The Issues Surrounding The Drug Approval Process
With The Food And Drug Administration

Paula S. Fuqua, Pharm.D.
Paula Fuqua, Pharm.D. is with Clinical Research Services,
Department of Pharmacy at University Medical Center.

The Food and Drug Administration (FDA) Drug Approval Process represents to many the ultimate governmental regulatory quagmire. The Drug Approval Process is a process criticized by many, but also unparalleled in responsibly bringing safe and effective drugs to market. One only has to be reminded of the thalidomide incident to realize the value of this process. In 1960, one FDA medical officer, Frances Kelsey, in the face of much criticism and great pressure, refused to approve thalidomide for marketing in the United States. Her steadfast concern over the safety of thalidomide ultimately prevented many cases of phocomelia in the United States.1 She was later recognized with the presentation of the President's Medal for Distinguished Service by President John F. Kennedy.

The subsequent public outcry following the thalidomide incident provided a much needed catalyst for revision of the Federal Food, Drug, and Cosmetic Act of 1938 which required that only the safety of a drug be demonstrated prior to marketing.2,3 In 1962, the Kefauver-Harris Amendments were enacted which required manufacturers to prove effectiveness of the drug for its intended use prior to marketing, as well as to notify the FDA of adverse reactions to drugs, to conform to uniform good manufacturing practices and to provide complete information regarding drug risks and benefits in advertisements.2,3

These laws provided the foundation for creation of a three phase process for human testing of new drugs before approval for marketing. The drug approval process is a risky and costly venture, with only 20% of original investigational new drug applications receiving approval for marketing at a cost of 125 to 250 million dollars over a 10 to 12 year time span.2,4 Herein lies the dilemma. How can a process which is designed to bring safe and effective drugs to market be improved? Public health, time, and money are all crucial factors. Frustration abounds over the limited access to drugs during clinical trial testing, the lack of existing therapies for rare disease states, new drug prices, and the length of FDA review time. These issues, coupled with increasingly demanding and politically savvy patient advocacy, consumer and industry groups and ever growing congressional criticism, have spurred the FDA to reform.

Some of the first FDA reforms included The Orphan Drug Act of 1983 (ODA) and the Drug Price Competition and Patent Term Restoration Act of 1984. The ODA provided for financial incentives to manufacturers of orphan drug products via patent exclusivity and advantageous tax treatment so that promising new treatments for rare diseases would be brought to market.5 The Drug Price Competition and Patent Term Restoration Act of 1984 extended the abbreviated mechanism
of approval for generic versions of drug products which were first approved for safety and efficacy after 1962. This act allowed generic drug manufacturers to submit an abbreviated new drug application (ANDA) for marketing approval in which they were required to demonstrate bioequivalence to a corresponding reference drug. In return, brand name manufacturers were given 17 years of patent life and allowance for restoration of up to 5 years of lost patent time due to delays in the drug approval process.6

Another FDA reform example includes the 1987 fast tracking of zidovudine for acquired immune deficiency syndrome (AIDS), which passed through the FDA in a record setting 4 months. This process represented the beginning of a new age of cooperation between the FDA and the sponsor.7 Another more recent example of this type of fast track approval process was saquinavir, which was approved in December 1995, just 97 days after FDA New Drug Application (NDA) receipt, under accelerated approval guidelines issued by the FDA in 1993.8 This was followed by a record breaking 42 day NDA approval of indinavir on March 13, 1996. Other medications to reap the benefits of accelerated approval have included ritonavir, lamivudine, stavudine, and bicalutamide.

The Prescription Drug User Fee Act (PDUFA) of 1992 provided the greatest leap forward in FDA reform by setting a goal of reducing the time for FDA approval of new drug entities. This act put in place a plan for FDA to charge user fees to pharmaceutical companies for review of NDAs. The revenue has been utilized to hire additional FDA examiners and meet the lofty goal of reducing the average review time for priority drugs by half over a 5 year period.9 This act has been extremely valuable since the median approval times for the 121 new original drugs in 1997 was 14.4 months, 6 percent shorter than in 1996 and significantly shorter than the median approval time of 32.5 months in 1989.10

The success of user fee implementation has been well received. As such, the FDA Modernization and Accountability Act (MAAA) signed into law on November 21, 1997 includes PDUFA II which calls for an extension of user fees for an additional five years, still shorter review times, and new administrative goals designed to further accelerate the drug development process. Other aspects of MAAA include an extension of a FDA pilot program to outsource NDA review to FDA certified independent third parties, the acceptance of data and research from other countries, and the provision of approval status reports to pharmaceutical companies.11

The FDA reform movement has created a ripple effect that has affected manufacturers, sponsors and even investigators by streamlining the clinical trial process, by utilizing contract research organizations and site maintenance organizations to conduct clinical trials, by establishing offices of research at academic medical centers, and by redesigning the traditional dosing process utilized in clinical trials. Innovative approaches are now being developed and applied to encompass pharmacodynamic and pharmacokinetic parameters early in the drug development process. Terms such as "front-loaded" trials and "enriched" trials are now being utilized to describe clinical trial designs that focus on clinical pharmacology and identification of specific patient populations that may benefit from new drugs.12 These approaches are designed to maximize the drug development process by providing dose and response relationship estimation and information leading to optimal, individualized patient dosing.13

Additional change can also be expected as genomics, the study of the genetic basis for disease, comes to the forefront of drug discovery. Genomics has created a whole new field of research in which drugs will be designed with specific biological targets in mind. As a result, manufacturers are increasing their new drug discovery goals at an astonishing rate, depending on genomics in combination with computer simulations to allow better design of clinical trials.14

The future is bright, indeed. If these new changes within the FDA and at the manufacturer and investigator levels can work in concert, the United States will have an efficient, proactive, and dynamic drug approval process. This process can be finely tuned to meet the needs of the agent it must evaluate and carefully honed to assure that adequate safety and efficacy of a potential new medication have been demonstrated prior to marketing for general public consumption.

REFERENCES

  1. Keifer DM. How an iron-willed FDA officer averted a birth defect disaster. Today's Chemist at Work 1997; 6(2):92-6.
  2. Mathieu M. New drug development: a regulatory overview. Cambridge: Parexel International Corporation, 1990.
  3. The evolution of U.S. drug law. FDA Consumer. 1988; 21(10):30.
  4. Halperin HA. From investigation to marketplace: moving drugs through the system. Drug Intell Clin Pharm. 1980; 14:694-97.
  5. Cramer R. Orphan drugs. Al J Med Sci. 1988;25(3):257-60.
  6. Rheinstein P. The generic drug approval process. Am Fam Phy. 1993; 48(8):1357-60.
  7. Fast tracking the first AIDS drugs. FDA Consumer. 1988; 21(10):39-41.
  8. Werble C., ed. FDC Reports. Chevy Chase: FDC Reports, Inc., 1995; 57(50):3-4.
  9. FDA user fees approved. Clin Pharm. 1993; 12:3.
  10. M2 Presswire. U.S. HHS FDA drug approval in 1997 set new records. January 16, 1998.
  11. Werble C., ed. FDC Reports. Chevy Chase: FDC Reports, Inc., 1997; 59(47):13-16.
  12. Werble C., ed. FDC Reports. Chevy Chase: FDC Reports, Inc., 1997; 59(25):17-20.
  13. Thompson L. A better pill to swallow. The Monitor. 1998; 12(1):31-5.
  14. Lightfoot GD, Getz, KA, Harwood F, et al. Faster time to market. The Monitor. 1998; 12(1):13-26.
Jacksonville Medicine / August, 1998

 

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