Vladislav Gurin :: BioTech & Pharma consulting

Given the large decline in expected sales that usually occur where generics enter the market, brand companies begin planning a strategic response to this entry in advance of the patent expiration of a commercially important product. These responses are typically referred to as Life-Cycle Management (LCM) strategies. The options used by brand firms:
1) the introduction of a new therapeutic class for the same indication;
2) the introduction of a new formulation (e.g., a new delivery system or a combination product) that has improved therapeutic benefits in terms of patient tolerance, compliance, safety or efficacy;
3) the introduction of an Over-The-Counter product.
Each of these strategies has been employed on a selective basis with some success by brand firms.
The most effective life-cycle management strategy seems to be the introduction of a new class of therapies. Competition evolves in pharmaceuticals by the introduction of new classes of entities with superior therapeutic properties to prior generations of products. Firms that have a commercially important product subject to patent expiration will frequently be conducting R&D on new therapeutic approaches for the same indication. However, there are no guarantees in this regard because the candidates for the next advance in therapeutics often span a large spectrum. Furthermore, the R&D process is subject to many technical, regulatory, and competitive uncertainties with long time durations.
Another life-cycle management option for the brand firm is the introduction of a product line extension such as a new delivery system. Under the Hatch-Waxman Act (1984), a new formulation involving additional clinical trials is eligible for a 3-year exclusivity period. Moreover, a new delivery mechanism or formulation may be covered by a new patent. One of the most successful cases in this regard was the introduction by Pfizer of Procardia XL, a once-a-day formulation of a leading calcium channel blocker for hypertension. The extended release Procardia improved the tolerability and the side-effects profile associated with the active ingredient.
As a consequence, Procardia XL appeared to be a much larger commercial success than the earlier formulation of Procardia. This life-cycle management strategy has been employed in several other situations with somewhat mixed success. The weekly formulation of Prozac, for example, has enjoyed only very limited success. The degree of therapeutic improvement is a key factor in the success of this life-cycle management strategy.
A third basic option available in the case of some therapeutic categories is to develop an over-the-counter version of a product subject to patent expiration.
The strategy has been employed for example for anti-inflammatory pain relievers such as Motrin and Naprosyn, anti-ulcer therapies such as the H2-blockers Tagamet and Zantac, proton pump inhibitors such as Prilosec, and in several other therapeutic categories. However, a shift to OTC status requires approval by the FDA that the drug is safe for self-medication (Juhl 2000; McCarran 1991; Schweitzer 1997). A company will normally need to submit new clinical trial evidence to that effect. If approved by the FDA, the company receives a 3-year exclusivity period for its OTC drug in recognition for the new clinical trial work.
A key driver of success in the OTC market is the ability to capitalize on the brand loyalty enjoyed by the prescription product. The number of category shifts to OTC status approved by the FDA has grown over time.
At the same time, there are many therapeutic categories where this is not as viable strategy because they would not meet the FDA’s requirement on safety for self-medication (e.g., mental health and cancer drugs). The FDA has also declined several product requests for shifts to OTC status, such as anticholesterol drug agents.

