The search for effective drugs has been called an “eternal quest." Until recent times, this was a process of blind trial and error, with enormous odds against a successful experiment. The history of medicine affords literally thousands of examples of substances and methods once thought to have medicinal value and subsequently discarded as worthless. Only a handful of folk remedies have turned out to be effective in the light of modern knowledge.

In marked contrast, the quest for effective drugs in the past 50 years has been more productive than in all previous history. The demonstration of drug safety, required by Federal law in 1938, also greatly stimulated research on drug effectiveness. Research technique has so advanced that it has become possible to determine whether or not a drug is effective. This was the underlying fact which enabled Congress to pass the drug effectiveness law of 1962.

The implications are profound and are still not fully realized. In effect, it is now the law of the United States that manufacturers of drugs must prove by rational scientific testing that their products can do what they are claimed to do. Theories and testimonials are no longer enough. Yet, at the same time, many people continue to cling to old beliefs, or rely on worthless treatments disguised by pseudoscience. Others make judgments warped by feelings of revolt against authority of all kinds. The Establishment is wrong-per se, an attitude which can influence health decisions as well as other actions. Finally, there is continued general confusion over the meaning of drug effectiveness due to the frequency of psychological effects and of unaided or unexplained recovery.

The Meaning of Effectiveness

Drug "effectiveness" can be a life or death matter.
But what makes a drug effective?

Who determines this? And by what authority does FDA take ineffective drugs off the market?

Consumers are asking such questions. They are important. And all are involved in the Supreme Court's June 1973 opinions.

Many bad drugs got on the market despite the stronger controls enacted in 1938. The 1962 amendments said explicitly that drug effectiveness must be shown by "substantial evidence," which was defined to

mean:

.. evidence consisting of adequate and wellcontrolled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly

and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have....

An effective drug is one backed up by the kind of sound, scientific, medical studies called for in this definition. But what is the meaning of terms like “adequate and well-controlled investigations" used to define substantial evidence? The FDA spelled out the answers to such questions in detailed regulations issued May 8, 1970, incorporating the scientific and statistical principles of drug testing considered necessary by authorities on clinical research. The regulations also provided that a drug could be summarily ordered off the market if its manufacturer failed to produce evidence meeting the standards prescribed by the regulations. These were the regulations attacked by the drug industry as not authorized by law.

The Supreme Court disagreed with the industry position. It held that such regulations have a sound legal basis, that they "express well-established principles of scientific investigation," and that they "make the FDA's so-called administrative summary judgment procedure appropriate."

One of the problems in establishing drug effectiveness is the tendency of many physicians as well as laymen to accept unsupported opinions and claims.

Over the years it was common practice both to justify drug claims, or to attack them, simply on the basis of "medical opinion." Many court cases were decided simply by the preponderance or consensus of medical experts. But this "popularity contest" approach to drug evaluation was rejected in the 1962 law and the FDA regulations. The regulations provide that "uncontrolled studies or partially controlled studies are not acceptable as a sole basis for the approval of claims of effectiveness. Such studies, carefully conducted and documented, may provide corroborative support. . . Isolated case reports, random experience and reports lacking the details which permit scientific evaluation will not be considered."

After quoting this, the Supreme Court commented:

Lower courts have upheld the validity of these regulations. . . . Moreover, their strict and demanding standards, barring anecdotal evidence indicating that doctors "believe" in the efficacy of a drug, is amply justified by the legislative history. The hearings underlying the 1962 Act show a marked concern that impressions or beliefs of physicians, no matter how fervently believed, are treacherous.

The Right to a Hearing

The 1962 law said FDA must give "due notice and opportunity for hearing" before it can withdraw approval

of a drug. Did this mean that a hearing was needed to withdraw approval of any drug-if the manufacturer requested one? The drug industry lawyers said yes.

FDA's regulations said no.

The Supreme Court approved the FDA regulations. Specifically, the Court agreed that when the request for a hearing contains no "adequate and well-controlled investigations" to support the claims of effectiveness, the FDA Commissioner may deny a hearing and withdraw the drug based solely on the data presented:

There can be no question that to prevail at a hearing an applicant must furnish evidence stemming from "adequate and well-controlled investigations." We cannot impute to Congress the design of requiring, nor does due process demand, a hearing when it appears conclusively from the applicant's "pleadings" that it cannot succeed.

