British National Formulary: its birth, death, and rebirth

0 L Wade

TheBritish NationalFormularyis adirectdescendantofthe National War Formulary, in which the tides ofthe preparations were in Latin and the doses inminims and grains. The British National Formularywas born in 1948, did a good job for about 20 years,but sickened and died in 1976. It was reborn in 1981.Parturition was painful with a very hostile receptionfrom the media and the drug industry, but it survivedand has grown in stature. The 25th edition waspublished in February. Wish it well for the next 25issues!

The 25th issue of the current British National Formularywas published in February, and it seems a goodmoment to look back at my association with theformulary, which started 30 years ago in 1963.

National War FormularyWhen war came in 1939 the minister for health

appointed a small committee to prepare a formulary forwartime use. Its introduction stated that it contained"a selection of medicaments sufficient in range to meetthe ordinary requirements of therapeutics." As Ithumb through my ancient copy I realise how muchmedicine has changed in my professional life. Therewere 380 preparations; the titles were in Latin; thedoses were in the apothecaries' system of minims andgrains; and there was an inappropriately large assort-ment of tonics, cough mixtures, and aperients, such asMistura Ammonii Chloridi et Morphini and MisturaCascarae et Nucis Vomicae. There were three enemas,and it is difficult now to understand why Enema FellisBovini (bovine bile enema) was needed for the wareffort. The formulary did, however, contain threeimportant chemotherapeutic drugs: sulphonilamide,sulphathiazol, and sulphapyridine (used to treatChurchill when he contracted pneumonia while visit-ing troops in North Africa).

Birth ofthe British National FormularyWhen the war ended it was the two non-govem-

mental bodies that had been most closely associatedwith the National War Formulary, the PharmaceuticalSociety of Great Britain and the British MedicalAssociation, which wanted to continue publication of aformulary for general use. Thus the British NationalFormulary was bom a direct descendant of the warformulary.The first edition was published in 1949, and new

editions appeared thereafter about every three yearsuntil 1976. When I was appointed a member of theJoint Formulary Committee in 1963, I did not knowthat I was to hold that appointment for 21 years.

It was an enormous committee with 38 members,doctors and pharmacists. Most of the doctors weregeneral practitioners and a lot of the work for themedical members fell on a few of us who were inacademic life. This included our chairman, AndrewWilson from Liverpool, and Graham Wilson fromSheffield, Alastair Macgregor from Aberdeen, RoyGoulding from Guy's, and myself from Belfast; all ofuswere to become close friends.Much of the time of the committee was spent in

deciding which drugs and preparations were to beselected for inclusion in the formulary. The generalpractitioner members were mostly elderly and veryconservative in their views, and they tended to resentany changes in the formulary. There was muchprolonged and detailed discussion, sometimes heated,about the notes for prescribers, which came at thebeginning of the book and at the beginning of eachsection about different groups of drugs-alimentary,cardiovascular, anti-infective, etc.The usual procedure was for a member of the

committee, usually one of the academic members, tobe asked to produce a draft of one of the sections, andthis was then discussed and modified in committee. Itwas a slow and often tedious business. The meetingswere held in a large and gloomy committee room atBMA House in Tavistock Square. They started atI0 am and seldom finished before 4 or 5 pm. I often haddifficulty in getting to Euston, only a few hundredyards away, in time to get the boat train to Liverpool at4-55 pm or to Heysham at 5.40 pm.By the time I joined the committee English had

already replaced Latin in the British National Formu-lary, and the old apothecaries' system of grains andminims was being replaced with what some membersthought was the new fangled metric system. Mono-graphs on new and important drugs such as thepenicillins, tetracyclines, and corticosteroids hadbeen included in the formulary, but there were still alot of traditional tonics and mixtures. I remember veryvividly dear old Dr Leak of Lee in Staffordshire, whoalways fought a strong rearguard action to prevent usdeleting any of them. I admired Andrew Wilson; hewas extremely tolerant and patient and very skilledat calming tempers, and I leamt a lot on how tohandle difficult meetings by watching him.

