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Thus far, I have dealt with inconclusiveness of data as a basis for action. Now I will take up problems of treatment, especially as related to child safety. Very little attention has been given to deleterious effects of treatment, including the incidence of death attributable to induced dietary insufficiency. Other side effects and complications of the PKU diet, which consists solely of an unpalatable preparation from which phenylalanine has been removed, include skin lesions, refractory anemia, bone changes, vomiting, lethargy, appetite failure, poor weight gain, retarded growth, and miscellaneous symptoms of malnutrition.30

31

Recently, investigators found that the immune responses of PKU children to certain infectious diseases were lowered by dietary treatment. Wooley has argued that PKU patients saved from idiocy might become schizophrenic when taken off their diets later in life.32 The Food and Drug Administration informed me it had no knowledge of deaths. The Children's Bureau informed me it had no evidence of fatalities occurring as a result of treatment. Yet references to treatment-induced death are indeed to be found in the medical literature.

The Committee on the Handicapped Child of theAmerican Academy of Pediatrics, while concluding that children with PKU can be helped through early detection and treatment, also reported: "This conclusion must not lead to unrealistic expectations or to over-enthusiastic application of treatment programs. Some parents are either unwilling or unable to maintain dietary treatment. Over-rigidity of dietary management has led to early death, presumably from insufficient protein intake or hypoglycemia. Over-hospitalization for rigid control has deprived children of the normal stimulation and affection of home and family thus preventing normal psychological maturation. Exaggerated predictions for normal development regardless of the age of discovery and irrespective of the strictness of the diet or of the hereditary endowment have led to frustration and discouragement on the part of both pediatricians and parents." 33

Careful perusal of the literature reveals both general and specific references to death.34-37 MacCready and Hussey reported two deaths of PKU children, but attributed one to pneumonia and the other to suffocation.38 Subsequently, in an exchange of correspondence published in the Medical Tribune, MacCready revised the report, in the light of subsequent information, and acknowledged that at least one of the deaths appeared to have been dietarily induced.39

The difficulty in attributing cause of death is that the child dies of one of a number of conditions brought about by withdrawal of essential nutrients. He may consume his own tissues. He may die of anemia. He becomes prone to infection. How does the physician attribute cause on the death certificate? Is he likely, in any event, to record a death as resulting from something done to the child? He can suspect, but does he really know?

A reported case of death, as an example, was attributed to megaloblastic anemia of nutritional origin. A phenylketonuric infant was started on a low-phenylalanine diet at age 2 weeks, suffered serious setbacks resulting in three hospital readmissions, and died at age 7 months.40 The reference to this death was published in a bibliography of the Children's Bureau.

Ed. note. References 1-46 are set forth in Exhibit 1, pp. 61-63.

As a commentary on public attitudes, one must observe that if any drug company were actively promoting the PKU program, which is not the case, it would be hoisted on the nearest lamppost if deaths were involved.

One of the problems in treatment, related to adverse reactions, is the need for exquisite balancing of nutrient intake to metabolic changes in the growing infant and child. Phenylalanine is an essential amino acid. It is necessary for growth, repair of tissues, and physical survival. The blood content or serum phenylalanine levels must be checked regularly to guide dietary management.41, 42

An argument of those who have promoted mandatory PKU-testing that is early diagnosis and treatment is eventually more than repaid by savings through avoiding or minimizing the need for custodial care of phenylketonurics. I won't go into the claimed economics. It would take too much time to do so. It would also impute some credibility to an argument which holds as much water as a sieve. Suffice it to say that a PKU child under treatment needs continuing follow-up. The growing consensus, also, is that he needs the back-up of a whole socio-medical team, including his attending physician, metabolic and laboratory specialists and technicians, visiting nurse, social psychologist-sometimes a psychiatrist, and a social worker to help the family in making adjustments.

This has implications for social choice which I will take up very shortly. To sum up again, (1) proofs of benefit from treatment are inadequate, especially as to effects of therapy on intelligence; (2) benefit may be more attributable to an intervention factor than to tampering with a child's biochemistry; (3) evidence of harm, including infant fatalities, has largely been ignored or given scant attention; and (4) treatment calls for substantially greater deployment of resources than originally expected.