The NAS-NRS panels evaluated approximately 16,500 claims. . . . Seventy percent of these claims were found not to be supported by substantial evidence of effectiveness, and only 434 drugs were found effective for all their claimed uses. If the FDA were required automatically to hold a hearing for each product whose efficacy was questioned. . . . we have no doubt that it could not fulfill its statutory mandate to remove from the market all those drugs

which do not meet the effectiveness requirements of the Act.

Here again, as in dealing with other questions, the Court acted to prevent the interminable delays which would have resulted from a narrow interpretation. And again, the Court interpreted the law in favor of rational standards of therapeutic efficacy:

... But Congress surely has great leeway in setting standards for releasing on the public drugs which may well be miracles or, on the other hand, merely easy money-making schemes through use of fraudulent articles labeled in mysterious scientific dress. The standard of "well-controlled investigations" particularized by the regulations is a protective measure designed to ferret out those drugs for which there is no affirmative, reliable evidence of effectiveness. The drug manufacturers have full and precise notice of the evidence they must present . . . and under these circumstances, we find the FDA hearing regulations unexceptionable on any statutory or constitutional ground....

After so concluding that the FDA's summary judgment procedure based on "substantial evidence" is valid, the Court nonetheless ruled that in the particular case before it, a hearing should be held on the data which the company had submitted.

During the years 1933-38, when the present food and drug law was being fought over in Congress, industry lobbyists and lawyers were battling to restrict the powers of Franklin Roosevelt's "New Deal" agencies. The proposed food and drug law was a special object of industry efforts to insure "a government of laws and not of men," and to "keep the door to the court house open," as they put it. Writing in 1939, the distinguished law professor Ralph F. Fuchs described the struggle as "a game of see-saw between the proponents of administration that would be equipped with teeth and advocates of the utmost opportunity for affected private interests to interpose objections to departmental regulations."

The original "Tugwell bill" of 1933 had no procedural or review provisions whatever, leaving it to the Agency to work out its own methods and relying on case-by-case enforcement action to provide affected parties with their “day in court."

Very different was the final outcome in 1938 when the Food, Drug, and Cosmetic Act was enacted—a law loaded with details of administrative procedure. Numerous specific provisions authorize or require the development of regulations, spell out the exact procedure

to be followed, impose limitations or exemptions, and specify the opportunities for hearings and judicial review. This has been both a source of strength in the law, and its greatest weakness. Intolerable delays have resulted from opportunities for litigation found in the rulemaking and hearing procedures.

For many years an impression prevailed that since FDA's regulation-making responsibility was spelled out to such an extent, its power did not go much beyond the specific statutory directives. True, there was a brief general provision (Sec. 701 (a)) which conferred "authority to promulgate regulations for the effective enforcement of this Act," but this was utilized mainly for procedural type regulations.

Faced with unprecedented problems in recent years, however, the FDA made numerous innovations in its rulemaking activities-for example, the regulations defining the "adequate and well-controlled" scientific investigations needed to establish drug effectiveness. Industry lawyers argued these regulations were illegal because they were not specifically authorized by the law.

The FDA lawyers met this issue head on. They argued that Sec. 701 (a) meant what it said, and the

Supreme Court agreed with them. As some legal authorities have said, the result is virtually a new law.

Court Endorses Mass Action Through Regulations Reversing assumptions common for more than 30 years, the Court held that the power to issue "regulations for the efficient enforcement" of the Federal Food, Drug, and Cosmetic Act should be broadly exercised and not limited to procedural matters. FDA regulations can spell out the specifics of what the law requires and how to comply. And FDA can and should devise new and better ways to insure compliance and put these into regulations not specifically authorized by the law. While seizing individual products and prosecuting shippers is often necessary, it is not always the best way to get compliance and protect the consumer. Using the regulation-making power, FDA can and should take mass action to insure safe and effective products.

These are the major implications from what the Supreme Court said about the way FDA has proceeded to insure safe and effective drugs during the past 10 years. Specifically, the Court endorsed FDA's undertaking to review all marketed drugs for their therapeutic efficacy; also its contract with the National Academy of Sciences/National Research Council to create expert panels to review by class the efficacy of each approved drug, and the Agency's decision to apply the findings to all drugs in each class, including "me-too" drugs. Dealing with this group of drugs (me-too's), the

Court pointed out that by 1969 it was estimated there were five identical or similar drugs for every one covered by an effective New Drug Application. "Enormous administrative problems were created. Each NDA contained about 30 volumes, a stack 10 to 12 feet high; and some contained as many as 400 volumes of data." The Court continued:

It is clear to us that the FDA has power to determine whether particular drugs require an approved New Drug Application in order to be sold to the public....

