Dealing with Teen Substance Abuse

One of the most painful experiences that parents can encounter is when their teenaged child falls in with “the bad crowd” and becomes actively involved with drugs or alcohol. For the majority of parents, any element that can cause harm or injury to their beloved child will worry and pain them. Substance abuse is an incredibly difficult facet of a teenager’s life for a parent to endure.

A large number of people believe that, to stop abusing drugs and/or alcohol, you simply cease to imbibe any further. They erroneously see drug dependency and substance addiction as a collective problem for those who are in some way ethically weak. Unfortunately, it has become widespread opinion throughout society that drug abusers can simply alter, modify or stop their drug use behavior at will. This is obviously not the case. Many argue that the concept of substance addiction is heritable, and that both genetics and family background play an immense role in how a person formulates their own attitude towards drug use.

Because addiction in teenagers is generally characterized by recurring relapses and other temporary setbacks, those who are substance dependent do not expect to overcome their addiction immediately. Sadly, this typically dissuades them from trying at all, and they continue on their downward spiral. In order of prominence, the three steps that teens usually encounter are:

1. Experimentation: A teenager may give cigarettes, alcohol or drugs a try, and some may not partake any further after the first time.
2. Substance abuse: Experimenting with substances may lead to more regular use. Symptoms include a prominent increase in arguments, aggression or violence, and a considerable drop in school grades and interest in recreational activities.
3. Substance dependence: Also known as addiction, this all-consuming aspect can make your teen both physically and psychologically reliant on a particular substance to an extremely intense degree. At this juncture, teens have a higher proclivity for engaging in high-risk behaviors such as unprotected sex, and can suffer from paranoia, hostile mood swings and severe bouts of depression. This final step is the chronically progressive and possibly fatal component of the disease, and will succeed in siphoning off a substantial part of your teen’s life.

A complicated process is needed to reverse drug dependence. If you suspect that your teen has become involved with alcohol or substance abuse, you must confront them and ask. Voicing your concerns will save them from a great deal of pain and suffering. Find out what substances your teen has experimented with, and try to gauge the extent of their usage. Listen carefully to what they liked about the experience in the first place, and ask about their thoughts on quitting this drug-related behavior.

Discuss every concern you have together, provide drug education and talk about the awful consequences and long-term effects. Finally, ask for the professional help that only a doctor or mental health professional can provide. A drug treatment center can offer a warm and comforting setting where you can discuss your problems with others who also suffer the same symptoms. You will not regret this important decision and, while it may not seem like it now, recovery is closer than you think.

A Place of Hope’s Center for Counseling and Health Resources can help those seeking addiction treatment for illicit substance abuse addiction, prescription drug addiction, or problems relating to gambling, steroids, sedatives or alcoholism. Under the expert tutelage of Dr. Gregory Jantz, our dedicated team of addiction medical professionals, psychologists, nutritionists and fitness trainers will help you to address the physical and mental issues behind your symptoms. For more information, please visit us online at A Place Of Hope For Addiction or call toll free on 888-379-3372. Everyone deserves a healthy, well-balanced and addiction-free life.

Deliverance: FDA is Sued Over the Applicability of 3-Year Exclusivity in the Context of Dueling Tacrolimus NDAs; Agency Gets a Short Reprieve to Make a Final Decision

By Kurt R. Karst –    

Queue up the dueling banjo scene from the film Deliverance. . . . 

Early last month we saw an interesting press release from Veloxis Pharmaceuticals, Inc. (“Veloxis”) announcing FDA’s October 30, 2014 tentative approval of the company’s 505(b)(2) NDA 206406 for ENVARSUS XR (tacrolimus extended-release tablets), 0.75 mg, 1 mg, and 4 mg, for prophylaxis of organ rejection in kidney transplant patients.  Why only a tentative approval?  According to FDA:

[T]he listed drug product Astagraf XL (NDA 204096), with which you share conditions of approval for which new clinical studies were essential, is subject to a period of exclusivity protection under sections 505(c)(3)(E)(iii) and 505(j)(5)(F)(iii) of the Act.  Therefore, final approval of your application under section 505(c)(3) of the Act [21 U.S.C. 355(c)(3)] may not be made effective until that product’s exclusivity period has expired.

