A Drug on the Market

By J. JACKSON

IN 1937, in the US, about 107 people died after taking a drug called elixir sulphanilamide. The active ingredient—sulphanilamide—is one of the well-known sulpha drugs, the discovery of which by Domagk was the first of a series of developments in chemotherapy which have revolutionised the practice of medicine, though the sulpha drugs have now been to some extent replaced by the antibiotics, such as Penicillin. In 1937, however, they were being much more widely used, and there was a need for a sulphanilamide preparation in liquid form. A reputable American drug firm therefore produced such a preparation, but made the mistake of doing so by dissolving the sul- Phanilamide in a liquid called diethylene glycol. Since, under the legislation then in force—the 1906 Federal Food and Drugs Act—no tests were required to determine the safety of new drugs before they were placed on sale, no such tests Were carried out by the company concerned. As it happens, diethylene glycol is poisonous, so that 107 people were killed instead of cured. To prevent further deaths, it was necessary to seize stocks of the elixir, but a legal basis for such action had to be found. Fortunately, the company had committed a technical infringe- ment of the law—the term 'elixir' normally im- Plies a solution in alcohol—and this provided a legal pretext for the seizure of the drug.

It seems that it is sometimes necessary for a catastrophe to occur before long overdue legis- lative changes are made—our own Clean Air Act is, after all, one of the consequences of the death of 4,000 people in the great London smog of December, 1952. A considerably smaller number of casualties was sufficient to demon- strate clearly the inadequacy of the 1906 Food and Drugs Act. A new Federal Food, Drugs, and Cosmetics Act became law in 1938, the triain purpose of which, like that of its 1906 Predecessor, was the protection of the consumer 133" the prevention of the adulteration and 'mis- branding' (a term which covers, among many

other things, false or misleading labelling) of the products with which it is concerned. As a result of the elixir sulphanilamide disaster, the Act also requires that all new drugs shall be tested to determine whether they are safe to use before they can be placed on the market. Thus another disaster, at least on the scale of that of 1937, should be impossible. Complete security is probably unattainable, since rare side-effects may be discovered only after a drug has been widely used, as in the case of the antibiotic chloramphenicol, which in a small proportion of patients causes severe blood disorders, such as aplastic anemia.

The true situation is, of course, considerably more complicated, thanks, in part, to the pecu- liarities of the Constitution of the United States and the legislative powers which are the pre- rogatives of the States. Thus the provisions of the Act apply only to food, drugs and cosmetics which cross the boundary between one State and another. Products which are sold within the State in which they are manufactured are not subject to Federal law, but to the corresponding State law. Ideally, of course, State and Federal law should be in harmony, a harmony accom- plished by the passing by all the States of a model food, drugs and cosmetics Act, based on the 1938 Federal Act. Needless to say, local politics have prevented this ideal from being achieved, and many States still have Acts based on the 1906 Federal Act, so that their legislation is out of date in many respects.

The testing of new drugs called for by the Federal Act is the responsibility, in principle, of the Secretary of Health, Education and Welfare, but is carried out in fact by a body called the Food and Drug Administration. In the casual way of so much legislation, the FDA is not mentioned in either the 1906 or 1938 Acts, and is virtually independent.

The duty of the FDA is merely to determine whether a new drug would be safe to use, and in no way to decide whether it would have any therapeutic value. In this, American legislation differs markedly from that of many European and Latin-American countries, where a licence is required before a new drug can be marketed, and the licensing authorities are required to de- termine whether the drug is effective, as well as safe. It seems that, in the US, the word 'licence' has become associated with State control, Socialism, and other political bug-eyed mon- sters, while the doctor's right to tteat a patient with a drug which though harmless, is also in- effective, seems to be widely regarded as sacred. In fact, there have been some complaints that the FDA has been slowly extending its powers so as to test new drugs for effectiveness as well as safety. This development is easy to under- stand, since it is not always possible to separate completely the two aspects of the mode of action of a drug, for example, where there is a known risk of undesirable side-effects, as with chlor- amphenicol, yet the drug is one of the best avail- able for the treatment of a serious condition.

In spite of the usual ambiguities, both in the Act itself, and in the regulations made by the FDA (it is a mistake to suppose that legal language sacrifices clarity for the sake of pre- cision) as well as the lack of consistency between Federal and State legislation, the American drug industry has seemed reasonably satisfied with the 1938 Act and with the way its provisions have been carried out by the FDA. The troubles of the drug industry began in December, 1959, when Senator Estes Kefauver appeared on the scene. Kefauver, the chairman of the Sub- committee on Antitrust and Monopoly, has used his position to carry out the most searching study that has ever been made of the drug in- dustry of any country in the world. .The hear- ings, which began on December 7, 1959, are still continuing, and the printed record already amounts to more than 16,500 pages.

Kefauver's attack on the American drug in- dustry, while no doubt made, at least in part, for personal political reasons, has nevertheless been seriously embarrassing to what is one of the major industries of the US. It has brought out, for example, the high rate of profit in the industry, and has exploded the excuse that such high profits are necessary to cover high -research costs, since the figures provided by the companies concerned show that about four times as much as is spent on research is accounted for by sell- ing expenses. This item includes the cost of the vast amounts of publicity material for drugs sent to doctors (much of which must be wasted, as doctors probably often throw it unread into the wastepaper basket), together with that of sending representatives to visit doctors to inform them of the virtues of the companies' latest products (so-called detailing).

