The Blunt Facts About Blunts

Mixing tobacco with marijuana.

People who smoke a combination of tobacco and marijuana, a common practice overseas for years, and increasingly popular here in the form of “blunts,” may be reacting to some unidentified mechanism that links the two drugs. Researchers believe such smokers would be well advised to consider giving up both drugs at once, rather than one at a time, according to an upcoming study in the journal Addiction.

Clinical trials of adults with cannabis use disorders suggest that “approximately 50% are current tobacco smokers,” according to the report, which was published in the journal Addiction, and authored by Arpana Agrawal and Michael T. Lynskey of Washington University School of Medicine, with Alan J. Budney of the University of Arkansas for Medical Sciences.  “As many cannabis users smoke a mixture of cannabis and tobacco or chase cannabis use with tobacco, and as conditioned cues associated with smoking both substances may trigger use of either substance,” the researchers conclude, “a simultaneous cessation approach with cannabis and tobacco may be most beneficial.”

A blunt is simply a marijuana cigar, with the wrapping paper made of tobacco and the majority of loose tobacco removed and replaced with marijuana. In Europe, smokers commonly mix the two substances together and roll the combination into a single joint, the precise ratio of cannabis and nicotine varying with the desires of the user. “There is accumulating evidence that some mechanisms linking cannabis and tobacco use are distinct from those contributing to co-occurring use of drugs in general,” the investigators say. Or, as psychiatry postdoc Erica Peters of Yale put it in a press release, “There’s something about tobacco use that seems to worsen marijuana use in some way.” The researchers believe that this “something” involved may be a genetic predisposition. In addition to an overall genetic proclivity for addiction, do dual smokers inherit a specific propensity for smoked substances? We don’t know—but evidence is weak and contradictory so far.

Wouldn’t it be easier to quit just one drug, using the other as a crutch? The researchers don’t think so, and here’s why: In the few studies available, for every dually addicted participant who reported greater aggression, anger, and irritability with simultaneous cessation, “comparable numbers of participants rated withdrawal associated with dual abstinence as less severe than withdrawal from either drug alone.” So, for dual abusers, some of them may have better luck if they quit marijuana and cigarettes at the same time. The authors suggest that “absence of smoking cues when abstaining from both substances may reduce withdrawal severity in some individuals.” In other words, revisiting the route of administration, a.k.a. smoking, may trigger cravings for the drug you’re trying to quit. This form of “respiratory adaption” may work in other ways. For instance, the authors note that, “in addition to flavorants, cigarettes typically contain compounds (e.g. salicylates) that have anti-inflammatory and anesthetic effects which may facilitate cannabis inhalation.”

Studies of teens diagnosed with cannabis use disorder have shown that continued tobacco used is associated with a poor cannabis abstention rate. But there are fewer studies suggesting the reverse—that cigarette smokers fair poorly in quitting if they persist in cannabis use. No one really knows, and dual users will have to find out for themselves which categories seems to best suit them when it comes time to deal with quitting.

We will pass up the opportunity to examine the genetic research in detail. Suffice to say that while marijuana addiction probably has a genetic component like other addictions, genetic studies have not identified any gene variants as strong candidates thus far. The case is stronger for cigarettes, but to date no genetic mechanisms have been uncovered that definitively show a neurobiological pathway that directly connects the two addictions.

There are all sorts of environmental factors too, of course. Peer influences are often cited, but those influences often seem tautological: Drug-using teens are members of the drug-using teens group. Tobacco users report earlier opportunities to use cannabis, which might have an effect, if anybody knew how and why it happens.

Further complicating matters is the fact that withdrawal from nicotine and withdrawal from marijuana share a number of similarities.  The researchers state that “similar withdrawal syndromes, with many symptoms in common, may have important treatment implications.” As the authors sum it up, cannabis withdrawal consists of “anger, aggression or irritability, nervousness or anxiety, sleep difficulties, decreased appetite or weight loss, psychomotor agitation or restlessness, depressed mood, and less commonly, physical symptoms such as stomach pain and shakes/tremors.” Others complain of night sweats and temperature sensitivity.