FDA approved Astellas Pharma US, Inc.’s (“Astellas’s”) 505(b)(1) NDA 204096 for ASTAGRAF XL (tacrolimus extended-release capsules), 0.5 mg, 1 mg, 5 mg, on July 19, 2013 for prophylaxis of organ rejection in adult patients receiving kidney transplants.  In addition to several patents, the Orange Book lists a period of 3-year exclusivity that expires on July 19, 2016 and that is coded “NDF” – defined in an Orange Book addendum to mean “NEW DOSAGE FORM.”

In the company’s press release, Veloxis expressed its discontent with FDA’s decision, saying that “Veloxis disagrees that exclusivity for Astagraf XL, which was not identified as a listed drug or relied upon to support approval of Envarsus XR, should require delay in the formal approval of Envarsus XR.”  The company also noted that it “plans to immediately appeal this decision within FDA, and will pursue all options available to it.” 

At the time, we thought about posting on the Veloxis tentative approval as part of a broader discussion of the scope of 3-year new clinical investigation marketing exclusivity provided for under the Hatch-Waxman Amendments, including the then-recent announcement that Zogenix, Inc. and  Purdue Pharma L.P. entered into an agreement under which the two companies exchanged waivers of 3-year exclusivity applicable to their respective single-entity, extended-release hydrocodone products.  But we didn’t.  Something told us – perhaps Veloxis’s comment that the company “will pursue all options available to it” – to hold off because the dispute might ripen into a lawsuit against FDA.  And that’s exactly what happened.

Earlier this week, Veloxis filed a Complaint and a Motion for Preliminary Injunction in the U.S. District Court for the District of Columbia challenging FDA’s denial of approval of the ENVARSUS XR 505(b)(2) NDA as a result of the exclusivity FDA granted to ASTAGRAF XL.  (In a separate motion, Veloxis  requests that the district court treat Veloxis’s Motion for Preliminary Injunction as a motion for summary judgment by consolidating the hearing on Veloxis’s Motion for Preliminary Injunction with a hearing on the merits.)  Veloxis alleges that FDA’s actions violate the Administrative Procedure Act (“APA”).  Specifically, says Veloxis, FDA’s decision is erroneous as a matter of law and a violation of the APA for three independent reasons:

First, according to the unambiguous statutory language of the [FDCA], Astagraf XL was never entitled to three-year exclusivity.  For drug products like Astagraf XL, exclusivity is only available if an application for approval was submitted to FDA after October 2008.  Because the initial NDA for Astagraf XL was submitted in 2005, FDA’s grant of exclusivity to Astagraf XL exceeded its statutory authority.

Second, even if Astagraf XL is eligible for three-year exclusivity (and it is not), that exclusivity, as a matter of law, cannot block approval of Envarsus XR because the Envarsus XR NDA did not rely upon any of the studies or data supporting approval of Astagraf XL.

Third, even if the reliance requirement was read out of the FDCA, Envarsus XR still would not be subject to the exclusivity granted Astagraf XL because Envarsus XR does not share conditions of approval with Astagraf XL.  In this regard, FDA arbitrarily and capriciously concluded that the two drugs share the same conditions of approval, ignoring the significant clinical differences between the two drugs and the material differences in the package inserts, and abandoning more than 20 years of its own precedent.

Before turning to each of these arguments, we have a some background and comments on 3-year new clinical investigation exclusivity. 

Under the FDC Act and FDA’s implementing regulations, an applicant (either a 505(b)(1) or a 505(b)(2) applicant) may qualify for a 3-year period of exclusivity if the application is for a previously approved active moiety and if the application contains: (1) “reports of new clinical investigations (other than bioavailability studies);” (2) that were “essential to approval” of the application; and (3) that were “conducted or sponsored by” the applicant.  All three criteria must be satisfied in order to qualify for 3-year exclusivity.  Each criterion is defined in FDA’s implementing regulations.

