The DESI Hit List: The story and reflections

Editorial III I II I I I

The DESI Hit List: The story and reflections

"Hit Lists" have come out of the underworld into politics and into the mainstream of American national life. There is now even a hit list of great interest to dermatologists.

Early this year most of the members of the Acad- emy of Dermatology received a letter from the Food and Drug Administration addressed "Dear Health Professional," enclosing a list of prescription drugs which have been classified as lacking adequate evidence of effectiveness. The agency indicates in the letter that over a period of 4 years these products will be removed from pharmaceuti- cal production and the market. The list is popu- larly known in Washington as "The DESI Hit List" (Drug Efficacy Study Implementation).

Several members of the Academy have ex- pressed concern about "the arbitrary, sudden, and senseless action of the FDA" and wanted to know if there were any measures that could be taken to retain some, if not all, the drugs on the list.

Since I have served for the last 11 years on various committees dealing with all sorts of problems pertaining to the FDA, I would like to share my understanding of the DESI problem and to offer a few comments about ways to influence the drug regulatory process.

The first comprehensive drug law in the United States was the Food, Drug, and Cosmetic Act of 1938. This act required only evidence of safety of a particular drug. The 1962 Kefauver-Harris Amendments to the 1938 Drug Law required that, in addition to evidence of safety, the manufacturers also had to submit substantial evidence of effectiveness of the drug for the cited indications for its use. The question of "substantial evidence of effectiveness" was developed in detail in the 1962 Drug Law, and it referred to the requirement of "adequate and well controlled investigations." This implied investigations employing the double- blind technic and using modern statistical methods

to analyze the results. Special regulations were developed to deal with the problem of fixed combination products. Adequate statistical evidence was required to show that each active ingredient contributed to the effect claimed for the product. That is to say, the ingredient either enhanced efficacy or enhanced safety by diminishing side effects. In addition, the combination product was to be shown statistically to be more effective than each ingredient when used alone. Thus, the problem of combination drugs becomes a very complex one. There may be several active ingredients to be evaluated by the double-blind technic and also by statistical methods that are acceptable to the FDA. Please note that the preceding regulations interpret the amendments to the Act enacted by Congress in 1962, and are now the law of the land. The process by which the regulations were adopted was confirmed by the Supreme Court in 1973. The FDA has no option but to administer, interpret, and enforce these laws as well as possible.

The 1962 amendments cover drugs approved on the basis of safety only between 1938 and 1962, as well as drugs marketed for the first time after 1962. To review the nearly 4,000 pre-1962 drug formulations in addition to the evaluation of new drugs was not within the capabilities of the FDA. The commissioner of the FDA enlisted the help of the Division of Medical Sciences of the National Academy of Sciences-National Research Coun- cil. The Division of Medical Sciences organized and administered the program of drug evaluation named Drug Efficacy Study. The program started in 1966 and was completed in 3 years.

The Advisory Panels of the Drug Efficacy Study consisted of nationally known experts in their par- titular specialty, who were officially described as "predominantly physicians with academic affilia- tions." Only a few physicians in full-time clinical practice were involved with the Drug Efficacy

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Study decisions. The composition of the three Dermatology Advisory Panels was similar to the other panels.

The panels initially were instructed to rate a particular drug as "Effect ive," "Probably Effec- t ive ," "Possibly Effective," and "Ineffect ive." The ratings of "Possibly Effective" and "Prob- ably Effective" indicated that further information was needed before a decision could be made.

Two more ratings were introduced as the study progressed: "Effective But" indicated vaguely worded or misleading claims, or types of drugs which were no longer the approved form of treatment for various reasons even though effective. "Ineffective as a Fixed Combination" was a logi- cal consequence of the application of the new drug law. It is extremely difficult to satisfy the legal requirements for a combination product having two active components and just about impossible if there are more than two active ingredients.

In 1969, the Drug Efficacy Study was completed and the FDA began to implement the various decisions. This is the origin of the term DESI (Drug Efficacy Study Implementation).

The manufacturers provided additional evidence of the efficacy of the various drugs. In some instances the evidence was adequate and the ratings were altered to "Effect ive," but often the data were not satisfactory, and the evaluation process required considerable time and manpower. In addition, the agency was involved in all types of litigation. The manufacturers were contesting every paragraph and comma of the new laws and the way the FDA was administering them. Also, the public interest groups or consumer advocates were taking the FDA to court for being slow and inefficient in administering the new law. In 1972, in the so-called Bryant decision, Judge Bryant required the FDA to speed up the implementation of the DESI review so that it would be completed by I976. For various reasons, the FDA was unable to complete the DESI review by 1976. Again, the same public interest groups and The American Public Health Association instituted litigation against the FDA in 1979 for not complying with Judge Bryant's order of 1972. In 1980 there was an out-of-court settlement in which the FDA agreed to complete all procedures for the ira-

plementation of the DESI review within 4 years. The publication of the DESI Hit List is part of the agreement.

Several significant aspects of this story should be emphasized at this point: the DESI process has been going on for 15 years; the discretionary power of the FDA has been markedly diminished by litigation; it is very likely that most drugs on the DESI Hit List will no longer be available in 4 years.