And the symptoms of nicotine withdrawal? In essence, the same. The difference, say the authors, is that cannabis withdrawal tends to produce more irritability and decreased appetite, while tobacco withdrawal brings on an appetite increase and more immediate, sustained craving. Otherwise, the similarities far outnumber the differences.

None of this, however, has been reflected in the structure of treatment programs: “Emerging evidence suggests that dual abstinence may predict better cessation outcomes, yet empirically researched treatments tailored for co-occurring use are lacking.”

The truth is, we don’t really know for certain why many smokers prefer to consume tobacco and marijuana in combination. But we do know several reasons why it’s not a good idea. Many of the health-related harms are similar, and presumably cumulative: chronic bronchitis, wheezing, morning sputum, coughing—smokers know the drill. Another study cited by the authors found that dual smokers reported smoking as many cigarettes as those who only smoked tobacco. All of this can lead to “considerable elevation in odds of respiratory distress indicators and reduced lung functioning in those who used both.” However, there is no strong link at present between marijuana smoking and lung cancer.

Some researchers believe that receptor cross-talk allows cannabis to modify receptors for nicotine, or vice versa. Genes involved in drug metabolism might somehow predispose a subset of addicts to prefer smoking. But at present, there are no solid genetic or environmental influences consistent enough to account for a specific linkage between marijuana addiction and nicotine addiction, or a specific genetic proclivity for smoking as a means of drug administration.

Agrawal, A., Budney, A., & Lynskey, M. (2012). The Co-occurring Use and Misuse of Cannabis and Tobacco: A Review. Addiction DOI: 10.1111/j.1360-0443.2012.03837.x

Photo credit:

(First published at Addiction Inbox on March 22, 2012).

Seven Powerful Ways to Find your Sunshine Again

Cathy TaughinbaughCathy Taughinbaugh is a guest blogger and a Recovery Coach working with parents of addicted children.   She can be reached through her website

“You must give up the life you planned in order to have the life that is waiting for you.” – Joseph Campbell
Are you feeling overwhelmed because of your child’s drug abuse?

When we take the time to get the support we need, our outlook can feel so much brighter no matter what our children choose to do with their lives.

I’ve found an Al-Anon parent meeting that works for me. We often laugh at our meetings, which may seem strange to you. I’ve discover that if you don’t laugh and seek joy, you remain in that well of despair.

To listen, to talk and to learn how you can live a peaceful and serene life even if your child chooses a life of chaos is immeasurable.

Many come to meetings with paper and pencil in hand ready to write down all the things that will fix their addicted child. They are surprised when their paper is blank and they have nothing to write down. There are no easy answers.

Support groups, such as Al-Anon will not fix your child, but they will help you handle the emotional toll of addiction.

We can offer treatment, and there is always hope that our kids will take us up on our offer. Our addicted child may make the decision that they want to make a change.

It is excruciating, but this is their personal journey. We want to control their progress, but they will cross the bridge to recovery when they are ready.

What can you do in the meantime?

You can work on yourself. You can take steps to ensure that you will remain healthy and find some joy.

Here are some ideas on how to let the sunshine back in your life when you are feeling overwhelmed by addiction:

1) Attend a Parent’s Support Meeting.

Finding a parent’s support group that works for you may take some work, but it is a wonderful way to interact with other parents who have experienced addiction with their children. You will realize you are not alone. You can share and listen openly without feelings of shame. Al-Anon meetings are easy to find in every city, but there are others types of parent groups that may better fit your needs.

2) Exercise

Even taking a walk on a regular basis can do wonders for relieving the stress of dealing with addiction. When you find an exercise plan that works for you and make it a regular part of your week. You will begin to feel better, stronger and more hopeful. Your focus will begin to change.

3) Talk to a Professional

If you are feeling excessively stressed, a counselor trained in addiction, can help to relieve your anxiety about your situation. An objective opinion can be a welcome help on even a short term basis. Just knowing you have someone to call if you need to can make a big difference. Get the support you need early on. Don’t wait until you are emotionally exhausted. Ask others for referrals and find someone you feel comfortable with.