From all experience-even poor experience-lessons ought to be taken. One big lesson from the PKU situation is that one should not commit any major endeavor on a broad scale without first having undergone pilot testing. Inevitably, such testing leads to correction of assumptions and procedural techniques. We did not have this in the PKU program. Rather, the cry went out that society owed it to every child to have a PKU test at birth and that it would be unethical to deprive any child of the dietary treatment once he had been diagnosed as phenylketonuric.

Just how the PKU program was determined to be service-ready ought to be examined, in order to learn more lessons therefrom. Mandatory PKU screening first became law in Massachusetts. As near as I can determine, universal screening was originally introduced in order to find cases for research programs, although I am sure the researchers must have felt this would also lead to public benefit.

At no point, however, has the public ever been told that the PKU program is still mainly investigational and that almost the entire population of newborn infants has been converted into a national laboratory of clinical research with attendant risks. Few physicians and hardly any parents have been made aware of these risks and of all the reasons for screening.

Ed. note. References 1-46 are set forth in Exhibit 1, pp. 61-63.

The claim has been made that the physician is still free to decide the course of treatment for the patient, the infant. Theoretically this may be so, but the specter of the malpractice suit must exert a powerful stimulus to prescribe in accordance with the cultural mores for these are what influence the court. Already, there have been two malpractice suits in which physicians have been charged with failure to treat.

The inauguration of screening programs was well along when the Committee on Fetus and Newborn of the American Academy of Pediatrics published the following criteria for screening of newborn infants for metabolic disease:

1. Does the seriousness of the disorder justify screening?

2. Is therapy for the disease in question available?

3. Is there a clearly identifiable segment of the population with an increased incidence of this disease?

4. Is it possible to perform reliable screening during the first few days of life? 5. Can the screening test be performed in a routine service laboratory?

6. Is the test acceptable to the physician and to a majority of parents?

7. Is the cost of the test acceptable?

8. Are there acceptable medical facilities prepared to confirm diagnosis and consult about the institution of therapy?

The committee did not say whether PKU screening came within its criteria, but it did draw attention to current difficulties. "Because of the difficulty of interpreting blood tests and the hazard of unwarranted dietary restrictions," said the committeee, "it is recommended that the screening tests be performed in a large central facility, such as a State health department, or at least regional, laboratory." 43

Readiness of that kind did not slow legislative enactments. I recall visiting the Children's Bureau program officer who happened to have in hand a copy of a letter from a State health department which reported that it had a law on the books calling for compulsory screening but it did not have adequate facilities with which to carry out the screening and subsequent treatment.

To underscore the state of confusion as regards PKU and to show how sharply opinions are divided even within the American Academy of Pediatrics, the following is quoted from a heretofore unpublished report of its Committee on Nutrition to the Children's Bureau, dated July 30, 1965:

1. The objectives and ways and means for implementing such widescale screening programs remain to be evaluated as do the methods for following through of patients with heritable metabolic diseases detected by such programs.

2. The beneficial effects of good dietary management of any of the heritable metabolic diseases detected in these programs or elsewhere, have yet to be proven unequivocally. Under the circumstances, the committee felt that caution was indicated in launching widespread screening programs until practical therapeutic programs, the effects of which are predictable in the majority of children participating, have been designed.

3. It must be demonstrated with certainty that any normal children who receive these restrictive diets through inadvertence or because of misdiagnosis will not suffer irreparable neurological or physical damage."

Notwithstanding such admonitions of caution, some investigators have pressed for screening and treatment programs for diseases of even greater rarity as to which even less is known.

Maple syrup urine disease, for example, affects about on in a quarter-million newborns. I don't know whether they have one or two or three cases. I know of a couple. One died.

Ed. note. References 1-46 are set forth in Exhibit 1, pp. 61-63.

More recently, dietary control of maternal PKU has been urged in order to prevent retardation of babies from developing in utero.45 Whether or not any benefit or harm to offspring would result is not known, but surely the experience would be a difficult if not dangerous one for the mothers.

Now, although most of this discussion has pertained to PKU, I am less interested in that rare phenomenon than in how decisions are made affecting public health and welfare. The PKU affair happens to be a well-contained example of how not to proceed. It also enables us to derive lessons from establishment workings, for there happens to be a PKU establishment.

(Whereupon, there was a short recess.)

Senator HARRIS. I want to say, Doctor, that this is a very fascinating commentary on the PKU situation, and I will be pleased to have you go ahead and discuss the general implications.

Dr. Ebbin says, "Find out how the story really came out," but the question that comes to my mind is a rephrasing of that old question, What is a nice girl like you doing in a place like this?" How did you get involved with PKU?

