30 years in postmarketing surveillance. A personal perspective

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL 2: 239-258 (1 993)

ORIGINAL REPORT

30 Years in Postmarketing Surveillance. A Personal Perspective

BILL INMAN FRCP FFPM Drug Safety Research Unit, Bursledon Hall, Southampton*

KEY WORDS - Drug safety, postmarketing surveillance, Committee on Safety of Medicines, Drug Safety Research Unit.

THE EARLY POST-THALIDOMIDE YEARS

The Committee in Safety of Drugs (CSD), chaired by the late Sir Derrick Dunlop was established as a direct result of the thalidomide tragedy. In 1963-4 a medical secretariat was recruited from outside the civil service, comprising the late Dr Dennis Cahal in overall charge, the late Dr John Broadbent who was responsible for assessment of new drugs prior to marketing and I was made responsible for developing the Yellow Card System. Stephen Hall and Diana Hine looked after pharmacy problems and the Secretary to the Committee, Wilfred Turner, a most experienced and respected civil ser- vant, taught US how to survive and retain a sense of humour in the service. We numbered less than 30 people and occupied a few rooms on the tenth floor of the, long since demolished, Queen Anne’s Mansions near St. James’ Park.

Sub-committees were set up to assess toxicity, clinical trials and adverse reactions. The Subcom- mittee on Adverse Reactions, chaired by the late Leslie Witts, defined the following objectives:

‘(1) To identify drug safety problems. (2) To investigate causality. (3) To establish incidence. (4) To facilitate risk-benefit judgements. (5) To inform prescribers and patients.’

It was clear at a very early stage that the third

*The DSRU is advised by the Drug Safety Research Trust, an independent registered chanty (No. 327206). The Unit oper- ates in association with the University of Southampton. Trus- tees: Sir Douglas Black MD FRCP, Professor D. J. Finney CBE ScD FRS FRSE, Professor C. F. George MD FRCP, Sir Gordon Higginson FICE FI MechE, Professor W. H. W. Inman FRCP FFPM.

objective could not be achieved by spontaneous reporting and the ‘Yellow Card’ scheme was never in fact designed as a method for measuring incidence. The Committee’s ability to achieve the second and fourth objectives was also questionable. Most of the ‘signals’ derived from voluntary reporting could be regarded as nothing more than internal signals, alerting the Committee to the need to initiate follow-up but not necessarily to make immediate judgements.

In 1965, in an attempt to investigate causality, I recruited a team of part-time medically qualified field workers, known affectionately as ‘Derrick’s Dolls’, whose task was to interview general practitioners (GPs) or specialists who had reported suspected adverse reactions (ADRs). This was an expensive but essential stage in the investigation of serious ADR problems which helped the doctor to focus on the key points in a medical history and relieved him of the burden of writing long letters to the Committee.

The yellow card scheme has played a limited part in the decision-making process. I do not measure success by the number of drugs removed from the market, indeed nearly all withdrawals are the result of failure of the licensing system to predict problems early enough. Drugs have been removed from the market at an average rate of about one per year. About one in five withdrawals has been due to toxicity in animals. The first @-blocking agent, pronethalol, for example, was withdrawn because of thymic tumours in mice. About one-third were withdrawn because of concerns about safety which had been debated, sometimes for many years, before the yellow card scheme was started, such as blood dyscrasias with phenylbutazone and allied

CCC 1053-8569/93/04-50239-20 0 1993 by John Wiley & Sons, Ltd.

240 W. INMAN

substances, or which were missed by the system, such as the oculomucocutaneous syndrome with practolol. The yellow cards have played a part in the withdrawal of most of the remainder, perhaps one drug every two years. The two most noteworthy successes, however, did not end in withdrawal but in the development of safer ways of using the drugs.

THROMBOEMBOLISM AND THE PILL

Undoubtedly the most important was the discovery, in August 1966, of the probable effects of certain oral contraceptives on the incidence of thrombosis. It is interesting to look back nearly 30 years to the emergence of a problem which, though it affected only a small fraction of women using the Pill, captured the attention of the media and became a focal point for public and official concern on a scale second only to that of the thalidomide disaster.

Although isolated anecdotal reports of thromboembolism among pill users had appeared in letters to medical journals as early as 1961, the yellow card system provided the first evidence that such cases could be occurring in significant numbers. With the help of Josephine Weatherall of the Office of Population Censuses and Surveys (OPCS) who rushed the mortality figures for the year ending August 31st 1965, I presented a report to the Com- mittee in October of that year. If we assumed that all or most deaths or hospitalizations from cerebral or coronary thrombosis and pulmonary embolism in women aged 15 to 44 years had been reported on yellow cards, there was no large difference between the events that had been reported and those that would be expected in an ‘at risk’ group of perhaps 400,000 women using the pill at that time. Sixteen deaths had been reported where 13 would have been expected from death certification together with 95 serious non-fatal events where 58 were expected from the Hospital In-Patient Enquiry. Obviously confidence in the proposition that all serious adverse reactions actually had been reported was zero and, on the first of January 1966, 1 started a national mortality study to investigate oral contraceptive use in all women who would die in England and Wales during that year.

All women whose deaths were certified in 1966 as due to cerebral or coronary thrombosis or pulmonary embolism, were identified by means of death certificates and followed up by the part-time medical officers who determined whether the dead

woman and several living age-matched controls from the same practice had been using the Pill. A few months later both the Medical Research Council (MRC) and the College of General Practi- tioners (later ‘Royal’ - RCGP) were approached by Leslie Witts and myself and encouraged to set up additional studies. The RCGP’s study in 60 general practices started in July 1966 and the MRC’s morbidity study in hospitalized patients started in December 1966.

In August 1966, I showed my early results to colleagues at the Department and to my mentor the late Tony (Sir Austin) Bradford Hill who confirmed that the relative excess of oral contraceptive use among women dying from pulmonary embolism was significant. Curiously, this same month, 1 had spotted an unexpected relationship between the sales of mestranol-containing products and reports of pulmonary embolism. I had noticed that 13 deaths from pulmonary embolism had been reported among women using mestranol compared with only two among those using ethinyloestradiol, while the ratio of reports of all other types of reaction was 441 to 413 which was believed to reflect the market distribution (x2 = 11.97, P < 0.001). It is important to note, in view of developments in post-marketing surveillance (PMS) discussed later in this review, that I had not been able to make this discovery solely with the facilities available to the Committee at that time. The Pill could only be prescribed privately or through the Family Planning Association and its use could not be monitored through NHS prescriptions. Fortunately I was able to obtain estimates for the use of various products from Intercontinental Medical Statistics (IMS) Ltd. which suggested that the dose of oestrogen might be the key factor.’ Many thousands of women, world-wide, were undoubtedly spared dis- ablement or death by switching, early in 1970, to the ‘Mini Pill’ containing lower doses of oestrogen or of progestogen-only products. I learned that numerators (case reports) are of little use without denominators (persons exposed) and estimates of background rates (population statistics).

Unfortunately, pharmacologists advised that the trend I had observed was more likely to be due to a greater thrombogenic effect of the weaker oestrogen, mestranol. I appreciated that it was generally given in larger doses but I was distracted by the argument that it took twice the dose of mestra- no1 to inhibit ovulation (in rats!) and that chemical differences rather than dose were thought to be the determining factor. It took many months to con-

0 1993 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 2: 239-258 (1993)

THIRTY YEARS POSTMARKETING SURVEILLANCE 24 1

0 1993 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLJJGY AND DRUG SAFETY, VOL. 2: 239-258 (1993)

firm that it was the higher dose of oestrogen, irrespective of its chemistry that was important.* Thus I learned not to undervalue answers to the question, ‘does it happen?’ (the epidemiologist’s approach) and not to be unduly influenced by speculations about ‘why does it happen?’ (the pharmacologist’s approach). Mechanisms can be sorted out at lei- sure.