4) Find Some Quiet Time

Sit quietly for a few moments each day. Find a comfortable spot in your home. Sit on a chair or on a cushion on the floor. Let your thoughts float by and don’t judge them. It will help to center your thoughts, and give you a chance to stop and focus on your breath. Your mind will welcome the short break. You will begin to access your inner thoughts. Sitting each day each day helps to make us feel happier. Try it and see if you don’t feel some relief.

5) Treat Yourself Well

Going to a movie, or getting together with friends can add a little fun in your life. It will make you feel better. Just the simple act of bringing in beautiful flowers can give you something to smile about. Take care of yourself and give yourself the loving care that you deserve. Don’t do it just once. Make it a regular part of your life. Treat yourself well and you will realize the benefits.

6) Write Down Your Feelings

Writing each day is a soothing way to express our feelings and get our thoughts down on paper. Find three things to be grateful for each day and write them down. Write about something positive that has happened in your life. You may find that making a goal of writing three pages a day gives you a clear starting and stopping point. Of course, you can add more when you feel the need.

7) Let Go of Trying to Control Your Child’s Disease

When you surrender and realize that your child’s addiction is out of your control, a huge burden is released. We realize that we cannot solve our children’s problems. We can love them, and we can support them in healthy ways. When our children take responsibility for their lives, they become stronger. They will become the person they were meant to be.

Find your sunshine again. You can have that good day you’ve been missing, one day at a time.

Cathy Taughinbaugh is a former teacher and mother of a crystal meth addict who has been in recovery for over 8 years. She writes on addiction, recovery and treatment at You can also follow her on Facebook at Treatment Talk and twitter @treatmenttalk.

No Leg to Stand On: Sandoz Takes on Amgen’s Bid for an Injunction in Filgrastim Biosimilar Litigation

By Kurt R. Karst –      

There’s been a lot of activity in the budding biosimilars world this year, and it’s only February.  On the FDA front, the Agency reportedly has 5 Section 351(k) biosimilars applications under review: (1) Sandoz’s version of Amgen’s NEUPOGEN (filgrastim); (2) Celltrion’s version of Johnson & Johnson’s REMICADE (infliximab); (3) Apotex’s version of Amgen’s NEULASTA (pegfilgrastim); (4) Apotex’s version Amgen’s NEUPOGEN; and (5) Hospira’s biosimilar version of Amgen’s EPOGEN (epoetin alfa) (also marketed by Johnson & Johnson as PROCRIT).  Earlier this year, FDA held the first advisory committee meeting for a biosimilar – for Sandoz’s filgrastim (see our previous post here).  A second advisory committee meeting for Celltrion’s infliximab was scheduled for March 17, 2015, but has been postponed “due to information requests pending with the sponsor of the application.”  FDA action on Sandoz’s Section 351(k) application for filgrastim is expected within the coming weeks; however, even if FDA approves the application, it appears that the launch of the product will be delayed.  In a recent court filing, Sandoz agreed that the company “will not launch its biosimilar filgrastim product in the United States until the earlier of April 10, 2015, or a ruling in Sandoz’s favor on Amgen’s Motion.”  And that’s our segue to the litigation front of the biosimilars world, where things remain hot. 

As we previously reported (here and here), last October, Amgen filed a Complaint in the U.S. District Court for the Northern District of California alleging that Sandoz has unlawfully refused to follow certain procedures created by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  In particular, Amgen alleges that Sandoz opted out of the information exchanges at PHS Act § 351 (l)(2)(A)-(l)(5), but that such option does not exist; and that despite Sandoz’s assertions that the company already provided 180-day notice of commercial marketing to Amgen required under PHS Act § 351(l)(8)(A), such notice cannot be provided until at least FDA approval of a Section 351(k) application.  In making these allegations, Amgen asserts three causes of action: (1) unfair competition under Cal. Bus. & Prof. Code § 17200 et seq.; (2) conversion; and (3) infringement of U.S. Patent No. 6,162,427 covering a method of using NEUPOGEN to treat a disease requiring peripheral stem cell transplantation in a patient in need of such treatment.

