FDA Orange Book - Request For Assistance

[187502]

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Hey everybody. I usually hang out in the med. student area, but I ran into something that I didn't quite understand regarding medications and thought I would ask the experts.

I was looking thorough the electronic FDA Orange Book for patent expiration information related to a few medications and realized I don't completely understand how the patent/exclusivity process for pharmaceuticals works.

Regarding patents:

http://www.accessdata.fda.gov/scrip...fm?Appl_No=020936&Product_No=003&table1=OB_Rx

It lists patent expiration times from Jan. 2009 all the way to Sept. 2017. How does that work? Wouldn't a medication be covered under a single patent? When is it possible for generics to be made, when the first patent expires, the last one, or something totally different?

Regarding exclusivity:

http://www.accessdata.fda.gov/scrip...fm?Appl_No=019962&Product_No=001&table1=OB_Rx

It shows the patents are expired but the exclusivity isn't expired. How does that work? If something is off-patent how can it still have exclusivity?

Any insight that can be imparted with regard to this subject is appreciated.

 

[MountainPharmD]

You would have to consult a patent lawyer. Even then I don't believe they would fully understand. Big Pharma has many tricks up thier sleeve to keep their over priced "block-buster" drug on patent.

 

[tobie]

You would have to consult a patent lawyer. Even then I don't believe they would fully understand. Big Pharma has many tricks up thier sleeve to keep their over priced "block-buster" drug on patent.

Even though i do not agree with most tactics that drug companies use to keep their patents, remember that for every 1 "block-buster" drug that got released there was millions upon millions of dollars that were invested in failed drug ideas. One problem i see in the near future, especially if Obama gets in is that drug companies may not spend as much in new drug research so they keep their stock holders happy.

 

[MountainPharmD]

There is a big difference between making a resonable profit and gouging the customer. I hope Obama puts the smack down on them. Its about time....All the rest of us have had the smack put down on us.

 

[bananaface]

Different formulations of a medication have different patents. Patents on Paxil tablets, Paxil CR tablets, and Paxil liquid would not be expected to expire simultaneously unless the patents were granted at the same time. If different strengths were formulated and patented at different times, you could see those patents expiring at different times. So, one strength might go generic before another.

The patents that are shown there are not all for new formulations. Some are for indications. Those indications wouldn't affect the exclusivity of product manufacture. The first patent for the specific drug product (eg: Paxil CR 25mg tablets) is the one that would matter.

The exclusivity data you linked to seems to apply to indications, not products. Of course a prescriber could just write for the generic off label. There is nothing illegal about writing off-label, just about promoting or labeling your product for an unapproved indication.

 

[Express08]

Actually, to be specifically clear - the patent is dependent on the chemical entity, dosing, product design (what bananaface was referring to) and indications. It must match EXACTLY what the NDC was which was submitted to the FDA.

In the course of using a medication, the dosing may be changed, the indication changed, the product design may be changed:
Dosing change - Dilantin from 100mg tid to 300mg hs
Indication change - propranolol from heart disease to panic disorder
Product design - Paxil vs Paxil CR (as previously noted)

These may be marketing decisions (note - no advantage for Paxil or Paxil CR in most individuals, but a BIG marketing change since the brand went generic). Or they may "tweak" the chemical - Clarinex (dud!) vs Claritin.

or...they may be real changes in the drug which allowed expanded use - propranolol for panic disorder (most of you are too young to know this allowed Inderal to stay patented for a looong time).

So - there are lots of reasons for patent decisions. Often, exclusivity is based on negotiations with the original patent holder - Oxycodone CR & Oxycontin is the big example currently. The patent holder granted exclusivity to 2 manufacturers of Oxycodone CR prior to patent expiration. But, the manufacturer of Oxycontin faced a huge fine secondary to a lawsuit & they needed the income back from the sale of the drug. So - they pulled exculusivity - thus, they are the only patent holders & no one else can manufacture or sell it (after Dec 2007). The product on hand is saleable, but you can no longer purchase generic Oxycodone CR - only because exclusivity was pulled.

However, other drugs have recently granted exclusivity - Lotrel (note - the generic capsule still has the Lotrel logo).

Drug patents are generally 17 years, but most are "infringed" within 14 years. It becomes too expensive to litigate after that - unless you have to pay millions in fines (like Oxycontin).

But - a generic manufacturer must have a bio-idential product. That means it must work exactly in the body (with a 5% allowable error) than the original patent holder. That is why there is generic phenytoin and Dilantin - those are not bioequivalent. There are a few that way. You might find in the Orange book there are some levothyroxine products which are bioequivalent to Synthroid, but not Levoxyl & vice versa.

That is a scandal for another day.......

 

[187502]

Okay, this all makes a lot more sense now. With regard to patents, which of the types of patents you mentioned below have to expire for a medication to be eligible for generic production?

To make sure I am understanding exclusivity correctly, this allows the original manufacturer to determine who can sell generics, if at all, until the exclusivity expires?

Actually, to be specifically clear - the patent is dependent on the chemical entity, dosing, product design (what bananaface was referring to) and indications. It must match EXACTLY what the NDC was which was submitted to the FDA.