It is estimated that only 1 out of 10 drug molecules that are selected for development and undergoes various preclinical and clinical development activities ultimately reaches the market. Because of such an attrition rate, drug companies are often forced to conservere sources during initial development and bring a product to the market that may not have optimal pharmaceutical and clinical attributes. This approach also leads to faster availability of new therapies to patients. After the initial launch, further development activities leading to superior products, known as the product LCM, continue. The LCM may lead to new dosage forms and delivery systems, new dosing regimen, delivery routes, patient convenience, intellectual property, and so on. An LCM program is considered successful only if it leads to better therapy and patient acceptance. There are numerous examples of successful LCM through the development of prolonged-release formulations. Development of nifedipine (Procardia® XL, Pfizer), diltiazem (Cardizem CD®, Aventis), and bupropion HCl (Wellbutrin SR® and XL®, GSK) prolonged-release products that not only provided more convenient and better therapy to the patients by reducing dosing frequency but at the same time greatly increased sales of the products are well-known examples. Even old compounds like morphine and oxycodone were turned into important products by the development of more convenient prolonged-release formulations (MS Contin® and Oxycontin®, respectively; Purdue Pharma).
Many of the future LCM opportunities may come through bioavailability enhancement. Solid dispersion, microemulsion, soft gelatin capsule formation, solubilization, lipid-based DDSs (drug-delivery system), nanoparticle or nanocomposite formation, etc., are some of the common bioavailability approaches that can be utilized for LCM. Development of Lanoxicaps® by Burroughs-Wellcome in 1970s by encapsulating digoxin solutions in soft gelatin capsules is a classic example of LCM by bioavailability enhancement and better pharmacokinetic properties. The development of a microemulsion preconcentrate formulation by Novartis (Neoral®), where the variability in plasma and the effect of food were reduced greatly, is another well-known example.
Life-cycle management through the development of fixed combination products, where two or more drugs are developed or copackaged into a single entity, is gaining increased popularity. The fixed combination products often provide synergistic effects, better therapy, patient compliance, patient convenience, increased manufacturing efficiency, and reduced manufacturing cost. However, a clear risk/benefit advantage is essential for the successful LCM by combination products; mere patient convenience may not be sufficient.
Common justifications for the development of fixed combination products include improvement of activity such as synergistic or additive effect, improved tolerance by reduced dose of individual ingredients, broadening of activity  spectrum, improvement of pharmacokinetic properties, and simplification of therapy for the patient.
The development of oral dosage forms that disintegrate or dissolve in the mouth is providing LCM opportunities for pediatric, geriatric, or bedridden patients who have difficulty in swallowing. They are also being used by active adult patients who may not have ready access to water for swallowing tablets or capsules.

In an apparent attempt to determine whether the American taxpayer is getting fair benefits from research sponsored by the federal government, the Joint Economic Committee of the U.S. Senate has been considering this question. Historically, basic research has been funded by the NIH and various philanthropic foundations to discover new concepts and mechanisms of bodily function, in addition to training scientists.
The role of industry has been to apply the basic research findings to specific treatments or prevention of disease. This is the appropriate manner in which to proceed. The industry cannot afford to conduct sufficient basic research on new complicated biological processes in addition to discovering new drugs or vaccines. The government does not have the money, time, or required number of experts to discover and develop new drugs.
The process that plays out in real life involves the focus of pharmaceutical industry scientists on desirable biological targets that can be identified in disease states, and to set up the program to discover specific treatments that will show efficacy in human disease.
The compounds that are developed successfully become drugs on which the company holds patents. In this manner, the huge cost of discovering and developing a new drug (estimated at $800 million plus over a period of some 10 years) as noted above can be recouped by the founding company since no competitors can sell the product as long as the patent is in force. Without such a system in place, drug companies simply could not afford to bring new prescription drugs to the market.
In the course of reviewing the matter, the Joint Economic Committee examined a list of 21 major drugs, which was put together apparently as an example of drug products that might justify royalty to the government. One of these agents, captopril (trade name Capoten), was discovered and developed by E.R. Squibb & Sons in the 1970s. At that time, one of Squibb’s academic consultants, Professor Sir John Vane of the Royal College of Surgeons in London brought the idea of opening a new pathway to treat the so-called essential hypertension by inhibiting an enzyme known as the Angiotensin Converting Enzyme (ACE). This biochemical system was certainly known at that time but, in Squibb’s experience in the field of hypertension treatment, was not generally thought to play a major role in the common form of the disease, then known as “essential hypertension.” The company decided to gamble on finding a treatment that was not used at the time and that would be proprietary to the company. Professor Vane (Nobel laureate in medicine in 1982) had discovered a peptide in snake venom that was a potent inhibitor of ACE. Squibb decided to pursue the approach he espoused, resulting in the development of a unique drug for the treatment of this very prevalent and serious disease.
In the first phase of their research, Squibb tested a short-chain peptide isolated from the venom of the viper Bothrops jararaca, with which Vane was working in the laboratory, in human volunteers and showed that it did, indeed, inhibit the conversion of angiotensin I to angiotensin II after intravenous injection. The peptide was also shown to reduce patients’ blood pressure when injected. Since the vast majority of peptides cannot be absorbed from the GI (gastrointestinal) tract, Squibb scientists set out to prepare a nonpeptide compound that could be used orally and manufactured at acceptable cost. The design of a true peptidomimetic that became orally active had not been accomplished at that time. Squibb then carried out a full-blown clinical program on a worldwide basis, which led to FDA approval of Squibb’s drug Capoten (captopril), an ACE inhibitor. Mark also marketed an ACE inhibitor in the same period. This work opened a new area of research that has resulted in a class of new drugs that share this mechanism of action for use as antihypertensive drugs.
In the minds of pharmaceutical researchers and, hopefully, the public at large, the above example illustrates the unique role of pharmaceutical companies in making good use of basic research to discover new treatments for serious and severe diseases. The colossal costs to discover and develop a new drug could not be borne unless the companies knew that, if their gamble worked (which is not the case in the majority of situations), they would be assured of a good financial return (ROI) for their shareholders. This system has served the country well in many fields of endeavor, in and out of the drug arena, and should be retained as such.

