Tips for estimating when generics might become available

[diana.papshev]

Often times managed care pharmacists are asked to estimate when a branded product will lose its patent protection and a generic alternative will become available. Although it might be tempting to make assessments based on patent expiration dates, in reality there are a lot of factors that can affect your forecast.

We’ve reviewed the FDA resources, spoken to industry experts, and used our personal experiences to provide you with some basic tips that can improve or qualify your estimates:

1. Start your research with the right question – patent expiration dates might be irrelevant if a generic manufacturer claims that a particular patent is invalid, unenforceable, or might not be infringed. A generic manufacturer can file an abbreviated new drug application (ANDA) and challenge a specific patent through a Paragraph IV certification. For example, some of Fosamax patents expire in 2019 but the generic alendronate became available in February of 2008.

So, the first step is to figure out whether a particular brand’s patent is being challenged:

o Check Drugs@FDA to see if a generic manufacturer has received a tentative approval letter for an ANDA with “Paragraph IV certification.” For instance, on August 11, 2008, Hospira received a tentative approval letter for generic docetaxel; the ANDA challenges all Taxotere patents through “Paragraph IV certification” (see excerpt below). If a tentative approval letter refers to “Paragraph III certification,” such as the case with the efavirenz tentative approval letter, patents are not disputed and final FDA approval will be granted after patent expiration.

o Search public sources to see if the manufacturer of the branded product filed a patent infringement lawsuit against a generic manufacturer. During the review process, the FDA cannot reveal whether an ANDA has been filed. However, when an ANDA contains “Paragraph IV certification,” the generic manufacturer is obligated to inform the manufacturer of the branded product, who in turn has a 45-day window to file a lawsuit. News stories on patent litigation might be found through public search engines (eg, Google). Also, there are several blogs dedicated to this topic. We were able to find a spreadsheet with the list of challenged patents as of 11/2007, you can download it at the following link (courtesy of the Orange Book Blog and their Hatch-Waxman Tracker)

2. Put patent expiration dates into context – patent expiration dates should be used as a loose proxy since so many developments can happen long before patents expire. The Orange Book is the best source for patent and exclusivity dates; it is more comprehensive and more up to date than the database from the US Patent and Trademark Office. But keep in mind that when a brand has been on the market for a while, its patents can be challenged at any time…

In cases of challenged patents, the key step is to follow the lawsuits. In general, the law grants brand manufacturers a 30-month stay (once the notice is served) to pursue the generic company in court. Even if the litigation is not resolved during the 30-month period, the FDA can grant a full approval to the original ANDA filer. There are also a few other possibilities:

o Settlement – a particular date is specified; for example, Pfizer settled with Ranbaxy to allow the launch of generic atorvastatin in November 2011 (see the original post on this topic)
o Court rules in favor of the generic company - patent found to be invalid or not infringed
o Court rules in favor of the brand company - patent found to be valid, patent expiration date is enforced
o Court extends the timeline beyond the 30-month stay – this might happen if the brand company fails to reasonably cooperate

And then there are exceptions, cases in point – Plavix and Oxycontin. In those cases, rulings were overturned by higher courts… Lastly, it is also important to consider when a company might launch the generic after final approval is granted by the FDA. (see the original post on Oxycontin)

Sources:

FDA. Alendronate approval letter. June, 2005.

FDA. Docetaxel approval letter. February, 2008.

FDA. Electronic Orange Book. Available at: Electronic Orange Book Home Page

Orange Book Blog. Available at: Orange Book Blog

FTC. Generic Drug Entry Prior to Patent Expiration. July, 2002. Available at: http://www.ftc.gov/os/2002/07/genericdrugstudy.pdf

[diana.papshev]

We decided to validate these tips by following our own recommendations in the search of information on the 7 top branded drugs, here’s what we found in less than 45 minutes:

1. Nexium

• Ranbaxy received a tentative approval for esomeprazole from the FDA on 2/5/2008 (the letter was not posted by Drugs@FDA)
• Ranbaxy reached a settlement with AstraZeneca to commence sales on 5/27/2014 (source: Ranbaxy Press Release, 4/15/08)

2. Plavix

• Apotex was the first generic company to receive approval for clopidogrel from the FDA on 1/20/2006; at that time, litigation related to the ‘265 patent was still ongoing (source: FDA letter)
• U.S. District Court ruled against Apotex in June of 2007, affirming validity of the ‘265 patent. Apotex is planning to appeal but even if they are unsuccessful the ‘265 patent expires on 11/17/2011 (sources: Apotex Press Release, 6/19/07; FDA’s Orange Book)

3. Prevacid

• Teva received a tentative approval for lansoprazole from the FDA on 1/18/2008 (the letter was not posted by Drugs@FDA)
• U.S. District Court ruled against Teva in April of 2008, affirming earlier decision on the validity/enforceability of the ‘098 and ‘321 patents. Teva is planning to appeal but even if they are unsuccessful the ‘098 patent expires on 5/10/2009 (sources: Teva Press Release, 3/31/08; Bloomberg.com news article; FDA’s Orange Book)
•U.S. Court of Appeals upheld the 3/2008 decision that the '098 patient is valid and enforceable. Teva plans to market 15, 30mg capsules no later than 11/10/2009 (Source:Teva press release 11/2008)
•Of note, Prevacid 24HR (OTC version of 15mg capsules) was approved by FDA 5/2009 and is scheduled to be released later in 2009 (Source: Novartis press release 5/09); see related link:New brand drugs approved in May 2009

4. Advair

• The FDA has not issued tentative approvals yet(source: Drugs@FDA)
• Information on patent challenges could not be located in the public domain
• Exclusivity expires on 4/30/2011 (sources: FDA’s Orange Book)

5. Singulair

• The FDA has not issued tentative approvals yet(source: Drugs@FDA)
• Merck filed a lawsuit against Teva, a 30-month stay on FDA approval should expire by 10/2009, note that patents expire in 2012 (sources: Pharmaceutical Online news article, 8/7/08; FDA’s Orange Book)

6. Seroquel

• FDA has not issued tentative approvals yet (source: Drugs@FDA)
• U.S. District Court ruled against Teva and Sandoz in July of 2008; Teva is planning to appeal but it is unlikely that they will succeed. The patent will expire on 9/26/2011. However, AstraZeneca is seeking a six-month extension for pediatric use, which may extend the patent to March 2012 (sources: News article 7/08; FDA’s Orange Book)
• FDA grants tentative approval of generic (source: Teva press release 12/08)

7. Effexor XR

• As of 10/09 Impax and Mylan have received a tentative approval for venlafaxine extended release capsule formulation from the FDA on 10/16/2007 (the letter was not posted by Drugs@FDA)
• Impax, Lupin and Anchen reached a settlement with Wyeth to commence sales by 6/1/2011 and in limited circumstances possibly as early as 1/01/2011 (sources: News article 7/2008; News article 8/2009)
• However, Teva's agreement allows them to launch in July 2010 (source:Wyeth SEC filings 2006)
Note that as of 5/2008, the FDA approved venlafaxine hydrochloride extended release tablets (37.5 mg, 75 mg, 150mg, and 225 mg; no therapeutic equivalents) by Osmotica Pharmaceutical (sources: FDA letter)

Let us know if there are other brands you would like us to investigate.

[chantell.reagan]

Singulair update:
A district court ruled in favor of Merck, blocking the approval of Teva's generic montelukast until the 8/2012 expiration of the patent (source: Merck press release 8/09)