PREFACE AND ACKNOWLEDGMENTS
This volume represents the findings of a symposium held at Columbia University on May 17, 1983. It is the first of a series of symposia which will deal with the state of the innovative process in medicine.
In addition to the participants, we are particularly grateful to Robert Dormer, Esq. of Hyman & Phelps, Washington, D.C. and William Wardell, M.D., Ph.D. of the University of Rochester Medical Center, Rochester, New York, for their contributions. We are indebted to Dr. Claudio Cavezza of Sigma Tau, S.p.A. of Rome, Italy and to Dr. Francesco Della Valle of Fidia S.p.A. of Abano Terme, Italy for their interest and kind encouragement.
We were all surprised to learn that few, including our colleagues in the business world, are well versed in the area of patentability of natural substances for medical use. We have, therefore, added a section concerning the patent system at the end of this volume.
Finally, we extend our sincere gratitude to Dr. Maurice M. Rapport, Chief of the Division of Neuroscience at the New York State Psychiatric Institute, for his generous hospitality.
Stephen L. DeFelice, M.D.
PARTICIPANTS
Louis Lasagna, M.D. Chairman
Professor of Pharmacology and Medicine
University of Rochester
School of Medicine and Dentistry
“The Promise of the Animal Kingdom”
Silvio Garattini, M.D.
Director
Istituto Mario
Negri Milan, Italy
“The Promise of the Plant Kingdom”
Joseph R. DiPalma,, M.D.
Dean Emeritus
Professor of Pharmacology in Medicine
Hahnemann University Medical School
“The Economic Problems”
Mr. Richard R. Stover
Vice President, Senior Pharmaceutical Analyst
Prudential 8ache Securities
“The Risks to the Physician”
William J. Curran, J.D., LL.M., S.M. Hyg.
Frances Glessner Lee Professor of Legal Medicine
Harvard Medical School
“Proposed Solutions”
Stephen L. DeFelice, M.D.
Chairman, Foundation for Innovation in Medicine
INTRODUCTION
The purpose of the meeting was to emphasize the promise of natural substances with therapeutic potential and the problems that they encounter in our present system.
For reasons that are not clear, the promise of natural substances has not been adequately recognized by the medical, scientific and government communities. The main interests have been manifested by consumer demand for natural substances as nutritional agents. Thus in the United States we find an expanding health food industry, frequently selling products with little scientific support for their claimed benefits. In contrast, there is a relative lack of natural substances approved by the Food and Drug Administration (FDA) for medical uses and an ever-increasing number of approved synthetic, unnatural drugs.
Nature’s medical track record is unsurpassed. The mere survival of living things as individuals and as species is the greatest testament to the success of nature. Yet all is not well. Ever increasing barriers too frequently inhibit or retard medical research and development of natural substances.
With the promise great and the barriers formidable, the following report contains an analysis of the situation and recommendations for solutions.
THE INNOVATIVE SYSTEM
Any proposed solution must be based on improving the creative or innovative system of discovery. First, innovation requires an idea and second, the testing of this idea. In the field of therapeutic agents, for example, innovation requires a substance (the idea) and the testing of that substance–clinical research. Any process which hinders the testing of such ideas–clinical research–must, of necessity, decrease innovation.
There are four major factors which play a role in innovation-technology, manpower, funding and environment, the last of which permits the others to interact productively. It is difficult to quantitate the effects of these four factors on clinical research of natural substances because of the lack of information available. On the other hand, there are data on the pharmaceutical industry in the area of synthetic drugs or new chemical entities (NCE’s). An NCE is a novel molecule which does not exist in nature and is usually strongly patented. If one steps back in history and examines the rate of NCE’s approved by the FDA, a peculiar phenomenon is obvious. During the decade of the 50’s the FDA approved an increasing number of NCE’s . During the decade of the 60’s there was a dramatic reversal of this phenomenon. It is historically evident that during the period of the 60’s there was a significant increase in skilled manpower and technology. In addition, pharmaceutical spending in research and development and government spending in research both increased dramatically. Based on this evidence, the conclusion could be that decreased innovation occurs with increased technology, increased skilled manpower, and increased funding. In order, therefore, to bring about a Renaissance of innovative new therapies, should we reverse technology, diminish training programs and dramatically reduce funding? Of course not!