Amgen, Biogen Idec and Genentech represent three pioneering biopharmaceutical companies that remain and grow in business.
Founded in the 1980s as AMGen (Applied Molecular Genetics), Amgen now employs over 9000 people worldwide, making it one of the largest dedicated biotechnology companies in existence. Its headquarters are situated in Thousand Oaks, California, although it has research, manufacturing, distribution and sales facilities worldwide. Company activities focus upon developing novel (mainly protein) therapeutics for application in oncology, inflammation, bone disease, neurology, metabolism and nephrology. By mid-2002, six of its recombinant products had been approved for general medical use (the erythropoietin-based products, ‘Aranesp’ and ‘Epogen’, the colony stimulating factor-based products, ‘Neupogen’ and ‘Neulasta’ as well as the interleukin-1 receptor antagonist, ‘Kineret’ and the anti-rheumatoid arthritis fusion protein, Enbrel). Total product sales for 2001 reached US$ 3.5 billion and the company reinvested 25% of this in R&D. In July 2002, Amgen acquired Immunex Corporation, another dedicated biopharmaceutical company founded in Seattle in the early 1980s.
Biogen was founded in Geneva, Switzerland in 1978 by a group of leading molecular biologists. Currently, its international headquarters are located in Paris and it employs in excess of 2000 people worldwide. The company developed and directly markets the interferon-based product, ‘Avonex’, but also generates revenues from sales of other Biogen-discovered products which are licensed to various other pharmaceutical companies. These include Schering-Plough’s ‘Intron A’ as well as a number of hepatitis B-based vaccines sold by GlaxoSmithKline (GSK) and Merck. By 2001, worldwide sales of Biogen-discovered products had reached US$ 3 billion. Biogen reinvests ca. 33% of its revenues back into R&D and has ongoing collaborations with several other pharmaceutical and biotechnology companies.
Genentech was founded in 1976 by scientist Herbert Boyer and the venture capitalist, Robert Swanson. Headquartered in San Francisco, it employs almost 5000 staff worldwide and has 10 protein-based products on the market. These include human growth hormones (‘Nutropin’), the antibody-based products ‘Herceptin’ and ‘Rituxan’ and the thrombolytic agents ‘Activase’ and ‘TNKase’. The company also has 20 or so products in clinical trials. In 2001, it generated some US$ 2.2 billion in revenues, 24% of which it reinvested in R&D.

