study and analysis of the data, to prepare the results for publication, and to see the paper published.

Finally, there is a theoretical difficulty. If, for a reason unknown when the experiment was designed, the drug being tested favorably affected some but not all of the subjects, this important fact might be altogether missed because the positive effect on the responders was diluted below the level of significance by the negative results on the nonresponders.

Despite all these difficulties, there is no doubt at all that such studies, if properly conducted, will permit finer distinctions than are possible by any other method now known. They will permit identification of the drug which has but little beneficial action, when simpler methods would fail. On the other hand, because the results of such an experiment do not demonstrate that a certain drug exerted a "significant" beneficial effect on a series of patients, one has no logical right to conclude that it is worthless, though persons of the reformer type often so conclude. When statistical significance is not attained, the logical conclusion is not condemnation but that judgment should be suspended. Those who insist on waiting for statistical significance before approving should logically wait for statistical significance, in the other direction, before condemning.

My expectation is that elaborate team research, despite the many advantages, will not supplant research carried out by the single doctor, who, in the full knowledge of what he is doing, gives therapeutic agents to patients he knows intimately and carefully and objectively observes the effects that follow. We all know the enthusiast so biased by his emotions that he confuses his hopes with the truth. But do we not also know the man whose intellectual attainment has put him far above this, the man who has schooled himself to see things exactly as they are? As my old teacher, Professor Conklin, used to say, "The truth is truth, even if it burns our eye-balls." When such a trained observer gave a drug, and the result on his patient, Mrs. Smith, was much different from that which his learning and experience had led him to expect, his attention was attracted. From following up such unexpected experiences, the profession has learned much; Cannon emphasized this in his physiological studies, and the process is often called "serendipity" from the experience of the Princes of Serendip who, in the legend, failed to find what they sought but returned with something far more valuable. In contrast, the elaborate team experiment, as at present designed, diverts the attention from the unusual response, and the man at the top who writes the paper may be altogether unaware of it. The great therapeutic discoveries in the past have been made by competent men, not by teams working blindly. I fully expect that this will be the case in the future also.

Conclusion

We have, as our heritage of the advances of recent years, powerful new methods of evaluating therapeutic agents, and the question must now be asked, "How can these new methods best be used to help doctors confronted with the decision whether to use, or not to use, some of the large array of reputable drugs which are being introduced every year?"

There are those who would say that nothing is more important than health, and that our patients deserve nothing but the best. Such idealists would oppose the use of any new drug until it met the most exacting requirements, that is, after it was subjected to an experiment designed to determine its value, relative to that of a placebo and to the drugs we now have, under the very clinical conditions in which doctors are expected to use it. Certainly, every effort must be made to stimulate testing of this kind which can do nothing but good, but to the practically minded doctor it should be immediately obvious that the insistence on such tests, by law or otherwise, would provide no solution to his immediate problem. Tests of the designed experiment type are so time-consuming, expensive, and difficult to carry out that only a few are being completed annually in this country, and, if from this small total, one subtracts those performed on patients with mental disease, cancer, and tuberculosis, very few remain. I am sure that this total will be increased, but we are far from the time when all of the approximately 450 new drugs and preparations introduced each year could be tested by this method within the year of their introduction.

In addition, it seems unfair to insist that drug manufacturers must meet standards of therapeutic efficiency of an accuracy and refinement that the medical profession has not yet met for a host of therapeutic procedures long in wide use. For example, no operation for cancer has been subjected to such a refined study; who among us, if afflicted, would volunteer to take the placebo? That part of the therapeutic field which has already had the advantage of such studies is a mere fraction of the total. Doubtless, when we catch up, it will be evident that many therapeutic measures in which we now have confidence will be found wanting. This was certainly the case with so many methods of therapy trusted by our medical forebears. Benjamin Rush was not alone in his errors.

Certainly, we can insist that new drugs be tested on animals for toxicity as well as for other common types of drug action that can be readily determined through such tests. We also have the right to insist that new drugs be tried on healthy persons for untoward effects, and that their action be determined in man. And if they pass these initial tests with flying colors, they should also be tried by

experienced doctors in the course of their ordinary practice on patients likely to be benefited. This has long been the policy of the Council on Drugs. The only question is, does it go far enough?

To go farther, we must do all we can to educate doctors to make better use of their experience by organizing it in order that finer and more reliable conclusions can be drawn. Perhaps this will mean the development of specialists in the field of drug testing in man, who might be appropriately called "Clinical Pharmacologists."

