LIST OF DRUGS SEARCHED AND DATA ON EARLY PUBLICATION. NUMBEROF ... P. Methyldopa . .10. 1954. 1960. 6. E. E. P. Methylphenidate ....... 6. 1944. 1954. 10 ... Range of number of papers publishedprior to first pa- per inwhich a ...
Publications on a Drug Before the First Report of Its Administration to Man BY DONALD A. WINDSOR, Chief Documentation Section, The Norwich Pharmacal Company Norwich, New York
ABSTRACT sidered as published papers (2). Public announcements at meetings, conferences, symThe early published literature on thirty drugs used clinically in humans was searched and ranked posia, etc., while certainly publications in the chronologically for each drug. The median num- sense of making known to the public, were not ber of papers appearing before the first report of considered as published papers unless a printed a human's receiving the drug (the "first-humanpaper," or FHP) was two. The median years that document was published; the actual date of the elapsed from the first paper until the FHP was one. published document was used, not the date of No significant difference was evident in these re- the meeting. Specific days of the month were spects between pharmacologic and antimicrobial considered to be earlier than the month alone; drugs. About 90 percent of the time fewer than ten and specific months were considered to be papers were published and fewer than seven years earlier than the year alone (for example: "March elapsed before the FHP.
USUALLY a drug is tested in animals before it is given to a human. In fact, the Food and Drug Administration so requires (1). As a result, there is a natural inclination to assume that the publications on a drug also appear in the same sequence. In order to see if this sequence actually occurs, literature searches were conducted on thirty common drugs used clinically. The papers obtained were arranged chronologically and were indexed as to whether the drug was given to a human.
22" earlier than "March," and "March 1960" earlier than "1960"). When two papers in the same journal had the same date, the one with the lower page number was considered to be the earlier. When two papers in different journals had the same date, priority was assigned to the paper in the journal which appeared more frequently; for example, a monthly was considered "earlier" than a quarterly when both had the same date. When two papers in different journals had the same date and the journals had the same frequency of issue, priority was assigned alphabetically according to the last names of the senior authors. All names of drugs are those used as main entries in The Merck Index, 8th Edition (1968)
MATERIALS AND METHODS Literature searches were conducted using a four-pronged attack: (1) secondary journals (3).For the sake of simplicity, the first report of such as Chemical Abstracts, Biological Abadministration Index and stracts, Medicus, Excerpta Medica ferred to as the of the drug to a human is re"first-human-paper," or FHP. were searched; (2) the primary journal articles obtained were read for more references which, RESULTS in turn, were read for more references, etc.; (3) appropriate review articles, books, compendia, The results are presented in Table 1 and are and symposia were checked; and (4) appropriate summarized in Table 2. Frequency distribuprimary journals were scanned, issue by issue. tions of numbers of papers published before the Only published papers were considered. A first-human-paper, and of years between first published paper was defined as a printed docu- paper and first-human-paper, are shown in ment readily accessible to the public, such as a Figures 1 and 2. Table 3 shows the rank order journal article or a book. Patents were con- of the drugs and the tests for significance of difBull. Med. Libr. Ass. 59(3) July 1971
433
DONALD A. WINDSOR
TABLE 1
LIST
OF DRUGS
SEARCHED AND DATA ON EARLY PUBLICATION
NUMBEROF
YEARS
PAPERS PUBLISHED PRIOR TO
DRUG
THE
FIRST
P'PER
IN
WA HICH A HUMAN RECEIVED THIE DRUG
Amantadine . ........ Bacitracin.