Earlier this year, Amgen filed a Motion for Judgment on the Pleadings or, in the Alternative, Motion for Partial Summary Judgment.  That triggered Sandoz to file a Cross-Motion for Judgment on the Pleadings and Opposition to Amgen’s Motion for Judgment on the Pleadings (Amgen’s opposition brief and Sandoz’a reply brief are available here and here).  But as the days went by and the date by which FDA is scheduled to act on Sandoz’s Section 351(k) application crept closer (in early March), Amgen finally decided that the company needed to seek emergency relief. 

On February 5th, Amgen filed a Motion for a Preliminary Injunction in a bid to restrain Sandoz from engaging in the commercial manufacture, use, offer to sell, sale within or importation into the U.S. of its biosimilar filgrastim product until the California District Court decides the parties’ Motions for Judgment on the Pleadings (and, if the court resolves those motions in Amgen’s favor, until, the parties have been placed in the position they would be in had Sandoz complied with the BPCIA).  “Sandoz has sandbagged Amgen,” says Amgen in its court filing. “It has refused to provide its BLA and manufacturing information, frustrating Amgen’s ability to determine which of its many patents it can assert against Sandoz.  And Sandoz intends to launch its product immediately upon FDA licensure, rather than waiting the 180 days required by the law. That is why Amgen brings this motion for a preliminary injunction.”  Among other things, Amgen says that “[i]f Sandoz is permitted to launch its product without having provided the information and time to Amgen as the statute provides, Amgen will be irreparably harmed by losing the opportunity afforded it under the BPCIA to exercise its exclusionary patent rights and seek a preliminary injunction before Amgen is injured by the entry of Sandoz’s biosimilar product.”  That irreparable harm will, according to Amgen, come in the form of harm to research and development, harm to new products in their infancy, price erosion for NEUPOGEN (and Amgen’s NEULASTA), and damage to customer relationships and loss of goodwill.

Hogwash!, says Sandoz in it opposition brief filed earlier this week.  Amgen hasn’t established any of the four factors necessary to support a preliminary injunction: (1) whether Amgen will be irreparably harmed in the absence of an injunction; (2) Amgen’s likelihood of success; (3) the balance between the harm to Amgen and the harm to Sandoz; and (4) the public interest.  It’s a chair without any legs – meaning that it’s either held up by magic, or that it must come crashing down to the ground. 

Sandoz argues that Amgen’s Motion for a Preliminary Injunction fails for myriad reasons:

First, Amgen cannot show it is likely to succeed on the merits.  Amgen seeks to convert a “notice” provision for resolving patent disputes into an “exclusivity” provision.  Adopting Amgen’s interpretation would defy Congress’s intent (as expressed in the statute’s plain language) by extending the exclusivity period from 12 years to 12.5 years. . . .

Second, Amgen cannot show irreparable harm for multiple reasons . . . . Amgen claims that it has been harmed because it did not receive Sandoz’s filgrastim application in July 2014, and so it allegedly could not determine what patents it might potentially be able to assert against Sandoz.  But that alleged harm is of Amgen’s own making.  The BPCIA contemplates a maximum of 60 days for a Sponsor to identify any applicable patents after receiving a 42 U.S.C. § 262(k) application.  Amgen cannot deny (and therefore ignores) that Sandoz offered to produce its Application seven months ago in July 2014, and multiple times since then, subject only to reasonable confidentiality protections.  Amgen chose to decline all of those offers. . . .  Amgen’s alleged harms are not only self-inflicted, they run afoul of two other black-letter rules governing preliminary injunctions: neither speculative injuries nor compensable monetary losses qualify as irreparable harm.

Third, the balance of equities heavily favors Sandoz.  Sandoz is poised to launch the first biosimilar filgrastim in the United States, and an injunction would jeopardize the first-to-market advantage in which it has invested years of effort and tens of millions of dollars.  By contrast, denial of the requested injunction would not impose any undue hardship on Amgen. . . .

Fourth, the public interest factor forecloses Amgen’s request.  The BPCIA expressly seeks to balance two key public purposes: innovation and consumer interests.  Amgen has been amply rewarded for its innovation, enjoying 24 years of exclusivity although Congress concluded in the BPCIA that 12 years meets the public’s interest in innovation.

A hearing on the outstanding Motion for Preliminary Injunction and Motions for Judgment on the Pleadings is scheduled for March 13, 2015 at 10:00 AM.

