Longterm Safety & New Drugs
Kitty Kelly
OMERACT
These are exciting times for patients with rheumatoid arthritis (RA).
For years patients have suffered from relative neglect by the
pharmaceutical industry. True, nonsteroidal antiinflammatory drugs have
proliferated. Little initiative or investment is required to rearrange
parts of the molecule within a basic chemical structure in order to
change efficacy by a modest amount.
This accepted recipe provides a guarantee of modest profits for the
shareholders at little financial outlay for development, but does not
necessarily profit the patient.
The more interesting collection of drugs with disease modifying action
in RA were initially borrowed from other diseases or used in the
condition through serendipity.
Some, for example antimalarials and injectable gold, were subjected to
little in the way of dose ranging studies to determine optimum dosage.
Others, such as azathioprine, relied upon studies performed for
different indications1. Penicillamine, by contrast, was the best of
several analogs that reduce the titer of rheumatoid factor,
imaginatively explored by Jaffe2, its optimum dose subsequently subject
to successive reductions as our understanding of the use of the drug
grew.
The gold standard for disease modification, arguably, remains
methotrexate or sulfasalazine.
The former, used in lower doses than in oncology, long championed in the
treatment of psoriasis and even psoriatic arthritis, was the subject of
a succession of trials in the USA, each successively showing benefit at
ever lower doses3.
In parallel, sulfasalazine was championed in Europe, initially
introduced by Nana Svartz for the treatment of rheumatoid disease but
later appropriated by gastroenterologists, only to be reclaimed by
rheumatologists once its benefit was confirmed by modern trials4.
All this is changing. Considerable effort, initially on the part of many
pharmaceutical companies but more recently consolidated through their
amalgamations, led to a new generation of disease modifying drugs
designed for RA. Some have recently been marketed. Global availability
will result, even though demand may initially outstrip supply.
One such compound is leflunomide, novel as a pyrimidine antagonist
although synthesized in conventional style at the biochemist's bench5.
Another is etanercept, an example of the new generation of biological
agents with specific action against the prime cytokine tumor necrosis
factor a (TNF-a), essentially the result of immunological research and
rather more complex to manufacture6.
Other specific blockers of TNF will follow, the next generation likely
to be manufactured through human DNA technology with no antigenicity.
Specific collagenase inhibitors, theoretically with a much wider
spectrum of use, will soon also emerge.
But all is not necessarily as cosy as it seems in the global village. A
trend in the last decade has been for pharmaceutical companies not only
to merge but to become much more efficient in their phase 2 and phase 3
studies. Competitive recruitment between centers is now the order of the
day and contract houses spanning many countries (in Europe now
stretching from the west into the east) guarantee rapid recruitment to
large multicenter trials of adequate power to show very small
differences between competing drugs.
The wide inter-center variation in subjective assessments, sometimes
performed in many different languages within the same trial, is
conveniently ignored, as are differences in the style of recruitment
between countries. Regulatory authorities are much faster in processing
applications, and the US Food and Drug Administration is now prepared to
"fast track" product licence applications for the indication of RA, as
they do anticancer drugs and drugs for AIDS.
This feature is not yet prominent in European licensing circles,
although the new mechanism for licensing through a small number of
Member States in the European Union saves the expense and delay of
working separately through up to 15 different licensing bodies in as
many countries.
The net effect has been a genuine risk that drugs reach the market with
inadequate attention to pharmacokinetics, the optimum dose, the optimum
duration of dosing, and whether drugs should be given by themselves or
in combination (either in series or in parallel).
Of even greater concern in respect of the newer biological agents is the
risk of late, relatively rare, side effects that might be produced by
these drugs as they manipulate the immune system, exclusively for the
relief of RA. These potent therapies may even alter the natural history
of neoplastic disease.
Rheumatologists have long discussed a possible association between RA
and lymphoproliferative disorders, the scope for such pursuits
invariably hinting at a "non-proven" verdict7. Oncologists note the
occurrence of Sjögren's syndrome with lymphoma in males with Felty's
syndrome8. Might disease modification also cause neoplasia in rheumatoid
patients?
On the whole, the evidence for azathioprine9 and methotrexate10 has been
reassuring, but the new generation of biological agents, much more
potent in this respect, lead us to territory hitherto unexplored.
It is against this background that OMERACT, at its next meeting (OMERACT
5: Toulouse, France, April 3–5, 2000) propose to discuss the
development of a large population cohort for longterm safety monitoring
in treated RA, described in more detail in this issue11.
Such endeavors are laudable and clearly to be welcomed. They are not
necessarily new. The Standing Committee of the European League Against
Rheumatism devoted to international clinical research studies including
clinical trials has long advocated the benefit of such a register at a
pan-European level.
Some governments, often those that spend the greatest proportion of
their gross national product on health care, have introduced such
registers, often in conjunction with their drug licensing authorities.
These databases are likely to be impartial, concentrating on general
associations between drugs, rheumatic disease, and neoplasia, not
necessarily restricted to those single specific therapies that,
arguably, are most likely to cause the problems.
The pharmaceutical industry certainly maintains such databases, but only
within a single company and each specifically devoted to an individual
product, their contents usually available upon request for licensing
authorities but not necessarily in the public domain.