4 0 3 Cephalothin. Chloramphenicol. . 8 Chlordiazepoxide . .1 1 Chlorphentermine. Chlortetracycline........... 0 3 Dextropropoxyphene Diazepam.................. 0 5 ............. Dicyclomine .. Griseofulvin ............. 81 2 Hexachlorophene. . Hexamethonium . . 5 Iproniazid ................. 1 2 Meprobamate ........ ..... Methyldopa . .10 6 Methylphenidate ....... Metronidazole ........ . 1 Nalidixic Acid . .1 18 Neomycin. 0 ............. Nylidrin ...... . .8 Nystatin Oxytetracycline. .3 0 Penicillin .................. Phenylbutazone . .1 1 Polyvinylpyrrolidone 0 ... Propranolol. 3 Reserpine. 6 Tetracycline. rhalidomide...... .. 1
YEAR OF
OP FIRST PAPER
YEAR
1959 1945 1962 1947 1959 1954 1948 1953 1961 1947 1939 1941 1910 1952 1951 1954 1944 1959 1948 1949 1950 1950 1950 1929 1949 1940 1964 1952 1952 1956
FIRST PAPER IN W'HICH A
HUMAN
RECEIV'ED THE DRUG
1963 1945 1962 1948 1960 1960 1948 1955 1961 1950 1958 1944 1950 1952 1954 1960 1954 1960 1962 1950 1950 1953 1950 1929 1949 1941 1964 1953 1953 1956
ELAPSED BETWEEN
FIRST
LANGUAGE OF FIRST
LA-NGUAGE
PAPER AND OF FIRST FIRST PAPER PAPER(a) IN
WlHICH
4 0 0 1 1 6 0 2 0 3 19 3 40 0 3 6 10 1 14 1 0 3 0 0 0 1 0 1 1 0
WHICH A
HUMAN RECEIVED THE DRUG(a
HUMAN RECEIV'ED THE DRUG A
PAPER IN
G E E E E E E E E F E E G E E E I F E E G E E E G G E G E G
E E E E E D E E E E E E E E E E G F E E G E E E G G E E E G
TYPE OF
I)RUG(b)
A A A A P P A P P P A A P P P P P A A A P A A A P P P P A P
(a) D = Danish, E = English, F = French, G = German, I = Italian. (b) A = Antimicrobial, P = Pharmacological.
434
Bull. Med. Libr. Ass. 59(3) July 1971
PUBLICATIONS ON A NEW DRUG
TABULATION
OF
DATA
ON
TABLE 2 EARLY PUBLICATIONS
Number of drugs searched Median number of papers published prior to first paper in which a human received the drug. Range of number of papers published prior to first paper in which a human received the drug Average median number of papers published prior to first paper in which a human received the drug Range of years of first papers Median year of first papers Range of years of first papers in which a human received the drug Median year of first paper in which a human received the drug Difference between median year of first paper and median year of first paper in which a human received the drug Languages of first papers:
English German French Italian Languages of first papers in which a human received the drug:
English German French Danish
ferences between antimicrobial and pharmacologic drugs. The references found to the drugs from the first papers to the FHP's can be obtained from the author. The median number of papers published on a drug prior to the FHP is two. Of the thirty drugs searched, six (20 percent) were reported as given to a human being in the first paper published, and eight (27 percent) had one paper published first. Of the thirty drugs searched, 90 percent (twenty-seven) had fewer than seven years elapse from the first paper on the drug to the FHP. The maximum was for hexamethonium which had a forty-year lapse. Only two drugs had a large number of papers published before the FHP, neomycin with eighteen and griseofulvin with eighty-one. Neomycin was difficult to obtain in sufficient quantities but only one year elapsed between the first Bull. Med. Libr. Ass. 59(3) July 1971
OF
DRUGS SEARCHED
DRUGS ALLALL DRUGS
DANTIMICROBIAL DRUGS
PHARMACOLOGICAL
30
14
16
2
3
1
0-81
0-81
0-10
5.8 1910-1964 1950
9.6 1929-1962 1948
2.5 1910-1964
1929-1964
1929-1963
1941-1964
1953
1950
1954
3
2
2
20 7 2 1
12 1 1 0
8 6 1 1
23 5 1 1
13 0 1 0
10 5 0 1
DRUGS
1952
paper and the FHP; griseofulvin was used for plants before being considered for animals. Only three drugs had a long lapse between the first paper and the FHP, hexamethonium with forty years, griseofulvin with nineteen years, and nalidixic acid with fourteen years. However, hexamethonium had only five papers prior to the FHP and nalidixic acid had only one. Griseofulvin is unique among the drugs searched in having both a large number of papers and a long time span prior to the FHP. Griseofulvin is also unique among drugs because of its antifungal properties together with its ability to attack superficial fungi upon systemic administration (4). There is no significant difference between the antimicrobial and the pharmacologic drugs. Although the median number of papers published prior to the FHP is two for all drugs, it is three for the antimicrobial and one for the phar435
DONALD A. WINDSOR
15
co
.z
x
10 U)
5 $4-
la .0
E
z
0
0
0
0 0
5
10
20
15
Number of papers published prior to the first-human-paper
FIG. 1.-Frequency distribution of number of papers published prior to the first-humanpaper.