Organizations engaged in the delivery of services or production of healthcare  goods incur special moral obligations. These moral obligations are sharpened in the event of a dire emergency. Yet non-governmental entities, whether technically ‘for profit’ or not, have a more tenuous relationship to the public good than government agencies. What is the relationship between their social obligations and their legitimate business interests? Under extreme conditions such as those that may be associated with a bioterror attack, privately held resources like pharmaceuticals or the time and skills of physicians that are normally strictly controlled by corporate interests could be needed for the public good.
A standard approach to the obligations of business entities is stakeholder theory, which states that corporate moral obligations are determined by the direct interests of shareholders. Yet a strict construal of stakeholder theory sanctions highly profitable products like child pornography that exploit the vulnerable and corrupt social life. Surely the narrow construction is unacceptable. Further, in the case of health care-related services and products, and especially in emergent circumstances, the stakeholders must be construed more broadly as including health care consumers. This broadened view of corporate stakeholders is incompatible with the notion that profit is the sole end of a business, but compatible with the view that profit is, and under ordinary conditions must be, an appropriate goal of business activity.
When extraordinary conditions prevail, then, private interests may be required to serve pressing social needs. Drug manufacturers, for example, should plan for special pricing strategies in the event of a widespread public health threat, a prudent step in any case as they risk losing control over a product if government chooses to assert its prerogatives for the greater good and withdraw patent protection. Similarly, although proprietary interests concerning sensitive product information should be protected, secrecy practices may extend beyond necessity and impinge on the public’s need to know. Industry-wide secrecy standards could eliminate concerns about competitive advantage while preserving the free flow of socially valuable information.
Corporations engaged in the production and distribution of substances that could be turned to terrorist advantage also have an obligation to put adequate security measures in place and to provide educational programs for their employees. Cooperation with local, regional, and, depending on the nature of the business, even national authorities may be required, especially if the company’s facilities could be directly exploited and toxic substances released.

Hundreds of federal, state, and local regulatory agencies define the legal regulatory environment for pharmaceuticals, agricultural and medical biotech. For example, in the pharmaceutical industry, the key agencies that define the business parameters include the Food and Drug Administration (FDA) and the U.S. Patent and Trademark Office (USPTO), as listed in table below:

The FDA, which is part of the U.S. Department of Health and Human Services (HHS), is responsible for promoting and protecting the public health by helping safe and effective products reach the market in a timely way, and by monitoring products for continued safety after they are in use.Its reach extends from food, drugs, and medical devices to biologics, animal feed and drugs, cosmetics, and radiation-emitting products. In the realm of pharmaceuticals, the FDA regulates the drug development process to ensure patient safety. FDA oversight includes preclinical safety assessment, preapproval safety assessment in humans, safety assessment during regulatory review, and post marketing safety surveillance.The goal of preclinical safety assessment is to identify drugs that are effective against a targeted disease in animals without causing significant toxicity. Preapproval safety assessment in humans involves a lengthy clinical trial process culminating in the preparation of a New Drug Application (NDA) seeking FDA approval for manufacturing, distributing, and marketing a drug in the U.S. During the approval process, pharma companies must supply the FDA with any additional safety information that it obtains. Post marketing safety surveillance, also known as Phase IV trials, may be required by the FDA or conducted voluntarily by the pharma company, depending on the frequency and severity of reactions noted in the clinical trials. Post marketing surveillance is highly regulated by the FDA. For example, pharma companies must inform the FDA of reports of serious, unexpected adverse drug reactions anywhere in the world within 15 days.Pharma firms that fail to follow the drug development process as outlined by the FDA aren’t allowed to market their products in the United States. Furthermore, even if drugs are thoroughly evaluated for efficacy and side effects, the FDA has the power to remove drugs from the U.S. market if significant side effects are reported in patients taking the drugs.Some of the major legislative initiatives implemented by the FDA that profoundly affect the pharmaceutical industry include the Orphan Drug Act, the Prescription Drug Marketing Act, the FDA Modernization Act, and the Health Insurance Portability and Accountability Act. The Orphan Drug Act is designed to encourage the development of drugs to serve markets of fewer than 200,000 patients. It provides a seven-year period of market exclusivity and a 50 percent tax credit for clinical research expenses involved in developing the drug. The Prescription Drug Marketing Act was enacted in 1988 to limit the diversion of prescription drugs into a secondary gray market. Another major piece of legislation affecting the pharmaceutical industry is the FDA Modernization Act of 1997, which streamlined many of the processes used by the FDA, and reduced and simplified many regulatory obligations of pharmaceutical manufacturers.The Health Insurance Portability and Accountability Act (HIPAA) was enacted by the Department of Health and Human Services (HHS) in part to ensure the privacy of patients who take part in clinical trials. HIPAA requires pharmaceutical companies to follow stringent security practices to prevent patient data from being accessed by those without access privileges.In addition to the Food and Drug Administration, the U.S. Patent and Trademark Office (USPTO) is a major constituent of the legal-regulatory infrastructure of the pharmaceutical industry. The USPTO establishes the limits of the temporary monopoly granted pharmaceutical companies by virtue of drug patents and other intellectual property protection.

