Does the Supreme Court decision announced June 17th, giving the FDA the right to sue pharmaceutical companies that enter into “pay to delay” agreements with generic drug makers represent a blow to big pharma, a gift to the generic sector, and a boon to consumers? I don’t think so, and here’s why:
The situations where this ruling might apply are not that common. What happened in this case is that a generic competitor to Solvay’s Actavis testosterone gel challenged Solvay’s patent. Rather than slugging it out, Solvay made a deal with the competitor to keep the generic off the market until Solvay’s patent expired. How much Solvay shelled out to protect their patented version, I don’t know, but it no doubt struck the generic outfit as better odds than what could have been a protracted court case. And in the event of a court battle over the patent, who knows which side would come out on top. And how much it might cost.
However, in my opinion, the drug patent system is flawed, not to say dysfunctional. How it works is that the original developer of a drug absolutely has to file a patent as soon as they’re looking at any promising drug entity. They cannot, cannot, cannot wait until their drug is approved to get it patented – doing so would risk that somebody else beats them to the finish line, and all their work is down the drain.
Drug patent life is 20 years (under normal circumstances) from patent approval. So if it takes the pharma company 7 years to move their drug through the regulatory process, they have 13 years of remaining patent life. And if it takes 12 years to get their drug approved – which is by no means unusual – they have 8 years of patent life. That’s the patent cliff you hear about. And the approval process is arduous, as it must be, if the regulators are going to be able to assure the public that the drug is both safe and effective.
The Drug Patent Situation outside the US
A “pay for delay” case is currently underway in the EU. The Danish pharma, Lundbeck, is the target of enforcement by the European Commission because of a deal with a generic manufacturer to keep citalopram off the market until the patent expired, about two years. Citalopram is marketed in the US by Forest as Celexa. But more about Celexa below, under Phase IV trials.
Meanwhile, in India the Supreme Court refused to grant Novartis (NVS) a patent on their leukemia drug Gleevec, permitting Indian drug manufacturers to sell a much cheaper version. The decision was acclaimed as an important step in making low-cost drugs available in poor nations – Gleevec would cost about $70,000 per years, while the generic version costs about $2,500 per year. Novartis counters that it makes Gleevec available to huge number of leukemia patients in India at no charge, and that if drug developers are not compensated for the enormous costs of moving a drug from the first glimmer of promise to full marketability, then innovation will be stopped dead in its tracks.
And, of course, India is the biggest manufacturer of generics in the world. India could flood the entire world market with cheap generics, a matter of considerable concern to the entire pharmaceutical community. And India did not even have patents on drugs until 2005 – and then only for drugs introduced after 1995 – so the concept might be said to be a bit alien to them.
But, returning to the US …
The Drug Approval Process in the US
First, the original developer identifies a promising agent that might have some useful activity. Let’s say, for the sake of inventing a case study, that they are looking around for antibiotics that might address some of these exceedingly troubling resistant microbes that are giving the infectious disease docs nightmares. They find that by tinkering with the structure of one of the existing antibiotics they can get it to penetrate the cell wall of some of these offending pathogens, and, by golly, stop these little devils from reproducing. So, immediately, they patent the new molecule.
Now they have to do a whole lot of lab work. They need to test against which pathogens their new agent will be effective, and they also need to make sure that the agent doesn’t harm the myriad human cells that are essential to life. (An essential difference between antibiotics and disinfectants is that the antibiotic specifically targets pathogens, while disinfectants tend to kill whatever cells they touch. You can put iodine on an infected scrape or cut, but you don’t want to take it internally or even cover it up, because the iodine will be absorbed and do a lot of damage to healthy cells.)
The lab work is termed in vitro – “in glass” – but early on they will also do a considerable amount of in vivo testing – i.e., in living animals. Small animals at first, and eventually larger animals, that, we hope, tell us how humans might react to the potential antibiotic. For example, they want to determine as accurately as possible what the minimum lethal dose might be. If it takes 10 milligrams to kill a mouse, and the mouse weighs 15 grams (about half an ounce), it would take about 6 kilograms (more than 12 pounds) to kill a 95 kilogram human, like me. Pretty safe.
Phase I Trials
Those tests (described above) are preclinical, meaning no human subjects are involved. But fairly early in the process, they need to start doing clinical trials. Phase I trials are short, involve maybe a few dozen subjects, and are focused mostly on safety and on determining things like dosage, how the drug is absorbed and eliminated, and how long it stays in the system.
Phase I trials also try to provide some information on whether the drug works in subjects with the target disease. This can be tricky, especially when there are already drugs with demonstrated effectiveness for that target disease, so sometimes the drug is tested in patients that have failed to improve with existing agents. In the case of an antibiotic, they might get the consent of a patient with a resistant infection. There are a lot of skin and soft tissue infections that don’t respond to standard antibiotics. They could obtain informed consent from a patient with one of those infections and try out their new drug on that brave person to see if it works.
Phase I trials do not compare the trial drug with another drug or with placebo, and they are not randomized or blinded. The level of information they provide is just a start. Needless to say, lots of potential drugs crash and burn in Phase I.
Phase II Trials
Now we start getting serious. If the drug didn’t raise any safety issues in the healthy volunteers in Phase I, and if it demonstrated some effectiveness in subjects with the target disease, the drug developer moves on to Phase II trials, which typically enroll a couple of hundred subjects with the target disease. These trials will be randomized, meaning that patients are assigned to different treatment groups at random, but at the same time making sure that the patient characteristics in the different treatment groups are similar (it wouldn’t do to have patients in one group be older or sicker than those in another group). The trials are double-blinded, meaning that neither the patients nor the investigators know which treatment they are taking. They may be placebo-controlled, or, in some cases, active-controlled, meaning that the ne