I’ve been trying to figure out how to write something meaningful about the many reports over the last several months about the safety, costs and quality of medicines. I finally concluded that rather than a too lengthy blog post, a series of snapshots would create a good description of the situation - sort of like a slide show rather than a feature film:
Safety of Generic Drugs: A recent LA Times article discussed patients who had adverse reactions when switched from a brand name to a generic medicine. This article includes physicians’ experiences with several types of generic medicines, e.g. for epilepsy, depression, high blood pressure, irregular heart rhythms, and to prevent rejection of organ transplants. Aside from epilepsy, these are different types of medicines from “narrow-therapeutic-index” (or NTI) medicines which have a small dosage range which produces the desired clinical effects before causing known side-effects. Also, the current safety concerns are not related to what happened in the early 1990s, when some generic companies where caught submitting false safety data — they used the brand name medicine for the bioequivalency testing required by the FDA instead of actually testing their generic versions. (Yes, people went to jail.)
Safety of Medicines Imported into the US: Medicines imported from other countries have raised safety concerns because of lack of quality oversight and the murkiness of the chain of custody. These concerns have recently been highlighted by the contamination problems of herparin from a factory in China, and reminds me of how the head of the Chinese State Food and Drug Administration was convicted last summer of taking bribes in exchange for approving generic drugs that hadn’t had the required testing. (They sentenced him to death, and actually hanged him shortly after he was convicted.)
Fake Medicines: Whether produced in the US or someplace else, there is a growing market in fake medicines. The economic incentives are huge, and unlike illegal recreational drugs, the risk of your customer to violently come after you for selling substandard products is very low. There have been cases of fake medicines made here in the US, and the World Health Organization estimates that up to 30% of medicines in some parts of the world are fake.
Fake antibiotics are of particular concern: Fake antimalarial medicines sometimes contain tylenol or asprin which lowers the malarial fever without actually treating the infection - so people think they are getting better while they continue to spread the infection. And subpar medicines that only contain a fraction of the antibiotic promote the spread of resistant strains of bacteria. So fake or substandard antibiotics may actually be worse than no pills at all.
Even the New York Times editorial board recognized the global dangers of fake medicines in a December 12, 2006 editorial.
Follow-On Biologics: There has been a lot of interest in new versions of biologic treatments. These have many names: generic biologics, biogenerics, biosimilars, and follow-on biologics. One of the great confusions with this issue is that drugs and biologics are different categories of treatments. Because of their different chemical natures they are covered by different parts of US law, and until recently they were regulated by separate divisions of the Food and Drug Administration.
While drugs and biologics are both made up of atoms, drugs are much simpler, generally much more stable, and produced by chemical reactions starting from raw chemical ingredients or from a natural compound purified from a plant or animal source. Biologics on the other hand are much larger compounds (often proteins), and are generally made by living cell cultures (or in some cases whole animals), with the active drug is purified from that source.
The different structural complexities of drugs and biologics is because small molecular drugs are based upon a limited number of configurations of their atoms - usually 1, or 2, or sometimes 4 variations that are either mirror images of each other, or forms that exist in a predictable equilibrium. Biologics on the other hand have 2 or 3 more levels of structural complexity beyond that found in small molecules. (See here for a description of the primary, secondary, tertiary and quaternary structures of proteins.) Printing is a good an analogy to the structure of drugs and biologic, with a drug being like a sentence, where the series of letter and punctuation defines it. Conversely, a biologic is a like a book, where the construction of the paragraphs and chapters are its secondary and tertiary structures, and the footnotes, references, bibliography and appendices are the quaternary structures. Obviously it is easy to copy a sentence to look like the original, but replicating a book, with the same pagination and structure is much more complicated.
As a semi-avid baker, another analogy I like for the difference between drugs and biologics is a comparison between baking powder and eggs. Baking powder is a combination of chemicals designed to produce a chemical reaction to yield the right chemical/baking effect when used in the right amount. It is generally stable, and lasts for a long time when not exposed to air. Eggs on the other hand, can easily spoil (particularly if the shell is cracked), and have two major parts - the yolk and the white. The whites are mostly protein, and yield very different results depending upon how they are used. For example, adding raw egg whites to cake batter produces a very different result than if they are heated first and then added. (Think about the difference between an angle food cake and a quiche.) Egg yolks are mostly fat are are nicely separated from the whites. Mixed with the whites they cook up one way, and separately are used in pudding, custards, etc.
Adverse Drug Events and Medical Errors in Hospitals: There have been many studies about medical errors in hospitals and how many of those relate to adverse drugs events because the patient received the wrong medicine or the wrong amount of the medicine. These studies clearly point out the value of electronic medical records which avoid handwriting mistakes, and can automatically check for drug-drug interactions. Another important organizational feature of hospital care is the integrated medical team that includes experienced pharmacists and nurses. Such teams ensure rapid and accurate communications about treatment issues among the clinicians writing the prescription and those dispensing it or delivering/administering it to the patient.
Conclusions: Medicines are extremely potent, they can be very complex, and they are central to one of the mantras of clinically and cost effective care: “The right treatment, to the right patient, at the right time.” Electronic medical records and electronic prescribing systems certainly can help achieve that goal, while substituting non-identical medications, or enabling the distribution or use of substandard of fake medicines undermines movement towards that goal.