A measure of the educational infrastructure in biotech is the annual investment in tools that support the biological and computer sciences. According to the National Science Board, about 9% of the annual budget for the biosciences is spent on tools like genomic sequencers, electron microscopes, and biological databases. In comparison, about 27% of the educational investment in computer sciences is devoted to infrastructure, predominantly on networks, software, data repositories, and data communications systems.

Given the increasing need for academic biological centers to create, maintain, and update vast genomic databases, the National Science Foundation (NSF) has earmarked the biosciences as one area in which the infrastructure investments have not kept up with expanding needs and opportunities. This is reflected in a preliminary estimate of NSF future infrastructure needs, based on reports from the NSF directorates and the Office of Polar Programs (OPP).

In addition to the key legal-regulatory agencies associated with the pharmaceutical and secondary biotech markets, numerous government acts and government agencies affect virtually every worker, employee, and business in the United States. For example, the Occupational Safety and Health Administration (OSHA), which is under the U.S. Department of Labor, is tasked with saving lives, preventing injuries, and protecting the health of U.S. workers, whether they are involved in agriculture or manufacturing pharmaceuticals. Other examples of sweeping legislation that have a direct impact on defining the biotech industry are the numerous federal cooperative research and development and technology transfer acts, including those listed below.

FIGURE. Federal Cooperative R&D and Technology Transfer Acts that directly impact the biotech industry.

Taken together, these acts encourage interactions between academia, the business community, and the government, and allow businesses to retain or gain the patent rights to technologies developed with government funding. For example, The Bayh-Dole University and Small Business Patent Act allows government contractors and grantees to retain title to inventions to encourage interactions between academia and the business. The Federal Technology Transfer Act established the Cooperative Research and Development Agreements (CRADAs) as a means of funding corporate research and development with U.S. government taxpayer money.