So the proposals of OMERACT for an independent international effort are
timely and worthy of serious consideration and discussion. It is not
entirely clear how they would be funded and it may be unrealistic to
expect individual sponsors in the form of pharmaceutical companies to
share their findings with other companies worldwide through such a
database, unless international law is altered to enforce this principle.
The authors of the proposal (intriguingly drawn from industry as well as
academia) concede the existence of other established databases, of which
ARAMIS (Arthritis, Rheumatism and Aging Medical Information System) may
be the most competitive.
National databases also exist, for example, the Norfolk Arthritis
Register in the UK, supported by the Arthritis Research Campaign
(formerly the Arthritis and Rheumatism Council)12,13, but these are
epidemiological ventures, concentrating on incidence and prevalence of
disease within a small circumscribed area, not necessarily adaptable to
small increases in the frequency of neoplasms that are in need of
detection.
Nevertheless, experience acquired with such a database does draw
attention to some of the pitfalls in their collection, presumably still
to be considered by OMERACT. One concern is continued contact with the
patients enrolled for a sufficiently long time period for late changes
to be detected.
OMERACT tantalizingly offer a survey by postcard, telephone, or
Internet on an annual basis, but it is not clear how patients can be
persuaded to notify the investigator of their change of address, always
assuming they maintain their interest and willingness to cooperate over
such a long period.
While the case control within the proposed database appears impeccable
and is easily described on paper at this early stage, enrolment to the
survey may present more problems. Should this be done by the patients,
their pharmacist (not only fastidious by training but perhaps encouraged
by a legal obligation), their primary care physician, their consultant
rheumatologist, a representative of the company manufacturing the drug,
or a trained research nurse? Enrolment may need to be adapted between
different countries to suit local customs.
The new drugs will not come cheap. Perhaps the database will be skewed
worldwide, restricted either to affluent countries or, of more concern,
to affluent sectors of society within a single country. Control subjects
will need to be recruited with discretion to ensure they provide
adequate control for the group of patients who have such access to
treatment. The authors concede the need for the control pool to
accommodate up to three simultaneous predispositions (of which disease
duration, number of prior therapies, and types of prior therapies are
those cited), but the last two of these must surely vary from country to
country.
Simple factors of age and sex as well as those as complex as industrial
carcinogens and other environmental influences will all need to be
considered if an association between drugs and neoplasia is demonstrated
beyond doubt. Endpoints will also need to be considered carefully.
Even the most basic, that of death, may be subject to variation in
reporting through death certificates between countries. In Third World
countries, often with a different genetic pool but where an increasing
number of new compounds are being tested, death may even go undetected.
As polypharmacy becomes more accepted14, the task of unravelling which
side effect has resulted from which drug will become even more complex.
Even the simplest ploy of adding steroid or methotrexate to a biological
anti-TNF compound (which may conveniently serve to reduce its use and
therefore cost) may seriously affect immunological activity, further
complicating an easy unscrambling of whether the drug alone or the drug
in combination was the culprit.
Perhaps those subjects who, on genetic grounds, were most likely to
develop the severest disease (and therefore need the most potent drugs)
are also those most genetically predisposed to neoplasia.
These many reservations apart, the authors of the OMERACT proposal11 are
still to be congratulated on their determination and should be
encouraged to develop their proposal at their meeting in April 2000,
after which their further deliberations will no doubt be presented to
the rheumatological community.
HOWARD A. BIRD, MA, MD, FRCP,
Professor of Pharmacological Rheumatology,
University of Leeds,
Clinical Pharmacology Unit,
Chapel Allerton Hospital,
Chapeltown Road,
Leeds LS7 4SA UK
Address reprint requests to Dr. Bird.
REFERENCES
1.Bird HA. Long term agents for rheumatoid arthritis (anti-rheumatoid
drugs). In: Bird HA, Wright V, editors. Applied drug therapy of the
rheumatic diseases. Bristol: Wright PSG; 1982:103–39.
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rheumatoid arthritis. Semin Arthritis Rheum 1991;20:317–31.
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arthritis. Drugs 1999;57:945–66.
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men with rheumatoid arthritis. J Natl Cancer Inst 1993;85:307–11.
8.Gridley G, Klippel J, Hoover R, et al. Incidence of cancer among men
with the Felty syndrome. Ann Intern Med 1994;120:35–9.
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10.Kamel OW. Lymphomas during long-term methotrexate therapy
[editorial]. Arch Dermatol 1997;133:903–4.
11.Lipani JA, Strand CV, Woodworth TG, et al. A proposal for developing
a large patient population cohort for longterm safety monitoring in
rheumatoid arthritis. J Rheumatol 2000:27:827–30.
12.Wiles N, Symmons DPM, Harrison B, et al. Estimating the incidence of
rheumatoid arthritis. Arthritis Rheum 1999;42:1339–46.
13.Wiles N, Barrett J, Barrett E, et al. Disability in patients with
early inflammatory polyarthritis cannot be "tracked" from year to year;
an examination of the hypothesis underlying percentile reference charts.
J Rheumatol 1999;26:800–4.
14.Kremer JM. Combination therapy with biologic agents in rheumatoid
arthritis: perils and promise [editorial]. Arthritis Rheum
1998;41:1548–51.
© 2000. The Journal of Rheumatology Publishing Company Limited.
All rights reserved.
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