Will advances in biotechnology usher in a new era of medicine?

The article by Avidor et al (1) discusses four main classes of biotechnology products currently in development: small molecular drugs, protein drugs (ie, hormones, enzymes, monoclonal antibodies, cytokines), gene therapy products, and antisense drugs. It is evident that the field of biotechnology has made remarkable strides within the past 3 decades (Table 1) and offers great promise for additional achievements in the future. The U.S. Food and Drug Administration (FDA) has already approved more than 130 biotechnology drugs and vaccines, and there are currently more than 370 biotechnology products and vaccines in clinical trials sponsored by 144 companies for approximately 200 diseases. This research includes new medicines for a wide spectrum of conditions, including cancer (178 products), infectious diseases (47 products), autoimmune diseases (26 products), neurologic disorders (22 products), and human immunodeficiency virus/acquired immunodeficiency syndrome and related conditions (21 products). (2) Several factors have contributed to this impressive growth: 1) rapid scientific discoveries, 2) efficient development processes within relatively small companies, and 3) an influx of investor capital for new biotechnology products.

No one disputes the increasing pace of scientific advancement. Perhaps the most remarkable achievement occurred earlier this year, when the Human Genome Project was finished 21/2 years ahead of schedule. The project involved the sequencing of 3 billion DNA letters that contained information regarding more than 99% of the human gene regions. Increased computer capability and the faster transfer of information will continue to facilitate the accelerating discovery process.

Models created in the biotechnology industry stress efficient development processes. In general, biotechnology companies are small compared with pharmaceutical companies and frequently have a limited number of products in development at any one time. Their financial requirements necessitate rapid development processes, whenever feasible, to bring their drugs to market as soon as possible.

According to industry reports, the size of the biotechnology industry has tripled since 1992, with 1,457 biotechnology companies located in the United States. Research and development expenditures totaled $15.6 billion in 2001, and in May 2002, the market capitalization of publicly traded biotechnology companies was calculated at $224 billion. (3)

However, the biotechnology development highway has also encountered several significant hurdles, including 1) ethical concerns about the research process and product capabilities, 2) greater regulatory oversight, and 3) development processes that are more complex than those required for traditional therapeutic medicines.

Three specific areas of biotechnology, which involve different aspects of genetics, have received the most publicity regarding ethical concerns: gene transfer research, the privacy of information on individuals' genetic susceptibility to serious diseases, and the safety of genetically engineered and/or modified plants and animals. Ethical concerns regarding gene therapy trials peaked in 1999, when Jesse Gelsinger, an 18-year-old patient with ornithine transcarbamylase deficiency, died shortly after undergoing an investigational gene transfer procedure using an adenoviral vector. Because of this experience, all gene therapy research involving adenoviral vectors was temporarily halted until the details of the research could be reviewed. Much discussion ensued about patient protection and investigator conflict of interest in human studies. Stricter oversight of these trials was enacted.

For biotechnology product studies in humans, the institutional review board and possibly other institutional bio-safety committees oversee patient protection. Federal agencies may also have oversight responsibilities, depending on the funding source and the type of therapy under study, such as the FDA or the National Institutes of Health and, for most gene therapy trials, the National Institutes of Health Recombinant DNA Advisory Committee.

During a recent roundtable meeting at the Manhattan Institute, Mark McClellan, the current FDA commissioner, stated that "while companies are investing heavily in genomics, research thus far has not 'paid off," and it could be another 10 years before methods are developed to use the data and to reduce the cost of drug development. (4) The Clinical Research Roundtable at the Institute of Medicine has heightened awareness of the urgent need to translate and implement new scientific knowledge to the patient, recommending a significant increase in resources to improve the clinical research infrastructure. (5)

In addition, two current regulatory issues in the United States may have significant effects on the development of new biotechnology products. First, effective June 30, 2003, the FDA moved responsibility for product oversight for the majority of biotechnology products (except products such as therapeutic vaccines, cell, and gene therapy products) from the Center for Biologics Evaluation and Research to the Center for Drug Evaluation and Research. The FDA stated that the move is expected to increase efficiency and consistency as drugs and biologics are developed for a broader range of illnesses. Second, the FDA has begun to explore mechanisms by which generic biologic products may be developed. The issues involved are complex and may require a long time to define.

