review, U.S. Food and Drug Administration. The CDER Handbook(Revised 3/16/98). Available at: http://www.fda.gov/cder/handbook/. Accessed October 9, 2003.
 
19. Randall B. The U.S. drug approval process: A primer. Congressional Research Service, The Library of Congress. Order code RL30989, June 1, 2001.
 
20. Center for Biologics Evaluation and Review, U.S. Food and Drug Administration. Report to Congress: Reports on Postmarketing Studies (FDAMA 130). Available at:http://www.fda.gov/CBER/fdama/pstmrktfdama130.htm. Accessed October 9, 2003.
 
21. Public Law 97-414.
 
22. Public Law 98-551.
 
23. U.S. Food and Drug Administration. List of orphan designations and approvals. Available at:http://www.fda.gov/orphan/designat/list.htm. Accessed October 9, 2003.
 
24. 52 Fed. Reg. 19,466 (1987).
 
25. Shulman SR, Brown JS. The Food and Drug Administration’s early access and fast-track approval initiatives: How have they worked? Food Drug Law J 1995; 50: 503–531.
 
26. Office of Special Health Issues, U.S. Food and Drug Administration. Expanded access and expedited approval of new therapies related to HIV/AIDS. Available at:http://www.fda.gov/oashi/aids/expanded.html. Accessed October 9, 2003.
 
27. 57 Fed. Reg. 13,250 (1992).
 
28. U.S. Food and Drug Administration warning letter to Betty Castor, President, University of South Florida, 12 June 1998 (CBER-98-017). Available at: http://www.fda.gov/foi/warning_letters/d1417b.pdf. Accessed October 9, 2003.
 
29. Center for Drug Evaluation and Review, U.S. Food and Drug Administration. Access to unapproved drugs. Available at: http://www.fda.gov/cder/cancer/access.htm. Accessed October 9, 2003.
 
30. 53 Fed. Reg. 41,523 (1988).
 
31. 21 C.F.R. § 314, subpart H (Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses); 21 C.F.R. § 601, subpart E (Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses).
 
32. U.S. Food and Drug Administration. Guidance for Industry: Fast Track Drug Development Programs—Designation, Development and Application Review, September 1998. Available at:http://www.fda.gov/cber/gdlns/fsttrk.pdf. Accessed October 9, 2003.
 
33. Center for Drug Evaluation and Review, U.S. Food and Drug Administration. Manual of Policies and Procedures. MAPP 6020.3, Priority Review Policy, April 22, 1996.
 
34. Center for Biologics Evaluation and Review, U.S. Food and Drug Administration. Manual of Standard Operating Procedures and Policies: SOPP 8405, Regulatory—License Applications, Complete Review and Issuance of Action Letters, August 8, 2003.
 
35. Rutan RL, Deitch EA, Waymack JP. Academic surgeons’ knowledge of Food and Drug Administration regulations for clinical trials. Arch Surg 1997; 132: 94–98.
 
36. The Research Roundtable. FAA regulations in clinical research. Available at:http://www.researchroundtable.com/FAA%20Regulations.htm. Accessed October 9, 2003.
 
37. U.S. Food and Drug Administration warning letter to Candace Brown, PharmD, FNP, 25 July 2001 (Ref. No. 01-HFD-45-0301). Available at: http://www.fda.gov/foi/warning_letters/g1682d.pdf. Accessed October 9, 2003.
 
38. Yessian MR. Testimony before the Committee on Government Reform Subcommittee on Criminal Justice, Drug Policy, and Human Resources, United States House of Representatives. Institutional Review Boards: A system of protections still in need of reform, 9 December 1999. Available at:http://www.oig.hhs.gov/reading/testimony/1999/finalirb.htm. Accessed October 9, 2003.
 
39. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement: Oversight of clinical research. J Clin Oncol 2003; 21: 2377–2386.
 
40. DeMasi JA. Trends in drug development: Costs, times, and risks. Drug Inf J 1995; 29: 375–384.
 
41. Tufts Center for the Study of Drug Development. News release: Total cost to develop a new prescription drug, including cost of post-approval research, is $897 million (May 13, 2003). Available at:http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=29. Accessed October 9, 2003.
 
42. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: New estimates of drug development costs. J Health Econ 2003; 22: 151–185.
 
43. Grabowski H, Vernon J, DiMasi JA. Returns on research and development for 1990s new drug introductions. Pharmacoeconomics 2002; 20( Suppl 3): 11–29.
 
44. Marwick C. Concern expressed about FDA reform legislation. JAMA 1997; 278: 459.
 
45. Kleinke JD, Gottlieb S. Is the FDA approving drugs too fast? Probably not—but drug recalls have sparked debate. BMJ 1998; 317: 899–900(editorial).
 
46. Landow L. FDA approves drugs even when experts on its advisory panels raise safety questions. BMJ 1999; 318: 944(letter).
 
47. Lurie P, Sasich LD. Safety of FDA-approved drugs. JAMA 1999; 282: 2297–2298(letter).
 
48. Friedman MA, Woodcock J, Lumpkin MM, et al. The safety of newly approved medicines: Do recent market removals mean there is a problem? JAMA 1999; 281: 1728–1734.
 
49. Steidle G, Hodges SE. The United States Food and Drug Administration’s risk management framework. Drug Inf J 2002; 36: 333–341.