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.