Disappointing biotech

October 6, 2008 by dadmin

Biotechnology offered the hope of cheaper and better drugs. Analysis of biotech products licensed in Europe shows the reality is somewhat different

The advent of DNA recombinant techniques and other biotechnologies has raised expectations for more selective drugs. The techniques promise "magic bullets" that are better tolerated because they are more similar to endogenous products and cheaper to make thanks to potential large scale production. Thus biotech products offer a good model for assessing the level of therapeutic innovation of drugs. We assessed the biotech medicines approved by the European Medicine Evaluation Agency from its inception in 1995 to 2003, when the European pharmaceutical law was revised.1 The agency approved 87 biotech products, corresponding to 65 active ingredients, during this period. Four were approved for diagnostic purposes. How innovative were the 61 licensed with more therapeutic indications?

Innovation of biotech substances

The box shows the 61 active substances classified according to their type of benefit compared with existing treatment or placebo, as appropriate (see bmj.com for details of the indications). We obtained the information from the European public statements, available on the EMEA website (www.emea.eu.int/index/indexh1.htm). Only 15 products represented therapeutic innovation, that is, drugs for diseases without effective treatment, more effective than existing treatment, or active in patients resistant to current treatment. Twenty two offered limited non-therapeutic advantages over existing products (10 in terms of safety and 12 in terms of convenience), and 24 were copycat or me too products.

The products with improved safety include coagulation factors, insulins, and sex hormones, where DNA recombinant techniques theoretically reduce the risk of viral infection compared with old extraction procedures. Examples of drugs that have pharmacokinetic advantages include darbepoietin, peginterferon alfa, and pegfilgrastim, which can be taken once a week instead of three or five times a week like their parent compounds. However, the optimal doses are not well established. Multiple vaccines are also categorised as increasing convenience.

Evidence supporting innovation

Dose finding studies were done for only seven of the 15 innovative substances (figure). Only 11 had their efficacy and safety tested in randomised controlled trials. Six of the substances were compared with placebo, even though an active comparator was available for three of these (mycophenolate mofetil for basiliximab; sulfasalazine and methotrexate for infliximab in Crohn's disease and rheumatoid arthritis respectively; and glucocorticoids for interferon beta 1b in multiple sclerosis). Four innovative substances were approved on the basis of superiority to active comparators in randomised controlled trials (becaplermin, desirudin, rasburicase, and trastuzumab). Hard end points were used for three drugs (basiliximab, infliximab, becaplermin), although the first two were tested against placebo. One trial of eptotermin alfa against an active comparator used soft end points (clinical healing of the tibia, in terms of stability, weight-bearing, and reduced pain).

The efficacy and safety of tasonermin were assessed in four open label, non-randomised trials and of alemtuzumab in three phase II non-comparative trials. No randomised trial to assess efficacy was done for rituximab, and the evidence for efficacy of pegvisomant came from post hoc subgroup analysis at the time of approval.

At the time the drugs were approved the trial results for only five out of 15 drugs had been published in peer reviewed journals.2-6 All four orphan drugs were approved on the basis of placebo controlled trials measuring soft end points (pain for algasidase alfa) or surrogate end points (glycosphingolipid reduction for agalsidase beta, suppression of insulin-like growth factor 1 for pegvisomant, and change from baseline forced vital capacity for laronidase).

These data suggest that biotech substances were often not assessed using rigorous methodological criteria. The small numbers of dose finding studies and controlled trials, especially comparing new drugs with an existing treatment, reflect more general deficiencies in the documentation supporting the applications for marketing authorisation. They give the impression that commercial priorities come before the sound development of drugs in the interest of patients. The licensed innovative drugs often had restricted therapeutic indications, either because they were orphan drugs or because they were tested in small, selected populations. Rituximab, trastuzumab, infliximab, anakinra, alemtuzumab, and tasonermin were all developed for second or third line indications.

The large proportion of drugs copying existing products suggests that market interests predominate in biotechnology as in other pharmaceutical research. Indeed, most such copies fail to offer new options for patients or public health, providing no advantage, even in terms of cost.

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