To the millions of consumers throughout the country our procedures and requirements at the Bureau of Drugs in processing Investigational and New Drug Applications are more than a matter of academic interest. They see our expectations as their guarantee of the safety and efficacy of the drugs they use. This is why we are constantly seeking new ways of both strengthening and streamlining our review methods, of providing added safeguards for those on whom drugs are tested, and of improving investigative reports.

Just recently we proposed to amend our regulations to provide a 30-day waiting period for the initiation of human drug tests after we receive the Investigational New Drug Application. And we have proposed to set up special institutional review committees to assure that clinical testing of persons in hospitals, prisons, research facilities, or other institutions is carefully supervised. At the same time, we are trying to speed up our actions so drugs can be marketed and made available to the physician and the patient without unnecessary bureaucratic delays.

We demonstrated our desire and our ability to achieve this purpose by approving New Drug Applications for L-dopa last May in half the time the law gives us to act on New Drug Applications. Our approval, for the first time, carried a requirement that the pharmaceutical firm maintain structured, prolonged clinical trials to provide information on the drug's long-term studies, not only to ascertain prolonged safety but also ultimate efficacy. Examples of the latter could include antihyperglycemic and antilipemic agents.

Our primary concern in all of our actions is the protection of the consumer. This responsibility is spelled out clearly in the first Food and Drugs Act in 1906 and in sub

sequent additions and amendments all the way up to the 1962 Kefauver-Harris Amendments. These amendments, among other things, increased the FDA's regulatory authority over the clinical testing of new drugs and required substantial evidence of a drug's efficacy, in addition to its safety, before it could be marketed.

Crucial to the marketing is the kind and extent of investigational drug testing. It is in the three testing phases that we expect the Investigational New Drug sponsor to carry on the adequate and wellcontrolled investigations that are basic to compiling and presenting to us the substantial evidence needed under the law to validate the New Drug Application. Before explaining what we mean by the phrase, “adequate and well controlled investigations," let us outline briefly the three phases and the information required in IND Forms 1571, 1572, and 1573.

In Phase I, pharmacology studies are used to determine toxicity, metabolism absorption and elimination, and other pharmacological action; preferred route of administration; and safe dosage range. These studies involve small number of persons and are conducted under carefully controlled circumstances by persons trained in clinical pharmacology.

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When Phase I demonstrates satisfactory results, the sponsor may proceed to Phase II-initial trials on a limited number of patients for specific disease treatment or prevention. Additional pharmacological studies performed concurrently on animals may be necessary to indicate safety. If the information obtained in Phases I and II demonstrates reasonable assurance

of safety and effectiveness or suggests that the drug may have a potential value outweighing possible hazards, proposals for Phase III, involving extensive clinical trials, are in or

der. These studies are intended to assess the drug's safety, effectiveness, and most desirable dosage in treating a specific disease in a large group of subjects.

The information in the IND Forms must include: 1. Chemical and manufacturing data. 2. Results of all preclinical studies, including animal investigations. 3. A statement of the investigators' training and experience. 4. Copies of all informational material supplied to each investigator. 5. The sponsor's agreement to notify the FDA and all investigators of any adverse effects resulting from the drug's use in either animal or human tests. 6. The investigator's agreement to obtain the consent of the person before the drug is tested on him. 7. Agreement to submit annual progress reports and commitments regarding disposal of the drug when studies are discontinued. 8. A detailed outline of the planned investigation.

It is on this last requirement that the IND usually stands or falls. The outline or protocol must set forth a clear-cut, comprehensive description of the procedures, measurements, controls, and analysis methods to be followed to obtain objective, unbiased, therapeutic information. Too frequently, however, the protocol has been unclear, insufficiently detailed, and poorly designed.

Perhaps we have been at least partly responsible because we failed to make absolutely clear just what we expected. We held workshops independently and at the invitation of the pharmaceutical industry to explain what we meant by adequate and well-controlled investigations and the kind of evidence to be elicited from those studies to justify an NDA approval. And we talked with individual drug manufacturers.