15
,_
,,I _
10
5.4
la .0
a4
5 0
0
0
0
a.
0
5
10
a -
0
0a- *
15
0 *
20
40
Years elapsed from publication of first paper to the first-human-paper.
Fio. 2.-Frequency distribution of number of years elapsed from publication of first paper to the first-human-paper.
436
Bull. Med. Libr. Ass. 59(3) July 1971
PUBLICATIONS ON A NEW DRUG TABLE 3 RANK ORDER OF THE DRUGS SEARCHED IN RESPECT TO THE NUMBER OF PAPERS PUBLISHED PRIOR TO THE FIRST-HUMAN-PAPER !NUMBER
macological drugs. At P = 0.95, both the Median Test using X2 and the Rank Test (5) accepted the hypothesis that these medians are equivalent and the difference between them is not significant.
OF
PAPERS
PUBLISHED PRIOR TO
DRUG
THE FIRST PAPER I-N WVHICH A
HUMAAN RECEIVED THE DRUG
I1 ___________ 1.16 Bacitracin ............ Chlortetracycline....
Diazepam .......... Nylidrin ............. Penicillin ............ Propranolol.......... Chlordiazepoxide. ..
Chlorphentermine.... Iproniazid..... Metronidazole ...... Nalidixic Acid...... Phenylbutazone ..... Polyvinylpyrrolidone. Thalidomide ......... Hexachlorophene... Meprobamate ........ Cephalothin........ Dextropropoxyphene. Oxytetracycline. .. Reserpine ............ Amantadine .......... Dicyclomine....... Hexamethonium ...... Methylphenidate. .... Tetracycline.......... Chloramphenicol..... Nystatin ............ Methyldopa.......... Neomycin ......... Griseofulvin.........
0 0 0 0 0 0 1 1 1 1 1 1
1 1
2 2 3 3 3 3 4 5 S 6 6 8 8 10 18 81
1.16 1.16 1.16 1.16 1.16 2.12 2.12 2.12 2.12 2.12 2.12 2.12 2.12 3.50 3.50 4.25 4.25 4.25 4.25 5.00 6.50 6.50 7.50 7.50 8.50 8.50 9.00 10.00 11.00
DRUG"
CONCLUSION About half of the time two or fewer papers are published on a drug prior to the first-humanpaper.
A A
respect between antimicrobial and pharmacologic drugs.
TYPE OF
RANKb
I
There are no significant differences in this P P A
P p p
A A
p p P
A
P
A A
A
A A p p p
(a) A = Antimicrobial, P = Pharmacological. (b) The sum of the ranks of A is T = 70. T' = Na(Na + Np + 1) - T = 364. Na = 14; Np = 16. The table value of T' is 155 at P = 0.99; therefore, A = P(5).
About half of the time, the FHP is published within one year after the first paper on a drug. About 90 percent of the time fewer than ten papers are published on a drug before the FHP. About 90 percent of the time fewer than seven years will have elapsed from the time the first paper on a drug is published to the appearance of the FHP. Therefore, when conducting a literature search on a drug it is safe to assume that papers in which human beings receive the drug will be among the earliest papers on that drug. Conversely, just because a paper reports administration of the drug to a human it cannot be assumed that many previous papers exist, and unless other evidence indicates it, time and effort need not be spent searching for earlier papers.
1. 2.
3. 4. 5.
REFERENCES Code of Federal Regulations, Title 21, Part 130.3, p. 5-13. Jan. 1, 1969. CHAPMAN, T. S. The patent as a technical publication. Res. Devel. 16: 18-19 Nov. 1965. STECHER, P. G., et al. eds. The Merck Index; An Encyclopedia of Chemicals and Drugs. 8th ed. Rahway, N.J.: Merck & Co., 1968. 1714 p. WILLIAMS, D. I.; MARTEN, R. H.; AND SARKANY, I. Oral treatment of ringworm with griseofulvin. Lancet 2: 1212-1213, Dec. 6, 1958. TATE, M. W., AND CLELLAND, R. C. Nonparametric and Shortcut Statistics. Danville, Ill., Interstate, 1957. p. 87-89.
Bull. Med. Libr. Ass. 59(3) July 197/743 437
