Case Studies

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Chapter: Pharmacovigilance: Introduction to Pharmionics

The history of adherence/compliance research is fitful, because of inconsistent efforts in clinical research to gather pharmionic data and understand their clinical, economic and, in the case of infectious diseases, public health consequences.


The history of adherence/compliance research is fitful, because of inconsistent efforts in clinical research to gather pharmionic data and understand their clinical, economic and, in the case of infectious diseases, public health consequences. There are, in the history of this field three landmarks that deserve review. They provide a basis for looking ahead at what can now be done with, for the first time, sound methods for compiling and sensibly analysing ambulatory patients’ dosing histories.

The three areas are (a) tuberculosis treatment and the role of directly observed therapy; (b) oral contraception and the problems of widely used but rather unforgiving oral contraceptive products; (c) the prevention of acute rheumatic fever, now an almost forgotten but once major public health problem. These three case studies teach what are probably the most important lessons to learn about clinical consequences of variable underdosing by ambulatory patients.



Patient adherence began to gain awareness in the early 1960s when anti-TB drug treatments were clearly failing because patients did not take the medicines properly, or at all. Several early attempts were made at that time to construct drug containers that could provide audible reminders, and/or compile a record of patients’ dosing, but these were one-off endeavours that never went beyond their developers’ hands.

In the mid-1980s, the problems associated with treating ambulatory TB patients with anti-TB drugs had reached a point that the combination of failed treatment and emergence of multi-drug resistant (MDR) tubercle bacilli were about to unleash an untreatable, exceptionally virulent form of the disease into the general population. The problem of emergent drug resistance is mainly attributable to on-again/off-again dosing that allows the concentrations of anti-TB drugs to pass through a range of concentration within which drug levels are low enough to allow TB bacilli to resume replication, but high-enough to exert selec-tion pressure, so that drug-resistant strains of tubercle bacilli thrive where drug-sensitive strains do not. It is a curious bit of biology that, while MDR tubercle bacilli are more virulent than the ‘wild’ bacilli, the situation with HIV is the opposite, in that the multi-drug resistant HIV is less virulent than the wild strains. Note however that ‘less virulent’ does not mean ‘no virulence’, or that drug-resistant HIV cannot infect or cannot lead to the full-blown acquired immunodefi-ciency syndrome (AIDS).

The New York City Department of Public Health and Mental Hygiene (NYCDPHMH) was particularly beset by these problems in their efforts to control TB, due to the coincidence starting in the early 1980s in increasing numbers of patients with both TB and AIDS, which weakens the body’s defenses against other infectious diseases, including TB. In desper-ation, and with a limited budget, the staff of the NYCDPHMH looked for ways to deal with the loom-ing crisis, and opted in the early 1990s to institute what is called ‘directly observed therapy’ (DOT), in which patients with a confirmed diagnosis of tuberculosis were required, if necessary by force of law, to attend the TB clinic the specified number of times per week, usually 3 or 4, at which times the clinic staff observed their taking of the requi-site doses of anti-TB medicines ( html/doh/html/tb/tb2a.shtml).

This manoeuvre required that individual admin-istered doses of anti-TB drugs be considerably increased, compared to the standard several-times-daily doses that had been in long use. Fortunately, the margins of safety for most of the anti-TB drugs were sufficiently wide to permit the requisite, several-fold escalation in the size of individual doses given on a four-times weekly basis instead of on a twice-/thrice-daily basis. The larger administered dose allows for longer-maintained concentrations of drug in plasma, but drives the post-dose peaks in concentrations higher by several-fold. The ability of the anti-TB drugs to be tolerated in the 3–4-times weekly dosing mode appears to be virtually unique to the field of tuberculo-sis. In contrast, it would be impossible, for example, to make a comparable escalation in administered doses of the present group of anti-retroviral drugs used to treat patients infected with HIV. Nor could one give the usual once-daily doses of anti-retroviral drugs on only 4 different occasions each week and expect them to reduce the HIV count in plasma (usually referred to as the ‘viral load’).

It is noteworthy, however, that, as experience with DOT grew, the doses of some of the drugs were reduced, so that, in the end, patients got less drug than they would have received with full adherence to the conventional several-times-daily dosing regimens. The reduced dose requirements reflect a prevailing tendency to overestimate dosing requirements during pre-market development of drugs, so that some phar-maceuticals enter the market with a recommended dosing regimen that calls for twice or more the dose or dose-frequency than is actually necessary for full effectiveness (Cross et al., 2002; Heerdink, Urquhart and Leufkens, 2002).