In the meantime the RCGP and MRC studies progressed and confirmed the results of the CSD study of 1966. In July 1967 there was no longer any reasonable doubt that the Pill was an occa- sional cause of thromboembolism. A joint report was published by an MRC working party which included the authors of the three studies and it was at this stage that I first met Richard Doll and Mar- tin Ves~ey.~ Several years later we persuaded the former to become Chairman of the ADR Subcom- mittee in succession to Leslie Witts and Owen Wade, while I invited the latter to help in the assessment of the data from the CSD’s case-control study which I had completed early in 1967 but was not written up until 196!L4 This was the start of several years’ invaluable collaborative work with Martin and his colleague Jim Mann in Oxford.

Although the CSD received less credit than it deserved for completing the first study to provide evidence that the Pill was a cause of thromboembolism and for persuading other groups to mount their studies, there is little doubt that the yellow cards had proved their value for generating hypoth- eses, and of the need for other systems capable of testing them.

HALOTHANE JAUNDICE

On only one other occasion has it been possible to make sophisticated use of the spontaneous reports. Whether or not jaundice was a complica- tion of halothane anaesthesia had been debated for many years and 130 reports had been sent to the CSM between 1964 and 1972. I noticed that, as the number of exposures to halothane increased, the time-interval between the most recent exposure and the onset of jaundice de~reased.”~ This obser- vation seemed likely to prove for the first time that jaundice could be caused by halothane. It also increased the risk of litigation against those who used it repeatedly for minor procedures. The evidence was contested by anaesthetists, a group of whom wrote suggesting that it was ‘time that Doc- tors Inman and Mushin sought a less-demanding

occupation!’ They were silent later when some of our most severe critics repeated our findings themselves.

No other comparable examples of sophisticated use of spontaneous reports have been published. Of course, there have been many isolated reports on individual patients or small groups of patients where the timing of events or rechallenge experience suggest a cause and effect relationship between drug and reaction.

PROBLEMS WITH THE YELLOW CARD SYSTEM

The proportion of adverse reactions that reach the CSM is unknown. For a quarter of a century, I have been quoted as having said that I believed that perhaps as few as 10% of life-threatening and 1% of trivial reactions are reported to the CSM. This estimate may have been true in the early days of the system but there is now some evidence of more complete reporting of serious reactions to new drugs during the first few months of marketing. The studies by the Drug Safety Research Unit (DSRU), which include most of the patients in Eng- land who could feature in a report to the CSM during the early months, have suggested that the proportion of serious ADRs notified to the CSM may be much higher, perhaps approaching 50-70%.

Although estimates for the total use of a drug are available from the Prescription Pricing Auth- ority (PPA), it is not usually possible to calculate the denominator. For example, one cannot deter- mine if 12,000 prescriptions have been given to 1000 patients at monthly intervals for a year or to 12,000 patients for one month only. This is because the PPA does not record the patient’s name on their computer. With spontaneous reporting the precise denominator is always unknown; only by some form of record linkage system such as the Value Added Medical Products (VAMP) database or Pre- scription-Event Monitoring (PEM) is there any chance of measuring incidence. Because of the difficulties in confirmation of causality and the mea- surement of incidence, the yellow card system has proved to be of only limited value in risk-benefit judgements.

BARRIERS TO COMMUNICATION

I am sure that the conditions for drug safety monitoring were easier during the years which preceded

242 W. INMAN

the Medicines Act of 1968 (which became effective in September 1971) and I wonder if the close liaison with outside bodies and individuals which we enjoyed before the passage of the Act would be possible today. There were few restrictions on the release of information gathered by the secretariat on behalf of a truly independent Committee, the main ones being the self-imposed wish to avoid public alarm through premature or misguided pub- licity. Active feedback to medical colleagues was encouraged.

In the sixties the work of the Committee was conducted informally. The industry collaborated on a voluntary basis. The three doctors who com- prised the secretariat had been recruited by Sir Der- rick on the understanding that our loyalties were to be to the Committee rather than to political masters and that we would be free to communicate with colleagues outside the Department. After the Act became effective in September 1971, we reported to lay administrators and freedom to con- sult externally or to publish the reasons for decisions by the Committee was severely restricted.

In 1986, in an attempt to enhance the use of yellow cards, the DSRU launched a ‘Red Alert’ scheme in collaboration with the CSM. The scheme was unpopular with the pharmaceutical industry from the start because (quite correctly) it cast doubts in the minds of potential prescribers about the safety of new drugs from the moment of licensing. Special yellow cards, overprinted with a red triangle and with sprocket holes to enable them to be printed on the DSRU’s computer, were issued to all prescribers of four drugs undergoing PEM. One card was printed for each named patient. It was intended that they should be kept in the patient’s notes and used only if an adverse reaction was suspected. All incoming reports were immediately re-routed to the CSM by the DSRU. Tempor- arily the flow of reports to the CSM was greatly increased. The Red Alert scheme could have enhanced our mutual ability to identify problems at an early postmarketing stage. It foundered however, because we were unable to cross-check un- modified yellow cards sent directly to the CSM with PEM follow-up questionnaires (green forms), even though the patients were all included in the cohort already identified by the DSRU. Had a problem arisen with any of these four drugs, the confidentia- lity of reports to the CSM could have seriously delayed its recognition and assessment.

ADVERSARY SCIENCE

Hammond and Joyce have shown how, in government departments the world over, scientists and policy-makers tend to exchange roles.7 The scientist feels he has a duty to assist the policy-maker and becomes drawn into the decision-making process. He is invited to join expert committees and even enjoys the impact of his advice on policies. Very soon he becomes an amateur policy-maker. The policy-maker on the other hand may start with no preconceived notions of science but rapidly assimi- lates the facts and figures given to him by the scientist. He starts to argue with the scientist because he believes he understands the social and political implications of what he has learned better than the scientist. He may organize expert committees in order to widen the range of advice and select the views that his political masters would like to hear. The scientist has become an amateur policy-maker and the policy-maker an amateur scientist. They have exchanged roles and nobody has benefited from this exchange! Hammond and Joyce drew attention to the dangers of increased conflict between scientists - adversary science - where research teams compete with each other in a ‘science court’, or sometimes a real one.’ They wrote in 1977:

‘Members of the pharmaceutical industry, medical profession and scientists should observe the situation carefully: it is a portent of things that may come in the field of drug regulations. The use of a science court and the adversary science that will accompany it is a tragedy because it involves scientists in a perversion of science - namely deliberate bias. ’

As an example of how these predictions may have come true, I will illustrate them with the ‘Opren’ affair.