School Talks

Another two days of school talks wrapped up. It is refreshing for me to do these even if it is only make believe that I am helping. But in critical reflection I believe it is making a difference.

  • Students that have heard me talk in previous years come back to listen again, to be refreshed I was told by a student.
  • Students stand up to the stigma and share what it is like for them and their families.
  • Non-student guests come in to listen and then suddenly share their story and pain opening up with strangers.

I cannot measure or gauge the impact six years of speaking to students has had on our schools, community and students. I don't know if there empirical data points I can plot. However, the anecdotal evidence is overwhelming, I have made an impact on individuals and that is the most important constituency I can touch.

You Are Not Alone, are sometimes the most important words you can say.


The Struggle to Say No – Setting healthy boundaries

One of the challenges that I face now that my daughter is in recovery and living responsibly is my desire to help. The problem is that part of her healthy recovery is learning to take full responsibility for her life. It is so easy for me to rationalize in my mind ‘She’s doing so well, she deserves the help’ or ‘If I don’t help and she struggles, won’t that hurt her recovery and possibly drive her back towards her addiction?’ I could go on and on with various examples. The point is that while it’s only natural to help our loved ones, it has to be weighed carefully with how it will actually ‘hurt’ them instead of ‘help’ them. Struggling with this actually makes me sad. I think of growing up in a family where we helped each other, it was just what we did. If I needed a little boost after college and in the working world, my Mom would often be there to help me through a rough patch or to reach a goal I was striving for. It didn’t come with lots of angst about what I might do with the money or if I would take a step back in growing into adulthood.

While I can ruminate all I want about this, the reality of the situation is that I am not my Mom and my daughter is not me. She is in recovery from addiction and I am a struggling co-dependent – our boundaries can go from healthy to dysfunctional in a very short cycle. The positive thing is that I am completely aware of this dynamic. I stop and think about what I am doing and question what is best, not only for my daughter, but also me. Will this help her in her journey to become a self-sufficient adult or will this hinder that very goal? The other positive aspect is that I can openly talk to her about it. Part of our respective recoveries is having the ability to deal with situations as they arise. It is a blessing to be authentic and open in any relationship, and I cherish this with my daughter.

District Court Rules that Maine Drug Importation Law is Unconstitutional and Preempted by the FDC Act

By Kurt R. Karst –      

In a 19-page decision handed down earlier this week by Judge Nancy Torresen of the U.S. District Court for the District of Maine, the court ruled that Maine’s 2013 law, titled “An Act To Facilitate the Personal Importation of Prescription Drugs from International Mail Order Prescription Pharmacies,”  2013 Me. Legis. Serv. Ch. 373 (S.P. 60) (L.D. 171) (West) (the “Maine Pharmacy Act Amendments” or “MPA Amendments”) permitting (as its title suggests) importation of drug products into the U.S. from licensed retail pharmacies located in certain foreign countries (i.e., Canada, Australia, New Zealand, and the United Kingdom), is unconstitutional under the theory of field preemption.  In doing so, Judge Torresen granted a Motion for Judgment on the Pleadings filed by two Maine pharmacists and three Maine trade associations (the Maine Pharmacy Association, Maine Society of Health-System Pharmacists, and Retail Association of Maine), and denied a Motion for Judgment on the Pleadings filed by Maine’s Attorney General (Janet T. Mills) and Commissioner of Administrative & Financial Services (formerly H. Sawin Millett, Jr., and now Richard Rosen). 

The February 23rd decision stems from a September 2013 Complaint filed by the Plaintiffs, as well as then-Plaintiff the Pharmaceutical Research and Manufacturers of America (“PhRMA”), challenging the MPA under several theories (see our previous posts here and here).  PhRMA was tossed out of the lawsuit last May after the district court ruled that the trade organization lacked Article III standing (see our previous post here). 