Dr. COOPER. I tell that in this story.

Senator HARRIS. Oh, you do? Good, let's go forward with it, then. Dr. COOPER. The term "Establishment" suggests an informally structured ingroup-those who control an area of activity, decide its leadership, pass upon applicants for membership, distribute rewards, and determine generally what goes and what does not. The notion of establishment provokes a wide range of reactions which correlate directly with how far in or out one may be.

Our society is full of establishments. They serve useful purposes when they are the means for advancing society's good interests. They can impose the stamp of authenticity and orthodoxy. They are stabilizers.

I'm in favor of establishment groups, but I have a few qualifiers to put forth. Power has its obligations which, if not exercised, inevitably leads to restrictions or withdrawals by society. The obligations include, among others, the acceptance of new personalities and viewpoints into establishment proceedings.

The PKU establishment embraces lay and professional personalities in academic institutions, hospitals, public health departments, the Federal Government, and voluntary health agencies. It has erred, I believe, in not submitting itself to the discipline of independent critique in not opening the channels of doubt and criticism. The principal Federal agency involved is the Children's Bureau. Of course, it has been involved in PKU establishment affairs and has, I believe, committed errors of its own, but to be critical of it on that score would be unfair. The Children's Bureau has done a tremendous job in developing clinical programs and aids in the area of mental retardation, overshadowing the PKU activity in importance.

The Children's Bureau is to be commended, in fact, for its efforts to promote constructive dialog through numerous symposia in which divergent points of view have often been expressed. Nevertheless, the Children's Bureau has been dominated as to PKU by a small group of outside program proponents who have also been the source of

Ed. note. References 1-46 are set forth in Exhibit 1, pp. 61-63.

guidance of Federal and State legislators, who have dominated the professional literature, who have advised lay voluntary groups, and who have been the main recipients of Federal grants for PKÚ activity. I criticize none of the members of this establishment individually, but collectively there seems to be a fair case for saying that their mutual enthusiasm has led them to block outside challenges to unbridled program execution beyond the state of knowledge.

I first became involved in the PKU situation when, as a political scientist and professor of government, I was invited to give the midday lecture at the scientific seminars of the Rosewood State Hospital for retardees at Owings Mills, Md., on November 21, 1965. My topic was "Problems of legislation in the field of mental retardation." Until then I knew nothing of either the technology or politics of PKU. As I plowed through the literature seeking truth, however, I became amazed and then distressed over the immensity of the structure of activity built on such a shallow foundation of knowledge. In particular, I was distressed by reports of harm to babies.

My talk before several hundred professional people was warmly received, to my surprise as a visiting layman in a medical environment. Subsequently, many observed to me in private that they were glad I had said things they could not. Some conveyed this message through cautious asides uttered as they passed me in the corridor.

Deeply disturbed, I began a correspondence with Federal health and science officials at summit and subsummit levels. All I requested was that some form of scientific evaluation be made of the evidence in order to derive lessons for future program installations. I touched just about all points, but no one wanted to do any touching of their own. Perhaps it was their preoccupation with other matters. Perhaps it was because I lacked credibility as a lay witness. As I pressed further I learned that even professional dissidents, highly qualified, lacked credibility. What really governed was that the PKU establishment had given its assurances and that was that. Besides, the Federal components of the PKU establishment had also committed themselves to the Congress and the public.

Reversal is hard to achieve in the Government, because it implies lack of good judgment. This is unfortunate. As we move more deeply into the inner fastnesses of medical science, we had better be prepared to reverse gears without implications of dishonor.

The first real confrontation between opposing biomedical views occurred in a widely unreported PKU malpractice suit tried in Federal court in Tulsa, Okla., this month. This trial was not reported in the lay press-except perhaps for some local paper in Oklahoma-even though the plaintiff asked for over $1.5 million damages, because the jury made no spectacular award. Although the trial legally involved Lewis and Fields versus Owen (the doctor), it was really the case of Koch, medical witness for the plaintiff and the establishment, versus Bessman and Allen, medical witnesses for the defense. Interestingly, after 6 days of testimony, a lay jury took only 90 minutes to find for the defendant, Dr. Owen.

In this case, Dr. Koch testified for the plaintiff even though the child had not come to the attention of the physician until age 23 months, when brain damage should have already taken place, according to the prevailing medical model of diagnosis and treatment. As re

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