The answer lies, therefore, somewhere in the fourth category-the environment. One event clearly divides the innovative 1950’s from the declining 1960’s — the Kefauver-Harris hearings and resulting amendments. This legislation resulted from the tragedy of thalidomide. From the point of view of its effect on the environment, it is clear that the change was related to substantially increased regulations.
Thus a system with increased skilled manpower, increased spending, increased technology and substantially increased regulations is anti-innovative.
THE PROMISE
“Natural substances and synthetic medicines represent two different approaches to therapy. Natural substances represent reality,” according to Dr. Silvio Garattini, Director of the Istituto Mario Negri of Milan, Italy. In discussing the promise of the animal kingdom, Dr. Garattini noted that of the 213 substances that the World Health Organization says are essential to meet the basic health needs of the developing as well as the developed nations, 59 compounds (vitamins, hormones, and vaccines among them) are of animal origin.
A resurgent interest in substances of animal origin has been stimulated by the enormous gains made in scientific techniques such as analytical technology — for example, the sequencing of amino acids. New methods of reproducing certain natural molecules through genetic engineering have meant that one of the basic limitations for using substances from this source–lack of enough basic material–has been diminished.
Many known products of animal origin hold out great promise, including the plasminogen activating factor, which could be useful for patients who develop vascular thrombosis; L-carnitine, which has broad promise including the relief of certain side-effects of renal dialysis; ERYTHROPOIETIN, which may be important for treating certain types of anemia; cerebral gangliosides for stimulating the regrowth of damaged or diseased tissue of the nervous system and interferon for a variety of diseases. The list is long.
Unfortunately, on the pharmacological level, the tests developed to study the action of synthetic drugs are not always relevant (or accurate) for natural substances. Among other problems is the need to define a strategy for each product to determine its toxicity, said Dr. Garattini, who also questioned whether it is necessary to establish the carcinogenicity of a compound naturally present in man. “What kind of toxicological testing in animals should be required if a substance is species-specific to man?” Dr. Garattini asked.
The promise of the plant kingdom was hinted at by Dr. Joseph DiPalma’s “conservative” estimate of 20 billion as the number of compounds present in the plant world. And the number increases annually, he noted.
“There is something very useful there to be developed,” said Dr. DiPalma, Dean Emeritus and Professor of Pharmacology and Medicine at the Hahnemann University Medical School in Philadelphia, Pennsylvania. He noted that plants are constantly developing new defense mechanisms and new chemical compounds to fight such natural enemies as insects, viruses or fungii.
There are 750,000 plant species in the world today, and only a small percentage of these have been exploited. Some striking examples of what the plant kingdom promises and delivers are quinine, digitalis and morphine.
Dr. DiPalma deplored the situation encouraged by regulatory policies and economic considerations, for researchers to “break apart the plant chemically to isolate and synthesize different entities, when they should work with the whole plant to determine its actions.” He emphasized it is probable that natural substances frequently work more efficiently in groups than singly though, aside from the area of nutrition, few scientific studies have tested this hypothesis. A recent example of group versus single entity activity is monoclonal antibodies. Tumor antigens are multiple and may require multiple antibodies for an optimum therapeutic effect. Another example is the combinations of various interferons to determine whether there is clinical synergistic activity, a promise already observed in animal and cell-culture models.
THE PROBLEMS
NCE’s are frequently strongly patented. This, in large part, is why they continue to be developed despite the barriers to development. Not so with natural substances. Shortly after the Declaration of Independence, Congress decreed that there should be a limitation of patent protection on products of nature. It understandably argued that salt and water were God’s gift to mankind. The Congress, however, permitted patents for a particular unobvious use, a process of production, and a novel composition of a natural substance. Thus if one discovers a process of producing interferon, someone else could obtain a patent on another process of production. Similarly, if someone discovers that interferon is effective against a particular disease that was not obvious to the scientific and medical communities, he could obtain a patent for that use. On the other hand, it is highly probable that interferon has multiple uses, substantially diminishing the value of a patent for a given use.
Like it or not, therapeutic substances are developed in an incentive economic system. This frequently necessitates exclusivity in the marketplace.
Mr. Richard Stover, Vice President and Senior Pharmaceutical Analyst at Prudential Bache Securities of New York, noted that the extremely high costs of research and development almost demand “exclusivity in the marketplace.” The patent system for NCE’s offers such exclusivity. The patent system with natural substances does not. The estimated costs for a U. S. company to have a successful NCE approved by the FDA is $50 to 70 million. The privilege of exclusivity justifies the costs and risks.
