Cancer Clinical trials Medicine

“Targeted” drugs not as “targeted’ as hoped?

I hate it when an article starts right out with a rather annoying usage of terminology, even when it provides information that interests me:

(AP) — Nearly a fourth of widely used new-generation biological drugs that treat several common diseases produce serious side effects that lead to safety warnings soon after they go on the market, the first major study of its kind found.

Included in the report released Tuesday were the arthritis drugs Humira and Remicade, cancer drugs Rituxan and Erbitux, and the heart failure drug Natrecor. All wound up being flagged for safety.

That might surprise some doctors who may have thought that these new treatments might be safer than traditional chemical-based medicines.

I guess what I dislike here the use of the term “chemical-based medicine.” After all, all medicines are chemical-based, because they are chemicals. It’s just a pet peeve of mine. I realize what the writer is referring to is the new generation of drugs, which have been referred to as “biologicals.” A lot of these new drugs are antibodies against specific biologically active proteins generated through monoclonal antibody and recombinant DNA technology. The idea is that they would be more specific and have fewer side effects because they target usually only one protein. At least, that’s the idea. Perhaps there was a bit of naivete among physicians in believing that these drugs would be less likely to pop up with unexpected toxicities after release, but such was the hype surrounding this new class of drugs that this belief was widespread. It wasn’t entirely unjustified, either. A lot of these drugs are incredibly precise in their effects.

However, if there’s one thing biology teaches us, it’s that interfering with the function of even a single protein can have unexpected and wide-ranging effects. Because our understanding of the biology is nearly always incomplete, the extent of such side effects and adverse reactions are often difficult to predict. Indeed, the tendency of nonsteroidal antiinflammatory drugs to cause stomach bleeding is not immediately obvious from their mechanism of action.

Curious, I looked up the study referenced in the news report above. Coming from a group of Dutch researchers, the study was published in the Journal of the American Medical Association and is entitled Safety-Related Regulatory Actions for Biologicals Approved in the United States and the European Union.

The problem with the approval of these new drugs is described in the introduction:

Knowledge of a new drug is incomplete at the time of approval, especially with reference to its safety profile, due to a variety of factors including constraints in the sample size and the design of randomized controlled trials.6-7 Although this also applies to small molecules, biologicals carry specific risks. In contrast to small molecules, which are synthesized chemically, biologicals are derived from living sources (eg, humans, animals, cells, and microorganisms). The production and purification process of biologicals is more complex, involving numerous steps with the risk of influencing the characteristics of the end product at any single step in the production cascade.8-9 Small differences and changes in the production process can therefore have major implications on the safety profile of biologicals. For example, the incidence of pure red cell aplasia in patients treated with recombinant human epoetin, an extremely rare complication induced by antibodies, was elevated in patients taking one particular formulation of recombinant human epoetin in which human serum albumin was replaced with polysorbate 80 and glycine.10-11 However, the exact mechanism underlying the increased risk of pure red cell aplasia after the formulation change is not yet fully understood.12 The risk of contamination with pathogens by the donor is another problem related to the production process (eg, for products extracted from human blood or plasma).13

Biologicals are specifically prone to the induction of immunogenicity. In many cases, the consequence of immunogenicity is not clinically relevant. However, in some cases immunogenicity can lead to loss of efficacy of the drug or, even worse, lead to autoimmunity to endogenous molecules. There can be a major clinical impact if a natural protein with essential biological activity is neutralized by antibody formation.8, 10, 14-15

In other words, biologicals are more difficult to make, more prone to lot-to-lot variability because they are often proteins, and they have a tendency to provoke an immune response. True, there are lots of molecular “tricks” that can be used to reduce the likelihood of provoking such unwanted immune responses. One is to “humanize” the antibody by taking the parts of it that recognize and bidn to the protein it targets and hooking them onto the “backbone” of a generic human IgG antibody. This is accomplished by merging the DNA that encodes the binding portion of a monoclonal mouse antibody with human DNA coding for antibody. Mammalian cell cultures are then used to express this DNA and produce these half-mouse and half-human antibodies, which are not as immunogenic as the mouse variety. Indeed, one of my favorite such drugs, bevicuzimab (otherwise known as Avastin), which targets an angiogenesis-stimulating protein known as vascular endothelial growth factor, was produced this way. As for other classes of biologicals, some are hormones; others cytokines, others growth factors, but most are proteins and thus share the problem of immunogenicity.