Over the next 14 years I was asked at one time oranother to put my hand to drafting almost every sectionof the formulary: drug dependence, prescribing for theelderly, adverse reactions to drugs, notes on drugs forthe alimentary, cardiovascular, respiratory, andnervous systems and for infectious diseases and onvaccines. It was rather like undertaking a continuouscomprehensive refresher course, and it helped me inmy teaching both to undergraduates and to generalpractitioners as I felt confident that I was fullyconversant with current thinking and practice.The constitution of the Joint Formulary Committee

was modified in 1969; it became smaller and a numberof younger and well informed people were appointed.The new chairman was Dr John Bishop Harman. Themeetings became shorter and more productive. By thistime there was a flood ofnew drugs and preparations ofdrugs being introduced and marketed. It was our aimto include in the formulary an appropriate selection ofthese. There were some groups of drugs, such as theantihistamines and the hypnotics, for which scores ofdifferent drugs and preparations were available. Wemade what we thought was an appropriate selection.We admitted that our selection was arbitrary, andwe tended to include those that were already mostcommonly used.We had great difficulty with new drugs. Would they

tum out as useful as the firms that marketed themclaimed? Our policy was to include only those whose

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26 West Street, Stratfordupon Avon, WarwickshireCV37 6DNO L Wade, emeritus professoroftherapeutics and clinicalpharmacology

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effectiveness was reasonably certain, but we knew thatthis was done at the expense of being out of fashion,and sometimes we were very late at including in theformulary really valuable new drugs.

DeathIt became increasingly clear during the early 1970s

that the formulary was being less and less used bydoctors. The pharmaceutial industry was publishingthe Monthly Index of Medical Specialities every month.Compared with this the British National Formulary,which was produced every three years, was very soonout of date. The monthly index was on the desk ofevery practitioner and in the pocket of every houseofficer. It was estimated that 80% of prescribing bydoctors was done with the index and only 20% with theformulary.

In 1975 the Medicines Commission, ofwhich I was amember, was becoming concemed that the prescribinghabits of doctors were being unduly influenced by thepharmaceutical industry, and it was suggested to theDepartment of Health and Social Security that a newand more comprehensive national formulary wasneeded that would (a) no longer be selective but giveinformation about all medicines available in the countryfor prescribing by doctors; (b) give information aboutthe price of medicines; (c) be easy to use; (d) be ahandbook and fit into a coat pocket; and (e) be kept upto date.

Discussion and negotiations between the Depart-ment of Health and Social Security, the BMA, andthe Pharmaceutical Society started in 1975 and con-tinued for the next three years. There was increasingconcem at the delay in concluding negotiations becausethe 1976 edition of the British National Formulary wasbecoming more and more out of date. It was realisedthat the production of a new type of formulary wouldentail a great deal ofwork and that the new book wouldnot be available for at least two and perhaps threeyears, by which time it might turn out to be unwantedbecause doctors had got used to obtaining informationon drugs from other sources. However, in 1978 theDepartment of Health and Social Security gave anassurance to the two societies that if they wouldproduce a new national formulary that met the speci-fications outlined above, it would purchase the bookand distribute it to all doctors and pharmacists in theNational Health Service. This important decisionowed a great deal to Dr Ed Harris-at that time deputy

chief medical officer at the department. Few if anydoctors and pharmacists know of the debt we owe tohim; without that decision the British NationalFormulary would not have been rebom.

RebirthIn December 1978 a new and smallerjoint Formulary

Committee was appointed. I was asked to be the newchairman.rThere were two secretaries to the committee,one from the BMA and one-from the PharmaceuticalSociety, and nine members, three from the BMA,three from the Pharmaceutical Society, and three fromthe Department of Health and Social Security (box).

We met for the first time in Febuary 1979. Weappointed Mr Ron Brown as the editor. That was asplendid appointment. He had worked on the pro-duction of the British Pharmacopoeia and Martindale:The Extra Pharmacopoeia for many years and brought awealth of professional experience to the production ofthe new formulary. He was supported by Mr AinleyWade (no relation, but nice to have another Wadearound) and three staffpharmacists.We had no doubt that the task ahead of us was a

daunting one. The main part ofthe book was to containmonographs of every preparation that was on themarket in the United Kingdom arranged in sectionsaccording to their use: gastrointestinal, cardiovascular,respiratory, etc. Each section was to be preceded bynotes on the use of the drugs. For these notes we chosean author and two referees for each section. The authorproduced a draft which was commented on by thereferees, and then the final decision on what was to beprinted was made by the committee. It was a great helpthat my colleagues and I knew personally most of thepeople whom we asked to be authors and referees, andperhaps for that reason we never had any prima donnanonsense.The preparation of the monographs was a much

heavier task than the preparation of the notes forprescribers and presented us with great difficulties.There was always a great deal of information availablefor every preparation, but we were producing ahandbook and we needed to confine the entry for eachpreparation to the information that doctors actuallyneeded in order to make a decision when treating apatient.

In the sping of 1979 I prepared a draft ofone sectionof the formulary, the cardiovascular section. I had helpfrom Dr Linda Beeley, lecturer in my department atBirmingham, who had had unique experience inpreparing drug information which could be called up

BMJ voLuME 306 17APRI 1993

Joint Formulary Committee, 1978-81

Chairman: 0 L Wade.Deputy chairman:, J P KerrFrom the British Medical Association: M Goodman,GM Mitchell, G RTudhopeFrom the Pharnaceutical Society of Great Britain: J EBalmford, C R HitchingsFrom the Department of Social Security: P R Green-field, J P Griffin, B A WillisJoint secretaries: J D J Havard (until Dec 1979), F 0Wells (from Jan 1980) for the BMA; S C Jolly for thePharmaceutical SocietyExecutive editor: G R BrownGeneral editor: A WadeEditorial staff: K B K Davis, Sheenagh M Langtry,Jasmine MillerExecutive secretary: Rosemary L Weston

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In the early 1 950s more powerful drugs were starting to become availablefrom pharmacies

on visual display units in the wards of the QueenElizabeth Hospital. I also had the advantage thatDr Beeley, Sir Michael Drury, professor of generalpractice, Miss Patricia Alesbury, a young pharmacist,and I had recently produced a loose leaf book, Treat-ment,' which contained drug monographs similar tothose I thought we needed for the formulary. It was avery tough job but I had two secretaries, Mrs Boumeand Mrs Stevenson, who took endless trouble to lay outthe typescript in such a way that the monographs didnot look crowded. We were all quite pleased with it.

This draft was examined by my colleagues on thecommittee and was modified slightly. Then the editor,Mr Brown, and his staff produced a mock up in printwhich showed that the information could be presentedin a clear and accessible printed form. By October 1979the committee had thus seen a definitive version of onesection of the new British National Formulary, and itlooked good. From then on, although it was hard workand an enormous amount of detail had to be checkedand rechecked, it was straightforward and copy wasready for the printer by December 1980. The print wasset by computer so that modifications, additions, ordeletions could be made with ease in subsequenteditions. The first edition of the new British NationalFormulary, bound in ultramarine cloth, rolled off thepress for publication and distribution throughout theNHS in February 1981. I received one of the firstcopies off the press, and every member ofthe committeesigned its title page. It is now in the library of theMedical School at Birmingham.

ReceptionThe initial reception of the new British National

Formulary from the media and the pharmaceuticalindustry was hostile and unpleasant. From the mediathis did not surprise me. Journalists who were familiarwith commonly used proprietary cough mixtures andmedicines used in their homes were amazed that mostof them, if they appeared at all (proprietary medicinesadvertised to the public do not appear in the BritishNational Formulary), appeared in small print, anindication of the opinion of the committee that theywere ofdubious value.The Association of the British Pharmaceutical

Industry and the staff of many of the pharmaceuticalcompanies complained that the British NationalFormulary was inaccurate, inadequate, and un-balanced. This harsh criticism was because the

formulary did not meet the requirements laid down bythe Medicines Act for pharmaceutical companies whenproducing official data sheets about the medicines theyintend to market. These requirements were aimed atensuring that data sheets include extensive andcompletely comprehensive information about theproduct. The British National Formulary was not,however, marketing drugs and therefore did not haveto meet the requirements of the Medicines Act. It isable to include in its monographs only such informationas it believes is needed by doctors. It can list someproducts in small print, or express preferences. It isnot bound to acquiesce to the idea that because apreparation has a licence it is necessarily desirable forwidespread use.The drug companies did not like, and possibly still

dislike, the British National Formulary because in thenotes for prescribers a group of preparations such asantidepressant drugs or thiazide diuretics are discussedtogether. This implies, of course, that there is littleimportant difference between the various preparationsand this is anathema to a company that spends a greatdeal of money trying to persuade doctors that itspreparation is the best.The reception of the new book by doctors and

pharmacists was very different. They found it usefuland were pleased with it. In hospitals it was soon seenin the pockets of all house officers and was wellthumbed. General practitioners increasingly used itinstead of the Monthly Index of Medical Specialities.Pharmacists found it an extremely convenient referencebook. Even medical students spoke well ofit and used it.It was appreciated and praised.We published a new edition of the British National

Formulary every six months. To many people thisseemed an extravagant policy but experience hasjustified it. I am sure that if it had not been kept up todate and republished frequently the drug industrywould have done its best to persuade doctors that it wasnot up to date and that they should use the monthlyindex instead of the British National Formulary. In eachnew edition there are 3000-4000 changes. Some ofthesemay be very important: a new product is introduced or apreparation is taken off the market because a seriousadverse reaction is reported, some new warning isneeded, or some dose schedule is changed. Manychanges are minor (at any rate to prescribers): achange in size or colour of tablets, a small change informulation, or a change in the name of the manu-facturing company or in the price of a preparation.

Every section of the notes for prescribers was revisedover each period of two years, with changes in theauthors and referees if appropriate. There wereinnovations. At the request of the Committee on Safetyof Medicines yellow cards were included in the book sothat doctors might more easily report their suspicionsthat a drug might be causing adverse reactions. Withthe help of the Royal Pharmaceutical Society guidancewas included concerning the written instructionswhich were to be given to patients when their medicineswere dispensed by their pharmacist. After a battle withthe Department of Health and Social Security andmuch encouragement from my wife, who is a dentist,a version of the formulary was prepared every twoyears for dental surgeons and is much appreciated bythem.

It was a problem to keep the British NationalFormulary as a handbook. There were always requeststhat i-nformation should be included which was moreappropriate for a textbook than for a handbook. Therewere continued arguments about the best way toindicate the cost of drugs. The committee believed thatdoctors needed to be able to compare the price ofpreparations that are used for similar purposes, such asthe many tranquillisers, analgesics, or diuretics that

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are available. For this purpose we gave the cost of 20tablets of each preparation. But we had to admit thatthis might be misleading, for it is difficult to comparethe cost of ordinary tablets of a drug with that of slowrelease tablets which, although much more expensive,only require one to be taken each day. Some peopleasked that we should give the cost of a week's treatmentwith the various preparations, although the problem ofdoing this is that the dosage for different patientswould differ, and any average dosage which we mightuse in calculating the weekly cost would be ratherarbitrary. We felt it was better to keep to the presentsystem, the accuracy ofwhich cannot be questioned.

ConclusionThis rebirth of the Bnitish National Formulary was a

wonderful example of what a small team can achieve,and it showed how effectively doctors and pharmacistscan work together. I like to think that we went a littleway along the road to heal a breach between the twoprofessions, which, in one way or another, has existedsince 1518, when the physicians separated themselvesfrom the apothecaries and Dr Linacre, physician toHenry VIII, founded the Royal College of Physicians.

The members of the Joint Formulary Committeemet initially as professionals but, as we workedtogether, we developed deep mutual respect and closepersonal friendships. We all felt that we were superblyserved by the editorial staff, led first by the late RonBrown and then by Anne Prasad, both of them totallyprofessional and dedicated to the formulary. We feltthat we were doing something really useful for ourprofessions and through them for patients, and wewere happy in our work. Would that other committeeswere as worth while to sit on.

I retired in 1984 after the 12th edition. The 25thedition may not have increased much in girth, but Ithink everyone will agree that it has grown in stature. Iwish it well for its next 25 issues.

This article draws on a talk given to the Department ofClinical Pharmacology at the Universitat Autonoma deBarcelona.2

1 Drury VWM, Wade OL, Beeley L, Alesbury P. Treatment. A handbook of drugtherapy, London: Kluwer Medical, 1978.

2 Wade OL. El formulario Nacional Britanico. Avances en Terapeutica 1992;16:204-10.

(Accepted 4 February 1993)

Hammersmith StaffRounds

Chronic liver disease due to hepatitis C

Difficult to diagnose and treat

Royal PostgraduateMedical School,Hammersmith Hospital,London W12 ONN

Case presented by:S Levi, senior registrar ingastroenterologyC Foster, senior lecturer inhistopathology

Chairman:H J F Hodgson, professor ofgastroenterology

Discussion group:KN Ward, senior lecturer invirologyA So, senior lecturer inrheumatologyJA Garson, senior clinicallecturer in virology, UniversityCollege London MedicalSchoolJ Waxman, reader in oncologyD Swirsky, senior lecturer inhaematology

Series edited by Dr MoiraWhyte.

BMJ 1993;306:1054-6

The low concentration of hepatitis C virus in theblood of infected patients has made it difficult todetect. Infected patients can now be identifiedby using more sensitive immunoassays and amplifi-cation ofviral RNAby the polymerase chain reaction.Nevertheless, the virus remains difficult to eliminate.We present the case of a woman with a history ofautoimmune haemolytic anaemia, thrombocyto-penia, and common variable immunodeficiency whodeveloped chronic hepatitis.

Case historyA 36 year old woman was admitted to this hospital

for investigation of abnormal liver function testsresults in March 1991. In 1979 she had felt tired andunwell and was found to have a haemoglobin con-centration of 28g/l with a Coombs' positive auto-immune haemolytic anaemia. This was treated withsteroids and a blood transfusion. She recovered welland has subsequently had negative results on theCoombs' test. In 1983, however, she developedidiopathic thrombocytopenic purpura, requiringplatelet transfusions and a splenectomy. Later thatyear she developed recurrent chest infections, andinvestigations showed panhypogammaglobulinaemiadue to common variable immunodeficiency. This wastreated successfully with immunoglobulin injections,and later with monthly immunoglobulin infusions.

In 1986 the thrombocytopenia recurred and she wastreated with platelet transfusions, steroids, andazathioprine. The following year she developedjaundice, pale stools, and dark urine in addition to apancytopenia. Azathioprine was stopped, and sherequired further blood transfusions. The jaundicecleared in six weeks, but during 1987-91 she continuedto experience malaise and anorexia, with fluctuatingliver function abnormalities.

Examination showed mild jaundice, palmarerythema, and spider naevi but no hepatic encephalo-pathy. Chest examination showed symptoms consistentwith mild bronchiectasis. Her liver was of normal sizeand not tender.

Investigations included a full blood count andcoagulation screen, which gave normal results. She hada low total protein concentration (51 g/l) but a normalalbumin concentration (38 g/l). She was panhypo-gammaglobulinaemic (IgG 4-6 (normal range 5-16),IgA <0 07 (1-25-4.25), IgM 0-08 (0-5-1-8) g/l). Herbilirubin concentration was 76 ,umol (<17), aspartateaminotransferase 209 (< 35) IUll, alkaline phosphatase414 (< 125) IU/1, and y-glutamyl transferase 414 (< 30)IU/1.

Importantly, an autoantibody screen, including anti-bodies to smooth muscle and nuclear bodies, gave nega-tive results. Her serum was tested and found negativefor antibodies to hepatitis A IgM, hepatitis B surfaceantigen and core antibody, hepatitis C antibody (firstgeneration test), infectious mononucleosis, and cyto-megalovirus antibody. Ferritin and copper studies gavenormal results and her thyroid function was normal.A liver biopsy showed normal vascular relations,

with some focal necrosis and compensatory hyerplasia.Portal tracts were infiltrated with large numbers oflymphocytes. Mild piecemeal necrosis was present.These features suggested chronic active hepatitiswithout cirrhosis (fig 1).The differential diagnosis included autoimmune

chronic active hepatitis as well as viral hepatitis.Autoimmune chronic active hepatitis would have beenconsistent with the patient's age, sex, and autoimmunehistory, and the negative autoantibody tests could haveresulted from the hypogammaglobulinaemia. Like-wise, viral hepatitis acquired from the multiple bloodproduct transfusions she had received was also areasonable diagnosis, and once again the low circulating

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