OPREN

That ‘Opren’ (benoxaprofen) would accumulate in the tissues of patients with declining renal function and eventually damage the liver, was entirely pre- dictable from a knowledge of its pharmacokinetics. The implications of the long half-life of the drug on its elimination in patients with renal impairment and the likelihood of secondary hepatic involve- ment were well known at the time benoxaprofen was first marketed.8 Prior to 1980, when I left the


243 THIRTY YEARS POSTMARKETING SURVEILLANCE

CSM, attendance at meetings sponsored by the drug industry was discouraged and it is possible that this incident came about because nobody from the secretariat was permitted to attend the 15th International Rheumatology Conference in Paris in June 1981 at which no fewer than 25 papers on benoxaprofen were presented, 15 of them authored or co-authored by Lilly employees. They included six papers on pharmacodynamics includ- ing one from France describing the dynamics of benoxaprofen in patients with impaired renal function. There were warnings of the risks of accumu- lation in elderly patients. Hamdy et al., for example, reported that:

‘These findings may have profound therapeutic implications as it may be sufficient to administer benoxaprofen to elderly patients less frequently or in lower doses with good therapeutic result^'.^

After this symposium, very clear warnings were incorporated in the company literature in Sep- tember 1981. In the following months hundreds of yellow cards, mostly reporting the well-known side- effect of photosensitivity, poured into the ADR office. I was told later that the clerical staff had been instructed to deal with the cards in a routine way, rather than to set aside reports of well-known reactions such as photosensitivity and give priority to assessment of reports of unfamiliar reactions such as jaundice. Thus the lesson of ‘triage’ - sort- ing reports into minor reactions, serious but recognized reactions and unusual reactions (the latter for immediate field investigation) - seemed to have been ignored. Months passed until May 8th 1982 when a journal letter reporting five deaths and knowledge of a sixth, noted that all six patients treated with benoxaprofen had died of jaundice.” This was the start of escalating concern in the media, parliamentary questions and pressure on the CSM, culminating in withdrawal of the drug in August 1982.

The DSRU at this stage had been conducting its first PEM study and by coincidence this was a comparison of benoxaprofen and fenbufen. We have been accused of having missed the jaundice problem. The truth is that a few days before the drug was withdrawn, I was in Indianapolis sharing the early results of the DSRU study with Lilly man- agement and expressing concern about the eight cases of jaundice that we were currently investigat- ing. I had reported them to the CSM and I did not feel at the time that a separate public statement by the DSRU was justified, especially since the fol-

low-up had not been completed. We were over- taken by the withdrawal of ‘Opren’ a few days later but went on to extend our study to include 24,000 patients. We investigated 54 cases of hepatic or renal failure. Only one non-fatal case was con- sidered to have been definitely related to benoxaprofen and there was a remote possibility in a few other cases.

Neither of the two national systems (yellow cards or PEM) suggested a risk of fatal liver failure greater than about one in 25,000 and then only in elderly patients treated with large doses. I have always held the rather unpopular view that the removal of ‘Opren’ was inappropriate and robbed some patients of treatment which was sometimes highly effective. All that was necessary was to warn against sun exposure and advise care with the dosage of elderly patients or those with suspect renal function.

THE DRUG SAFETY RESEARCH UNIT (DSRU)

In 1974, a serious problem occurred with the p- blocking drug practolol. It was discovered that it caused an ‘oculomucocutaneous syndrome’ leading in some cases to severe skin reactions, blindness, deafness or even death.’’ Although several thousand severe reactions occurred before astute skin and eye specialists identified the problem and published their observations, only one report of a minor eye reaction among the first 100,000 patients had been sent to the CSM. The yellow card system had failed to identify this problem because doctors did not recognize these events as signs of toxicity. Individually commonplace events such as skin eruptions resembling psoriasis, dry eye or deafness, did not stimulate thoughts about drug reactions even though the same patient may have developed several of the reactions simultaneously. New methods of monitoring were needed and after the practo- lo1 experience I became intensely preoccupied with the search for them.

I pay tribute here to the late Franz Gross of the University of Heidelberg who tirelessly campaigned for improvements in drug monitorihg in the ’70s and who was largely responsible for organizing a conference at the East-West Centre in Hawaii in January 1977. This was a turning point in recognition of the importance of postmarketing surveillance and I was given an opportunity to develop my ideas for ‘Recorded Release’ of new drugs.


244 W. INMAN


The resulting book of the conference which we jointly edited and my much larger textbook which was modelled on it, laid the foundations on which the DSRU was to be built three years

The idea behind Recorded Release was that new drugs would be granted some form of provisional licence which would permit doctors to prescribe them on condition that a report on each patient’s subsequent progress would be sent to the CSM. Recorded Release would utilize the potential of the Prescription Pricing Authority (PPA) to identify large groups of patients by means of prescription forms and would develop the concept of ‘event monitoring’ proposed by Finney 13 years earlier.I4

After several modifications the scheme was presented to the Department but was rejected on grounds of complexity and expense and also, probably because it was thought likely to increase the difficulty experienced by companies marketing new products in the United Kingdom. Had it been adopted, it would have prevented the problem of promotional ‘pseudo-PMS’ that I shall describe later but it would have encountered other major difficulties.

In retrospect, I believe Recorded Release would have required legislation before it could have been operated effectively by the Department. The CSM had always maintained that research was outside its remit and beyond the capabilities of the Depart- ment. It saw its role and that of its officials as advi- sory and its responsibility to encourage the initiation and financing of external research by independent bodies. I believed that only minor improvements could be made to the voluntary spontaneous reporting system and so in 1980, at the invitation of Professor Donald Acheson, Dean and founder of the Medical School in Southamp- ton, who was later to become the Chief Medical Officer, the Unit was set up at the University. For finance it depended on pledges of ‘no-strings’ support from a number of pharmaceutical companies and a grant arranged by the office of the Chief Scientist at the Department. It was known at first as the Post-marketing Drug Surveillance Research Unit (abbreviated to DSRU).*

In 1986 the Unit was reconstituted as a charity (No. 327206) and also renamed the Drug Safety Research Unit (retaining the ‘DSRU’) because of

*Not to be confused with the Post Marketing Surveillance Unit set up later by Intercontinental Medical Statistics (IMS) Ltd. to conduct studies for the pharmaceutical industry.

the emotive overtones of the word ‘surveillance’. The DSRU is advised by the Drug Safety Research Trust. The trustees are Sir Gordon Higginson, the Vice-Chancellor, Sir Douglas Black, a Past Presi- dent of the Royal College of Physicians, Professor David Finney, a founder member of the CSM’s adverse reactions Subcommittee, Professor Charles George, Professor of Clinical Pharmacology and Dean of Medicine at the University, and Professor William Inman, the Director of the DSRU, for- merly the CSM’s first Medical Assessor of Adverse Reactions.

The DSRU had four objectives:

(1) To establish a second nationwide drug safety screening programme called Prescription- Event Monitoring (PEM) in collaboration with the Prescription Pricing Authority.

(2) To conduct epidemiological investigations into specific drug safety problems on a local or national scale.

(3) To develop training and conference facilities. (4) To study methods for improving the public’s

perception of the balance of drug risks and benefits.

With varying success, progress has been made towards achieving all four of these objectives. Pre- scription-Event Monitoring (PEM) has become the largest national scheme for surveillance of new drugs anywhere in the world, involving 4/5ths of the general practitioners who care for the population of about 50,000,000 people in England. PEM has not been developed in the other three countries of the United Kingdom which have their own arrangements for processing NHS prescriptions. Because prescriptions for selected drugs written by all general practitioners in England are collected by the PPA, PEM gives the most rapid access to the largest possible number of patients. However, it has to be limited to about 10 new drugs at any one time.

Several ad hoc hypothesis-testing studies have been successfully completed, the most noteworthy being the one, already referred to, which demon- strated the safety of mianserin when depressed patients overdose. Others have investigated jaundice with erythromycin, oesophageal ulceration with emepronium, persistent photosensitivity after benoxaprofen, suicide after fluoxetine etc.

A start has been made in training. One member of the staff, Nigel Rawson gained his PhD and we have arranged for several home and overseas students to work in the Unit. In 1985 the University

THIRTY YEARS POSTMARKETING SURVEILLANCE 245

recognized my work with a personal chair in Phar- macoepidemiology, believed to be the first with this title in the world.

