Published May 11th, 2008
in 505(b)(2) Issues.
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).
Published May 5th, 2008
in Events.
 |
Even this holiday is linked to 505(b)(2) activity - at least for me and some of my staff. Dr. Ruth Stevens (Exec. VP and Chief Scientific Officer) , Cindy Phurrough (Dir. Clinical Operations), Stacey Ayres (Sr. Research Associate) and Bill Stoltman (Dir. Regulatory Compliance and QA) and I were together at Duramed on that fateful day May 5, 1997 when Janet Woodcock (her first stint at FDA Commissioner) refused to approve the ANDA for conjugated estrogens, the proposed generic to Premarin. |
That decision led us to use the 505(b)(2) route to obtain approval of Cenestin (conjugated estrogens, A) on March 24, 1999. The approval was based on the pharmacokinetic studies completed for the ANDA and a single Phase 3 3-month clinical trial (a vasomotor symptom study) in 120 healthy menopausal women and on extensive data from the published scientific literature on estrogens and conjugated estrogen. The toxicology section was built using well established publicly available studies on estrogens. [Learning: Some Divisions will accept data from the closely related therapeutic class.] The Cenestin NDA was filed before the Agency came out with their 505(b)(2) Guidance.
The content of the NDA was worked out in pre-NDA meetings with the Division and Commissioner’s staff. The experience we had developing Cenestin led us to start Camargo: at Duramed we had individual consultants who were superior at their function but left many gaps between each other and well-known CRO’s didn’t want to bother with small clinical studies typical of 505(b)(2) approvals. We felt that by building a focused inter-disciplinary team, we could bring real value to this market. Testimony by our clients indicate we are on the right track.
Published May 4th, 2008
in 505(b)(2) Issues.
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).
Published May 2nd, 2008
in How to:.
According to some observers, the US Patent system is undermining innovation. In KSR International versus Teleflex Inc., the US Supreme Court ruled that patents must be “more than the predictable use of prior art elements according to their established functions” or in my layman’s words, you can’t patent something that should have been obvious. The drug industry is worried that this obviousness test could apply to controlled-release drugs, polymorphs, new dosages and formulation, enantiomers, etc.
An alternative to patenting ideas is to keep the IP a trade secret. A trade secret can be defined as Any information that is (i) secret, (ii) used in a business, and (iii) which confers upon its owner a business advantage over competitors who do not know or use the information. This information can include formulas, patterns, designs, compilations, programs, devices, methods, techniques, data or processes. An example of a trade secret is Coca-Cola’s formula for its flagship brand.
| Use Patents When: |
Use Trade Secrets When: |
| -Long market life |
-Not eligible for patent protection |
| -Can be reverse-engineered |
-Short life cycle |
| -Protection can/will be enforced |
-Patent hard to enforce |
| -Corporate policy |
-Hard to reverse engineer |
Published May 2nd, 2008
in 505(b)(2) Issues.
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.
| Paragraph I |
Required patent information has not been filed |
FDA may approve 505(b)(2) immediately; |
| Paragraph II |
Patent has expired |
FDA may approve 505(b)(2) immediately; |
| Paragraph III |
Patent has not expired but will expire on a certain date |
FDA may approve 505(b)(2) effective on patent expiry date; |
| Paragraph IV |
Patent is invalid or non-infringed by applicant |
Applicant provides notice to NDA holder; approval may or may not occur |
Published May 2nd, 2008
in 505(b)(2) Issues.
I was recently asked how you can have a 505(b)(2) application for an Orphan drug. The reasoning behind the query was that Orphan drugs are new chemical entities (NCE). This perpetuates the misconception that 505(b)(2) cannot be used for NCEs, which by now readers of this blog know is wrong. We have discussed the use of 505(b)(2) for DESI products, which, by definition are unapproved drugs (meaning that a submission of these drugs gets 5 years exclusivity because they are NCEs).