Regulatory agencies have by the requirements of particular statutes usually proceeded on a case-bycase basis, giving each person subject to regulation separate hearings. But there is not always a constitutional reason why that must be done. . . . The comprehensive rather than the individual treatment may indeed be necessary for quick effective relief. . . . A generic drug-which is found to be unsafe and/or lacking in efficacy-may be manufactured by several persons or manufacturers. To require separate judicial proceedings to be brought against each. ... would be to create delay where in the interests of public health there should be prompt action. A single administrative proceeding in which each manufacturer may be heard is constitutionally permissible measured by the requirements of procedural due process.

FDA maintains that a withdrawal of any NDA approval covers all "me-too" drugs. For the reasons

stated, that procedure is a permissible one where every manufacturer of a challenged drug has an opportunity to be heard.

Court Endorses Mass Review

Of Over-the-Counter Drugs

Looking to the future, FDA's attorneys had informed the Court in their briefs that across-the-board action was also necessary to insure the effectiveness of drugs advertised and sold without prescriptions. The Court responded with an endorsement:

FDA also realized that it is impossible to apply the 1962 amendments to over-the-counter (OTC) drugs on a case-by-case basis. There are between 100,000 and 500,000 of these products, few of which were previously approved by FDA. In May 1972, FDA adopted a procedure for determining whether particular OTC products, not covered by NDA's are safe products, not ineffective, and not misbranded.

.. The procedure involves the establishment of independent expert panels for different categories of OTC drugs (e.g., antacids, laxatives, analgesics) which would review all available data and prepare monographs prescribing drug composition, labeling, and manufacturing controls. OTC's conforming to the monograph will not be considered either misbranded or a "new drug" requiring an NDA. The regulation provides for a hearing before the expert panel, comments and rebuttal comments on the monograph, and finally a hearing before the Commissioner and judicial review.

*

We think that it is implicit in the regulatory scheme... that FDA has jurisdiction to decide with administrative finality, subject to the types of judicial review provided, the . . . . status of individual drugs or classes of drugs. The deluge of litigation that would follow if "me-too" drugs and OTC drugs had to receive de novo hearings in the courts would enure to the interests of manufacturers and merchants in drugs, but not to the interests of the public. . . . We are told that FDA is incapable of handling a caseload of more than perhaps 10 or 15 de novo judicial proceedings in a year. Clearly, if FDA were required to litigate, on a case-by-case basis, the "new drug" status of each drug now marketed, the regulatory scheme of the Act would be severely undermined, if not totally destroyed. Moreover, a case-by-case approach is inherently unfair, because it requires compliance by one manufacturer while his competitors marketing similar drugs remain free to violate the Act....

FDA Has "Primary Jurisdiction";

Its Decisions Have "Administrative Finality"

The consumer is the loser when lengthy court battles delay the enforcement of protective laws. The loss can be enormous when firms are able to continue sale of

big volume products while litigation drags on. The courts are overwhelmed with matters which administrative agencies should handle.

The Supreme Court said Congress gave the job of administering the food and drug law to the FDA, not to the courts. Putting new emphasis on a well-established principle, the Court said:

This is an age of ever-expanding dockets at the administrative level as well as at the judicial level. If the administrative controls over drugs are to be efficient, they must be exercised with dispatch. Only paralysis would result if case-by-case battles in the courts were the only way to protect the public against unsafe or ineffective drugs....

The heart of the new procedures designed by Congress is the grant of primary jurisdiction to FDA, the expert agency it created. FDA does not have the final say, for review may be had not in a district court (except in a limited group of cases. . .), but in a court of appeals. FDA does not have unbridled discretion to do what it pleases. Its procedures must satisfy the rudiments of fair play. Judicial relief is available only after administrative remedies have been exhausted.

Such qualifications, however, do not lessen the scope of "administrative remedies," which the Court also referred to with approval as FDA's "summary judgment" procedure. In short, it approved the FDA's drug regulations and the manner in which they have been applied over the past 10 years and said the Agency has the power to decide questions of compliance with “administrative finality." Industry was again put on notice that it is futile to ask the courts to substitute their judgment on scientific, medical, or public health matters which the law assigns to the enforcement authorities. Again, as in hundreds of other cases, the role of the courts was defined as that of umpire-to decide only whether the Agency made a fair decision and one not arbitrary, capricious, or unreasonable.