In the course of using a medication, the dosing may be changed, the indication changed, the product design may be changed:
Dosing change - Dilantin from 100mg tid to 300mg hs
Indication change - propranolol from heart disease to panic disorder
Product design - Paxil vs Paxil CR (as previously noted)

These may be marketing decisions (note - no advantage for Paxil or Paxil CR in most individuals, but a BIG marketing change since the brand went generic). Or they may "tweak" the chemical - Clarinex (dud!) vs Claritin.

or...they may be real changes in the drug which allowed expanded use - propranolol for panic disorder (most of you are too young to know this allowed Inderal to stay patented for a looong time).

So - there are lots of reasons for patent decisions. Often, exclusivity is based on negotiations with the original patent holder - Oxycodone CR & Oxycontin is the big example currently. The patent holder granted exclusivity to 2 manufacturers of Oxycodone CR prior to patent expiration. But, the manufacturer of Oxycontin faced a huge fine secondary to a lawsuit & they needed the income back from the sale of the drug. So - they pulled exculusivity - thus, they are the only patent holders & no one else can manufacture or sell it (after Dec 2007). The product on hand is saleable, but you can no longer purchase generic Oxycodone CR - only because exclusivity was pulled.

However, other drugs have recently granted exclusivity - Lotrel (note - the generic capsule still has the Lotrel logo).

Drug patents are generally 17 years, but most are "infringed" within 14 years. It becomes too expensive to litigate after that - unless you have to pay millions in fines (like Oxycontin).

But - a generic manufacturer must have a bio-idential product. That means it must work exactly in the body (with a 5% allowable error) than the original patent holder. That is why there is generic phenytoin and Dilantin - those are not bioequivalent. There are a few that way. You might find in the Orange book there are some levothyroxine products which are bioequivalent to Synthroid, but not Levoxyl & vice versa.

That is a scandal for another day.......

 

[Express08]

I'm not exactly sure what you're asking.......

When a completely new entity receives a patent - it already has FDA approval for its chemical structure, dosage form(s), dosing, indication, etc..... Take Clarinex for example - it its an entirely new chemical structure (altho just a "tweak" of loratadine actually). This was an interesting marketing strategy for the makers of Claritin (any business/pharmacy majors out there???).

The patent holder knew Claritin was coming up on its patent expiration, so they knew they'd be vulnurable for patent infringement if they didn't do something. Rather than let generic manufacturers get in on the rx market - they applied to the FDA for a patent for the OTC version (this was simple - they just had to show safety & labeling....if diphenhydramine can be OTC - so can loratidine). Since this was not a new drug - just a new application (OTC rather than rx), generics could apply as well with what is called an ANDA (they don't have to submit the same whole, big process as one would for an NDA). But - Claritin got the patent first for OTC, had the name recognition & had about 6 months head start on the OTC market.

But - they knew once it went OTC, many third payors would stop paying & they still had Zyrtec & Allegra on rx. If you only pay $5 co-pay, why buy OTC? They didn't want to lose the rx market for the sake of gaining the OTC market. (The same strategy worked with Prilosec as well). So - they "tweaked" the chemical & came up with Clarinex - still rx. Yes - they had to submit an NDA, but all those studies were done concurrently with Claritin (they're no dummies). With Prilosec - the company developed Nexxium at the same time, but didn't release it until a year or so before Prilosec went OTC.

Now - for indication changes - take Gabapentin for example. It is already generic, but I don't think it has neuropathy as an indication approved by the FDA for labeling, although that is its use in 70% of the pts who use it. There is no value in getting a patent on that - its already generic. First, they would have to process an ANDA with the FDA, then go thru the patent process. Since its used off-label already, generic manufacturers would also just submit an ANDA, but theirs is easier - they only have to show they match the first patent holder in dissolution, absorption, kinetics, etc - not safety/efficacy, age & organ system variations, etc...

The original drug patent must be close to expiration (remember "infringement") for generics to start marketing.

Yes - for exclusivity - the original patent holder can determine who can use their patented entity. I gave you the example of Oxycontin, but the more common examples are the transdermal patches. The original patent holder was not even a drug company. The technology was patented & then licensed to drug companies - the first was Transderm Scop. Now we have fentanyl, nicotine, alzheimers drugs, antipsychotics, ntg, estrogen, birth control - and a whole slew in the pipeline. The technology has also changed. It started out being simple controlled diffusion, but now there are matrix, vapor, single & multilayer & many, many more. These are licensed to drug companies - so there may be multiple patents on Climara for example. Each generic company will have to purchase a license for the same patch to be able to market the drug as A/B rated. Often the patent holder of the patch itself is not a drug company at all - it is a biotech company.

It is very, very complicated & actually is being followed by the FTC. They are watching exclusivity & had a ruling last May. Google the Hatch-Waxman Act. That is the legislation which allowed faster processing of generics. Later legislation allowed "exclusivity", but it has bordered on anti-trust issues as well - thus the FTC.

Hard to understand - huh?