Finally, the DSRU has acquired a reputation for accessibility and has published a number of papers on the risks and benefits of drugs. It has not, however, been possible to assemble the resources required for a major effort in communications research. Possibly the recently proposed Medicines Benefit Risk Foundation would be better placed to undertake this function.

The DSRU maintains its independence from the pharmaceutical industry by avoiding contract studies. Decisions about research priorities are made by the Unit and not the manufacturer concerned. The selection of drugs for study usually depends either on whether they are new chemical entities with unknown toxicity potential or drugs with safety problems which have already been recognized during clinical trials or marketing in other countries. On completion of each study the DSRU looks to the manufacturer to provide adequate funds retrospectively on a strictly non-profit basis consistent with its status as a charity. Currently it receives no government funding.

PROMOTIONAL STUDIES

Promotional studies may add over Slm to the cost of introducing a new drug without adding to our knowledge of its safety or efficacy. Recently Waller and colleagues from the Medicines Control Agency (MCA) and the CSM, in an analysis of 31 such studies, have confirmed that the scientific value of such exercises is marginal.15

The problem created by promotional studies is that they adversely affect the response to independent studies such as PEM and sometimes lead to excessive prescribing of new drugs before their true potential for harm has been determined. In many of the early PEM studies it was usual to expect a response rate of about 70%. More recently, promotional studies or other forms of inducement to prescribe have competed with PEM and have encouraged a minority of doctors to prescribe new drugs for astonishingly large numbers of patients. We have never had any reason to believe that a poor response means that important information is being concealed or that the patients cared for by GPs who do not participate in PEM are in any way different from the majority of patients. Nevertheless, failure to respond has frequently

been a major criticism of PEM and one that has been difficult to research. We have therefore recently completed a massive study of the pattern of prescribing in 27 PEM studies which have involved more than half a million treatments with new drugs.16

We selected more than 28,000 GPs who had been identified during PEM studies in England and we divided them into six groups according to the numbers of patients for whom they had prescribed one or more of 27 drugs. We then studied those characteristics of the doctors themselves which could be ascertained from the Medical Register or Medical Directory, specifically their sex and the year and place of their first medical qualification. Since the ‘quota’ of patients included in commercial studies is often stated to be a maximum of 15 we divided the doctors into six groups according to whether they had either not prescribed any of the 27 drugs or had prescribed one or more of them for up to 15,30,45,60 or for more than 60 patients. The main findings are summarized in Table 1.

Progressing from the first to the sixth group, the proportion of female prescribers decreased from 46% of the non-prescribers to only 9% of the heaviest prescribers. The most recently qualified doctors were the most conservative prescribers, having on average been qualified for about eight years. The doctors in the 60+ prescribing group had been qualified, on average for about 20 years. The most striking difference, however was in the country of qualification. Doctors qualifying in Asia formed only 5% of the group who did not prescribe any of the 27 drugs, the proportion rising to 40% of the group of heaviest prescribers. The proportion of doctors qualifying in Ireland or other non- UK, non-Asian, countries was more or less uniform throughout (8% of non-prescribers and 7% of heaviest prescribers) and it was noted that Asian doctors qualifying in the UK generally followed the UK prescribing pattern.

The prescribing of the 27 drugs was examined individually. The top 10% of prescribers accounted for, on average, 42% of all the patients treated during the early months of marketing (range 32% to 54%) and the top 1% accounted on average for 10Y0 of all treatments (range 6%0 to 15%). The top 10% accounted for a total of 230,000 treatments and the top 1% for 53,000 within the period of between three and 12 months covered by most of the studies.

The reasons why a small minority of doctors qualifying in Asia are responsible for a disproportion-


Tab

le 1

- Se

x, m

edia

n ye

ar a

nd c

ount

ry o

f qua

lific

atio

n

Gro

up

1 2

3 4

5 6

Pres

crib

ing i

n 27

G

Ps w

ho d

id n

ot

Pres

crib

ing

one

Pres

crib

ing o

ne

Pres

crib

ing

one

Pres

crib

ing

one

Pres

crib

ing

one

PEM

stud

ies

pres

crib

e any

or

mor

e dr

ugs

or m

ore d

rugs

or

mor

e dr

ugs

or m

ore

drug

s or

mor

e dru

gs fo

r of

the

27 d

rugs

fo

r 1-

15

for 1

6-30

fo

r 3 1-

45

for 4

6-60

m

ore t

han

60

Num

ber

%

Num

ber

%

Num

ber

YO

Num

ber

%

Num

ber

%

Num

ber

YO

patie

nts

patie

nts

patie

nts

patie

nts

patie

nts

Tot

al N

o. a

nd Y

O

of a

ll G

Ps*

Tre

atm

ents

? and

YO

of to

tal

Mal

es

Fem

ales

N

o. G

Ps sa

mpl

ed

Med

ian

year

of

first

med

ical

de

gree

and

rang

e C

ount

ry o

f firs

t m

edic

al d

egre

e A

sia

Irel

and

Oth

er N

on-U

K

Tot

al n

on-U

K

Uni

ted

Kin

gdom

620 1

Non

e 73

7 63

1 13

68

1980

73

52

56

181

1187

22 0 54

46

1924

-89

5 4 4 13

87

1775

5

3746

25

707

223

930

1972

91

30

13

134

796

63 69

76

24

1933

-90

10 3 1 14

86

3774

8616

8 47

3 48

52 1

1968

181 16

10

207

314

13

16

91 9

1938

-87

35 3 2 40

60

45 1

4519

1 41

0 41

45 1

1968

139 19

10

168

283

2 8 91 9

1932

-88

31 4 2 37

63

125

1558

2 11

7 8 12

5

1967

44 3 2 49

76

0.4 3 94 6

1937

-86

35 2 2 39

61

126

2222

2 11

5 11

126

1968

50 6 2 58

68

0.4 4 91 9

3 e

1942

-82

40 6 2 47

53

-

*28,

402 G

Ps (E

ngla

nd o

nly)

. ?O

nly

the

first

of p

ossi

bly

seve

ral p

resc

riptio

ns f

or an

y on

e dru

g is

incl

uded

. The

sam

e pat

ient

may

rece

ive m

ore

than

one

dru

g at

the

sam

e or

diff

eren

t tim

es.

THIRTY YEARS WSTMARKETING SURVEILLANCE 241

ately large volume of prescribing are not completely clear. We suggested that, in the medical schools in which they trained, they way have been unable to prescribe expensive western medicines or they may have been less well-briefed about the questionable methods employed to sell them in this country.

I will not attempt to discuss all of the data we obtained on prescribing of the individual drugs. Those who read the original article will have little difficulty identifying the drugs that were heavily promoted or subjected to promotional ‘PMS’. We concluded that:

‘No differences in medical need can account for such variations in prescribing practice. Heavy prescribing by a minority of doctors during the period immediately following licensing for marketing may be placing patients at unnecessary risk’.

The recommendations by the CSM that postmarketing surveillance should be applied to all new drugs, while highly desirable in theory, had the unfortunate effect of opening the floodgates to pseudo-scientific promotional ‘PMS’, so much so that the true meaning and purpose of PMS has been lost sight of.

Our concern about the results of the prescribing survey were submitted to the Department of Health and the Minister, Dr Brian Mawhinney who wrote:

‘The Government is concerned by your data which have shown that, over the past few years, some doctors have prescribed new medicines for large numbers of patients in postmarketing surveillance (PMS) studies, and agrees that this is undesirable.