We also need to improve our knowledge of the untoward effects of new drugs and to that end we need your help. These undesirable effects are not likely to occur often enough in any one doctor's practice to justify a report. But if each practitioner who observes such an effect will inform the Secretary of the Council on Drugs, the data collected by the end of each year will be of great interest. If the Council receives evidence indicating serious trouble with any new drug, the profession will be informed immediately by means of THE JOURNAL. The character and frequency of less serious reactions will be reported each year by an article in the Council's Annual Therapeutic Number of THE JOURNAL.

While struggling to do better in the future, we must not neglect the immediate problem-the problem of the modern doctor confronted by his patient, Mrs. Smith. The new "remedies" dangled before the eyes of this doctor each year, judging from the averages of the last 10 years, include 42 new single chemicals, 80 duplicate single products (i.e., products sold by more than one manufacturer), 237 compounded products (i.e., products having more than one active ingredient), and 108 new dosage forms. This is an average of 468 new "remedies" for him to consider each year. Some of these new drugs may be better than any he has previously used, some are worthless, and the majority are not very different from similar drugs and preparations long in use. And all these new "remedies" are being pushed by persons who have a monetary interest in having the doctor use them on Mrs. Smith.

No one actively practicing medicine has the time and few have the ability to examine and evaluate the original sources of information about all these new remedies. The doctor must have help. He gets help from the law, which has done much to make known the true composition of what he prescribes, to root out and bring to an end the more extravagant lies found in their promotion, to prevent the sale of truly harmful products, and to warn him about the dangers inherent in many active drugs. This protection has improved during my medical lifetime, but it could be improved still further. However, it often seems to take a long time for the law to catch up with blatant offenders and to bring to an end methods of promotion which,

too subtle to employ downright lies, are clearly misleading.

The doctor gets aid from the better grade of pharmaceutical manufacturers who often distribute with their new drugs, package inserts and brochures which give an excellent description of the action. usefulness, and dangers of their products. But too often this descriptive material contains statements and attitudes which lead one to suspect that the firm's advertising department, rather than ther medical department, had the last word.

The doctor can also get help from the Council on Drugs of the American Medical Association which for over 50 years has been publishing an annual volume, first called New and Nonofficial Remedies and now called New and Nonofficial Drugs. Information about the new drugs has been assembled in these volumes by a group of experts who may make mistakes, but they have no financial interest in selling those drugs whose properties they describe.

Efforts are being made to improve this service. of which the initiation of this Annual Therapeutic Number of THE JOURNAL is one. Our aim is to make unbiased information about the new drugs rapidly available to all practitioners in such a form that they can more readily use it.

For, in the final analysis, the safety of Mrs. Smith, when she is given a new drug, depends only in part on the skill and honesty of the manufacturer, only in part on the law and on the vigilance of law enforcement officials, and only in part on the proper distribution of necessary information about the drug. Mrs. Smith's safety depends chiefly on the vigilance of the doctor who has prescribed for ber No tests done in advance can do more than indicate the likelihood that Mrs. Smith will be benefited. As our methods of testing new drugs improve, this likelihood will be brought to a higher level, but in most cases it will still be far from 100%. If Mrs. Smith is harmed by the treatment, the drug must be stopped, no matter what the books say and no matter what committee of disinterested experts recommend it. And no one can make this decision but the doctor himself.

Although our methods of testing drugs have improved greatly and the likelihood of our finding a drug to benefit Mrs. Smith has greatly increased, trial and error remains the final arbiter.

854 Gates Memorial Pavilion, Hospital of the University of Pennsylvania, Philadelphia 4.

References

1. Powell, J. H.: Bring Out Your Dead: The Great Plag of Yellow Fever in Philadelphia in 1793, PhiladelphiaUniversity of Pennsylvania Press, 1949.

2. Bernard, C.: Introduction to the Study of Exper mental Medicine, translated by H. C. Greene, New York: The Macmillan Co., 1927.

YOU SAVE MONEY IF YOUR PHYSICIAN DID NOT USE TRADE NAMES IN PRESCRIPTIONS? WOULD THIS INVOLVE HEALTH RISKS TO YOU AND YOUR FAMILY?

