Drugs can have remarkable differences in molecular complexity. Generally we classify drugs into two categories - either "small molecule" or "large molecule."
Small molecule drugs are often able to be formulated into pills (though many are also given IV) and have relatively simple molecular formulas. Take a drug like tylenol or ibuprofen - they are comparatively simple. Most good chemists could whip it together with a few basic chemicals in their lab much like any good chef could pull together a nice meal with whatever you have in the refrigerator. Some of the new research drugs like ibrutinib, idelalisib, and ABT-199 are in this category. This doesn't mean the science behind the drugs is simple by any means. Some of these drugs are based on years of elegant lab research - but the molecule itself is often comparatively simple.
Large molecule drugs on the other hand include antibodies like rituximab, ofatumumab, or brentuximab (the "mab" on the end stands for monoclonal antibody). These types of drugs are most frequently administered intravenously. In fact if you were to swallow rituximab your body would digest it in much the same way you would digest a fried egg. They are both protein structures and neither remain intact following the acid of the stomach or the digestive enzymes of the small intestine.
To put the size difference into proper comparison think of a small molecule as a bicycle. Using the same analogy, a large molecule drug would be like an aircraft carrier (Scroll to bottom for image). The molecular complexity is truly astounding. The fact that these drugs can be reproducibly manufactured to be nearly identical (single chemical entity - SCE) from batch to batch is a testimony to the incredible sophistication of chemical engineering.
It probably comes as no surprise then that small molecules have been subjected to "generic drug competition" for quite a while. Typically once a drug patent expires, generic drugs flood the market and the price drops by 90% in a very short period of time. The reward for innovation has expired. When Pfizer's drug lipitor went generic a few years back, it went from something like 7 billion dollars of revenue per year several hundred million with breathtaking speed (I am probably missing the numbers by a fair margin - but you get the point). There was a reason that the company laid off a ton of their marketing staff around the same time.
Generic "small molecule" drugs are often pretty simple to make. Furthermore, the FDA standard for what it takes to be an approved generic drug is straight forward enough that many generic drug manufacturers can get their drugs to market quickly. In everyday cancer practice, small molecule chemotherapy drugs like cyclophosphamide, fludarabine, adriamycin, vincristine, and etoposide are virtually entirely all generic. Unfortunately the comparatively low cost of these medications has made it hard for many generic drug manufacturers to consider them worth their while and this has resulted in chronic drug shortages for many of the lifesaving drugs we consider standard.
Between the "small molecule" and "large molecule" drugs are a number of "intermediate size drugs." These may include growth factors like neupogen, neulasta, aranesp, etc. While these drugs are often considerably more complicated than tylenol, you might think of them as a city bus instead of a bicycle or aircraft carrier.
While these drugs are certainly an order of magnitude more difficult to manufacture than small molecules, it should probably come as not surprise that generic drug makers have decided to tackle this market. Since single doses of neulasta can cost thousands of dollars, being able to make a generic version of these drugs could definitely be worth the effort.
With increased molecular complexity comes a lot more difficulty in reproducibly manufacturing a copy cat drug. While you can probably go out to your garage and put a bicycle together, making a city bus is probably out of your league - and unless you are a modern day Noah - an aircraft carrier is simply out of the question.
The problem is that very small differences can result in enormous biologic consequences. In some cases "generic" erythropoeitin have been associated with extremely dangerous allergic reactions, or in other cases caused the immune system to shut down all red blood cell production (a huge problem for a drug that is supposed to treat anemia). Despite these well publicized failures generic drugs have moved much more quickly in India (where different market forces, regulations and intellectual property rights have allowed earlier utilization of generic drugs) and even in much of Europe.
You can probably guess where this post is going next.
Generic "aircraft carriers" or large molecule drugs are next. There are something like 8-10 companies getting ready to move forward with a generic version of rituximab as soon as the patent expires. This is part of the reason Roche has worked so hard to make a better version of the drug and looks for obinituzumab to be rituximab 2.0.
Due to the incredible complexity of producing drugs on this scale, the FDA has taken quite a while putting out the rules for what it takes to become a generic large molecule drug. Most of these drugs will require a clinical trial in which the standard drug is compared to the generic drug. The generic manufacturer wants the results in both arms of the study to be equivalent - not better. If the results are better it is probably not the same drug after all.
You can imagine how this can turn clinical trials on upside down. Instead of trying to get on a study for access to the next best drug, now you are just trying to get a drug that is exactly the same as the innovator molecule. A lot of patients may find that less than compelling. Perhaps there would be a financial incentive? You have to be extremely careful if that is the case that it is not coercion or that there is a financial interest for the doc recommending the study.
These studies will be showing up in the next 12-24 months. They pose a bunch of challenging questions. I am not sure I can predict how they will go, but I am eager to see how the process unfolds.
Thanks for reading.