Another aspect of this is not specific to biologicals, and that’s the process by which drugs are tested before being approved. It is financially impossible to test all drugs on numbers of people huge enough to detect uncommon adverse reactions and side effects. Most pharmaceuticals in phase III trials are tested in a few hundred or, at most, a few thousand subjects before being released. Drug testing is already incredibly expensive and difficult; so it’s simply not feasible to test a drug using more subjects in most cases. Moreover, the population of subjects in clinical trials is not always generalizable in terms of side effects and complications to the population treated. Often, they tend to be healthier, because of the selection criteria of clinical trials designed to make the different experimental groups as similar as possible. Consequently, when drugs are approved, post-approval monitoring is important, because when a drug is suddenly used in many thousands, even millions, of people, suddenly uncommon or even rare complications can become an issue.

Basically, what this study showed was simple. First, out of 136 biologics approved in the United States and 105 in the European Union between January 1995 and June 2007, total of 41, or nearly 24%, provoked safety warnings issued through June 2008. Second, “first in class” biologicals (meaning the first biological targeting a specific protein) were more likely to provoke a safety warning. It’s hard to estimate, but these appear either somewhat higher than or equivalent to the percentage of “chemical” drugs that provoke such warnings after FDA approval. One reassuring observation was that the vast majority of these safety problems were identified soon after the biologicals became available. Another is that none of the safety concerns were severe enough to result in the removal of one of these drugs from the market. On the other hand, this study is based on a relatively small number of biologicals, and these agents are still pretty new, which means that it’s unclear whether this will be the rate of problems in the future. There is, after all, a “learning” curve, and it’s quite possible–even likely–that we’re getting better at designing and testing biological agents. Time will tell.

As the authors state:

Some of the biologicals (for example, monoclonal antibodies) differ essentially from naturally occurring substances and might therefore be especially susceptible to adverse drug reactions. Although the 95% CIs were broad, our study confirmed that these and other biologicals, including cytokines, growth factors, interferons, and receptors were specifically prone to safety-related regulatory actions. Within the group of monoclonal antibodies, the murine antibodies had a lower risk for a first safety-related regulatory action compared with the humanized monoclonal antibodies. However, this finding should be interpreted with caution due to the small number of monoclonal antibodies and safety-related regulatory actions.

The conclusion:

Warnings issued in the system organ class of infections and infestations were often related to the immunomodulatory effect of many biologicals. Although the limitations of preclinical trials for biologicals are acknowledged, results from pharmacology studies, preclinical studies, and clinical studies might result in the prediction of potential risks related to the drug for which close monitoring is needed in the postapproval setting. Health care professionals should be aware of the specific risks related to the relatively new class of biologicals to be able to provide a link between the use of the biological and the patient presenting with a clinical problem. In addition, the classes of antibodies (monoclonal), cytokines, growth factors, interferons, and receptors and the first biologicals approved in a chemical, pharmacological, and therapeutic subgroup are specifically prone to a first safety-related regulatory action; close monitoring of these biologicals is therefore recommended.

New biological agents are proliferating, as well they should. They show great promise of improved treatments for various diseases and conditions with lower toxicity. However, they are not panaceas and do have potential adverse affects that may not be obvious from mechanism of action, although that might be predicted better as we understand the biology better. Also, one thing I particularly like about this study is the way it shows that science- and evidence-based medicine represents a self-correcting, self-monitoring system that does detect adverse outcomes.

Can anyone picture a naturopath doing a survey like this?

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

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