There is general agreement that clinical research, the critical phase of innovation, is heavily regulated according to Dr. William Curran, Professor of Legal Medicine at the Harvard Medical School.
Clinical research is currently being practiced in a virtual straight-jacket of regulation. There is now more innovation, more inclination to “try something different in professional practice than in a research setting,” said Curran.
The regulatory arena has developed into one which uses all known negative sanctions, i. e.: prior restraints, prior approval with aftermath sanctions, aftermath sanctions for poor results, etc. — to impede the development of new products, Dr. Curran said. The delay process itself is a negative sanction, he added. Rewards for rapid achievement have been removed. “The process itself has become the objective, not the end result of successful research.”
If the pharmaceutical industry sponsors clinical research on one of its products it covers the physician investigator under the umbrella of its product liability insurance. If, however, an imaginative researcher believes that a traditional Chinese herb should be tested clinically for particular properties in his own research setting, but without industry backing, the researcher would need to provide his own insurance protection, a coverage which is extremely difficult if not impossible to obtain. Furthermore, the Institutional Review Board (IRB) at his own institution would require all necessary preclinical information to justify a clinical trial in man, even though the natural substance had been available and had proved harmless to man for centuries.
We mention this as an example of a series of barriers which confront the entrepreneurial physician if he or she, like other innovators in the past, wanted to clinically test certain products.
Usually these physicians are not interested in the economic aspects of the product development and would clinically test an idea–patent or not. They are an essential component in our innovative system.
In conclusion, the need for exclusivity in the marketplace, the absence of strong patent protection for natural substances, and the barriers to the innovative physician in clinical research all add up to an anti-innovative system which is clearly greater for natural substances than NCE’s.
THE SOLUTIONS
A solution must be based on two approaches: first, to address itself to the basic cause of the problem, and second, to be feasible. For example, if Congress would increase exclusivity opportunities for natural substances, companies would spend more money taking natural substances from the idea to the clinic for evaluation. But it is unlikely that Congress will pass such legislation. It is important, therefore, to create a series of feasible steps to encourage early clinical research – the basis for innovation. The great risks and costs in product development involve the evaluation of many products in order to discover one that is clinically effective. If, however, a product is clearly shown to have clinical activity — patent or no patent — someone in our pluralistic society will develop it. This has been the case, for example, with orphan drugs. 8ased on this premise, Dr. Stephen DeFelice, Chairman of the Foundation for Innovation In Medicine, offered three recommendations:
1. Physician volunteers: There are approximately 455,000 physicians in the United States, many of whom are also patients. It is proposed that a physician-patient be permitted to freely volunteer to a physician-therapist if the latter wishes to clinically evaluate a natural substance. This physician to physician relationship must be outside of any Federal or institutional regulations or policies. In addition, the physician-therapist must be free from all liability.
This step would result in an enormous increase in early clinical research of natural substances leading inevitably to the discovery of their medical utility.
2. Deregulation of early clinical research in medical schools: The early phases of clinical research of natural substances should be deregulated and placed under the supervision of medical schools for a five year period. Physicians would present their clinical research proposals to IRB’s for approval. The IRB’s would decide whether more data were needed or not. In addition, the IRB’s must be immune from liability in order to encourage reasonableness in judgment. History has taught us that IRB’s are frequently more rigid and demanding than the FDA. A non-governmental commission should be established to assess the net benefit of the pilot program. If successful, the system should become permanent. There are already moves to deregulate the early phases of clinical research. Recently, the McMahon Commission recommended the deregulation of early clinical research for both artificial and natural substances. In Great Britain deregulation of clinical research has been proposed and is presently being implemented.
And finally, medical schools should receive a no-strings-attached government subsidy for the five year period to be used for the evaluation of natural substances.
3. Create a new specialty – Clinical Developer: At present we have cardiologists, psychiatrists, surgeons, clinical pharmacologists, etc., but to guide a substance – artificial or natural – from the laboratory through the scientific, medical, legal, economic, ethical and political barriers is a challenge equal to the most difficult medical specialty. There are very few clinical developers in the United States. We need a pool of such specialists for individuals, foundations, industry and government to turn to for guidance. The rapid establishment of a training program for this specialty is essential for our innovative system.
All three recommendations, if implemented, would immensely accelerate the discoveries of new medical therapies both in preventative and therapeutic medicine. In this fashion even health foods can be clinically evaluated at low costs. The consumer, therefore, could be informed of the value of natural substances via the medical community instead of through other, less reliable sources.
Finally, it should be emphasized that because of the greatness of the promise of natural substances, they are being studied to a certain degree. In addition, the present patent system for natural substances is not being adequately exploited. More attention to the limited exclusivity offered by the present patent system must be given. In fact, if international countries would modify their patent laws to include, for example, use patents, further U. S. research and development of natural substances would be encouraged.
A new industry, based on methods of drug delivery, has blossomed during the past decade. Many of these delivery systems are patented or involve a substantial amount of know-how in production. These delivery systems offer the additional opportunity for limited exclusivity possibilities for natural substances.
In the final analysis, the Congress must resolve the problem that orphaned natural substances confront. Unfortunately it is unlikely that Congress will act to implement these or other recommendations unless the media brings the message, as it did with orphan drugs, to the attention of the public.
Special Note
The participants appreciate the need for the regulation of substances for medical use. It is their belief, however, that when such regulations balance the scales too far in the direction of anti-innovation then it is time for remedial adjustments.
PATENT PROTECTION FOR NATURALLY OCCURRING SUBSTANCES
The extent to which patent protection is available for naturally occurring substances may tend to affect significantly the amount of research and testing that takes place with such substances.
During the conference on natural substances, no consensus could be reached on the definition of the term “natural”. Had a definition been agreed upon, however, that definition almost certainly would have been different from the manner in which the term “natural” is interpreted in the patent law. A brief examination of some basic principles of patent law will demonstrate the problems that exist in this area.
Under the patent statute, 35 U.S.C. Sec. 101, anyone who “invents or discovers any new and useful process, machine, manufacture or composition of matter, or any new and useful improvement thereof” may obtain a patent for the invention, provided it is not obvious. In addition to the general patent statute, there are two laws that specifically address the patentability of plants. In the Plant Patent Act of 1930 Congress allowed certain plants that reproduce asexually to be patented, and in the Plant Variety Protection Act of 1970 Congress permitted certain sexually reproduced varieties to be patented. The purpose of these statutes was to reward the inventiveness of plant breeders who created new living organisms.
In 1980, the Supreme Court addressed the issue of whether a living organism, other than a plant, could be patented. Diamond v. Chakrabarty, 447 U.S. 303 (1950). Chakrabarty involved a patent for a human-made, genetically engineered bacterium which was capable of breaking down multiple components of crude oil. The Supreme Court held that the bacterium could be patented because it did not naturally occur in nature. In so doing, the Court stated that Congress intended the patent laws to “include anything under the sun that is made by man.” 447 U.S. at 309. The Court further recognized that “the relevant distinction was not between living and inanimate things, but between products of nature, whether living or not, and human-made inventions”. 447 U.S. at 313. The patent laws do not, however, embrace the “laws of nature, physical phenomena, and abstract ideas”. 447 U.S. at 309.
In the area of “natural” substances, therefore, it is possible to patent a plant if the plant is the product of man’s ingenuity. A new process for extracting a pharmacologically active constituent of a plant could also be patented, even if the plant could not. Genetic engineering techniques which enable scientists to create analogues of naturally occurring products are also patentable even if the organism cannot be patented.
The patent laws provide considerable protection for novel products produced by man and, therefore, should provide some economic incentive for researchers who wish to conduct studies with natural substances. The patent laws, however, provide limited economic protection for research with a naturally occurring substance, even if research shows that the substance is effective in the treatment of a particular disease.
In the absence of patent protection marketing exclusivity may be obtained only if the researcher obtains approval of a new drug application (NDA) from the Food and Drug Administration. An NDA is a license that authorizes the manufacture and distribution of a particular drug for a designated purpose. It is individual to the person who holds it. No one else can lawfully market that product without first obtaining approval of his own NDA. In any event, the NDA process is very costly.
In conclusion, patent protection is available on a limited basis for those who develop innovative processes and uses for natural substances and for those who create new substances. Natural substances that occur in nature, however, may not be patented.
FUTURE SYMPOSIA
1. NATURAL SUBSTANCES: WHEN DRUG, WHEN FOOD?
2. PATIENT RIGHTS IN CLINICAL RESEARCH
3. BLOOD-BRAIN BARRIER: A THERAPEUTIC DILEMMA
4. ENDO DRUGS