18 Evidence Based Medicine’s Perspective on Biologics
B. Rzany, A. Nast
18.1
What is EBM?
Since the first articles by Sackett in the 1990s (Sackett and Rosenberg 1995), evidence based medicine (EBM) has developed considerably. Defined as “the integra- tion of the best research evidence with clinical exper- tise and patients’ values”, EBM is an attempt to improve the care of our patients.
There are certain misconceptions about EBM. It is not a standard recipe and there are no standard patient and individual factors that have to be taken into account for definite decisions to be made. EBM is also not an exclu- sive concept, neither is it a sophisticated “l’art pour l’art” for specialists. If EBM were only practiced by spe- cialists, it would be dead – EBM should thrive in daily practice. Last but not least, EBM is not a cost regulating instrument. Often, the best documented therapies – like biologics – are the most expensive ones.
18.2
EBM Steps to Treating an Individual Patient
In order to clarify what EBM means in daily practice, it is important to bear in mind the steps of EBM in the treatment of an individual patient. First a structured and answerable set of questions based on the patient encounter needs to be generated. Next is the search for valid external evidence and then the critical appraisal of that evidence for its relevance and validity. At the end of this process the results of the appraisal of evi- dence should be applied to the patient, and last but not least one’s own performance should always be recorded and evaluated.
Imagine therefore a 50-year-old patient with severe plaque psoriasis in your private practice. The past his-
tory reveals recurrent hospitalisation in the previous couple of years, intolerance of fumaric acid, unsatisfac- tory results with oral cyclosporin and an increase in liv- er enzymes while under treatment with methotrexate.
Based on this case history, one question would be
“What is the best and safest therapy for this patient?” As this question is quite broad, it is recommended to focus the question a bit more. Therefore if biologics are being considered as a treatment choice the question could be:
“What is the best and safest biologic for this patient?”
Based on either question the next step will be the search for evidence. Here there are several possibilities. One step is to search the primary literature, which means going to Pubmed or Medline and making the necessary searches to retrieve the relevant literature. As this is quite an exhausting way of finding the evidence, other possibilities, such as searching the secondary litera- ture, should be considered. Depending on the question, systematic reviews from the Cochrane library, evidence based books such as Clinical Evidence (Naldi and Rza- ny 2005) or Evidence-Based Dermatology (Williams et al. 2003) as well as the evidence-based guidelines (Nast et al. 2006) might be helpful in gathering the relevant evidence.
During searches of the evidence based literature for biologics, it has been quite clear that there are no sys- tematic reviews for this group of new drugs in the Coch- rane library. The Evidence-Based Dermatology book from BMJ/Blackwell does not discuss biologics either.
There is a chapter in the most recent Clinical Evidence book from the BMJ group which discusses two of the four biologics used in the treatment of psoriasis.
The EBM-based secondary literature might give rec- ommendations for the use of biologics based on the evidence for efficacy and safety but it does not usually consider other aspects such as practicability and cost.
These aspects might be covered by a set of guidelines.
Chapter 18
At the moment, two evidence based sets of guidelines for the treatment of psoriasis exist: a set of British guidelines (Smith et al. 2005), which consider only the use of the presently available biologics, and the German S3 guidelines (Nast et al. 2006), which focus on all the systemic and topical treatments of psoriasis including biologics.
18.3
German S3 Guidelines for the Treatment of Plaque Psoriasis
As evidence-based guidelines, the German S3 guide- lines follow a structured approach. The first step in the guideline process is to nominate the people who will contribute to the guidelines. This includes the guideline project team who coordinate the guidelines, the team of experts who review the literature and last but not least the extended committee who formulate and pass the proposed recommendations. The next step is to review the literature. As the hits based on the different litera- ture databases are not very sensitive and specific, the relevant articles need to be pre-screened and selected for the review process. In the review process itself the papers are evaluated for inclusion/exclusion criteria, quality of the methods and presentation of the results.
Finally, a grade of evidence is given to each paper. As several definitions for the “grade of evidence” exist, the grade of evidence itself needs to be defined. Usually, it is based on the recommendations from the Oxford Centre of Evidence Based Medicine.
Using the Oxford classification as a basis, the Ger- man Guidelines Team developed an adapted version, ranging from systematic reviews with meta-analyses (the highest level) to expert opinions (the lowest level).
As the grade of evidence is based on a single paper, a
“level of evidence” was assigned to sum up the evidence
Table 18.1. Efficacy of biolog- ics: comparison of “Number Needed to Treat” according to biologic and dosage
Time of evaluation/dosing Number of patients needed to treat to reach a75% PASI reduction
Source
Infliximab 10 weeks; 5 mg/kg in weeks 0, 2, 6
1.22 (1.1 – 1.37) Gottlieb et al. 2004
Etanercept 12 weeks Leonardi et al. 2003
a) 2 × 25 mg/week a) 3.3 (2.62 – 4.44) b) 2 × 50 mg/week b) 2.18 (1.65 – 2.66)
Efalizumab 12 weeks; 1 mg/kg; 1/week 4.49 (3.62 – 5.91) Menter et al. 2005 of all reviewed papers for one intervention. Here again, the highest grade would be for an intervention that is based on systematic reviews or the consistent results of good clinical trials.