In the past year, welfare departments in several States have adopted rules designed to save money on prescription drugs bought for welfare cases. Other State welfare departments are considering similar action. These savings are sought by requiring that drugs be purchased by generic instead of trade names. This means that a prescription can be filled with a number of products which are considered to be essentially the same drug bearing a common-or generic-name. In many cases, these generic-or branded-products cost less than the trade-. name drugs of that type.

THE PRICE OF DRUGS

un

In the wake of congressional investigations into the cost of drugs and of the various State actions, you may wonder whether generic prescribing would not be a way to reduce your own drug bills. At first glance, and based on a superficial knowledge of the pertinent facts, the answer to some people, apears to be yes. However, the matter of generic versus trade-name prescribing is a complex one that goes beyond any real or imagined price saving. To understand the key elements in this issue, it is first necessary to know that there can be three types of names applied to every drug-scientific chemical, generic and trade name.

The chemical name of a drug, because of its complexity, is rarely used in medicine. Prescriptions are written in either the generic or trade name. All drugs have a generic name, which may be utilized by any manufacturer. A brand, or trade name, though, is copyrighted and is the property of the manufacturer owning the copyright. For example, one of the new blood-pressurereducing drugs has the chemical name 3,4,5trimethoxybenzoyl reserpate. Its generic name is reserpine. Its trade names include Rau-Sed, Reserpold, and Sandril.

The pharmacist, presented with a prescription for a trade-name drug, will dispense only that product. Given a prescription for a generic drug, he can supply a brand product, or any equivalent product, depending on his stock.

Senator ESTES KEFAUVER, chairman of the Senate subcommittee which investigated drug prices, has introduced a bill in Congress that would require every drug label to carry a generic name in as large letters as the brand name. It also provides that the Food and Drug Administration establish an official list of generic names for drugs. The

bill sets up a licensing and inspection plan for all drug manufacturing plants so that doctors can be sure all drugs meet Federal quality standards. The FDA and other members of Congress who have considered the problem believe that consumers should be able to buy any drug with confidence, regardless of its name or price.

Those who favor generic-name prescribing argue:

Many State and local welfare agencies and various Federal Government departments— military hospitals. the Veterans' Administration, the U.S. Public Health Service-buy drugs by generic names. If it is right and safe enough for them to do so, it is argued, why should it not be equally right and safe for the individual?

All drugs are legally required to meet certain standards, so quality should be uniform. Therefore, generic proponents say, individual physicians have no reason to hesitate to prescribe generically.

Generic prescribing will mean big savings on drug costs and will lower drug prices gen- 4| erally.

་

To such arguments, those who oppose generic prescribing for all drugs reply:

It is one thing for large hospitals and government agencies to buy by generic names, but it is an entirely different matter for the individual to get prescriptions on this basis. Institutions and agencies have the means to check quality and potency.

The fact that standards are set by law and are supposed to be met does not mean they are being met. The Food and Drug Administration has stated it cannot check all drugs produced, and admits that the amount of checking it is able to do is far from adequate to assure reliability of all drugs.

Generic prescribing does not necessarily mean lower prices. In a significant number of instances, it may mean no price difference at all if the drug is patented, and therefore available from only one source. In others, the difference may only be a few cents on a dollar. Manufacturers believe their costs of research and quality-control procedurescosts they say are not borne by manufacturers who produce only generic drugsnecessitates a price difference between some generic and trade-name products.

Generic drugs are not always available. and, then, the prescription probably would be filled with a trade-name product. Even when generic drugs are available, the quality, it is claimed, is not always guaranteed.

It would be wrong to deprive the individual physician of the free choice to prescribe drugs that he feels are best suited to his patient.

Trade-name manufacturers stand behind any product carrying their brand. Pharmacists know that in instances where there has been any question about a brand-name product, the manufacturer steps forward to take responsibility.

What do physicians think about generic prescribing? The American Medical Association and the American Public Welfare Association have adopted a joint set of guiding principles for doctors treating welfare patients. Included is a suggestion that welfare patients be given prescriptions for lower cost drugs "of equal therapeutic effectiveness when available (and) when the quality of the product is assured." However, it should be noted that this statement hinges on the assurance of quality. The New York County Medical Society has gone beyond the AMA position by urging that all prescriptions be written in generic terms. In a resolution, it urged that, "where the prescribing physician or the licensed pharmacist can be assured of the quality of the drugs... members use generic names rather than ... brand names in prescribing." perhaps, significantly, the society left the question of assuring the quality primarily to the pharmacist. This means that physicians writing generic prescriptions would depend upon the druggist to make sure the drugs meet legal standards.