Creating completely new drugs is the most expensive, time-consuming, and risky approach to keeping the pipeline filled. Thus, keeping the product pipeline of a pharmaceutical firm filled is often as dependent on a good legal team as it is on a crack research and development department. Many of the successful legal and regulatory maneuvers employed by pharmaceutical firms involve extending existing patent protection on a product. Extending the patent protection on a blockbuster drug by only a few months can enhance the coffers of a pharmaceutical firm by a billion dollars or more. One mechanism for extending the patents on a blockbuster drug is obtaining supplementary protection. This added patent protection, which can extend a patent up to five years, is a means of compensating pharmaceutical firms for loss of market exclusivity during a lengthy regulatory review process. Another approach is to acquire orphan drug designation from the Office of Orphan Products Development at the FDA for drugs with a market potential limited to fewer than 200,000 patients. The Orphan designation, available since 1983, qualifies the pharmaceutical firm for seven years of marketing exclusivity, with a 50 percent tax credit for research expenses, and a waiver from certain FDA fees in exchange for developing the drug. The drug must then go through the new drug approval process like any other drug. However, because orphan drugs are developed for rare, often life-threatening diseases, including certain forms of cancer and genetic disorders, the review process is usually shorter and less comprehensive than the review of a typical drug. According to the FDA, as of the first quarter of 2003, over 1,000 orphan products have been designated and over 220 have been approved for marketing. Orphan drug programs, such as “Tin Mesoporphyrin and Heme Therapy in Acute Porphyria” have been enacted by the EU, Japanese, and Australian governments. A list of orphan drug programs funded by the FDA can be found on Web: www.fda.gov/orphan/grants/awarded.htm.
Pediatric exclusivity is one way to obtain six months of added patent protection for a drug. Most drugs undergo clinical trials with adult subjects. However, for drugs that have application in pediatric populations, and in which the clinical trials consider pediatric uses, it may be possible to qualify for pediatric exclusivity. Discovering a new indication for an existing blockbuster drug, while not as good as discovering a completely new drug, can be worth billions. For example, Minoxidil® was originally introduced by UpJohn in the late 1970s as an oral antihypertension medication, and later used as a topical treatment for male pattern baldness. In the late 1990s, the cholesterol-lowering drug Pravachol® by Bristol-Myers Squibb was approved by the FDA for a new indication—reducing the risk of a transient ischemic attack (a miniature stroke) and a recurrent attack in patients who have had a heart attack. The most difficult and time-consuming of the various maneuvers to extending a patent involves developing a new formulation of a drug that is just different enough from the blockbuster to be granted a patent. A new formulation, such as adding particles to a cream to hold the active ingredients can add a decade to the life of a patent, regardless of its effectiveness relative to the original drug. Finally, switching to a marketing strategy in which a drug just off patent is reintroduced into the market as a generic, is a low-cost option to capture revenue once other options have been exhausted. In addition to extending patent protection, a more controversial approach to keeping the competition off-guard is to actually discontinue a drug before its patent has expired. This practice confounds not only the competition, but physicians and patients as the scenario slowly unfolds. One example is the practice of withdrawing a drug from the market while the drug is still under patent protection, and introducing a similar drug before the competition has a chance to introduce generics into the marketplace. During the window of opportunity created by the overlap in patents, physicians may have no choice but to transfer their patients to the newly released drug. Months later, when the patent on the original drug expires, many patients will already be on the pharmaceutical firm’s second drug. As a result, fewer patients are transferred yet again to the generic drug when it becomes available. This approach was apparently used by Shering Plough when it withdrew Clarityn® (loratadine) before its patent expired and immediately introduced Neoclarityn® (desloratadine).To better appreciate the role of legal