The State Defendants argue that the MPA Amendments “simply reduce the reach of the MPA,” “that it is within [the State’s] authority as a sovereign to choose not to regulate certain conduct,” and that to hold otherwise “would violate the Tenth Amendment principle that states may not be compelled to administer federal regulatory programs.”  On the other side, the Maine pharmacist and trade association Plaintiffs argue that the FDC Act “creates a comprehensive and ‘closed’ regulatory scheme, which strictly limits the introduction of prescription drugs into interstate commerce,” and that preempts the MPA Amendments under three theories of preemption: (1) field preemption (i.e., when  “[t]he intent to displace state law altogether can be inferred from a framework of regulation ‘so pervasive . . . that Congress left no room for the States to supplement it’ or where there is a ‘federal interest . . . so dominant that the federal system will be assumed to preclude enforcement of state laws on the same subject.’” Arizona v. United States, 132 S. Ct. 2492, 2501 (2012) (quoting Rice v. Santa Fe Elevator Corp., 331 U.S. 218, 230 (1947)); (2) direct conflict preemption (i.e., a form of implied preemption that occurs when there is an inescapable contradiction between state and federal law); and (3) obstacle preemption (i.e., when “the challenged state law ‘stands as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress.’” Arizona, 132 S. Ct. at 2501 (quoting Hines v. Davidowitz, 312 U.S. 52, 67 (1941)).

Focusing on the Plaintiffs’ contention that the MPA Amendments violate the Supremacy Clause, U.S. Const. art. VI, cl. 2, and 42 U.S.C. § 1983, under the theory of field preemption, Judge Torresen first defined the “field” at issue:

The FDCA does not regulate the licensure of pharmacists; it instead leaves that area to individual states.  If the MPA Amendments were truly limited to the regulation of pharmacy licensure, then evidence of “a congressional decision to foreclose any state regulation in the area” would be lacking.

But by its plain language, the MPA Amendments extend beyond the regulation and licensure of pharmacies and pharmacists within Maine.  The MPA Amendments do not, as the State asserts, simply repeal state licensure regulations; the MPA Amendments select five countries whose licensed retail pharmacies “may export” prescription drugs to Maine residents. . . .  [T]he MPA Amendments extend beyond the traditionally local arena of public health and safety and into the traditionally federal spheres of foreign commerce and affairs.  [(Internal citations omitted)]

As such, the properly defined “field” for preemption purposes in the case, said Judge Torresen, is “the importation of foreign pharmaceuticals.”  From there, it was all downhill for the State Defendants, because the relevant question for the court to address was then whether the FDC Act forecloses Maine’s encroachment into the realm of pharmaceutical importation.

Citing the complex new drug approval process Congress created as part of the FDC Act, as well as provisions included as part of the 2003 Medicare Modernization Act concerning the importation of drugs from Canada, Judge Torresen was compelled to conclude that there’s a clear “Congressional intent to tightly control prescription drug importation,” and that the FDC Act “occupies the field of importation of pharmaceuticals from foreign countries” rather than state law.

No matter how they are applied, the MPA Amendments regulate within the field of pharmaceutical importation.  The State has not suggested any limiting construction which would allow a portion of the law to stand, and the parties have not briefed the issue of severability.  It is apparent that removing the portion of the statute that touches on foreign commerce would defeat the purpose of the law. Because they are contrary to clear Congressional intent to occupy the field of pharmaceutical importation, the MPA Amendments violate the Supremacy Clause and are therefore preempted.

It is unclear at this time whether or not an appeal will be made to the U.S. Court of Appeals for the First Circuit.  According to press reports (here), the sponsor of the bill that was enacted as the MPS Amendments, State Senator Troy Jackson, thinks an appeal is in order. 

Moving down the Eastern Seaboard to Capitol Hill, earlier this year Senators John McCain (R-AZ) and Amy Klobuchar (D-MN) introduced S. 122, the Safe and Affordable Drugs from Canada Act of 2015, which would amend the FDC Act to require the Department of Health and Human Services to promulgate regulations within 180 days permitting individuals to import a prescription drug purchased from an approved Canadian pharmacy under certain specified conditions.