Three-year exclusivity, extends to the “conditions of approval [of an] original application” (emphasis added) and prevents FDA from approving a 505(b)(2) application (or an ANDA) for a drug for those new conditions for 3 years.  With respect to 505(b)(2) applicants, the law (at FDC Act § 505(c)(3)(E)(iii)) states:

If an application submitted under [FDC Act § 505(b)] for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application approved under [FDC Act § 505(b)] is approved after September 24, 1984, and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, [FDA] may not make the approval of an application submitted under [FDC Act § 505(b)] for the conditions of approval of such drug in the approved [FDC Act § 505(b)] application effective before the expiration of three years from the date of the approval of the [FDC Act § 505(b) application] ifthe investigations described in clause (A) of subsection (b)(1) of this section and relied upon by the applicant for approval of the application were not conducted by or for the applicant and if the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. [(Emphasis added)]

FDA explained the limited scope of 3-year exclusivity in the preamble to the Agency’s proposed regulations implementing the Hatch-Waxman Amendments (54 Fed. Reg. 28,872 (July 10, 1989)):

Exclusivity provides the holder of an approved [application] limited protection from new competition in the marketplace for the innovation represented by its approved drug product. . . .  If the innovation is a new dosage form or route of administration, then exclusivity protects only that aspect of the drug product, but not the active ingredients.  If the innovation is a new use, then exclusivity protects only that labeling claim and not the active ingredients, dosage form, or route of administration. . . . 

In explaining what applications would be blocked by 3-year exclusivity, FDA also stated:

If these requirements are met [(i.e., new clinical investigations conducted or sponsored by the applicant that are essential to approval)], approval of an ANDA or of a 505(b)(2) application for a duplicate drug product or an ANDA submitted pursuant to an approved petition under section 505(j)(2)(C) for a similar drug product that relies on the information supporting the new conditions of approval of the first approved application, may not be made effective before the expiration of 3 years from the date of approval of the original new drug application. [(Emphasis added)]

More recently, FDA explained in a Letter Decision the scope of 3-year exclusivity (at least insofar as ANDAs are concerned and in relation to an NDA Supplement).  According to FDA:

The statute sets up a relationship between the “new clinical investigations” that are “essential to the approval of the supplement,” and the scope of exclusivity.   That is, if an applicant submits a supplement and gets 3-year exclusivity for a change in the use of the drug product supported by new clinical investigations, the FDA may not approve an ANDA referencing that drug product for the “change approved in the supplement” during that 3-year exclusivity period.  Because the change in the drug product or use of the drug product that was approved in the supplement was based at least in part on the new clinical investigations, it naturally follows that the scope of any exclusivity also will relate to the scope of those new clinical investigations.

FDA’s regulation similarly emphasizes a relationship between the change in the use of the drug product supported by the supplement and the scope of the exclusivity that the supplement earns.  The regulation provides that the agency will not approve an ANDA referencing a drug product for three years if the ANDA “relies on [] information supporting a change approved in the supplemental new drug application.” 21 C.F.R. § 314.108(b)(ii)(5).  The regulation, in context with the definition for “new clinical investigation,” emphasizes this relationship between the information from the new clinical investigation, the change approved in the supplement, and the scope of what the ANDA seeks to rely on for approval.  [(Emphasis added)]

Although the 3-year exclusivity provisions in the FDC Act state that such exclusivity prevents a subsequent 505(b)(2) applicant from being approved for the same protected conditions of approval if the subsequent applicant relies on the previous applicant’s information, and although FDA has stated that 3-year exclusivity prevents the Agency from approving another 505(b)(2) application (or an ANDA) “that relies on the information supporting the new conditions of approval of the first approved application,” one statement in the preamble to FDA’s proposed rules implementing the Hatch-Waxman Amendments suggests that approval of a 505(b)(2) application with exclusivity would prevent approval of a subsequent 505(b)(2) application for 3 years even though the subsequent 505(b)(2) applicant did not rely on data in the first 505(b)(2) application.  That statement reads as follows:

The exclusivity provisions of sections 505(c)(3)(D) (iii) and (iv) of the act delay the effective date of approval of any 505(b)(2) application that is for the conditions of use of a previously approved application that contained new clinical investigations essential for approval.  Consequently, if two 505(b)(2) applications are under review at the same time and one is approved before the other, the effective date of approval of the second application to be approved will be delayed, regardless of the date of submission, if the first contained new clinical investigations essential for approval and thereby qualified for exclusivity.