maneuvering in keeping a large pharmaceutical firm solvent, recall the 10 drugs in 2002. Note that, with the exception of Pharmacia and Pfizer’s Celebrex® and AstraZeneca’s Prilosec®, the top products all experienced significant growth. The reasons for the 19 percent contraction in sales of Prilosec® illustrates some of the major legal challenges and tactics associated with the pharmaceutical industry. In 2001, Prilosec was the number two drug in terms of global sales, contributing $6.1 billion in sales, just behind sales of Pfizer’s Lipitor® at $7 billion. However, with the primary patent for Prilosec® expiring in October of 2001, AstraZeneca undertook a multipronged approach to maintain its share of the market for heartburn drugs. One tactic was to shift marketing resources behind its follow-up product, Nexium®, with a $478 billion campaign in 2001 aimed at moving patients on Prilosec over to Nexium, which, by many accounts, provides no real benefit over Prilosec. In fact, the two drugs are simply isomers (mirror images) of each other. Even so, the mirror image is technically a different drug from the original, and is protected by a patent.Meanwhile, AstraZeneca filed for patent extension, maintaining that four generic drug makers infringed on AstraZeneca PLCs patent on Prilosec. A federal judge ruled that the U.S. Andrx Corporation, Genpharm Inc., an affiliate of German Merck KgaA, and Reddy-Cheminor, a unit of India’s Cheminor Drugs, infringed on AstraZeneca’s patent on Prilosec. The ruling was based on AstraZeneca’s patent for the formulation of the subcoating used on Prilosec that protects the active drug from being digested by the stomach acids. The secondary patent on the subcoating doesn’t expire until 2007.
The ruling didn’t entirely stop the competition from lower-cost generics, however, because the fourth company, KUDCo, a unit of the German company Schwarz Pharma AG, uses a different coating. However, given the delay caused by the litigation, sales of KUDCo’s generic amounted to a mere $150 million during 2002. The other three companies were forced to reformulate the coating used with their generic versions of the drug. The delay gained by the litigation provided AstraZeneca with ample time to build up a campaign around its new patent-protected Nexium product, which is under patent until 2014.AstraZeneca is also encouraging large hospitals and health-care enterprises to use the new drug through substantial rebates that make the new drug significantly cheaper than the drug it replaces, resulting in savings for the hospital. Pharmaceutical houses customarily maximize the use of a new drug through this type of incentive. In exchange, the physicians with the hospital gain experience prescribing the new drug, and they’re more likely to prescribe it in the future. In addition to competition from generics, AstraZeneca’s heartburn offerings are is being chased by established pharmaceuticals, including TAP/Abbott (Prevacid®), Eisai/Johnson & Johnson (Aciphex®), and Wyeth (Protonix®).One reason that patent litigation is so popular in the pharmaceutical industry is The Drug Price Competition and Patent Term Restoration Act, more commonly referred to as the Hatch-Waxman Act, enacted in 1984. The law allows pharmaceutical firms to “stop the clock” on the normal 20-year patent term expiration by excluding litigation from the 20-year term during which the FDA is exercising regulatory oversight and review. Because of the Hatch-Waxman Act, drug patents receive an average of 11 to 12 years of protection once they’re released to the market, instead of only 4 to 5 years. The Hatch-Waxman Act also created the generic drug industry in the US by softening the blow the extended patent protection has on the makers of generics. A component of the act created the Abbreviated New Drug Application (ANDA), which requires a generic drug manufacturer to prove that its product is bioequivalent to the original, patented drug. What’s more, the generic drug manufacturer needn’t wait for the original drug to come off patent before testing for bioequivalence. As a result, the generic drugs can be advanced on the market as soon as the innovative drug’s patent expires. Hence the interest of the top drug manufacturers in delaying the entry of a competing generic drug.
In addition to engaging in strenuous patent litigation and introducing follow-on products, switching the original products from prescription only to over-the-counter status is another tactic to extend the life cycle of a pharmaceutical product. Direct-to-consumer advertising is proving to be just as useful for prescription drugs as it is for over-the-counter products.