Directly observed therapy has turned out to be a remarkably successful addition to the treatment of tuberculosis (Weis et al., 1994; http://www.who. int/mediacentre/factsheets/fs104/en/). It has worked so well that it has been widely adopted, including by the World Health Organization (http://www.who. int/mediacentre/factsheets/fs104/en/). Of course, it is something of a ‘brute force’ approach to the problem of assuring continuity of drug exposure in ambulatory patients, as they have to show up in clinic 3–4 times a week, to be seen to be taking their prescribed anti-TB medicines. As a recent bulletin on the present status of TB treatment from the New York City Depart-ment of Public Health and Mental Hygiene put it: ‘The physician who decides not to place a patient on DOT assumes responsibility for ensuring adher-ence and completion. It is unwise to assume that patients will take medications on their own.’ Those words apply equally well to every instance in which a patient has the responsibility for initiating and execut-ing a prescribed drug dosing regimen throughout the prescribed period of time in any chronic disease situation.

Note that the effectiveness of a DOT programme depends not only on the medicines used, but also on the quality of management of the programme, so that patients can receive their assigned treatments with minimal delay in an efficiently run clinic. The few published studies that report unsatisfactory results with DOT would appear implicitly to be confessing to poor management of the programme.

Several noteworthy features of the DOT process, since its implementation began in the early 1990s, have been (a) a shorter course of treatment with anti-TB drugs, known as DOTS (for DOT-short course); (b) reduction in the number of clinic visits from 4 to 2 per week, with corresponding reductions in the weekly amounts of drug taken, resulting in some reduction in drug-related adverse effects. These changes have made the DOT process easier to manage, more conve-nient for patients, and less expensive than the orig-inal DOT dosing regimen – effects subsumed under the ‘learning curve’ rubric. Moreover, these changes are another example of how recommended regimens for drug dosing can change over time, based on grow-ing experience and careful observation of what works and what does not work when deviations occur from the currently recommended dosing regimen.

Suggested citation for data in this publication: Tuberculosis in New York City, 2003: Information Summary. New York: New York City Department of Health and Mental Hygiene, 2004.



The original oral contraceptive ‘pill’, the combina-tion of an oestrogen and a progestational steroid, was introduced in 1961. Adoption of this revolutionary means of contraception was very rapid, resulting in a high proportion of women, mostly in their first decade of reproductive life, using the ‘pill’, as patients quickly began to call it. Oral contraceptives were the first pharmaceuticals to be used on a long-term basis by normal humans; prior to 1961, pharmaceuti-cals were limited in their uses to short-term treatment of patients with some kind of pathological process underway.

In the latter 1960s, an unexpectedly high inci-dence of strokes, myocardial infarctions and sudden death began to be apparent among users of the contraceptive ‘pill’. These ‘thromboembolic phenomena’ are extremely rare occurrences in pre-menopausal women, which facilitated recognition of their increased incidence among oral contraceptive users. After due consideration, the decision was made to reduce the oestrogen dose by half. The antici-pated result was realized, namely that the incidence of thromboembolic phenomena dropped to levels that, at the time, were not distinguishably different from women who did not use the oral contraceptive ‘pill’.

An unanticipated result of the dosage reduction, however, was a notable increase in the number of unwanted conceptions among women who were using the new, low-dose ‘pill’, compared to the prior expe-rience with the original, high-dose ‘pill’. It was correctly hypothesized at the time that the low-dose, combined oestrogen–progestin oral contracep-tive ‘pill’ was much less forgiving of delayed or omitted doses than was the original high-dose prod-uct. That hypothesis was confirmed during the 1980s  by five studies in which controlled substitution of placebo ‘pills’ for active ‘pills’ was carried out in groups of women who had previously had tubal liga-tions so that they could not conceive, although they continue to ovulate. The key question was ‘how long was it, after a last-taken active “pill”, before ovulation occurred?’

During the 1980s, ovulation could not be visualized directly, as is now possible, but could be inferred from the occurrence of rise in progesterone concentrations in plasma and/or a preceding, sudden sharp rise in the concentration in plasma of the pituitary hormone, luteinizing hormone (LH). This rise in LH levels is referred to as the ‘ovulating surge’ of LH.

The data from the placebo substitution for active ‘pills’ showed that the risk of ovulation begins to rise after about the 36th hour following a last-taken low-dose, oral contraceptive ‘pill’. This finding means that a patient whose usual dosing time is, for example, 7 am, and who, on a particular day misses the usual 7 am dose, will begin to incur elevated risk of ovulation by 7 pm in the evening of the same day. It is therefore possible that ‘breakthrough’ ovulation might have occurred in a patient who missed her usual 7 am dose, but at 11 pm recognized that she had missed that morning’s dose, and then took the missed pill. Obviously, ovulation puts the patient on the pathway to conception. In this scenario, one can see how a patient can have taken 100% of the prescribed doses but still conceive; this scenario also shows how a simple error in dose-timing can nullify the contra-ceptive action of the contraceptive ‘pill’. The notion is clearly wrong that taking 80% or more of prescribed, once-daily ‘pills’ would constitute effective contraception.