Being Vulnerable

One of the main reasons we have problems in early recovery is our inability to be open and honest with others. Most of us have spent a good part of our lives hiding one truth or another from the people around us. Telling the truth about our addictive behavior would endanger it, and we protect our […]

A New Variation on an Old Theme: FDA Refuses PTE Regulatory Review Period Revision Based on Filing Refusal Decision

By Kurt R. Karst –      

It’s been a long time since we last posted on a Patent Term Extension (“PTE”) controversy  – a little more than a year it seems (see here) – but that doesn’t mean we’re not keeping an eye on decisions coming out of FDA and the Patent and Trademark Office (“PTO”).  We still diligently track issues and cases of interest, whether with respect to so-called “reverse Photocure” issues (see our previous post here, and here for a recent FDA decision in Docket No. FDA-2014-E-0025), first permitted commercial marketing issues (see, e.g., here), or regulatory review period determination issues.  That last topic is the subject of today’s post.

Under 35 U.S.C. § 156, certain patents covering products regulated by FDA are eligible for a PTE if patent life was lost during a period when the product was undergoing regulatory review.  The “regulatory review period” is composed of a “testing phase” and a “review phase” (also referred to as an “approval phase”).  For drugs approved under the FDC Act, the “testing phase” begins on the effective date of an IND, and ends on the date an NDA (or BLA) is initially submitted to FDA.  The “review phase” is the period between the initial submission of the NDA (or BLA) and approval.  (The term of a patent may be extended for a period of time that is the sum of one-half of the time in the “testing phase,” plus all the time in the “review phase,” and minus any of the “regulatory review period” that occurs prior to the patent grant or where the sponsor did not act with due diligence.)   FDA’s regulations implementing the statute’s PTE provisions state that “[t]he approval phase begins on the date a marketing application under section 351 of the Public Health Service Act or section 505(b) of the Act is initially submitted to FDA . . . and ends on the date the application is approved” (21 C.F.R. § 60.22(a)(2) (emphasis added)), and that “[f]or purposes of determining the regulatory review period for any product, a marketing application . . . is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application” (21 C.F.R. § 60.22(f) (emphasis added)). 

Over the years, questions have cropped up as to when the review phase begins – that is, when is an application considered initially submitted to FDA – in the context of “rolling” or modular submissions.  Insofar as NDA and BLA “fast track” submission are concerned, FDA has determined that receipt of the last module (or application component) makes the application complete, and thus “initially submitted” for PTE purposes.  This has been the topic of several letter decisions, including in Docket No. FDA-2005-E-0310 concerning KEPIVANCE, in Docket No. FDA-2009-E-0237 concerning DEXILANT, and in Docket No. FDA-2007-E-0278 concerning ZOLINZA.  FDA has come to a similar conclusion involving modular PMA (medical device) submissions (see our previous post here).

Perhaps most famously, both FDA and the PTO were sued over their determinations as to what it means for an animal drug application to be initially submitted to FDA.  In Wyeth Holdings Corp. v. Sebelius, Wyeth contended that a 16-day approval phase for a New Animal Drug Application reviewed under FDA’s Phased Data Review Policy and Administrative NADA process was unreasonable, and that the NADA was initially submitted to FDA when the company submitted the first technical section to its application.   In May 2010, the U.S. Court of Appeals for the Federal Circuit affirmed a March 2009 decision from the U.S. District Court for the District of Columbia granting summary judgment to FDA and the PTO (see our previous posts here and here). 

The case of U.S. Patent No. 6,087,380 (“the ‘380 patent) covering Boehringer Ingelheim Pharmaceuticals, Inc.’s (“BIPI’s”) PRADAXA (dabigatran etexilate) Capsules offers up a new twist on the question: “When is an NDA subject to a rolling review initially submitted to FDA?” 

PRADAXA is the subject of NDA 022512, which FDA approved on October 19, 2010, and for which the final “piece” of the submission arrived at FDA on December 15, 2009.  Almost two months after receiving that final NDA component, however, FDA, on February 12, 2010, issued a Refuse-to-File (“RTF”) letter refusing to file the December 15, 2009 submission for clinical reasons.  Nevertheless, FDA continued to review other parts of the application (e.g., Chemistry, Manufacturing, and Controls).  On April 19, 2010, BIPI resubmitted the NDA and the application was later accepted for review and approved.