Certainly, the hope is that biotechnology, particularly through advances in genomics and proteomics, will dramatically change the way in which clinicians diagnose and treat patients. Drug therapy will be targeted much more toward the pathophysiologic basis of disease, and clinicians will routinely consider the patient's ability to respond to the therapeutic agent through membrane receptor and transporter genetic polymorphisms. Adverse effects should be reduced through greater knowledge of genetic differences in drug metabolism and through targeted mechanisms of action. Holtzman and Marteau, (6) however, have cautioned that genetics will have limitations in preventing and minimizing disease because lifestyle and socioenvironmental differences generally account for higher proportions of disease than do genetic differences.

The complexities of medicine will undoubtedly continue to increase with advances in biotechnology, and there is an urgent need for clinicians to remain informed to discuss this flood of new information with patients. (7) The ultimate decision regarding whether these advances will usher in a new era of medicine depends on the ability to bring the scientific advances to the bedside (8) and on patients' perceived benefits and risks. To maximize the benefits, researchers must ensure that ongoing research proceeds in an ethical and responsible manner. With diligence, dedication, and commitment, we can then realize the great promise of biotechnology and drug development.

Table 1. History of key therapeutic advances in biotechnology (a)

Year                          Event

1975  First monoclonal antibody produced

1978  First production of recombinant human insulin

1980  Diamond v Chakrabarty decision by the U.S. Supreme
        Court, allowing recombinant organisms to be patented

1982  First biotechnology drug approved by FDA (recombinant
        human insulin)

1984  Bayh-Dole Act enacted, allowing private development of
        federally funded discoveries

1985  NIH guidelines for human gene-therapy experiments
        approved

1986  First biotechnology human recombinant vaccine (hepatitis
        B) and first biotechnology anticancer drug produced
        (interferon)

1998  First antisense drug approved (fomivirsen), for
        cytomegalovirus retinitis in AIDS patients

2000  Draft of human genome sequence announced

2003  April 14: Completion of the Human Genome Project
        announced by the International Human Genome
        Sequencing Consortium

(a) FDA, U.S. Food and Drug Administration; NIH, National Institutes of
Health; AIDS, acquired immunodeficiency syndrome.

Accepted September 30, 2003.

References

(1.) Avidor Y, Mabjeesh NJ, Matzkin H. Biotechnology and drug discovery: From bench to bedside. South Med J 2003;96:1174-1186.

(2.) Pharmaceutical Research and Manufacturers Association. 371 biotechnology medicines in testing offer hope of new treatments for nearly 200 diseases (Oct 21, 2002). Available at: http://www.phrma.org/mediaroom/press/releases/21.10.2002.600.cfm. Accessed September 25, 2003.

(3.) Biotechnology Industry Organization. Guide to biotechnology: Biotechnology industry statistics. Available at: http://www.bio.org/er/statistics.asp. Accessed September 25, 2003.

(4.) U.S. Food and Drug Administration. Commissioner downplays role in drug approvals. The Pink Sheet 2003;65(21):7-8.

(5.) Sung NS, Crowley WF Jr, Genel M, et al. Central challenges facing the national clinical research enterprise. JAMA 2003;289:1278-1287.

(6.) Holtzman NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med 2000;343:141-144.

(7.) Bergeron B. Postgenomic medicine: The evolution of clinical medicine-and the clinician. Medscape Gen Med 4(4), 2002. Posted 10/23/2002. Available at: http://www.medscape.com/viewarticle/442898_print. Accessed September 25, 2003.

(8.) Rosenberg RN. Translating biomedical research to the bedside: A national crisis and a call to action. JAMA 2003;289:1305-1306 (editorial).

Sharon Wyatt Moore, MD, MBA, MPH

From Medical and Regulatory Affairs, Clinical Trial Management Services, Inc., Bristol; James H. Quillen Veterans Affairs Medical Center, Mountain Home; and Department of Geriatrics, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Reprint requests to Sharon Wyatt Moore, MD, MBA, MPH, Medical and Regulatory Affairs, Clinical Trial Management Services, Inc., 1241 Volunteer Parkway, Suite 950, Bristol, TN 37620. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9612-1169