But,

In a time, though, when there are thousands of drugs available, is it reasonable to assume that the individual pharmacist can actually test each and every generic drug to ascertain or guarantee the quality-something even the FDA says it cannot do? As a matter of practical fact, regardless of how conscientious the druggist may be, this is just not possible. Instead, the pharmacist, even as the physician, has come to rely on the reputation and integrity of manufacturers. Trade names, in many instances, are their main guides to quality. For most drugs already on the market, the FDA says it can only detect errors after they occur. Consequently, the burden of maintaining quality standards falls on the drug manufacturers.

The problem created by having drugs listed by so many different names is being met in some Government and private hospital pharmacies by establishing drug formularies. A formulary is a list of generally used drugs stocked in a pharmacy. Under a hospital formulary system, usually only one drug of a kind is stocked. The American Hospital Association and the American Society of Hospital Pharmacists have both said that a valid hospital formulary is based on use of generic terms. One private hospital, for example, has about 400 drugs in its for

mulary. If it stocked these drugs under all their various names, it estimated it would have to keep 10,000 items. But in some hos pitals, however, a physician can prescribe by brand name outside the formulary list if he considers that best for his patient.

Money can be saved by generic prescribing under a formulary system where drugs ordered in large quantities. But just how much is saved on the individual prescrip tions outside of hospitals is open to ques tion. A study made by one manufacturer, Smith Kline & French Laboratories, showed the cost of 15 drugs by brand-name prescriptions averaged about 12 percent mort than generic (unbranded) prescriptions Some State welfare agencies estimate that generic prescribing has saved 5 percent of drug costs. (To encourge use of brand-nam drugs by welfare departments, two large manufacturers, Merck-Sharpe & Dohme and E. R. Squibb & Sons, provide a 10 percent rebate on drugs bought for welfare purposes in certain States.) When a State like New York spends $5 million annually on welfare drugs, an overall saving of, say, 5 percent adds up to many thousands of dollars.

But to an individual taking a prescription to his local drugstore, such percentage savings would amount to from 5 to 12 cents on each dollar spent, and that saving might not seem enough to warrant taking any chances at all on quality. Some manufac turers say in certain instances they produce same generic drug. brand drugs that are lower priced than the

To prepare this article, Good Housekeeping editors spent several months interviewing representatives of a wide variety of organizations governmental, public health and welfare, medical, pharmaceutical and phar macist. A broad range of opinion was ob tained. From almost the start, it became obvious that the central issues are complex Despite the widespread press attention to the overall subject of the cost of drugs, became equally obvious that the specific point of whether drugs should be prescribed by generic instead of trade name is not shutply a matter of price. To the editors, ther is a more basic consideration:

Can the individual physician now prescribe drugs by generic names with assurance that their quality, in all instances, is equivalent to the trade-name products he has prescribed and is familiar with?

Until that can be answered with an unequivocal "yes," you can only rely on the judgment of your own physician as to how he will write your prescription-by trade or generic name.

Generic prescribing? It could be dangerous

Can you help keep down the cost of patients' medical care by prescribing drugs under their generic names? Some New York doctors have decided they can and should. Through a New York County medical society resolution, they've made generic prescribing official policy.

But now the society is concerned that this "laudable goal" may only create new problems. Patients could end up with inferior drugs. And druggists could be held legally responsible for the quality of drugs thus dispensed. Here's the way the society's publication, New York Medicine, sees the situation:

"The Society seeks to reduce the costs to the patient of those ethical drugs which are in open competition and for which there are alternate sources of manufacture." Thus, the argument

goes, if the physician prescribes by generic name, the druggist can fill the prescription with a low-priced version of the drug.

"This system works fine in major hospitals where genericname formularies are under control of the hospital pharmacist," notes New York Medicine. But can this "same kind of dedicated control on quality . . . function at the level of the local drugstore?"

It appears impractical, the publication points out, because with "literally hundreds of firms, big and small, making ethical drugs, the Food and Drug Administration admits it cannot make more than casual checks" on quality. Can the pharmacist? Will he? The editorial concludes:

"Many druggists who used to praise generic prescribing as a swift way to lower the cost of drugs to the patient. . . have now taken a second look at it." The druggist is finding that as he "picks the bottle off the shelf and fills the generic prescription, [he] thereby accepts the professional responsibility for the quality of the drug." END