Fast-forward to May 2012, after BIPI timely requested a PTE for the ‘380 patent, and FDA’s publication of a notice in the Federal Register that the regulatory review period for PRADAXA is 2,633 days, of which 2,449 days occurred during the testing phase and only 184 days occurred during the approval phase.  The FDA notice states, in particular, with respect to the approval phase that:

The date the application was initially submitted with respect to the human drug product under section 505(b) of the FD&C Act: April 19, 2010.  The applicant claims December 15, 2009, as the date the new drug application (NDA) for PRADAXA (NDA 22–512) was initially submitted.  However, FDA records indicate that NDA 22–512, received December 15, 2009, was incomplete.  FDA refused to file this application and notified the applicant of this fact by letter dated February 12, 2010.  The completed NDA was then submitted on April 19, 2010, which is considered to be the NDA initially submitted date.

BIPI timely requested reconsideration of the regulatory review period determination asking that the initial submission date of NDA 022512 be corrected from April 19, 2010 to December 15, 2009.  According to BIPI, “[a]ll of the required elements of the NDA were submitted to FDA as of December 15, 2009,” and “[a]lthough FDA issued a [RTF] letter to BIPI on February 12, 2010, the agency continued to review the NDA.” 

FDA did not agree, however, that the continued review of NDA 022512 was material, and did not agree that the NDA could be considered initially submitted on December 15, 2009 as a result of the subsequent RTF determination.  In a Letter Decision that cites legislative history, a regulatory review period determination of a 1994 vintage, and (of course) the Federal Circuit’s Wyeth decision, FDA says:

For determining the regulatory review period, the application filing review provides a measure of whether an application contains all the information necessary for Agency review to begin.  If an application can be filed, then it is considered sufficiently complete.  If the application is sufficiently complete, then the end date of the testing phase of the regulatory review period and the beginning of the approval phase can be declared and the initially submitted date is the NDA receipt date.  However, if the application cannot be filed (RTF), then it is not sufficiently complete and the approval phase has not yet begun. . . .

FDA permitted BI to submit its application on a “rolling review” basis, so that segments of the application that would be reviewed by different disciplines within FDA could be submitted when they were ready.  It was clearly understood, however, including by BI, that the application itself would not be considered to be submitted to FDA until such time as the last segment of the application was submitted for FDA review so that the complete application was before the agency. . . .

Thus, the fact that BI had submitted, and FDA had begun to review, modules of the application —and continued to review them after the application was refused for filing based on the promise that the application would be resubmitted— has no effect on the date that the application is considered to have been “initially submitted” for purposes of 35 U.S.C. 156(g).  While, as the Wyeth court found, this statutory provision may be considered ambiguous, the FDA interpretation is clear, and it is binding here.  Accordingly, no application is considered to be “initially submitted” if it has not been found to be sufficiently complete to meet the filing requirement for an application.

Interestingly, FDA says that BIPI had the chance to secure a date earlier than April 19, 2010 as the date of initial submission, but lost it when the company decided not to raise the rarely used “filing over protest procedures” at 21 C.F.R. § 314.101(a)(3).  According to FDA:

While BI had an opportunity, under FDA regulations, to contest FDA’s position, assert that its application was in fact sufficiently complete to be reviewed, and ask FDA to file the application over protest, BI did not do so.  FDA accordingly refunded 75% of the user fee for this application and awaited submission of additional and corrected data that would permit the application to be considered suffrciently complete such that FDA review of the entire application could commence.  On April 19, 2010, BI submitted the necessary data to complete its application, together with a user fee required for the resubmission of a new drug application.

FDA’s RTF regulation provides that if the Agency issues a RTF decision, “the applicant may request in writing within 30 days of the date of the agency’s notification an informal conference with the agency about whether the agency should file the application,” and that “[i]f, following the informal conference, the applicant requests that FDA file the application (with or without amendments to correct the deficiencies), the agency will file the application over protest . . . , notify the applicant in writing, and review it as filed.”  In that case, “the date of filing will be the date 60 days after the date the applicant requested the informal conference.” 

Although it’s unlikely that FDA’s decision means that we’ll see a rush of “filing over protest” actions by NDA and BLA sponsors, it’s certainly a tool to keep in mind if the PTE calculus warrants such an action.