What can the denlaatologic community do now to preserve the dermatologic preparations on the DESI Hit List? Not very much! Most of these formulations are combinations, and any attempt to prove their efficacy to the satisfaction of the FDA is not likely to be successful. Also, most manufacturers would be reluctant to invest the substantial amount of money necessary for such an undertak- ing. However, I believe there are two steps that can be taken:

If enough members of the Academy of Dermatology are sufficiently interested, the Academy can appoint a task force or ad hoc committee to review the DESI Hit List and discuss with the manufacturers the feasibility of providing further data.

Substitutes can be developed for the dermatologic preparations on the DESI Hit List. Theoretically, it should be possible to add several active ingredients to a single ingredient preparation that is already on the market. It may also be possible to add two or more single ingredient preparations together. The problem here may be the compatibility and stability of the various components.

Other more aggressive countermeasures are not practical in my opinion. Even the AMA, with all of its resources, is not planning to contest the DESI implementation procedures.

Please note that the DESI implementation procedures of the FDA do not interfere with the right of an individual physician to prescribe any drug that he feels will benefit a particular patient. How- ever, any drugs not approved by the FDA cannot be marketed in interstate commerce, and will not be available in federal and some state medical fa- cilities. Also, it is very probable that third party reimbursement (Medicare, Medicaid, etc.) will not be available for such medications.

I personally use a number of the combination drugs on the DESI Hit List in my practice. In

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1973, in response to a suggestion from the FDA, the FDA Liaison Subcommit tee of the Academy of Dermato logy requested information from the local dermatologic societies in regard to their feel- ings about dermatologic combination products. A large number responded and surprisingly about 60% of the members indicated that when using a topical combination formulation they preferred a compounded prescription to a manufactured product. The respondents did not seem to be much upset by the possible demise of dermatologic combinat ion drugs.

Reflect ing on the DESI episode, the dermatologic community may be interested in my conclusions, which are offered without bias. These m a y be of some use in dealing with future problems in the field of drug approval:

1. Any major change in the administration of drug laws requires action by Congress. It is totally useless to expend energy fighting the FDA, particularly when it involves a law already in effect. Many of our editorial writers waste a great deal of time in belaboring the FDA. Making the agency a whipping boy may be satisfactory emotionally, but it accomplishes very little.

2. Dermatologists are a small segment of those practicing medicine and a very small fraction of the general public. Therefore, to be successful in a course of action we need to enlist the help of nondermatologist physicians and the interest of the general public.

3. Congress, like any elected representative body, can be influenced by the opinion of the constituents. Major or minor changes in laws can be effected if the particular issue has enough genuine popular support.

There are several instances of this attitude in the Food and Drug area, where Congress clearly interfered with the power of the FDA to enforce the Food and Drug Laws. Saccharin was not removed from the market in spite of the question about its carcinogenic po- tential. Also due to intense pressures from various special interest groups, Congress passed the Proxmire Amendment to the Food and Drug Laws in 1976, limit- ing the agency's authority to develop regulations con- cerning vitamin and mineral products.

At the present time there is a change in the general attitude of the government in Washington. Numerous groups are calling for the abolition of the efficacy requirement of the drug laws. Several of my corre- spondents indicate that the specialty of dermatology involves considerable "practical art as well as sci- ence"; therefore, the efficacy requirements should be

relaxed. In my opinion, the strict application of the efficacy requirements of the present drug law will spell the doom of time-honored dermatologic preparations such as Castellani's paint, Lotio Alba, and many others. No manufacturer is interested in investing money to prove the efficacy of such drugs. I feel that there should be a practical commonsense solution to the efficacy problem, but I am afraid that under the present circumstances the FDA cannot produce a satisfactory answer. Clearly, some legislation from Congress is needed to allow some flexibility in the efficacy requirement.

4. In any open society all parts of the government pay great attention to events in the communications media such as newspapers and television. I would like to cite two examples:

Sometime during the seventies valproic acid, an anticonvulsant, was introduced in Europe for the treatment of simple and complex absence seizures. In this country, Abbott Pharmaceuti- cals was beginning to accumulate the necessary data, but for various reasons not enough data was generated. After a national television program about the plight of epileptics who needed and could not get this drug, the FDA joined with the drug company in a so-called "acceler- ated review." More data were submitted and valproic acid was approved by the FDA in rec- ord time.

Recently (3/9/81) there was a hearing before the House Health Subcommittee on "Orphan Drugs" (drags of little commercial value). The hearing was timed to foIlow the March 4 episode of "Quincy" (NBC-TV) dealing with the Tourette syndrome. The lead-off witness was Jack Klugman, the actor star of "Quincy."

If there is a good issue to be brought before the public such as the problem of suntan parlors or that of the synthetic hair implants, a proper discussion on television or in the newspaper may be extremely helpful.

5. It is wise to reconcile our differences on a major issue before it is presented to a regulatory organization. The recent controversy about marketing 0.5% hydro- cortisone creams for over-the-counter use is an example of this kind of problem. Another is the continuing controversy about PUVA therapy.

6. There should be regular features in the dermatologic journals dealing with various regulatory ac- tivities, particularly routine FDA actions. This would increase the understanding of the regulatory process

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and could also provide a positive input from the dermatologic community.

I do not feel discouraged by the present drug regulatory situation. The Academy of Dermatol- ogy has excellent legislative representation in Washington. There are expert and talented dermatologists serving on the FDA advisory committees, with a good balance between academicians

and practitioners. Our relations with the FDA have been fruitful and will continue to be effective as long as we understand how the agency operates and we also understand the limits of our ability to influence this process.

Peter N. Horvath, M.D. Washington, DC

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The DESI Hit List: The story and reflections