It became evident from these discussions that written clarifica

tion was needed. Accordingly, last May, the FDA published the final version of regulations outlining the principles constituting the essential elements of controlled clinical drug testing (see FDA PAPERS, June 1970). They form the ground rules for determining the substantial evidence the law requires for us to approve drugs for marketing.

And in June of this year, we proposed to the Pharmaceutical Manufacturers Association that we each develop written clinical guidelines for specific classes of drugs, that we meet in the fall to discuss our respective protocols and decide upon jointly approved guidelines, and that these then be submitted to advisory panels of academic experts for their review. It should be emphasized that these guidelines are suggestions and recommendations for desirable clinical studies. They are in no way intended to mitigate against the introduction of additional well-planned clinical trials or substitution of these trials for certain of the guidelines when circumstances or newer information so dictate.

The true function of the controlled trial is twofold: to separate the valid advances in drug therapy from a host of false leads and unverifiable clinical impressions, and to delineate scientifically and objectively the extent of and limitations surrounding the drug's safety and effectiveness.

As Dr. D. R. Laurence says in his book, Clinical Pharmacology, "Progress is delayed when

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vinced opinions are offered in place of convincing facts. The former, though not necessarily wrong, are unreliable, despite the great assurance with which they are often advanced."

A confirming opinion is voiced by the New York Academy of Medicine's Committee on Public Health in a 1962 report: "It is the judgment of competent authorities

that the relative effectiveness of specific therapeutic measures can be reliably established only in wellcontrolled comparative clinical investigations."

What should the protocol include? Certainly, as in any other plan, it must state its objectivethe question or questions to be answered by the clinical trial.

Next, the protocol must contain criteria for accurately diagnosing and defining the disease involved, along with appropriate confirming laboratory tests. The initial diagnosis, therefore, must be correct and based on uniform and fully described methods so other clinicians may use them with the same result.

The third factor to be included is a method of selecting patients and allocating them to treatment groups in such a way as to minimize the risk of bias. In the words of Dr. Louis Lasagna, "It is difficult to conceive of a rule more important for the clinical investigator than that of avoiding bias in the allocation of cases to different treatment groups." Experience has shown that the best way to avoid bias and eliminate influencing variables, both known and unknown, is deliberate randomization.

Dr. A. B. Hill, in a 1952 article, "The Clinical Trial," in the New England Journal of Medicine, explains that this method of allocation accomplishes two aims: "It insures that neither our personal idiosyncrasies (consciously or unwittingly applied) nor our lack of balanced judgment has entered into the construction of the different treatment groups .; it removes the danger that believing we may be biased in our judgments we endeavor to allow for that bias and that in so doing we may overcompensate and introduce a lack of balance from the other direction...."

To obtain valid data, the clinical

trial must be conducted on a valid, unbiased basis. No analysis, however high-powered, can compensate for data of dubious validity.

The fourth protocol requirement also involves the elimination of bias-this time, bias by both patient and observer in reporting results of the clinical tests. It should explain the methods of observation, the recording of results, and a description of the scoring system. In sum, the protocol must detail what measurements will be taken, how they will be taken, and precisely when.

Fifth, we expect the protocol to include a description of the steps to be taken to compare variables such as age, sex, duration of disease, and use of drugs other than those under study. If the groups of patients in the study are similar in observable characteristics at the outset, it would be logical to assume that, in a rigidly designed protocol, changes that take place in the groups subsequently may be attributable to the only known difference between them-the treat

ment.

An extension of this requirement is the next step-that of describing the methods to be used in analyzing the patient responses. This involves use of standard record forms, uniformity in completing them, and appropriate methods for storing and retrieving the information easily and promptly.

Not only is it important in a controlled trial to avoid bias in setting up the treatment groups to be compared; it is equally important to minimize the introduction of bias that may arise during the experiment because of the preconceptions and expectations of the investigator and patient. The protocol, therefore, should list the methods to be followed to avoid that kind of bias. In general, the double-blind control should be incorporated into the experiment whenever it is feasible, although the single-blind technique is sometimes used, particularly in early stages of investigation or where the results to be measured are truly of the objective type.

The use of a patient as his own control seldom provides a valid study. Some exceptions include powerful diuretics, drugs for the treatment of malignancy, and oral contraceptives, namely, situations where the effect of a drug is so marked that its efficacy is obvious or where facts on historical controls are well established.

The double-blind technique refers to a treatment, the specific nature of which is unknown to both subject and observer. Single-blind refers to a trial in which one participant, usually the patient, is unaware of the treatment being received at any specific time. To be a valid control, of course, the placebo should closely imitate the test drug in shape, taste, smell, and any other action perceivable by the patient and physician.

Another vital factor in a protocol is a precise statement of the nature of the control group against which the effects of the new treatment can be compared. In a controlled experiment, comparison is obviously implicit. To use personal experience as a basis of comparison, personal experience that was obtained under different circumstances, certainly at another time, and perhaps at another place, would frequently and usually lead inevitably to erroneous conclusions because it fails to provide comparable bases for examinations of control and experimental groups.

Finally, the protocol must include a summary of statistical methods to be used in analyzing the data derived from the subjects. There may be times when results of a clinical trial are so clear-cut that a test of statistical significance is unnecessary. But medications are seldom so startlingly effective. For that reason, the sponsor of an ex

Marion J. Finkel, M.D., deputy director, Bureau of Drugs, since last April, joined FDA as a medical officer in May 1963.

perimental drug would be wise to seek the advice of a competent statistical consultant in preparing his protocol.

We at the Bureau of Drugs feel that the standards and requirements outlined in the foregoing are essential to a valid conclusion of a drug's safety and efficacy. Without them, the testing procedure can neither be considered adequate nor well controlled.

There is another consideration that can be opportunely mentioned. The Food and Drug Administration has for some time deplored the "therapeutic orphan" aspect of the labeling of many drugs. Too many package inserts contain a statement such as "Contraindicated in children because studies have been inadequate to demonstrate safety in this age group." We, like Dr. Harry Shirkey, feel that this situation requires correction when feasible. Accordingly, we are adopting the policy that it is possible that a New Drug Application for a drug that would have considerable therapeutic utility in children and/or will be used by the practicing physician in the absence of adequate investigational studies in children will not be approved unless the necessary studies are performed.

It would be logical to assume that after the pharmacological and clinical studies have been carried out as well and as comprehensively as we expect, the New Drug Application would sail through our offices with little difficulty. Unfortunately, many NDA's founder on the rock of inadequate data with regard to the manufacturing processes to be used in producing the new drug. Some of the major deficiencies include:

1. Failure to name. all the components of the drug, including inert substances and those used in the synthesis of the new drug. 2. Failure to state the quantities of inactive ingredients per dosage form unit-that is, per tablet or per mil

Joshua Zatman, assistant for medical communication to the director, Bureau of Drugs, joined FDA in April 1969.

liliter. 3. Failure to list the components of the batch formula in the finished product. 4. With regard to facilities and personnel, reference is sometimes made to a master file or another New Drug Application which has become outdated. Such information is useless unless it is on a current basis. 5. Inadequate information on the sterilization, sampling, and labeling procedures. 6. Inadequate information on the characteristics and testing of containers to demonstrate their suitability for the intended use, especially for plastics, metal tubes, and aerosols.

To remove many of the often observed manufacturing controls deficiencies in both IND's and NDA's, we have set up joint FDA-PMA committees to establish written guidelines for the use of all manufacturers. These committees are in the final stages of agreement on the detailed guidelines.

To those who would dismiss all of these requirements as so much unnecessary paperwork, we can only say that long experience has demonstrated conclusively that they are, indeed, vital components of procedures designed to protect the public.

Adapted from an address by Dr. Finkel

to the University of Wisconsin INDNDA Conference at Milwaukee October 4.

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BALTIMORE DISTRICT The District held two training courses recently-one for industry personnel and the other for FDA'ers. With the assistance of the Department of Justice Bureau of Narcotics and Dangerous Drugs, District personnel set up a training course for employees of Barre Drug Co., Baltimore, dealing with responsibilities of those who work with narcotics and control drugs. The principal speaker was Vincent Lozowicki, compliance officer with the BNDD Baltimore office. FDA people from the Baltimore, Philadelphia, and Boston Districts attended a training course in the operation of the Technicon Autoanalyzer, with instruction by Harvey Miller, supervisory chemist from the Chicago District. Beverly McCarthy from FDA's Training Institute attended in conjunction with a visit to the Baltimore District.

BOSTON DISTRICT When District inspectors found during an investigation of a local firm that it was repacking one type of fish into cartons labeled as other types, seizures were ordered. Blocks of frozen cod were found in cartons labeled as flounder, and the inspectors took samples which, when examined electrophoretically, confirmed that the blocks were indeed codfish. Massachusetts' State inspectors embargoed the 38,000-pound lot until a U.S. marshal received orders to seize it. The lot was valued at approximately $11,000 as codfish and would have been valued at $15,000 as flounder. Electrophoretic examination of another lot of frozen fish blocks labeled as sole showed that the fish was Greenland turbot. This 2,500-pound lot was also seized.

BUFFALO DISTRICT A New York firm recently voluntarily destroyed 3,000 pounds of egg noodle products which it had recalled from the market because of Salmonella contamination. The firm estimates that the amount destroyed represents about 12,000 to 15,000 individual servings.

CHICAGO DISTRICT FDA's message of concern for the consumer and how the Agency implements its programs in relation to this concern are brought to the public's attention in various ways by the District's consumer specialists, Marguerite Robinson and Marie Ekvall. Miss Robinson developed and coordinated the third annual Consumer Problems Conference held recently at Southern Illinois University, Carbondale, which zeroed in on food and nutrition and introduced a new consumer problem relating to housing. Miss Robinson's presentation was titled, "How Safe Is Your Food?" The conference, cosponsored by FDA, Illinois Home Economics Association, Illinois Public Aid, and the University of Illinois Cooperative Extension Service,

is an areawide meeting attended by over 400 people, including educators, public aid employees, and the consuming public.

Both Miss Robinson and Mrs. Ekvall have made plans to work with the Health and Welfare Section of the Illinois Home Economics Association. They have developed their programs to include a workshop at the District and to implement the White House Conference on Food, Nutrition, and Health. This section of the association includes over 100 home economists who represent Cook County and the Illinois Departments of Public Aid, as well as hospital dietitians, nutritionists, and home economists from voluntary agencies throughout the State. The purpose of this program is to provide a greater impact for FDA's work with low-income people.

The consumer specialists are also planning to conduct ten regional workshops in consumer education at the request of the State of Illinois Department of Public Instruction. Over 2,000 teachers attending from throughout the State will hear the message, "FDA Looks at Consumer Education."

Using the radio as another medium, the consumer specialists have carried on an extensive program with radio stations throughout the State, ranging from three-hour live broadcasts to taped 30-second public service announcements. Among these was their participation in the series sponsored by WMBI in Chicago called "One Step Forward," which was designed especially for low-income areas of the city.

CINCINNATI DISTRICT T. C. Maraviglia, deputy regional food and drug director, and Carl R. Baeuerlen, District chief inspector, met at Columbus, Ohio, with John M. Stackhouse, director of the Ohio Department of Agriculture; Dr. David A. Hill, chief, Division of Foods, Dairies, and Drugs, also of the Department; and Max Weimer, his assistant. The meeting was held to discuss the feasibility of establishing specific, formal work-sharing agreements between Cincinnati District and the Department in certain food areas. The State officials have taken the matter under consideration.

Informal working agreements with Ohio in the medicated feed area and in sharing pesticides sampling and analytical results are already in effect.

DALLAS DISTRICT Hendrich Deelstra, Ph.D., professor of organic chemistry at the University Officielle, Republic of Burundi (Central Africa), visited the District laboratory to discuss FDA's methodology for determining pesticide residues in fish. Dr. Deelstra said that cotton is a large crop in Burundi and that the fields are being sprayed aerially with pesticides. He is concerned about the runoff that may drift into nearby rivers and streams and possibly contaminate the fish.

DENVER DISTRICT New Improved W.M.C. Baking Specialty, a bright yellow powder used in bakery products and manufactured by Wheat Product Co., Colorado Springs, was ordered seized in Kansas City, Missouri, because of the presence of nitrites and nitrates, food additive compounds that are not permitted in such products.

KANSAS CITY DISTRICT On-the-job training started in late August for those State feed inspectors from several States who attended a basic training school earlier in the summer at Keokuk, Iowa. Omaha resident inspectors worked with an inspector from Nebraska and one from Iowa. Similar training was expected to get under way in Missouri during the latter part of September.

Kansas City and Chicago Districts and FDA's State Services office in Washington held the medicated feed training school at Keokuk for the State inspectors. Attendees were from Idaho, Illinois, Iowa, Kentucky, Missouri, Nebraska, and Tennessee. The training course agenda included FDA inspection techniques, discussion of State and Federal laws and regulations, report writing, and training inspections.

Both District offices made plans at that time to give on-the-job training to participants in the Keokuk school as the final step toward obtaining FDA commissions.

As a result of what the District calls "forty well-spent weeks" of training with its personnel, Lorraine Burns can now preside at exhibits and can present slides, films, and other visuals to small neighborhood groups not otherwise reached in the Kansas City area.

Mrs. Burns, a local elderly citizen, was assigned to the Kansas City District for a period of 40 weeks as a consumer education aide. The assignment came through the Senior Community Services Aides Project of the American Association of Retired Persons and the National Retired Teachers Association for her to assist the District's consumer specialist in reaching a greater number of consumers, particularly senior citizens.

Mrs. Burns' tenure with the project contributed a valuable service to FDA's consumer education program, and she plans to continue her interest in consumer education on a volunteer basis with the Scouts, and church and other small groups.

LOS ANGELES DISTRICT The presence of live insects resulted in the seizure of a 26-ton carload of soy grits and soy flour shipped from Decatur, Illinois, to a milling firm at Los Angeles. The cause of the infestation has not been determined.

A consumer complaint that a can of beef and rice product purchased at a Los Angeles food market was swollen was followed by District investigation of the dealer's stocks. Other swollen cans were found, and the firm decided to recall all stocks of the article from its branch stores. Although it was not determined what caused the swelling, examination of samples by the District laboratory were negative for food poisoning bacteria.

MINNEAPOLIS DISTRICT A local drug wholesaler asked the District to witness destruction by burning of over 900,000 special formula amphetamine-vitamin tablets. The firm had been warehousing and repacking the tablets for a doctor who discontinued his weightreducing clinic, thus creating a large surplus of an unusable drug. The tablets were valued at $3,258, and when the firm decided to destroy them, the doctor agreed to share the loss on a 50-50 basis.

NEW ORLEANS DISTRICT An entire shipment of imported sardines has been recalled because of problems found after the District's import officials had released the shipment into domestic commerce. The problems involving the 300,000-can lot of Danish "Clupea Canning" brand sild sardines went unnoticed and the lot escaped detention because it had been under refrigeration. Removed from refrigeration, the cans remained intact on the wharf long enough to pass examination and to be shipped. Then as temperatures rose, they began to explode. When the manufacturer was informed of the problem, which appeared to be faulty can seams and possible underprocessing, he came to the District office accompanied by the consignee, Emmanuel Stecker of the Maine Canners Sales Corp., who voluntarily recalled the shipment for return to Denmark.

NEW YORK DISTRICT To help combat a serious problem of food spoilage due to insect infestation and rodent contamination in Puerto Rico, FDA has offered training to those who might be involved in trying to correct the problem. The San Juan Section (commonly called SanSec) of the New York District conducted a warehouse inspection and sanitary maintenance training for Puerto Rico Health Department officials and other government representatives during the week of August 17-21. Along with the New York District, SanSec is planning a two-day seminar-workshop for sanitation in the food manufacturing and storage industries in Puerto Rico. The program, tentatively set for November 5-6, will cover insect, rodent, and bacteriological problems, and controls for achieving and maintaining a safe and clean food supply.

Plans for offering such training were made following a recent request for help from Sylvia Lopez de Perez, Director of the School Lunch Program, Puerto Rico Department of Education, in solving what appeared to