Specific questions which the Court said FDA should decide with "administrative finality" involved whether a drug is a "new drug" subject to FDA approval for safety and effectiveness, or is an old drug exempted by the so-called "grandfather clause" in the 1938 Act. The Court said the FDA should make the initial decisions in such matters-thus relieving the Agency from having to initiate a court proceeding to get the answer. It said that in order to have a product exempted from FDA clearance, the manufacturer must (1) have the same substantial evidence of safety and effectiveness as for a new drug, (2) show that this data has been published and is readily available, and (3) show that the product has been marketed to a material extent for a material length of time. Thus, the decision virtually wiped out the distinction between drugs "generally recognized as safe and effective" and "new drugs." It also greatly reduced the opportunity for delaying tactics detrimental to the consumer's interest. (continued)

In summary, the Court held that the Federal Food, Drug, and Cosmetic Act should be interpreted and administered for maximum benefit to consumers and equal treatment of regulated firms, persons, and products. The authority of the Food and Drug Administration to make regulations for efficient enforcement extends to substantive as well as procedural matters and is not limited to what is spelled out in the Act. The FDA has "primary jurisdiction" to administer the Act and regulations, and the regulations have "administrative finality" so long as they are not arbitrary, capricious, or unreasonable. Regulation on a mass, industry-wide, or product classification basis is proper, fairer, and preferable to case-by-case litigation in the courts. These principles can be taken to apply to all areas covered by the Act.

As to drugs, the law calls for effectiveness to be established by substantial, scientific evidence that is

found adequate by the Food and Drug Administration, and this principle applies across the board in resolving technological questions.

It is obvious that the Food and Drug Administration has enormous responsibilities under these interpretations to insure that its decisions and actions are scientifically supported, fair to all parties concerned, and consistently in the interest of consumers.

The opinions were delivered by William O. Douglas, longest sitting Justice in the history of the Supreme Court. In his book Almanac of Liberty, published in 1954, Justice Douglas selected for each day in the year the event he considered most significant in American history. For June 30, he chose the passage of the original Food and Drug Act of 1906 as the happening most worthy to be commemorated.

Wallace F. Janssen is FDA's historian.

Weinberger et al. v. Hynson, Westcott & Dunning, Inc., No. 72-394, and Hynson, Westcott & Dunning, Inc. v. Weinberger, et al., No. 72-414.

Lutrexin was allowed to be marketed under the 1938 law as "safe" for premature labor, threatened and habitual abortion, and dysmenorrhea At the same time, FDA advised the manufacturer that its data did not justify the claims of effectiveness, and urged that the drug not be marketed.

After the 1962 amendments, the firm submitted effectiveness data which did not satisfy the medical experts who reviewed it. When FDA gave notice of its intention to withdraw approval, the company filed suit in the district court seeking a judgment that Lutrexin was exempt from having to prove effectiveness because it was not a "new drug," or, if not exempt, that it was proven effective. The suit was dismissed, and the company raised its objections before FDA, which ruled against the firm and ordered the drug off the market.

The court of appeals reversed, holding that while the drug was not exempt, the firm was entitled to a hearing on Lutrexin's effectiveness. The court stated that Lutrexin's current status as a new drug was for the district court to decide, not FDA. Both FDA and the company sought review in the Supreme Court.

The Supreme Court held that the company's evidence on Lutrexin raised issues requiring a hearing, and that any ruling on its "new drug" status should come from FDA after the hearing. The Court also held that Lutrexin is not exempt under the "grandfather" clause

of the 1962 amendments, and that such an exemption is only for drugs which have never been regulated as "new drugs."

Weinberger et al. v. Bentex Pharmaceuticals, Inc., No. 72-555.

Based on review by medical experts, FDA gave notice that there was a lack of substantial evidence of effectiveness of pentylenetetrazol, a drug sold for treating symptoms of senility. Because many drugs of similar composition were on the market (so-called "me-too" drugs), the notice stated that all drugs containing pentylenetetrazol would be affected by any order withdrawing approval of the NDA's for the products, and invited "any interested persons" to submit "adequate and wellcontrolled studies" to establish the effectiveness of the drugs. Only one applicant requested a hearing. Orders were then issued withdrawing the approvals. None were appealed.

Bentex and some 20 other firms, all "me-too" manufacturers who did not request a hearing, filed suit in a district court for a judgment that their drugs containing pentylenetetrazol are generally recognized as safe and effective and therefore are not "new drugs" and are exempt under the "grandfather clause" of the 1962 amendments from having to show proof of effectiveness.

The district court held that FDA should resolve the "new drug" and "grandfather" exemption questions in administrative proceedings. The court of appeals, holding that FDA had no jurisdiction to decide what is a