Bioterrorism is the term used to describe the offensive employment of biological substances or toxins with the objective of causing harm to an individual or a group of individuals. These activities, in general, cause damage, intimidation, or coercion, and are usually associated with threats causing public panic. The most common biological agents used as weapons are microorganisms and their associated toxins, which can be used to promote disease or death in people, animals, and even plants. The agents of contamination can be dispersed in the air, water, food, and elsewhere.

Bioterrorism has been a problem throughout human history. One of the first reports of bioterrorism dates back to the 6th century B.C., when the Assyrians poisoned the wells of their enemies with ergot, a toxin-producing fungus often found in rye. A more recent report suggests that in the 1500s, Pizarro, in the conquest of South America, gave clothes contaminated with smallpox to native Indians. Another similar report alleges that Britain might have used pathogens to weaken their opponents during the colonization of North America. The country might have deliberately distributed blankets contaminated with smallpox to Native Americans. Terrorism using chemical or biological weapons often spreads quietly, but it can have devastating impacts.

The first convention banning biological weapons was signed in Geneva in 1925. In 1972, under United Nations leadership, 103 countries signed the Convention on Biological Weapons, which prohibits the development, production, stockpiling, and use of biological weapons. The objective of this convention was to completely eliminate the use of biological agents and toxins as weapons of mass destruction.

During a conference on bioterrorism held in San Diego, California in early 2000, experts concluded that the US was not prepared for a biological attack with pathogens such as smallpox, anthrax, Ebola, botulism, and others. At the second National Symposium on Bioterrorism in Washington, DC in 2000, one of the conclusions was that the American public health system was not prepared to respond to an attack with biological weapons. Additionally, in March 2001, researchers at the Center for the Study of Bioterrorism and Emerging Infections at the St. Louis University School of Public Health revealed that 75 percent of health agents feared that some city in the United States would suffer an attack with biological weapons within the next 5 years. The forecasts by the experts were correct: In October 2001, just four months after the meeting, the United States had its anthrax attack.

Anthrax and especially smallpox are considered the most serious threats of biological bioterrorism, due to the high fatality rate among infected individuals, the possibility of transmission in an aerosol form, and the relative ease of large-scale production. Various government-sponsored biological warfare programs have researched many other pathogens as well.

The list of pathogens with potential terrorist applications ranges from salmonella to super virulent (highly infective) strains of the bacteria that causes bubonic plague (Yersinia pestis) genetically modified by recombinant DNA technology. There are also toxins such as ricin, the organic phosphorous sarin gas, or the Ebola virus. Recently, the North Atlantic Treaty Organization (NATO) listed 39 biological agents that could be used as weapons by terrorists.

A wake-up call for the risk of bioterrorism occurred when sarin, a gas affecting the nervous system, was used in an attack carried out by the religious cult Aum Shinrikyo in a Tokyo subway in 1995. Interestingly, according to the Monterey Institute of International Studies (http://www.miis.edu), of more than 100 other terrorism acts recorded since 1960, the great majority has failed. However, interest in bioterrorism has increased significantly after the anthrax cases that occurred in late 2001. The U.S. Department of Health spent, as of the last decade, about $160 million annually on bioterrorism prevention. After the September 11 terrorist attack and the anthrax cases that followed, it is believed that investments in this area will rise substantially with an increase in the reality of terrorist threats.

As discussed, biotechnology can be used in the development of pathogens with higher virulence and increased antibiotic resistance, when in the wrong hands, but the science can also be used in the development of biodefenses as well. Early warning indicators, more precise diagnostic procedures, therapy, vaccines, pathogen identification, and new pharmaceuticals are only some of the areas in which biotechnology can be of help in the area of bioterrorism.

The main objectives in preventive bioterrorism are the production and stockpiling of vaccines and the development of early warning systems in the event of an attack. Genome sequencing also promises to facilitate the development of biodefenses and decontamination. An ongoing project at the University of Michigan is developing a mechanism to kill anthrax, using a solution of droplets of soybean oil in aqueous suspension. The droplets of this emulsion fuse with the bacterial membrane by means of a chemical reaction, thereby generating sufficient energy to destroy bacterial spores. Another interesting area of research is the production of synthetic antibodies to improve the treatment of infection.

Experts know that most of the progress in biotechnology is not only useful to combat biological agents spread intentionally, but also for naturally occurring disease epidemics. Considering that the real threat of bioterrorism is present worldwide, preventative measures are catching the attention of governments and of the public.

The use of bioweapons requires the cultivation, purification, stabilization, and large-scale production of the pathogen, as well as the development of an efficient means for dispersal. For instance, the dispersion of bacterial spores with a size ideal for uptake into the bronchioles of the lung can be an additional challenge for terrorists without scientific knowledge. Experts believe, however, that it is not difficult to find leads to bioterrorism programs in the international market. It is widely believed that thousands of trained scientists with expertise in biological warfare lost their jobs after the collapse of the former Soviet Union in December 1991.