Drug Kennel

A reader recently inquired about Orphan drugs and asked me if I thought an Orphan drug developed under 505(b)(2) could be approved based on just a Phase 1 study - a pharmacokinetic or pharmacodynamic comparison to the RLD.

At first I thought I couldn’t think of an example.  Generally, an Orphan drug fulfills an unmet need in 200,000 or fewer people in the U.S. and requires a clinical study for approval.  In return, among other benefits, the drug is given 7 years exclusivity - except, and here is a potential answer to the subject question:

If the new drug is shown to be different from the approved orphan drug because the new drug is “clinically superior” (e.g., shows greater efficacy,safety or contribution to patient care).

Thus, for example, you might find that a revised formulation significantly reduced adverse events.  An Orphan injectable formulation is changed to reduce the injection site reactions, for instance.  In this case, it is likely that only a Phase 1 study would be needed.  We would recommend a pre-IND meeting with FDA to assure that FDA would consider the change ‘clinically superior’.  The FDA has indicated that it would decide these matters on a case-by-case basis ( 57 Fed Reg 62079 - see particularly comment 27).

The 505(b)(2) process is used to obtain approval of an isomer of an already approved racemate.  An example is cetirizine.  The original product approved (Zyrtec)  is a racemate.  In May 2007, UCB, Inc. obtained approval for levocetirizine dihydrochloride 5 mg tablets, using the 505(b)(2) process.  That approval was based on replicate clinical studies.  On 1/28/2008 UCB obtained approval of a oral solution (2.5mg/5mL) of levocetirizine dihydrochloride also using 505(b)(2).  The latter NDA was approved based on a single BE study comparing the oral solution to the 5 mg tablet in normal healthy adults.

A couple of interesting learning points. 

The oral solution also received approval for pediatric population, satisfying the PREA commitment made when the tablet was approved.  Yet the BE study was done in adults.  UCB found a pk study in the literature that showed the systemic exposure (as measured by AUC) is twice as high in children aged 6 to 11 than adults - UCB then didn’t need to do the study!

How did I learn all of this?  If you go to the FDA website drugs@fda you will only see the approval letter and label.   Where did I get the medical review?  According to section 505B(h)(1) of the Pediatric Research Equity Act of 2007 (PREA), as amended in fall of 2007 by FDAAA, the FDA must publish the medical, clinical pharmacology and statistical reviews of all approved submissions conducted in response to a written request by FDA.  In this case, the letter approving the UCB levocetirizine 5 mg tablet had specific pediatric requests under PREA.  The full listing of submissions appears here .

Lesson learned:  Don’t leave any stone unturned when seeking public information to support your 505(b)(2).

In our webinar last week on Patent & Marketing Exclusivity we received an interesting question that I would like to pass along to readers of this blog.

Q: If there are two RLDs, one with IP and one without IP, does a Sponsor have to certify against both RLDs?

A: If you reference a RLD, you always certify. In the case you cite, for the RLD without outstanding IP, you use a paragraph 1 certification.  For the RLD with IP you certify using paragraph 3 (you’ll wait for approval before launching) or 4 (you challenge the patent validity).

To expand, there are 4 potential categories of certifications, as listed in the following table.  As you can see, there is always at least one classification that fits your RLD.

IP attorney Stephen Albainy-Jenai and I just concluded a webinar hosted by DIA entitled 505(b)(2) Patent & Exclusivity.  23 different companies attended, showing the increasing interest in 505(b)(2) issues.  Earlier this year, DIA hosted my overview of the 505(b)(2) drug development process where the attendees had many questions asking specifically about patents and exclusivity, many of which I couldn’t answer because of time and scope of the topic. 

In this webinar we distinguished and explained two concepts: patents and marketing exclusivity.

• Patents are issued by the US Patent and Trade Office based on intellectual property.  A patent lasts for 20 years yet, can be challenged and found invalid. 
• Marketing Exclusivity is granted by FDA as an incentive to conduct studies.  The term ranges from 3-7 years and can be extended by 6 months in some cases by pediatric studies.  Exclusivity cannot be challenged or taken away.  Drug sponsors like this certainty!

Specifically, the marketing exclusivity terms are:
 

The term “clinical studies” is defined in the regulations as any clinical study other than bioavailability.  This same regulation defines ‘essential for approval’ as “there are no other data available that could support approval of the application”.  See this link for the Orphan Drug exclusivity regulation.

Marketing Exclusivity means that a generic cannot be marketed during the applicable term.  Moreover, for 3-year exclusivity, an generic cannot be approved until the 3 years expires, while for 5-year exclusivity a generic application cannot be filed until the 5 years expired ( 4 years if a generic uses a Paragraph IV challenge).

Importantly, there are 505(b)(2) applications that receive no exclusivity - those applications that did not need to conduct a clinical study.  These drugs are approved on the basis of only bioavailability studies.  An example that receives no exclusivity would be developing an extended release oral product when the reference listed drug (RLD) is an immediate release drug product.  Another recent example is here.

Generally, you find out what exclusivity you might get at the pre-IND meeting.  But the FDA only determines exclusivity at the time of approval.