Towards the end of the 1950s, acute rheumatic fever was a leading public health problem, not only because of its case fatality rate, but also because of both short-term and long-term consequences of cardiac valve disease, leading gradually to either or both valvular stenosis or insufficiency. The operative theory, then as now, is that acute streptococcal infections can, in some patients, trigger the onset of acute rheumatic fever, as an auto-immune phenomenon, without evident bacte-rial involvement. This sequence suggested a path-way to eliminating acute rheumatic fever and its malign sequelae: prophylactic administration of peni-cillin to prevent the streptococcal infections, thus blocking the basic sequence of events leading to acute rheumatic fever.

To study the effectiveness of this approach, Harri-son Wood, Alvan Feinstein and their colleagues designed and executed a 5-year, 431-patient trial, summarized in (Urquhart, 1993), in which patients who had previously had one episode of acute rheumatic fever were randomized to one of three treat-ment groups: professionally administered, monthly depot penicillin injections, daily oral penicillin, or daily oral sulfadiazine. A placebo group was judged to be unethical. The randomization assured that all three groups had equal representation of any special, disease-modifying or drug response– modifying factors.

The results showed that the depot injections of peni-cillin uniformly prevented both recurrent streptococ-cal infections and acute rheumatic fever. In contrast, in the two oral medication groups, the unsatisfac-tory compliers (who numbered about half of each of the two oral medication groups) had high rates of recurrent streptococcal infections, and, even among the satisfactory compliers, the streptococcal infection rate, though low, was appreciably higher than in the recipients of the monthly depot injections. The logi-cal interpretation is that strict continuity of penicillin exposure is not only capable of preventing recur-rent streptococcal infections, but necessary to provide absolute protection against these infections. Strict continuity of penicillin exposure was unequivocally provided by the professionally administered, monthly depot injections of penicillin, but was not neces-sarily always strictly maintained by patients whose interview results indicated them to have complied well (but probably sometimes not perfectly) with the daily oral dosing regimens. Another conclusion was that acute streptococcal infection could occur during brief gaps in treatment with either of the two oral dosing regimens. Given that the authors used an interview technique to ascertain how well the trial participants executed their respective drug dosing regimens, it is not surprising that they could only discern three different levels of compliance amongst the trial patients: consistently correct dosing, ques-tionably correct and definitely incorrect. In their final analysis, they combined the questionable patients with the definitely incorrect patients.

About 15 years ago, the late Alvan Feinstein and one of us (JU) discussed some of the background to the design and execution of this study. Feinstein related that, in searching for a method for assessing drug intake by the trial patients, they rejected the counting of returned, unused dosage forms because of the evident ease with which patients could create a fake record of good compliance by simply discarding all or most of the untaken dosage forms. What they selected, in the absence of anything better, was a monthly interview with each patient, plus summary review at 6-monthly intervals, always probing for inconsistencies.

A noteworthy result in this trial was the finding that poor compliers with oral sulfadiazine, even though they had high rates of streptococcal infections, never-theless had very low rates of recurrent acute rheumatic fever, in sharp contrast to the poor compliers with oral penicillin, who had high rates of both strepto-coccal infection and recurrent acute rheumatic fever. This surprisingly large difference between the two agents has never been explained, in part because acute rheumatic fever almost completely disappeared in developed countries as both a public health problem and a subject of research within a few years after this study was reported. This finding, however, is proba-bly the first demonstration of a forgiving drug, in that one could delay or omit many doses in an oral sulfa-diazine regimen without loss of its ability to prevent recurrence of acute rheumatic fever.

In the aftermath of this study, Feinstein and his colleagues went on to try to find an oral regimen of penicillin administration that, when evidently well complied with, could provide effectiveness compa-rable to that of the monthly injections of depot penicillin. That work, summarized and reviewed in (Urquhart, 1993), never succeeded in reaching that goal. In retrospect, it seems logical to assume that the occasionally missed daily dose of oral peni-cillin, which would escape detection by the interview method, could open enough of a drug-free window to permit streptococcal infection and its sometime sequel of recurrent acute rheumatic fever to occur. Electron-ically compiled drug dosing histories should be able to resolve such uncertainties.

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