Need an example of an Orphan drug aproved under 505(b)(2)? How about the 1999 approval of caffeine citrate (Cafcit®) for apnea of prematurity. I’ll wait until you choke on your last gulp of coffee. Caffeine? Yes, a NCE. Apnea of prematurity - an Orphan indication (presumably, in treating the premature baby the mother is known, so the babies are not orphans). This product has since gone generic. I use this example in my 505(b)(2) workshops to lighten the mood (near coffee breaks).
Can you take an existing approved drug and re-position it for with an Orphan designation? Sure. You need to keep in mind how the existing drug might cannibalize your sales, but generally you make significant changes to the dose (often route of administration). A company that appears to use the 505(b)(2)/Orphan route is TheraQuest Biosciences. In 2005, TheraQuest received Orphan designation of tramadol hydrochloride for management of postherpetic neuralgia and treatment of painful HIV-associated neuropathy. According to the TheraQuest’s web site, the product being developed is a once-a-day sustained-release product.
The reward of an approved Orphan is 7 years marketing exclusivity.
Published April 23rd, 2008
in 505(b)(2) Issues.
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:
|
Marketing Exclusivity Terms
|
|
Term
|
Requirements
|
| 3 Years |
Clinical studies essential for approval |
| 5 Years |
New Chemical Entity (NCE) - usually, older drugs never approved |
| 7 Years |
Orphan Drugs |
| 6 months |
Pediatric - an extension to an existing exclusivity or patent |
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.
Published April 16th, 2008
in 505(b)(2) Issues and Events.
In another fine example of a formulation change, Biocompatibles International reported that its very small beads were used to sequester Doxorubicin (adriamycin). The resulting beads were delivered via a catheter directly into the liver of patients with liver tumors. The tumor growth was suppressed for long enough in 12 of 18 patients to receive a transplant.
We have previously reported the use of a special carbohydrate that sequesters a tumor fighting agent and delivers the drug directly to the tumor (click thumbnail below to enlarge).

These examples show the use of novel excipients in conjunction with previously approved drugs - a classic 505(b)(2) drug product.
Fospropofol turned down or approved by FDA Advisory Committee?
Published May 14th, 2008 in 505(b)(2) Issues and News Commentary. 0 CommentsMGI Pharma’s Aquavan(R) (fospropofol) is a phosphate prodrug of the anesthetic propofol. Propofol must be administered by an anesthesiologist because of its rapid onset.
The phosphate prodrug’s time to onset is delayed due to the conversion to the active moiety.
A slow onset of sedation would reduce the likelihood of sudden and unexpected general anesthesia. MGI hoped that this delay would allow it to obtain an indication that would lift the restriction on use only by anesthesiologists, vastly increasing the value. Additionally, while propofol’s low aqueous solubility requires a lipid emulsion, fospropofol is water soluble. Alas, the advisory committee voted 8-2 against the broadened indication, meaning it will compete head-to-head with propofol.
The news and company press release headlines indicated the advisory committee approved fospropofol, 6-3. True - for the same labeling as propofol. Comment: Why do news wires always reuse the headline of press releases without thinking them through?
Predictably, the American Society of Anesthesiologists were against the expanded use by non-trained doctors.
For background see FDA’s briefing and MGI’s briefing documents.
Due to pk differences, MGI conducted a Phase 2 dose-ranging study. Once dose was selected, they conducted 2 Phase 3 studies with an arm of midazolam, a drug of choice for non-anesthesiologists. The Phase 3 studies were performed by non-anesthesiologists. Yet, the advisory committee noted that the protocol for these studies wasn’t real-world. They worried that AE’s would be like propofol and thus truly require an anesthesiologist. Hence, the final result.
Prodrugs are submitted under 505(b)(2). The advisory committee said the safety and efficacy were similar to propofol, only dosing and product form differed. The phase 3 studies were conducted to get labeling that differed from the RLD. It would appear that MGI failed to get this labeling.