The final “therapeutic recommendations” are formu- lated considering the evaluated evidence-based litera- ture on efficacy, as well as other aspects such as safety, practicability and costs. These therapeutic recommen- dations should be real consensus statements and great efforts have to be taken to make sure that the majority of the guideline group agrees on the formulation.
18.4
EBM and Biologics
Biologics are quite new drugs. The pre-marketing stud- ies follow the high present standards of good clinical practice. Therefore, it is not surprising that the level of evidence is better for biologics than for many of the other older treatments of psoriasis, e.g. methotrexate.
On the other hand, for most available biologics the clin- ical experience is limited and issues such as rare side effects and the results of long term treatment cannot be discussed conclusively.
Comparison of the published trials on the efficacy of biologics will lead to the assumption that there is noth- ing like “THE” biologic. The biologics differ in efficacy and safety. Based on the recommended dosages, the highest efficacy can be found for infliximab, followed by etanercept and efalizumab. The Number Needed to Treat (NNT), an established EBM tool to clarify effica- cy, gives numbers from 1.22 (1.10 – 1.37) for infliximab, 3.30 (2.62 – 4.44) for etanercept at the low dose and 2.18 (1.65 – 2.66) at the higher dose, to 4.49 (3.62 – 5.91) for efalizumab (Table 18.1).
So what does it mean? For infliximab it means that if you treat approximately four patients with infliximab
18.4 EBM and Biologics 185
three will achieve a reduction of the PASI of 75 % or more. This means that only one patient will fail the benchmark of a reduction of the PASI of 75 %.
However, it should be taken into account that effica- cy is not everything. Effectiveness that means “How well does the drug do in clinical practice” is very important. The next most important factor is safety.
You want to have a drug that is safe for this chronic inflammatory disease. Other factors to consider are the practicability for patients and doctors as well as costs.
When talking about costs it is important to remember that it is just not the price of the drug but also the cost of laboratory investigations, other investigations such as X-rays and in addition the days not lost to hospitali- sation.
We would like to finish this chapter with some thoughts on safety. It is important to remember that safety cannot be measured effectively by clinical trials.
Only a limited number of patients are included in clini- cal trials. If 3,000 subjects are exposed prior to drug marketing, one can only be 95 % certain that any event which does not occur in this population will occur in no more than 3 in 3,000 subjects or has an incidence rate of less than 0.001. Therefore, post-marketing surveillance is very important to discover rare and also delayed reac- tions, especially in biologics, which apart from a few exceptions have not been on the market for long.
18.5
Where Do Biologics Stand Among Other Systemic Treatments of Psoriasis?
In order to answer this question, all the aspects have to be considered: efficacy, effectiveness, quality of life, safety, practicability, and pharmacoeconomics. As pre- viously mentioned, biologics are a quite heterogeneous group and each biologic needs to be evaluated sepa- rately.
Since biologics are a new group of drugs and clinical experience is still limited, it is too early to make final recommendations on the use of biologics. Over time, guided by EBM, biologics will find their proper place in the treatment of patients with psoriasis.
References
Follmann M, Sterry W, Rzany B für die Psoriasis-Leitlinien- kerngruppe (2005) Development of the evidence-based guidelines for psoriasis – a project of the German Dermato- logical Society (DDG). J Dtsch Dermatol Ges 3(9):678 – 689 Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, Bala
M, Marano CW, Menter A (2004) Infliximab induction ther- apy for patients with severe plaque-type psoriasis: a ran- domized, double-blind, placebo-controlled trial. J Am Acad Dermatol 51(4):534 – 542
Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB (2003) Etanercept as monotherapy in patients with psoriasis. N Engl J Med 349(21):2014 – 2022 Menter A, Gordon K, Carey W, Hamilton T, Glazer S, Caro I, Li
N, Gulliver W (2005) Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol 141(1):31 – 38 Naldi L, Rzany B (2005) Chronic plaque psoriasis. Clin Evid
13:2070 – 2098
Nast A, Kopp I, Augustin M, Banditt KB, Boehncke WH, Foll- mann M, Friedrich M, Huber M, Kahl C, Klaus J, Koza J, Kreiselmaier I, Mohr J, Mrowietz U, Ockenfels HM, Orze- chowski HD, Prinz J, Reich K, Rosenbach T, Rosumeck S, Schlaeger M, Schmid-Ott G, Sebastian M, Streit V, Webers- chock T, Rzany B (2006) S3 Leitlinie zur Therapie der Psoria- sis vulgaris. J Dtsch Dermatol Ges 4 (Suppl 2):S1 – 126 Sackett DL, Rosenberg WM (1995) The need for evidence-
based medicine. J R Soc Med 88 (11):620 – 624
Smith CH, Anstey AV, Barker JNWN, Burden AD, Chalmers RJG, Chandlers D, Finlay AY, Griffiths CEM, Jackson K, McHugh NJ, McKenna KE, Reynolds NJ, Ormerod AD (2005) British Association of Dermatologists guidelines for use of biological interventions in psoriasis. Br J Dermatol 153:468 – 497
Williams H, Naldi L, Bigby M, Herxheimer A, Diepgen T, Rzany B (2003) Evidence-based dermatology. BMJ Bookshop, BMA House, London
186 18 Evidence Based Medicine’s Perspective on Biologics