This statement, which has been referred to as “FDA’s dueling 505(b)(2) application policy,” has not, to our knowledge, been further publicly discussed by FDA since stating it in 1989.  (This policy was raised in 2005 in the context of a citizen petition about the appropriate type of exclusivity to award to 505(b)(2) applicants for hyaluronidase drug products (Docket No. FDA-2005-P-0005); however, because FDA ultimately determined that 5-year new chemical entity exclusivity, instead of 3-year exclusivity, should be granted to each hyaluronidase applicant, the Agency did not address the scope of 3-year exclusivity and whether the first company to obtain 505(b)(2) application approval would block the approval of subsequent 505(b)(2) applicants for the same conditions of use, even where subsequent 505(b)(2) applicants did not rely on data in the first applicant’s 505(b)(2) application.)

The current dispute over FDA’s ability to approve Veloxis’s NDA 206406 for ENVARSUS XR given the 3-year exclusivity FDA granted with respect to NDA 204096 for ASTAGRAF XL does not specifically concern FDA’s dueling 505(b)(2) application policy – because ASTAGRAF XL was approved as a 505(b)(1) NDA and ENVARSUS XR is the subject of a 505(b)(2) NDA – however, it may be functionally equivalent.  That might explain, at least in part, why FDA refused to grant final approval of ENVARSUS XR depite no reliance on the ASTAGRAF XL approval.  In any case, on to the current dispute . . . .

Veloxis’s first argument that FDA’s decision is erroneous as a matter of law implicates the 2008 QI Act, which, among other things, added Section 505(v) to the statute.  FDC Act § 505(v) provides that so-called “old antibiotics” (i.e., antibiotic drugs, like tacrolimus, for which the first application was received before the November 21, 1997 enactment of the Food and Drug Modernization Act of 1997) are not eligible for 3-year exclusivity for any condition of use for which the old antibiotic was approved before October 8, 2008 (i.e., the date of the enactment of the QI Act), but also that an old antibiotic is eligible for 3-year exclusivity for a new condition of use if that application is submitted to FDA after October 8, 2008.  As we previously reported, FDA was successful in defending the only challenge to the Agency’s application of FDC Act § 505(v). 

According to Veloxis:

The Astagraf XL NDA initially was submitted in 2005 and, in fact, was pending at FDA prior to, during, and after the enactment of the QI Act on October 8, 2008.  Accordingly, as a matter of law, Astagraf XL was not entitled to three-year exclusivity when the QI Act was passed. . . .  It appears that FDA granted exclusivity to Astagraf XL on the basis that – even though it was the subject of a pending NDA at the time of the enactment of the QI Act – Astellas withdrew its NDA in 2009 and refiled it in 2012.  The prohibitions of the QI Act, however, cannot be avoided through such manipulation of the regulatory process. FDA’s grant of exclusivity to Astagraf XL was contrary to Congress’s intent and inconsistent with the incentive structure created by Congress in the QI Act, and therefore in excess of FDA’s statutory authority.

Veloxis argues next that even if ASTAGRAF XL is eligible for 3-year exclusivity, that exclusivity cannot block approval of ENVARSUS XR because the Veloxis NDA did not rely upon any of the studies or data supporting approval of ASTAGRAF XL.  As noted above, FDA has, in most circumstances, keyed the applicability of 3-year exclusivity to reliance.  Thus, argues Veloxis:

The FDCA provides that if an NDA is approved and awarded three-year exclusivity based upon “reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant,” FDA may not approve a pending 505(b)(2) application “for the conditions of approval” of the first drug for a period of three years if the safety and effectiveness studies “relied upon by the [505(b)(2) applicant] for approval of the [505(b)(2)] were not conducted by or for [the 505(b)(2) applicant] and if [the applicant] has not obtained a right of reference or use from the person by or for whom the investigations were conducted.” 21 U.S.C. § 355(c)(3)(E)(iii) (emphasis added).  This statutory language unambiguously requires an overlap in the relied upon studies to trigger the period of exclusivity.  In the absence of such overlap, exclusivity is inapplicable as a matter of law. . . .

The language, structure, and purpose of the Hatch-Waxman Amendments all establish that Congress intended three-year marketing exclusivity under Section  505(c)(3)(E)(iii) to block approval of only those 505(b)(2) applications that rely upon the data supporting the approval of the drug with exclusivity.  As the Envarsus XR NDA does not rely upon the clinical studies conducted by Astellas in connection with the Astagraf XL NDA, FDA’s application of Astagraf XL’s exclusivity to Envarsus XR is contrary to the FDCA’s plain language, in excess of the FDA’s statutory authority, and in violation of the APA

Finally, Veloxis argues that even if the reliance requirement was read out of the statute, ENVARSUS XR still would not be subject to ASTAGRAF XL’s exclusivity because the drug products don’t share conditions of approval.  “Consistent with longstanding FDA precedent,” writes Veloxis, “because the two drugs have markedly different (i) dosage forms, (ii) dosing strengths, (iii) dosing regimens, and (iv) pharmacokinetic profiles, they cannot be considered to share conditions of approval.”  Citing several FDA approval precedents, Veloxis says that they

confirm that, throughout the twenty years since the Hatch-Waxman Amendments were enacted, FDA repeatedly has approved 505(b)(2) applications for products that share a common active ingredient, indication, dosage form, and dosage frequency with a drug subject to exclusivity.  FDA has done so because the later-in-time applications did not rely on data necessary to the approval of the drug with exclusivity.  Indeed, Veloxis is not aware of a single instance in which FDA has applied exclusivity to block approval of a product with a different dosage form that did not reference or rely upon the drug with exclusivity.

In a Motion to Stay Proceedings Pending Final Agency Action FDA says that the case is unripe.  “On December 12, 2014, FDA informed Veloxis that it intends to issue a final decision on the underlying merits in this matter no later than January 12, 2015.  Because the agency is diligently considering the complex scientific and regulatory issues presented by Veloxis’ submissions, Veloxis’ lawsuit is unripe.”  As such, FDA requests that the district court stay the proceedings until January 12, 2015 to give FDA time to issue a final decision in the matter.  After that decision is issued, FDA “would be happy to discuss an expedited schedule for merits briefing and production of the Administrative Record, if necessary.” 

On December 18th, the district court granted FDA’s motion, denied Veloxis’s Motion for Preliminary Injunction without prejudice, and ordered the parties to appear before the court for a status hearing on January 14, 2015 (10:45 AM).

National Impaired Driving Prevention Month

drunk_driving.jpgThe holiday season is a special time for family and friends to celebrate the end of one year and the beginning of another. While many of these celebrations involve the consumption of alcohol, it is imperative for people to think twice before getting behind the wheel. Data from the National Highway Traffic Safety Administration shows an increase in DUI-related incidents in the month of December, and as such, increases the risk of traffic accidents. In an effort to bring awareness to this problem, President Obama proclaimed December 2014 as National Impaired Driving Prevention Month.

All Americans deserve to live long and full lives, and every child should have the chance to seize his or her future. But throughout our Nation, too many lives are tragically cut short in traffic crashes involving drunk, drugged, or distracted driving. Impaired driving not only puts the driver at risk—it threatens the lives of passengers and all others who share the road, and every year it causes the deaths of thousands of loved ones. This month, and especially during the holiday season, we dedicate ourselves to driving safely and responsibly, and to promoting these behaviors among our family and friends…To help save lives, States and local communities across our Nation will participate in the national Drive Sober or Get Pulled Over campaign from December 12 to January 1, reminding all Americans of their important responsibility…This holiday season, all Americans can drive responsibly and encourage their loved ones to do the same, including by designating a sober driver or making alternative transportation arrangements.” – President Barack Obama

National Impaired Driving Prevention Month

drunk_driving.jpgThe holiday season is a special time for family and friends to celebrate the end of one year and the beginning of another. While many of these celebrations involve the consumption of alcohol, it is imperative for people to think twice before getting behind the wheel. Data from the National Highway Traffic Safety Administration shows an increase in DUI-related incidents in the month of December, and as such, increases the risk of traffic accidents. In an effort to bring awareness to this problem, President Obama proclaimed December 2014 as National Impaired Driving Prevention Month.

All Americans deserve to live long and full lives, and every child should have the chance to seize his or her future. But throughout our Nation, too many lives are tragically cut short in traffic crashes involving drunk, drugged, or distracted driving. Impaired driving not only puts the driver at risk—it threatens the lives of passengers and all others who share the road, and every year it causes the deaths of thousands of loved ones. This month, and especially during the holiday season, we dedicate ourselves to driving safely and responsibly, and to promoting these behaviors among our family and friends…To help save lives, States and local communities across our Nation will participate in the national Drive Sober or Get Pulled Over campaign from December 12 to January 1, reminding all Americans of their important responsibility…This holiday season, all Americans can drive responsibly and encourage their loved ones to do the same, including by designating a sober driver or making alternative transportation arrangements.” – President Barack Obama

Fair Weather Friends

One of the dilemma’s with drug and alcohol rehab is lack of readiness of the addict to want sobriety. Usually as parents we want it for them more than they do for themselves. Each time my daughter went into rehab she was given a fork in the road – go to rehab or go out to the street – her choices were limited since she had narrowed her world to other people also making poor choices. This in retrospect was a gift. The ‘friends’ she had made were like ‘fair weather’ friends only their version was ‘share the wealth’ – as long as my daughter had money or drugs, she had lots of friends, when either of these ran out, the ‘friends’ were nowhere to be seen. This worked in our favor when we came to the cross roads. As anyone reading this and who has a child or loved one struggling with addiction – the crossroad comes – sometimes quickly, sometimes slowly, but it always comes.
One of the learning’s along the way is that I was still ‘managing’ my daughter’s life and her recovery. While this can appear to be very loving and very supportive, it is just prolonging the true impetus for the addict to make a change. It’s easy for people when others make decisions for them – when it doesn’t work out then all the blame can go back to the person who made the decision. It also keeps the person from learning responsibility. All through this part of the journey I was teaching my daughter that she was not capable – that I had to be involved for her to survive. It is the essence of co-dependency. I had learned this along the journey. I gained the awareness that I needed to make changes with myself if I truly wanted what was best for my daughter.

That Time of Year

As the first first snowfall of the season blankets Kansas City there brings a feeling of peace for the season in me. Although I am not a religious person I appreciate this time of year. When traditionally a feeling of peace and love is suppose to overtake us all and sweep everyone into a blissful state good cheer it doesn't always happen that way for all.

Parents of an addict know how painful it is during the holiday season. Our expectations lead us to imagine this perfect season. We ache for that time before the monster of addiction invaded our family. Then all of a sudden reality snaps us back to the heartache of a loved one afflicted with this terrible disease.

On another blog long ago, I don't remember who said it but I have always remembered the thought. "An expectation is nothing more than a premature disappointment." When I first read that I remember thinking to myself what a sad life that must be to be a parent that believes something like that to be true. Like I said, that was a long time ago. As I lived I learned more about myself and more about addiction, no longer is that phrase sad, that phrase is freedom.

This holiday can be a time of peace for parents of an addict as long as we remember to accept what is given and accept that our loved one is suffering from the disease of addiction.

Addiction takes no holiday. