Research and Regulations - ACS Publications - American Chemical

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Report

Research and Regulations Robert M. Hodges Warner-Lambert/Parke-Davis Pharmaceutical Research Division 2800 Plymouth Road Ann Arbor, Mich. 48105

In scientific meetings an increasing proportion of the presentations is di­ rectly or indirectly related to meeting requirements of regulatory agencies. I will talk principally about the phar­ maceutical industry since this is where I have some knowledge and experi­ ence. The effects of government regu­ lations are ubiquitous in our everyday lives and professions but are often suf­ ficiently unobtrusive that we are not conscious of them. In an editorial in the newly founded journal Regulation, the scholarly Irving Kristol has asked if we are not becoming a regulated so­ ciety (ί). As he points out, no reason­ able person is in principle opposed to government regulation. Most of the population is not sufficiently expert to decide if carbon tetrachloride is toxic to the liver and bone marrow or if a fire repellent for clothing is a car­ cinogen or if the wide use of fréons will have deleterious effects upon the upper layers of the atmosphere. Therefore, we approve the efforts of Congress, or the state legislatures, in establishing agencies which will take care of these problems for us. Even for experts it may be difficult to arrive at the correct decision, as witness the last example of the fréons. A prestigious committee of the National Acad0003-2700/78/0350-531 A$01.00/0 © 1978 American Chemical Society

emy of Sciences has properly adopted a wait-and-see attitude, while further studies are being carried out to see what is happening to the ozone in the stratosphere. It is worth noting that although we expect regulatory bodies to look after complex matters, this complexity may itself make regulation difficult to perform in a properly balanced manner. For these difficult functions we have created new agencies such as the Environmental Protection Agency (EPA), Occupational Safety and Health Administration (OSHA), and the Food and Drug Administration (FDA). Although the forerunner of the latter was first formed 70 years ago, in the context I am talking about, it has really only functioned since 1963. In these agencies we find as wide a variety of people as in any academic or industrial organization. Many of the officials are experienced and knowledgeable individuals who work as hard, for less money, than they would in the business world. The one feature that characterizes most of the career individuals is a belief in a planned and regulated system that will create a better way of life for all of us. They are generally not particularly sympathetic toward private enterprise and

are often indifferent to the economic implications of their regulatory actions. Regulatory Agencies There are 16 regulatory agencies that currently inspect our research facilities in Ann Arbor or require us to submit detailed reports annually. In addition, inspections on a regularly scheduled basis are carried out by other agencies such as AAALAC for the accreditation of facilities for laboratory animal care and the National Institutes of Health inspections related to grants and contracts. Table I shows the major inspecting agencies. There is a considerable overlapping of functions between agencies at the federal, state, and local levels. The Environmental Protection Agency inspects waste and air pollution. The Nuclear Regulatory Commission does the same for radioactive materials. The Department of Justice and Veterans Administration are concerned with equal opportunity employment. The Drug Enforcement Administration inspects our handling of scheduled drugs. The Department of Agriculture and the Michigan Department of Natural Resources both regulate animal quarters and handling

ANALYTICAL CHEMISTRY, VOL. 50, NO. 6, MAY 1978 · 531 A

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Table I. Major Inspecting Agencies Environmental Protection Agency Nuclear Regulatory Commission U.S. Department of Justice Veterans Administration U.S. Department of Treasury Drug Enforcement Administration U.S. DepaVtment of Agriculture Michigan Department of Natural Resources Federal and State Occupational Safety and Health Administration Michigan Department of Health Washtenaw County Health Department Food and Drug Administration

procedures. The Michigan Department of Health, Federal and State OSHA agencies and the County Health Department have overlapping functions with regard to employee health. The agency having the most profound effect upon the pharmaceutical industry is the Food and Drug Administration. The forerunner was formed in 1906 to regulate the interstate commerce of food and drugs to eliminate substandard materials constituting a danger to the public health. There was little effect upon the pharmaceutical industry as a whole until 1938 when the elixir of sulfanilamide incident occurred. The solvent for the sulfanilamide, ethylene glycol, was chosen on the basis of suitability as a solvent for the sulfa drug and for its formulation properties. Simple toxicology studies would have revealed its dangers; unfortunately through lack of knowledge and experience these studies were not made. The tragic results which ensued upon the marketing of this product were magnified by the fact that the product was directed toward pediatric use and caused the deaths of many children. As a result of this unfortunate and preventable accident, the Food, Drug and Cosmetic Act created the rudiments of the present regulatory structure. Before a drug could be marketed in interstate commerce the manufacturer had to file a New Drug Application (NDA) with evidence to support the safety for use under conditions specified in the accompanying literature or labeling. The FDA was allowed 60 days to review the application. Unless rejected during this time the drug could be marketed. To provide the necessary studies to show safety of a new drug, the use of drugs by qualified investigators was exempted from the NDA requirements. The clinical and preclinical tests were therefore not subject to any regulatory control, and the degree of supervision and monitoring of clinical investigators was minimal. In addition, the state-of-the-art of clinical in-

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532 A · ANALYTICAL CHEMISTRY, VOL. 50, NO. 6, MAY 1978

vestigation was empirical, and in the early years the double blind controlled study was uncommon. In the 1950's when I was a resident in a large teaching hospital, I observed the use of investigational drugs under conditions which provided no useful information with regard to efficacy and in which the patients were protected from adverse results mainly by the fortunately benign nature of the drug and the condition being treated. This state of affairs was improved by the Kefauver-Harris Drug Amendments passed in 1962, as a result of the thalidomide experience, and effective since June 1963. As a passing note, it is of interest to observe that our present preclinical toxicity tests would not detect the teratogenicity of thalidomide, but it is probable that the better control and monitoring of clinical studies existing today would pick up the phocomelia at an early stage. In the 15 years since the amendments were passed by Congress, they have radically changed the way in which drug research is performed. While the initial impact was principally on clinical research, ever broader interpretations by the FDA of their powers and responsibilities under the law are affecting all aspects of ongoing pharmaceutical research, from chemical synthesis to marketing experience with approved drugs. Problems in Development of New Drugs Drug regulation, while not the only factor, has had a marked effect upon the time and costs required for the development of drugs in the United States. This is illustrated by the following: • In 1938 Parke, Davis & Co. submitted an application for Adrenalin in Oil (Epinephrine). The submission comprised a folder containing only 27 pages. The product is still in use after almost 40 years. • In 1948 an application was submitted for Benylin Expectorant. The submission consisted of a single bound volume of 73 pages. Nearly 30 years later it continues to be a major antitussive agent worldwide. • In 1958 an application was submitted for Povan Suspension (pryvinium pamoate). This required two volumes for a total of 439 pages. The product is still marketed in most countries, including the United States, as an effective treatment for pinworm infestation. • In 1962 an application was submitted for Norlestrin, now 12 370 pages in 31 volumes. Like the previous products, Norlestrin continues on the market as a safe and effective product. • Six years later, in 1968, an application was submitted for a new type

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RIBERMAG 49 quai de Halage 92505 Rueil-Malmaison, France (1)977.92.05 Telex 692419 CIRCLE 177 O N READER SERVICE CARD ANALYTICAL CHEMISTRY, VOL. 50, NO. 6, MAY 1978 · 533 A

of anesthetic agent, Ketalar (ketamine). The data now comprise 72 300 pages in 167 volumes, each 2 in. thick. • Finally, in 1977 an NDA was submitted for an anti-inflammatory agent Meclomen (meclofenamic acid). The data required by the regulations have now risen to the level of 95 400 pages in 276 volumes, each 2 in. thick. These increasing requirements are not unique to one company. Although I do not know which firm holds the dubious record of having the largest application, it is reported that in 1973 the Norwich Pharmacal Co. submitted a NDA for a muscle relaxant, Dantrium, consisting of 456 volumes. One set of the NDA documents weighed about a ton and comprised 75 linear feet of bound documents (2). There has been a prolongation of the developmental time for drugs from a matter of 1 to 2 years for products marketed in 1938 to 10-15 years from products being submitted for approval in 1977. The record of the drugs marketed by Parke-Davis in earlier years, such as Adrenalin and Benylin, show that a relatively short, expeditious development is not inconsistent with the production of a safe and effective drug. Increased regulatory requirements are certainly not the only factor in prolonging the time taken to develop drugs. However, the effects of United States regulatory requirements are shown by two quite comparable drugs discovered in the same year in our research laboratories (3). Both of these drugs were synthesized in 1968 in a program that sought agents which would be useful for the treatment of hyperlipidemias. These two compounds were selected as showing the most promise from nearly 9000 compounds tested in this program. Both were subjected to full pharmacologic and toxicological evaluation; by 1971 we felt we had adequate data to justify introducing the two compounds into man. The two compounds, gemfibrozil and gemcadiol, were similar in their effectiveness in lowering triglycerides in experimental models. Gemcadiol, being superior in its effects on serum cholesterol in primates and rodents, showed a better spectrum of activity. Toxicological findings were similar for both compounds. Gemfibrozil has some similarity to compounds (such as clofibrate) that are known to be active in this therapeutic category. We could therefore extrapolate with some degree of certainty from the experimental animal to man with regard to the qualitative effects that would be seen. On the other hand, gemcadiol is a totally unique chemical with a greater potential for being qualitatively and quantitatively different from existing

Table II. Developmental Phase Timetable Clinical studies

Phase Phase Phase Phase

I started II started II completed III completed

Gemfibrozil

August 1971 (USA) December 1973 (Europe) June 1975 December 1976

agents, both for efficacy and for side effects. Because of these differences between the two drugs and bearing in mind the attrition rate of drugs selected for clinical development (only about 1 in 8 completes the full developmental course to marketing), we decided to develop both products at the same time. Because of gemcadiol's uniqueness we assigned it priority where needed. After the initial human tolerance trials, we carried out all of the clinical therapeutic studies for gemfibrozil in Europe, whereas gemcadiol was studied exclusively in the United States. Table II shows the difference in the time taken for the development of the drugs to the end of phase III. The date of December 1976 is an actual date for gemfibrozil. The 1979 date for gemcadiol was an estimate, and I think a rather optimistic one. There is a difference of 2V4 years in favor of the developmental time for a comparable drug in Europe vs. the United States. This difference is more marked with regard to the time of first marketing since major European regulatory agencies take only a third to one quarter of the time for review and approval, compared with the United States. Although it would be of great interest to pursue this parallel development to final marketing, we have elected to concentrate our efforts on gemfibrozil. The comparison between the developmental time of these two drugs through phase II is significant because both were developed by the same organization using comparable caliber of investigators and similar protocols. Again, this longer developmental time in the United States is not an experience unique to one company, as has been well documented by Wardell in his exhaustive studies of the "drug lag" (4). Few knowledgeable people will dispute the fact that the clinical development of a drug takes longer in the United States than in most other scientifically advanced countries. In theory these differences should not exist. The FDA has competent scientists at the top managerial levels. They will acknowledge that three separate studies by independent qualified investigators of appropriate design are adequate to prove efficacy. Additional

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December 1971 (USA) September 1973 (USA) August 1976 June 1979

patients should receive the drug in sufficient numbers to ensure that the common adverse reactions which may occur are known and that the drug can be used in conditions approximating the expected clinical use. These requirements and the numbers involved are usually sound and, in fact, do not differ too much from those in other countries. The difference lies in the application of the regulations at the working level—an application conditioned by external factors such as Congressional oversight and close scrutiny by consumer advocates. If any FDA official has received public praise for approving a needed new drug, I am unaware of it. On the other hand, one can point to a number of instances of criticism of positive actions on the part of FDA which were intended to make new medications available for the treatment of disease. The criticism is often based on a lack of knowledge or understanding of what constitutes an acceptable therapeutic index for a drug and is often couched in such derogatory terms that one wonders how the FDA manages to keep scientists of competence and integrity. The answer, of course, is that at the higher levels they often do not. The regular procession of agency heads since 1963 bears testimony to the strains involved. With this background it is no wonder that procrastination is common—a decision delayed by asking for additional data, for one or two more studies, will put off the making of difficult decisions. Unfortunately, these delays stretch out into years.

Good Manufacturing Practice Regulations The effects of regulation upon research have been felt perhaps most acutely by those engaged in clinical studies, although scientists in the field of toxicology had a longer experience of the problems involved. Most of the other disciplines were not directly affected by regulatory requirements. We could be sympathetic to our colleagues in the government relations sections, with their reporting requirements and the multitude of minor submissions required for changing a label or a supplier or a manufacturing site. We

could be sympathetic toward our colleagues in quality control and manufacturing when the Good Manufacturing Procedures (GMP) were first proposed. I, like other responsible executives of the pharmaceutical industry, strongly support the concepts expressed in the proposed current Good Manufacturing Practice Regulations. In fact, PMA guidelines entitled "General Principles of Quality Control in the Drug Industry" anticipated the Federal regulations on this subject. We will continue to develop and update refinements and improvements that will support the process of ensuring the high quality of pharmaceutical products. Our concern then lies not with the regulations but with the manner in which they are implemented and the implications that this may have for similar regulations applying to research functions. Because of these implications, I will take a few minutes to discuss some of the aspects of the GMP regulations which disturb me. For example, one section requires laboratory assay reports to be signed with a full signature. If the report were only initialed, there would be a technical violation, but it would be a very arbitrary and capricious act to declare the products as adulterated solely because of this technical violation. An earlier section of the proposed regulations suggests that the person responsible for failure to comply with any current Good Manufacturing Practice regulation will be subject to regulatory action. I find it hard to believe that the civil and criminal penalties of the act should be invoked simply because of failure to comply with any provision of the regulations. Other sections of the regulations are objectionable because they issue very specific and rigid instructions on how to accomplish stated objectives. For instance, certain components must be stored in a specific manner. Other sections require the physical separation concept. Such detailed controls as these, without allowing alternatives, have the effect of reducing, if not eliminating, the flexible use of physical facilities by manufacturers. Another example of the "overkill" in the regulations is the extent of the written procedures required for describing specific operations. Although considerable reliance should be placed on written procedures, it is excessive to extend this requirement to include such things as methods for disassembling and reassembling every piece of equipment used. An overemphasis on written procedures can actually undermine concepts of good quality by reducing flexibility and innovation.

Another section that could have an inhibitory effect upon technological advances relates to the use of computers. In effect, a hard copy of data must be maintained to back up computerized data. In research we are moving away from the use of hard data in many instances, by the use of on-line computers. We can guard against accidental erasure of the computerized information by technological advances that minimize the possibility of such accidents occurring. Alternatively, duplicate computer records can be stored separately. There are many other similar comments which I could make regarding these specific regulations, but I will add only one. The inflationary impact statement accompanying these regulations is significantly understated, ignoring a number of major economic factors. As a result, the increased costs may be out of proportion to the benefits obtained.

Proposed Good Laboratory Practices The current Good Manufacturing Practices Regulations were, for research divisions, an indication of the shape of things to come. Just one year ago the FDA issued a proposal entitled "Non-Clinical Laboratory Studies; Proposed Regulations For Good Laboratory Practice". In this instance also I strongly endorse the philosophy involved. The quality of nonclinical laboratory studies is of the greatest importance. In fact, a committee was designated by the PMA to develop guidelines that were proposed in March 1976. With or without the regulations, industry and academia will continue to develop practices to improve the quality of preclinical studies. There is reasonable doubt whether the FDA has the authority to issue specific regulations on this subject. They may believe that they are required. However, the Federal courts recently stated in the methadone case that although the FDA may believe that effective regulations are required in the public interest, under the present statutory framework, argument should be addressed to Congress. The Court felt that if it accepted the FDA's argument, there would be no limit to FDA's authority. They were, in effect, stating that Congress did not grant to the FDA the power to regulate on any subject they select. The subject matter must be within the substantive authority of the agency, and it is doubtful if this exists for Good Laboratory Practices. It would certainly be a proper function of the FDA Commissioner to issue guide-

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lines to be followed, and failure to do so could be regarded as negating the significance or acceptance of the results obtained. The studies covered by the proposal, principally toxicology studies, involve a degree of unpredictability with regard to the results. Guidelines must permit proper modifications in the study to accommodate such unexpected findings. This particular area of research is undergoing rapid evolution and, as much as any other type of research, requires flexibility and the opportunity for innovation. The proposed regulations mandate organizational structure, responsibilities of the study director, and reporting and evalution requirements that are often duplicative and unnecessary. They suggest a high degree of inflexibility. This is further highlighted by the inclusion of various instructions for accomplishing stated objectives, paralleling many in the good manufacturing practices. The public interest would be better served by stating the objectives in specific terms and allowing each facility the flexibility of using appropriate procedures and systems, without compromising the quality of the studies. The factor leading to the issuance of the regulations may be found in studies by a major pharmaceutical house and a large contract laboratory which were considered by the FDA to have grave defects which made them unreliable and unacceptable. Without minimizing the seriousness of these events, such things can occur as a result of human error and inefficiency and do not necessarily imply an intent to mislead or defraud. One can point to the carcinogenesis studies carried out with red dye No. 2 in government laboratories (5). In this case, there were frequent changes of personnel and poor record keeping, animals died and were discarded without proper examination, and there were major uncertainties about the administration of drugs at the correct times or to the correct animals. While I would consider this study totally unacceptable for making a definitive judgment, I would not suspect any criminal intent in the way the study was carried out and reported. I would certainly make some sweeping changes in the management and conduct of studies in this same laboratory, if it were under my direction. The proposed regulation deals with a concept that we strongly support, that of quality assurance to assure that good laboratory practices are carried out. This should be the responsibility of individuals knowledgeable in the particular area concerned. However, the Good Laboratory Practices Proposal requires a separate quality

assurance unit with specific reporting relationships and with responsibilities that may be impossible to achieve. The unit would be required to assure compliance with specific requirements, implying a guarantee of quality of data. The unit is only a part of the total process and is certainly not in a position to guarantee a specific result. Its functions should be to assure that good laboratory practices have been followed and that documentation and record keeping have been correct. The same unit is required to perform internal audits which are proposed to be available to the FDA on a mandatory basis. Such audits, if properly performed, can be expected to include criticisms and recommendations requiring improvements in procedures, facilities, and staff. The knowledge that the report of the audit may appear in the public domain may make it less candid and complete than is needed. We will thus lose an effective tool which would help assure quality of studies. The FDA itself has stated with regard to certain of their audit functions that the objectivity of the program would be compromised if the working data were made public. Their entire quality assurance program would be seriously compromised or even destroyed. This same principle should apply to nongovernment audits of the type under discussion. The regulations propose that a total facility may be disqualified for failure to comply with the Good Laboratory Procedures. This failure could be based upon the unacceptability of a single study from one small section in a large department. It could also be based upon subjective determinations such as the number of personnel, their training, or a dissatisfaction with the facilities. This certainly seems to run contrary to our whole history of common law, which does not allow broad charges to be brought against a whole section of the population but only specific charges against specific individuals. In our laboratories, the direct costs of the Good Laboratory Practices requirements will amount to over 20% of our total toxicology resources. The same proportion of our clinical research resources is devoted to meeting regulatory requirements. In addition, the extensive documentation, testing, and verification procedures have a significant impact on future research, diverting effort from other important research. The impact of the Good Laboratory Practices will depend upon the manner in which they are implemented. The Warner-Lambert/Parke-Davis Research Division has two separate toxicology facilities. Each of these has been inspected within the last six

months under a preliminary FDA program, presumably designed to develop their guidelines and procedures for carrying out inspections, once the regulations become final. Both inspections were carefully carried out and comprised a thorough examination of the facilities, staff, and procedures currently employed. There was then a detailed inspection in each facility of two studies which had been completed and the data submitted to the Food and Drug Administration in applications presently on file. At both laboratories there was a painstaking evaluation involving a review of data, tissues, the manner in which the studies were performed, and full audit of all available material. Some indication of the extent of the audit can be obtained from the fact that in one of the studies the FDA inspectors checked 350 000 separate pieces of information in following the daily conduct and recording of a rodent 2-year chronic toxicity study. It is reasonable to wonder if the results obtained justify this elephantine effort. On the other hand, perhaps we can feel fortunate that they were not looking at a current rodent tumorigenicity study which may involve two and one-half million separate pieces of information. If the latter inspection is to be a prototype, we can look forward to major disruptions of our working schedule with a resulting loss in scientific productivity. On the other hand, the first inspection provided a useful audit of our operations and procedures. This type of inspection could be a useful complement to appropriate guidelines. Unfortunately, I am not very hopeful that the FDA will accept the principle that these should be guidelines and not rigid and inflexible regulations. As with GMP, the regulatory trend is toward legal-technical compliance, which is unfortunately not the same as assurance of quality. I am also concerned that the scope of the inspections will extend to cover every toxicology study performed, and not solely those the Food and Drug Administration has indicated are of importance. Former Commissioner Schmidt testified before Congress and reiterated in the introduction to the proposed regulations that the carcinogenesis, reproduction, and teratology studies are those that are unique and critical for the determination of the safety of a product. It appears, therefore, that the public interest would be adequately served by limiting the scope of the guidelines to these specific studies when such animal studies are intended to be a part of a submission to the FDA in support of an application. It would not be fruitful to discuss in detail the many regulations pro-

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posed or in late stages of consideration which will affect our ability to carry out research or utilize the results from that research. For instance, we are being asked to submit a detailed schedule on proposed toxicology studies that would be carried out in our laboratories, with a timetable to be set by the Food and Drug Administration for reporting the results from these studies. The periods suggested are not realistic and suggest a lack of familiarity with the work involved in sacrificing and examining grossly and histologically large numbers of animals and then interpreting and reporting the results. We are also being asked to prepare detailed summary sheets for clinical studies already submitted or to be submitted in investigational applications to the Food and Drug Administration apparently to aid in a computerized data program. This will duplicate data already on file with the FDA, increasing our work and presumably enlarging their files with no assurance of any great benefit. Other Regulations Let us consider briefly some other types of legislation and their effects on research. In 1973 an article in the New England Journal of Medicine reported on tissue levels of antibiotics administered to a group of pregnant women admitted to hospitals for legal therapeutic abortions in the first half of pregnancy (6). Because of this publication, the physicians involved were indicted in Boston under the provisions of an archaic law aimed at restricting grave robbing. As a result of these cases the National Institutes of Health formulated regulations, and effective limitations have been placed upon the use of dead abortuses for scientific purposes. Such a policy can effectively prevent research essential to the understanding, and eventual control, of factors causing congenital malformations and neonatal disease. In the same city of Boston 20 years ago I was prohibited from giving any birth control information to patients in the clinic in which I worked, the maximum penalty for such an offense being, if I remember rightly, up to 2 years in prison. Two decades later, across the Charles River from Boston, the Cambridge City Council joined in the debate on recombinant DNA research, by prohibiting such research within their jurisdiction. At the national level the National Institutes of Health published guidelines that effectively control the conditions under which such research may be done if sponsored by NIH; the issue has been debated at the National Academy of Sciences without any apparent meeting of the minds of those opposed and

those in favor. Congress is proposing legislation b u t unfortunately is n o t q u i t e clear on w h a t should be proposed. At t h e closing session of t h e National Academy of Science conference on r e c o m b i n a n t D N A research, t h e s t a t e m e n t was m a d e by Donald K e n n e d y , who h a d t h e n been design a t e d t o be t h e new F D A Commissioner, t h a t t h e N I H guidelines a r e "regulations in i n t e n t a n d t o some d e gree in practice . . . why should t h e r e be more regulation? T h e simple a n swer I t h i n k is because it is politically inevitable". T h i s sort of basis for a n action t h a t could profoundly affect scientific knowledge a n d p e r h a p s have a significant effect on t h e future of m a n k i n d would be familiar to Charles Darwin whose theory of evolution was a subject of considerable controversy more on moral a n d political grounds t h a n on scientific facts; it would be t o H a r v e y who d a r e d n o t publish his findings on circulation until he was nearing t h e e n d of his life, m a n y years after t h e discoveries were m a d e , a n d t o Galileo who was arrested a n d forced t o recant his s u p p o r t of Copernicus t h a t t h e e a r t h was n o t t h e center of t h e universe. L e t m e briefly m e n t i o n a different t y p e of regulation t h a t , in t h e short t e r m s , worries m e as m u c h as m a n y

of t h e things I have discussed. T h e Int e r n a l R e v e n u e Service h a s recently published a regulation which says t h a t unless research is specifically required t o be d o n e in t h e U n i t e d S t a t e s , they will only credit one-half of t h e research expenses against t h e income of t h e U n i t e d S t a t e s corporation—and in future years t h e proportion t o be credited will be reduced even more. On t h e other h a n d , most foreign countries will n o t allow expenses incurred in t h e U n i t e d S t a t e s for research t o offset income derived from sales or p r o d u c t s in their countries. T h i s will result in a large proportion of t h e research expenses of high technology corporations such as those in t h e electronics, c o m p u t e r , a n d p h a r maceutical industries being n o n d e d u c tible for taxation purposes. T h i s can, in effect, almost double our costs. O n e solution t o this is t o move t h e research t o foreign countries so t h a t we can o b tain t h e a p p r o p r i a t e tax credit. T h i s will accelerate a process t h a t h a s been going on for t h e last decade a n d can result in t h e export of scientific positions a n d t h e d i m i n u t i o n of our scientific a n d technological p r e e m i n e n c e — especially in basic research. T h i s t r e n d is seen in our organization, where t h e i n t e r n a t i o n a l research b u d g e t s have increased a t twice t h e r a t e of t h e U n i t -

ed S t a t e s research budget during t h e last five years. I s t a r t e d o u t by saying t h a t t h e r e is a need for regulation. W i t h o u t this we will revert t o those conditions t h a t called for t h e regulations in t h e first place. W h a t we ask is t h a t in applying t h e laws t h a t affect research, good science a n d common sense should prevail. I will close with a q u o t a t i o n written by T h o m a s Jefferson in 1821 when he was a n elder s t a t e s m a n , full of years a n d , I hope, wisdom, " W e r e we directed from Washington when t o sow a n d when t o reap we should soon w a n t for bread". References (1) Irving Kristol, "A Regulated Society", Regulation, Vol 1, # 1 , pp 12-13, 1977. (2) J. F. Sadusk, Jr., ''The Effect of Drug Regulation on the Development of New Drugs", in "Principles and Techniques of Human Research and Therapeutics", F. Gilbert McMahon, Ed., Future Publ., 1974. (3) R. M. Hodges, Gemfibrozil-Proceedings of the Royal Society of Medicine, Supplement # 2 , Vol 69, pp 1-2, 1976. (4) Wardell, in Drug Development and Marketing", R. B. Holmes, Ed., pp 16581, Pub. American Enterprise Institute, 1975. (5) FDC Reports, March 1976. (6) Philipson et al., "Transplacental Passage of Erythromycin and Clindamycin", New England J. Med., 288,1219-21. Presented at the Fourth Federation of Analytical Chemistry and Spectroscopy Societies Meeting, Detroit, Mich., November 1977.

Shandon electrophoresis unit at a new, low price Here's real versatility. This u n i t designed for maximum flexibility, convenience and economy—easily performs these six techniques: (1) Cellulose Acetate . . . adjust the length of the separation to suit your technique . . . unit is ideal for large-scale, small-scale and micro techniques, also short distance HVE; (2) Starch, Agar and Polyacrylamide Gels . . . for superb resolution . . . and for immuno techniques; (3) Paper . . . for unrivaled economy; (4) Micro-immuno and Crossed-over Techniques . . . special accessories do the job with no trouble; (5) Thin Layer (TLE) . . . fast set-up time, fine results with 1000 volts; (6) Cooling System . . . to maintain constant temperature. Catalog U77 details the advantages and accessories. Write Shandon Southern Instruments, Inc., 515 Broad St., Sewickley, PA 15143.

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SHANDON SOUTHERN

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CIRCLE 191 ON READER SERVICE CARD 540 A · ANALYTICAL CHEMISTRY, VOL. 50, NO. 6, MAY 1978

R o b e r t M. H o d g e s is p r e s i d e n t of Warner-Lambert/Parke-Davis Pharmaceutical Research Division. Dr. Hodges h a s a broad medical background, having served on t h e staff of several hospitals. H e h a s also held teaching a p p o i n t m e n t s a t t h e Universities of W a s h i n g t o n a n d Ottawa. B e fore coming t o P a r k e , Davis a n d Co., Dr. Hodges was associate director of t h e B u r e a u of Medicine, Food a n d Drug Administration.