An unusual aspect of the drug industry is that the ultimate consumer—the patient—is not free to buy a product of his own choice. The doctor prescribes the drug that the patient is to con- sume, and the pharmacist has no right to de- viate from what is prescribed, even if he knows that, by so doing, he could save the customer from needless expense. It is this situation, of course, that is responsible for the flood of pub- licity material to doctors mentioned above. It is also responsible, for example, for the fact '

that the scientific names of new products are often unwieldy and difficult to remember, while the brand names are deliberately made short and catchy. The aim is, naturally, to encourage the doctor to prescribe his drugs under brand, and not scientific, names. In his evidence to the Sub- committee, Abraham Ribicoff, then Secretary for Health, Education and Welfare, mentioned one drug which was sold at seven dollars under a brand name, but could be obtained for one dollar as desoxycorticosterone acetate As a consequence of the hearings of the Sub- committee, a Bill was introduced by Kefauver in April, 1961, which would, if passed, replace the 1938 Federal Food, Drugs and Cosmetics Act. Certain aspects of this Bill relate to ques- tions of patents for drugs, but others would ex- tend the powers of the FDA a good deal beyond those which it has at present. Under Kefauver's Drug Industry Antitrust Bill, each drug would be allotted an official name which doctors could use in prescribing instead of a brand name, and thus the pharmacist would be free to supply customers with the cheapest variety. In addition, drug companies would be required to circulate information about new drugs more widely, and in particular to circulate information about un- desirable side-effects in this way, since it is believed that there may be a tendency to play down such side-effects in the struggle to convince doctors that Brand X really is inferior to the brand the company concerned is trying to sell. Most revolutionary of all, the FDA would have the power to prohibit the marketing of drugs not found to be effective in use.

The need for the last provision is shown by the fact that, at the present time, the FDA must Oft en allow a new drug to be marketed, although xt believes that the claims made for it are un- substantiated. This is no rare occurrence, since the Council on Drugs of the American Medical Association has stated that 22 per cent of the drugs introduced in the US since 1955 have been promoted by claims some of which the Council considers to be unproved. An example of this is a brand of heparin potassium in tablet form, to be taken sublingually, the sales of which exceed 300,000 dollars annually. Advertisements for this drug claim that it has demonstrated value in post-coronary management, and that, in a significant number of cases, it has prevented re- current heart attacks. Yet it is stated in the 1961 edition of New and Nonofficial Drugs, pub- lished by the Council, that 'as yet no convincing objective evidence exists that heparin, given sub- lingually, either prevents or ameliorates any manifestation of cardiovascular disease.'

The American drug industry, of course, has reacted sharply against Kefauver and against his 1),ung Industry Antitrust Bill. Thus A. L. Ringuette, who is on the staff of Abbott Lab- oratories, Chicago, has claimed that the decision

Whether or not to make drugs available to the medical profession is not a proper matter for an

administrative agency, since the empirical nature of medicine requires that the decision to use a particular drug, or not to use it, must be based

°n the facts of each individual case. The Bill

Would leave little room for the exercise of re- sPonsibility by honest industrial firms or by the

medical profession, and is based on the evidence of biased witnesses who presented a distorted image of the drug industry. Similarly, McMurray, another spokesman for the Ameri- can drug companies, has said plaintively that the Bill implies that the pharmaceutical industry has not done its duty to the medical and pharma- ceutical professions, and to the public.

In spite of these protests, it now seems that the American drug industry has finally accepted Kefauver's proposed new-drug legislation and is prepared to submit to the control already accepted as normal in many other countries. Its opposition to Kefauver's proposals with regard to patents is continuing, and here it may well be more successful.

The strongest opposition to Kefauver's pro- posals for new drugs has come, strangely enough, from the American Medical Association, which has even opposed the wider dissemination of in- formation called for by the Bill. This was par- ticularly unnecessary, since the FDA has itself just issued regulations prescribing precisely that, and thus rendering this part of Kefauver's Bill superfluous. It is one of the curiosities of American legislation, incidentally, that this re- quirement cannot be made to apply to advert- isements in medical journals, since such advert- isements are the province, not of the FDA, but of the Federal Trade Commission. Logically, Of course, journal advertisements should also be controlled by the FDA, but logic and law-making do not necessarily always go together.

The achievements of the American drug in- dustry in developing new drugs of real value to medicine cannot, clearly, be denied, and should not be underestimated. Nevertheless, the drug companies, in the last resort, are not in busi- ness for their health—nor even for ours (to quote the British Medical Journal). For this reason, they cannot be relied upon to regulate their own activities (a British Kefauver might perhaps make some interesting discoveries). However mixed Kefauver's own motives may be, there seems no doubt that, at least as far as new drugs are con- cerned, his new Bill follows in the footsteps of its 1906 and 1938 predecessors, in protecting the consumer, where, because of the technicalities involved, he is unable to protect himself. Even in an era of organisations for the defence and enlightenment of consumers, such legislation is still needed, and its adequacy must be ensured.

The Minister of Health, Mr. Enoch Powell, stated in Parliament on July 23 that he was seek- ing advice through his standing medical ad- visory committee on the question of the testing of new drugs. This is as a result of the anxiety caused by the unfortunate experience with the drug thalidomide, which has been associated with certain congenital abnormalities, e.g., gross limb deformities in babies whose mothers re- ceived the drug during pregnancy (although it is unlikely that any system of testing could have detected so unexpected a side-effect). The story of elixir sulphanilamide, and what happened afterwards, has its relevance for us too.