Initiatives in three areas are, we believe, capable of addressing the problems. Firstly the intro- duction of prescribing, analysis and cost (PACT) data and appointment of family health services authority’s (FHSA’s) prescribing advisers has meant that significant overprescribing is now being identified and action taken against persistent offenders. PACT data are currently being improved with a view to highlighting use of new drugs. Secondly, proposals for revising and strengthening the existing postmarketing surveillance guidelines are under discussion. One of the proposals is to place a limit on the number of patients that may be entered into a study by a single doctor. Other measures are designed to improve the scientific value of PMS studies and minimize promotional aspects. Finally the EC

Advertising Directive is presently being imple- mented into UK law and will provide controls on inducements to prescribe. Thus there will soon be a statutory basis on which action will be taken against those who offer or accept inducements to prescribe. We shall be monitoring the effects of these measures on the problems you describe’. This is encouraging if it puts an end to the prac-

tice of buying prescriptions under the guise of PMS but it still does not address what I believe to be one of the main issues raised by promotional studies. This is the moral and ethical responsibility of doctors to inform the patient of the reasons behind any change of treatment and the involve- ment of the patient in a choice of whether or not to participate in a postmarketing study.

PRESCRIPTION-EVENT MONITORING (PEW

The development of PEM can be divided into three phases. From 1980 to 1985 the first 14 studies helped us to develop the method and establish a highly satisfactory relationship with general practitioners. The drugs studied during this period are indicated by a single asterisk in Table 2. The Pre- scription Pricing Authority (PPA) has the capacity to provide prescriptions for PEM for 10 drugs at any one time. This number is probably as much as general practitioners can adequately monitor. During the first phase of PEM, studies of terazosin, betaxolol, gemiibrozil and auranofin failed. The use of these four drugs was so limited and the number of patients so far short of the number required for a useful cohort, that they were abandoned in order to free ‘slots’ for studying other drugs with wider use. More recently the same problem has been experienced with ramipril, enoxacin, and isradipine and two other drugs, xamoterol and flosequinan, were withdrawn from the market. On other occasions we have aborted studies in order to accommodate other more important drugs, usually because there was already wide experience of their use or because their prescription status was changed. Several benzodiazepines, for example were placed on the limited list after we had started to work on them.

The second phase from 1985 to 1990 was charac- terized by stabilization of the technique and greater experience in the analysis data. During this period we learned the value of comparing the rates of

0 1993 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 2 239-258 (1993)

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events with related drugs and with estimates of baseline rates from the very large and increasing population of patients in PEM studies. We decided to standardize the studies in such a way that the collection of records covered a fixed six-month period in order to raise signals as soon as possible after the drug had first been marketed. For anti- infective agents used only for short periods, we frequently commence studies within two or three months, while at the other extreme, studies of the hormone replacement drug, tibolone, the hypolipi- daemic agent, simvastatin and the new treatment for prostatic hypertrophy, finasteride, are regarded as long-term studies where the forms will be sent to doctors several years after the start of treatment. The timing of these studies has not yet been decided but could be five or more years.

The third phase has been greatly accelerated by the expertise in microprocessing of one of our overseas colleagues, Dr Kiyoshi Kubota, who has suc- ceeded in a very short time in co-ordinating the mathematical procedures which will be described below, in developing a comprehensive dictionary of events and a number of other sophisticated pro- grams for analysing the vast collection of data that has accumulated.

Most general practitioners are now thoroughly familiar with the procedure for completing and returning green forms, but little has been published about the way the reports are processed or the sequence of analytical procedures and follow-up investigations that may be carried out subse- quently.

The procedures include the following: (i) Coding of events. (ii) Analysis of response by general practi-

(iii) Determining the age-sex structure. (iv) Analysing indications. (v) Dosage, duration and co-prescription.

(vi) Efficacy. (vii) Adverse reactions.

(viii) Analysis of the events. (ix) Pregnancy outcomes and congenital abnor-

mali ties. (x) Deaths.

(xi) Detailed study of rare or serious events. (xii) Consultation and publication.

tioners.

Coding Many events are related to the disease being treated rather than to the treatment itself so, to avoid con-

fusion we do not code the indication as an ‘event’ even if it has been mentioned in the section of the green form used to list the events. For similar reasons, unrelated pre-existing diseases are not coded unless an exacerbation occurs. Where the same event occurred more than once, only the first epi- sode is coded.

Recently the dictionary used to code events has been extensively revised. The events are arranged in system-organ classes such as skin or alimentary system and within the classes the events are grouped under high-level terms and within them the individual events are described by low-level terms. When coding the reports the operators choose the term which most closely fits the description used by the practitioner. Where no term can be found the reports are set aside for discussion about the need to create new terms. An extract from the dictionary is reproduced as Table 3.

The data from PEM are stored on an IBM AS- 400 B45 computer with 34 Gb storage capacity and 30 terminals. A bespoke program was developed by Pacific Associates. The system has ‘bolt on’ facilities for additional capacity. For analysis, the data are transferred to one of two IBM PCs with 74 Mb capacity which are Macintosh-compatible and used for almost all the mathematical analyses (‘number crunching’) that will be described in this paper. Most documentation is out on five networked Macintosh PCs, one of which is attached to a wide-screen for desk-top publishing.

Analysis of response by general practitioners The response rate is closely linked to the number and rate of posting of green forms to the general practitioner. The more forms, the lower the response rate. To avoid overloading doctors we are now limiting each mailing to a maximum of four forms. Exceptions are made to this procednre when the overall use of an important drug is low because the disease is relatively uncommon. In such circum- stances the limiting instruction to the computer may be cancelled. An example of a typical response analysis from a PEM study of fluoxetine is shown in Table 4. This study was conducted before the limiting procedure was adopted.

Routinely we prepare ‘league tables’ showing the individual response rates from the 90 FHSA areas and the 11 regional groups. Usually the highest responses are from the rural areas.

0 1993 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOMGY AND DRUG SAFETY, VOL. 2: 239-258 (1993)

250 W. MMAN

Table 3 - Example of event dictionary

Abscess anorectal Diarrhoea Haemorrhage gastrointestinal upper Abscess dental Distension abdominal Haematemesis Abscess liver Dry mouth Hernia hiatus haemorrhage Angiodysplasia colon Dumping syndrome Mallory-Weiss syndrome Anorexia Dysentery Melena Appendicitis Dysentery Oesophageal haemorrhage

Appendicitis Salmonellosis Ulcer duodenal haemorrhage Appendix perforated Shigellosis Ulcer gastric haemorrhage

Ascites Typhoid fever Ulcer oesophageal haemorrhage Bowel obstruction Dyspepsia Ulcer peptic haemorrhage

Bowel obstruction Barrett’s syndrome Haemorrhage oral Hernia strangulated Duodenitis Haemorrhage rectal Ileus Dyspepsia Haemorrhagic diarrhoea

Bulimia Gastritis Haemorrhoids Calculus salivary Heartburn Halitosis Campylo bacter Oesophageal reflux Hepatic failure Candidiasis oral Oesophagitis Encephalopathy hepatic Cardiac achalasia Dysphagia Hepatic failure Cardiospasm Enterocele Hepatitis, jaundice Cheilitis Faecal impaction Bilirubinuria Cholelithiasis, cholecystitis Faecal incontinence Hepatitis infectious

Cholangitis Fissure anorectal Hepatitis infectious A Cholecystitis Fistula colo-vaginal Hepatitis infectious B Cholelithiasis Fistula colo-vesical Hepatitis Colic biliary Fistula gastro-pulmonary Jaundice Gall bladder perforated Flatulence Jaundice cholestatic

Cirrhosis Gastroenteritis Jaundice obstructive Cirrhosis Giardiasis Hepatomegaly Oesophageal varices Gilbert’s syndrome Hernia

Coeliac disease Gingivitis Hernia hiatus Constipation Glossitis Hiccough Cyst pancreas Gum hypertrophy Ileum perforated Cyst peritonsillar Haemorrhage gastrointestinal Inflammatory disease colon

Age-sex structure Some events and treatments are obviously sex- specific, and the computer program takes account of this when calculating rates. Ratios above 1.0 indicate a relative excess of females and below 1.0 a relative excess of males. There is an overall pre- ponderance of females, especially in the older age- groups. The female to male ratios average 1.6 and are shown in Table 5. A relative excess of males was noted with diltiazem (angina) and a small excess with xamoterol (heart failure), nizatidine and famotidine (peptic ulcer) and nedocromil (asthma).

Indications It has sometimes proved difficult to distinguish the true indication from some other condition linked with it. For example we have seen obesity given

as the indication for antidepressive therapy. Simi- larly a road traffic accident has been given as the indication for an NSAID, rather than the injuries caused by it. We have occasionally seen a well- known side-effect of a drug exploited as a treatment. Patients with Raynaud’s disease or chilblains have benefited from vasodilation produced by nicardipine.

Dose, duration and co-prescription Information about the dose is obtained either from the prescription forms or, less frequently, from the green forms, particularly when dose-changes are linked with side-effects. For the duration of treatment we rely mostly on the green form, sometimes supplemented by the repeat prescriptions. PEM is particularly suitable for long-term studies because of the ease with which repeated follow-up can be


THIRTY YEARS POSTMARKETING SURVEILLANCE 25 1

Table 4 - Proportion of forms returned during study of fluoxetine

Number of Number of Number of Number of Percentage

Der doctor returned returned patients doctors patients forms of forms

1 2 3 4 5 6 7 8 9

10 11-20 2 1-30 31-40 41-50 50 +

Totals

4418 1613 118 434 290 172 143 117 81 78

336 67 12 4 3

8546

4418 3226 2334 1736 1450 1032 1001 936 729 780

4746 1565 420 175 190

24738

3111 2194 1510 1072 870 61 3 603 539 314 337

2366 637 167 33 78

14444

70 68 65 62 60 59 60 59 43 43 50 41 40 19 41 58

Table 5 - Female to male ratio for 34 drugs

Drug FIM Drug FIM Drug FIM ratio ratio ratio

Fluvoxamine Fluoxetine Paroxetine Buspirone Flunitrazepam Zopiclone Diltiazem Nicardipine Amlodipine Isradipine Doxazocin Betaxolol

2.5 Xamoterol 0.9 Acrivastine 1.7 2.4 Enalapril 1.1 Cetirazine 1.4 2.1 Lisinopril 1.2 Loratadine 1.3 2.1 Ramipril 1.2 Nedocromil 0.9 2.1 Etodolac 2.0 Terodiline 2.6 1.9 Nabumetone 2.0 Acyclovir 1.7 0.7 Tenoxicam 1.9 Cefixime 1.5 i .o Nizatidine 0.9 Enoxacin 4.8 1.1 Famotidine 0.9 Fluconazole 16.0 1.4 Omeprazole 1 .o Itraconazole 8.2 1.2 Cisapride 1.4 Average for 34 1.3 Misoprostol 1.7 drugs 1.6

conducted. The procedure for multiple contact with the doctor is very simple. It is usually advantageous to send a photocopy of his first green form, to remind him about the case and reduce the risk of time-wasting repetition of details that have already been reported. We use multiple-contact studies sparingly and selectively in order to minimize the workload on general practitioners. Normally this would be limited to situations in which a specific risk was being investigated, for example we investigated reports of photosensitivity by repeat follow- up with the specific aim of determining whether or not permanent photosensitization might have occurred. In the case of current investigations of

anticonvulsants, secondary follow-up will be limited to those patients who remained on treatment six months after the initial prescription.

Most information about concurrent therapy is derived from a systematic random sample of 1000 prescriptions (about 10%). We do not have the resources to code all the information that could be extracted from the forms. Arrangements are currently being made with the PPA to process all prescriptions directly on their computer rather than transfer them manually to ours by means of photo- copies. By the end of 1993 four of the PPA’s 11 divisions will have ‘converted’ to this system and the remaining seven will do so, hopefully in 1994.

0 1993 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOU)(;Y AND DRUG SAFETY, VOL. 2: 239-258 (1993)

252 W. INMAN

This may improve the collection of co-prescription data.

A major advantage of PEM over other methods is that it identifies all the patients who are exposed to the drug during the early postmarketing period in the whole of England. Even if the practitioners do not respond to the first approach, the patients could be traced through the Family Health Service Authority (FHSA) if important problems arose at any time in the future.

Escacy Although subjective, we believe the answers given by the majority of doctors do reflect the value of the drug fairly accurately and they correlate well with the information given about the duration of treatment. Future development of PEM may pay more attention to efficacy, which I believe has been neglected in postmarketing studies. Most drugs are extremely safe but some are not particularly effective and greater appreciation of the fact that resources are limited increases the need to measure benefit as well as risk. This is particularly true of long-term benefit which is not measured in clinical trials because of the commercial pressure to market a new drug as soon as the authorities can be persuaded to release it. PEM could provide a wealth of data on long-term benefit and especially on survi- val and quality of life.

Adverse reactions We record events that are suspected to be adverse reactions to the monitored drug or to other drugs administered concurrently and we also note if they have been reported to the CSM. Many events that are suspected to be adverse reactions are not confirmed by follow-up.

Analysing the events The first stage in any PEM analysis is the preparation of a full list of all events reported on the green forms, An example is shown in Table 6. All the events experienced at any time after the first prescriptions are listed in the right-hand column, irrespective of whether or not the patient was still taking the drug. The events in each of the first six months are listed separately and the total number of events during the first six months is shown in the left-hand column. Separate denominators are shown for males and females.

The next step in the analysis is to compare the data with those obtained in other studies of related and unrelated drugs. We usually start by comparing the rates of events which occurred in one or more per thousand patients during the first month of treatment (we refer to this as time-period T,) with the average rates for the same events calculated for other similar drugs and with pooled data from about 30 other studies. Table 7 shows such a comparison for the calcium channel blocking agents and the pooled data from 34 studies. The first month rates for ‘rash’ and ‘flushing’ are shown in this figure, the latter being a well-known side-effect. The ‘pool’ includes most of the PEM studies completed since 1985.

In Table 7 it can be seen that the rate of rash with diltiazem, although only 6.4 per thousand, is actually the highest recorded in all 34 studies. In contrast the now well-recognized side-effect of flushing is very low with diltiazem and appreciably higher with the other three calcium channel blocking agents. Several doctors in the nicardipine study had started female patients on ‘HRT’ believing them to be suffering ‘hot flushes’! The figures for isradipine should not be relied on because of small numbers. Recently we have included the median and percentiles in the calculations in order to enhance the sensitivity of the analysis and these are also shown in Table 7.

Adverse reactions tend to occur early, most com- monly during the first month after the initial prescription. Although many different comparisons are possible, one of the most useful is the comparison of the rates of events during the first month of treatment (T,) with the average rates for the same events during the subsequent follow-up period (T2), irrespective of whether or not treatment is contin- ued.

Experience has shown that, where the rate ratios (TI/T2) exceed 3.0, the events are likely either to be the result of a reaction to the drug, or a sign or symptom of the disorder being treated. Some- times, the rate during the period T2 is reduced as a result of successful treatment. For example, the frequency of headache may diminish as a response to an analgesic.

In Table 8 the rate ratios for the four drugs may be compared with each other and with the average rate ratio for all the drugs. Signals for rash are raised by diltiazem and nicardipine but the ratios for the other two drugs are below the average for all drugs. All four drugs raise signals for flushing.

We do not believe that formal tests of statistical



Table 6 - Example of six-month list: skin events with diltiazem

Event Mth 1 Mth 1 Mth2 Mth3 Mth4 Mth5 Mth6 Total to 6

Total Males Females Using at mid-point of month % using at mid-point Skin

Acne Alopecia Cyst sebaceous Dermatitis Dermatitis contact Dry skin Eczema Eczema varicose Eruption bullous Erythema Fixed eruption Folliculitis Granulomatosis Haematoma nail Hair change Hair loss Herpes simplex Herpes zoster Hyperkeratosis Infection Lichen planus Molluscum contagiosum Nail change Onychomycosis Photosensitivity Pigmentation Pressure sore Pruritus Psoriasis Purpura Pyoderma gangrenosum Rash Scabies Seborrhoea Tinea Ulcer Ulcer varicose Urticaria Vitiligo

Total

10111 6000 397 1

2 1 3 6 4 6

20 2 1 4 1 1 1

1 2 1

22 1

37 1 1 7 1 1

2 39 8 1 1

135 1

3 4 2

13

336

-

-

-

-

10111 m 397 1

5 1

10 18 6

13 59 9 2 6 1 1 2 1 2 6 5

55 6

82 3 1

11 4 4 2 4

73 13

1 1

210 1 5

17 14 6

21 1

682


254 W. INMAN

Table 7 - Rates for rash and flushing during the first month of treatment with calcium-channel blocking agents

Event Median percentiles Average SD Range DTZ NDP ADP IDP 25th 75th Min Max

~~~~~~~

Rash 2.4 1.5 2.8 2.4 1.2 0.7 6.4 6.4 2.9 1.5 3.8 Flushing 0.2 0.1 1.2 2.2 6.8 0.0 36.4 1.7 17.4 7.6 36.4

DTZ = Diltiazem, n = 10,099. NDP = Nicardipine, n = 10,906. ADP = Amlodipine, n = 12,967. IDP = Isradipine, n = 3,678.

significance should be applied to non-experimental studies in which the denominators may be incom- plete (e.g. when a doctor has failed to record an event).

When an event is a serious one which is unlikely to escape the doctor’s notice such as a fracture, the monthly recording rate tends to be fairly con- stant (i.e. the rate-ratios approach unity). Minor events on the other hand are often under-reported during the second and subsequent months. One reason for this is that the patient does not see the doctor so frequently when he or she visits a surgery merely to collect a repeat prescription so there are fewer opportunities for the doctor to record these minor events.

Figs 1 and 2 illustrate how a rate-profile may reflect a well known adverse reaction or a pre- viously undetected and unexpected one. Fig. 1 shows the well-known side-effect of flushing with the calcium channel blockers nicardipine and amlodipine. Fig. 2 shows the expected records of nightmares in depressed or anxious patients or in those using sleeping tablets, but a signal with nabumetone was quite unexpected. Although the incidence was less than one in 1000, when the reports were examined they all told the same story of severe nightmares in patients who normally were unaccus- tomed to them and were quite obviously attribu- table to nabumetone. I do not believe this side- effect has been reported elsewhere.

The number of patients included in PEM studies, usually about 10,000, is sufficient to detect events with a true frequency in excess of about one in

3000 provided the background rate for the same event is low. Rarer events will not be detected by PEM or will be encountered only by chance. Spon- taneous reporting systems such as the CSM’s yellow card system provide the only affordable method for detecting rare ADRs. The rarity of the reactions, however, makes it unlikely that they will be identified during the immediate postmarketing period in the first 10,000 patients who receive the drug in general practice. Spontaneous reports do not enable the incidence of adverse reactions to be measured. If the events that are reported are of a type that has an appreciable background incidence, they are valueless for early warning purposes unless there are unusual features which distinguish them from spontaneously occurring events.

Congenital abnormalities We would normally not follow up less than 50 pregnancies unless there was some earlier concern about possible teratogenicity. Even small numbers of monitored pregnancies, however, might be useful if the data could be shared with other monitoring centres. We have not encountered any evidence of teratogenicity of any of the drugs we have studied.

Deaths In studies of drugs used in predominantly elderly patients we have recorded a death rate of up to 10% per annum. Even though many are due to cancer or cardiorespiratory disease we attempt to

Table 8 - Rate-ratios for rash and flushing with calcium channel blocking drugs

Diltiazem Nicardipine Amlodipine Isradipine Average 34 drugs

~ ~

Rash 4.6 3.2 1.2 1.9 2.6 Flushing 3.7 7.0 5.6 6.4 2.4

~~~~~~ ~


ETODOLAC NAB UMETONE TENOXICAM NlZATlDlNE FAMOTlDlNE OMEPRAZOLE ClSAPRlDE MISOPROSTOL NEDOCROMIL TERODlLlNE

by Mr David -Hands, Chief Pharmacist at the Southampton General Hospital which houses the Wessex Drug Information Service and which pro- vides rapid access to international data. There is no shortage of technical help from the University or from outside experts. We have worked closely with Professor Fred Smith’s Department of Mathe- matics, whose research students have explored

establish the cause of death in all cases. We write to the doctor and secure permission to examine the medical records which have been returned to the FHSA. Usually at least 90% are successfully retrieved, but if necessary the cause of death may be confirmed by obtaining a copy of the death certi- ficate.

Detailed study of rare conditions When assessing serious events with a frequency appreciably below one per 1000 in the first month it is invariably necessary to examine the individual reports and sometimes to write to the practitioner

I


256 W. INMAN

Table 9 - Publications by the DSRU Year Papers Letters to Technical PEM PEM

1980 1 1981 4 1982 5 2 1983 7 2 No. 1 1984 3 4 No. 2 1985 1 1 No. 3 1986 5 4 1 1987 3 2 2 No. 4 1988 6 3 3 No. 5 1989 2 2 5 1990 3 8 No. 6 1991 1 1 5 No. 7 2 1992 1 8 2 1993 1 2 No. 8 6 1980-9 42 24 32 8 10

reviews editor reports News Reports

the statistical rationale behind our signalling methods.”

For 13 years our ability to keep up a steady stream of DSRU publications in step with numer- ous PEM studies has been limited by shortage of funds and staff and we are not satisfied with our output. As can be seen in Table 9 we use five main routes. We publish papers or reviews in scientific journals. We write letters to journals. We distribute technical reports. We discuss our results in our house-journal PEM News, and, recently, we have started to publish monographs in our PEA4 Reports series.

It has proved to be very difficult to get publications accepted in wide-circulation international journals when the news is good. I have often said that most of the drugs we have worked on seem to be ‘boringly non-toxic’. This of course should be good news for patients and prescribers but it does not sell newspapers.

Frequently we have used ‘letters to the Editor’ as a rapid means of disseminating important mes- sages. Such letters may not have the weight of a scientific paper, but they are often circulated by the editor to other colleagues who may have their comments published at the same time. I see little difference between letters and short papers.

Our technical reports have taken various forms, but mainly comprise computer-generated lists of events, demographic and sample data, without interpretation. They have been circulated to regula- tory agencies and the relevant manufacturer but

are not generally available. Their main use has been to draw attention to areas of interest which may be worth further research.

PEM News has proved to be a most valuable outlet. We understand it has been widely read by general practitioners in the United Kingdom to whom it is distributed free of charge and we have a large home and overseas mailing list. With the permission of various editors I have been able to reprint articles which have appeared in other journals or books in order to disseminate ideas about postmarketing PEM News has contained brief summaries of large numbers of studies together with notes about various activities of the Drug Safety Research Trust and the DSRU over the years.

Our new series of PEM Reports comprises monographs on single drugs or groups of related drugs. The presentation of detailed information in these reports is far too detailed and lengthy, frequently running to 50 or more pages, for publication in scientific journals. Wherever possible the event- profiles of related drugs that have been subjected to PEM are compared and contrasted. We concen- trate on positive findings and try not to bore the reader with repetitious references to problems which do not appear to be drug-related or with minute details about individual patients. If, however, there have been reports of certain types of adverse reaction, we occasionally include brief clinical summaries of individual cases in the form of appendices.

0 1993 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLQGY AND DRUG SAFETY, VOL. 2: 239-258 (1993)

THIRTY YEARS WSTMARKETING SURVEILLANCE 257


Available now: In preparation:

No. 1. Nicardipine Acyclovir No. 2. Terodiline* Amlodipine No. 3. Fluconazole Antihistamines No. 4. Ciprofloxacin Bronchodilators No. 5 . Fluoxetine Buspirone No. 6. Paroxetine Cefixime No. 7. Itraconazole Doxazosin No. 8. Cisapride Hrantagonists No. 9. Omeprazole Misoprostol No. 10. Zopiclone Nabumetone No. 11. Lisinopril Quinolones *Drug withdrawn Sumatriptan

We plan, ultimately, to prepare monographs or reports on small groups of related products for all the drugs shown in Table 2, with the probable exception of those marketed before 1985.

DISCUSSION

The latter half of this review has been concerned with the work of the DSRU. Its main strength is its independence and its weakness under-funding. Independence has given it credibility and influence, reflected in the magnificent and sustained response by general practitioners who have collaborated without any thoughts of remuneration. The fact that a minority of prescribers have had a major effect on the overall response assumes lesser importance when it is realized that the response from the modest prescribers who are in fact the majority of doctors has provided a consistent flow of good quality reports.

Even the best commercial studies differ consider- ably in the way their protocols are written, so it is not often possible to compare one set of results with another. In PEM we have standardized the method so that all studies are conducted in the same way. Its value as a means of signalling new problems lies in its ability to provide comparisons of rates and in the consistency of the data.

The House of Lords Select Committee on the European Community*’ recently drew attention to the need for pharmacovigilance in the Community and wrote:

‘(66). In this context we recommend that the Commission considers the use of Prescription- Event Monitoring (as described in paragraph 38) throughout the community. Its method of in- depth analysis of a carefully selected group of

new products on the basis of data from a large random sample seems both effective and well adapted for Community policy’.

So it would appear that a small independent charity, with limited funds, millions of prescription forms and enormous support from thousands of enthusiastic GPs has, against the odds, set the ‘gold-standard’ for postmarketing surveillance for a sizeable fraction of the developed world.

ACKNOWLEDGEMENTS

I would like to thank the Editor of the Lancet for permission to reproduce Table 1 and my immediate colleagues who have made many helpful sugges- tions. Above all I thank thousands of general practitioners who have given me a run for my money over 30 years of enormously satisfying work in developing both national drug-safety monitoring systems, the yellow card scheme and PEM.

REFERENCES

1. Inman, W. H. W. Role of drug-reaction monitoring in the investigation of thrombosis and ‘The Pill’. Bri- tish Medical Bulletin 1970; 26 3: 248-256.

2. Inman, W. H. W., Vessey, M. P., Westerholm, B. and Engelund, A. Thromboembolic disease and the steroidal content of oral contraceptives. British Medical Journal 1970; 2: 203-209.

3. Medical Research Council. Risk of thromboembolic disease in women taking oral contraceptives. British MedicalJournall967; 2 355-359.

4. Inman, W. H. W. and Vessey, M. P. Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of child-bearing age. British Medical Journal 1968; 2: 193-199.

5 . Inman, W . H. W. and Mushin, W. W. Jaundice after repeated exposure to halothane: an analysis of reports to the Committee on Safety of Medicines. British Medical Journal 1974; 1: 5-10.

6 . Inman, W. H. W. and Mushin, W. W. Jaundice after halothane: a further report. British Medical Journal

7 . Hammond, K. R. and Joyce, C. R. B. Psychological influences on human judgement, especially of adverse reactions. In: Drug Monitoring, Gross, F. H. and Inman W. H. W. (eds), Academic Press, Lon- don, 1977, pp. 269-287.

8 . Rainsford, K. D. and Velo, G. P. (eds). Side-effects of Anti-injlammatory Drugs. Proceedings of 2nd International Meeting, 1985 Cambridge. MTP Press Ltd., Lancaster, 1987.

9. Hamdy, R. C., Murnane, B., Perera, N., Woodcock,

1978; 2: 1455-1456.

258 W. INMAN

K. and Koch, I. M. The pharmacokinetics of benoxaprofen in elderly subjects. Second Benoxaprofen Symposium. 15th International Rheumatology Con- gress, Paris, June I , 198 1. European Journal of Rheu- matology and Injammation 1982; 5 2 69-75.

10. Taggart, H. M. and Alderdice, J. M. Fatal cholestatic jaundice in elderly patients taking benoxaprofen. British Medical Journal 1982; 284: 1372.

11. Wright, P. Untoward effects associated with practo- lo1 administration: oculomucocutaneous syndrome. British Medical Journal 1975; 1: 595.

12. Gross, F. H. and Inman, W. H. W. (eds) Drug Moni- toring. Academic Press, London, 1977.

13. Inman, W. H. W. (ed.) Monitoring for Drug Safety, 2nd edn. MTP Press Ltd., Lancaster, England, 1986.

14. Finney, D. J. The design and logic of a monitor of drug use. Journal of Chronic Diseases 1965; 18: 77- 98.

15. Waller, P. C., Wood, S. M., Langman, M. J. S., Breckenridge, A. M. and Rawlins, M. D. Review of company postmarketing surveillance studies. Bri- tish Medical Journal 1992; 204: 1470-1472.

16. Inman, W. and Pearce, G. Prescriber profile and post-marketing surveillance. Lancet 1993; 342: 658- 661.

17. Andrew, J. E., Presscott, P., Smith, T. M. F., Inman, W. H. W. and Kubota, K. Testing for adverse reactions using prescription event monitoring. Personal communication, submitted.

18. Inman, W. H. W. Risks in medical intervention. In: Risk, Man-made Hazards to Man. 35-53. Wolfson lecture January 1984. Cooper, M. G. (ed.), Oxford University Press (Reprinted) in PEM News No. 2, October 1984), 1985.

19. Inman, W. H. W. Side-effects of drugs essay 1985. Let’s get our act together. In: Side Eflects of Drugs Annual No. 9, Dukes, M. G. N. (ed.), Elsevier, Amsterdam (Reprinted in PEM News No. 3, December 1985), 1985.

20. Inman, W. H. W. Prescription-event monitoring. Its strategic role in post-marketing surveillance for drug safety. In: Specialised Strategies in Benefit and Risk Monitoring. Caracas February 1987, Ministry of Health and Social Assistance of the Republic of Venezuela. (Condensed version reprinted in PEM News No. 4, March 1987), 1987.

21. House of Lords: Select Committee on the European Communities. The European Medicines Agency and Future Marketing Authorization Procedures. Session 1991-92,3rd Report HMSO, London, 1991.


30 years in postmarketing surveillance. A personal perspective

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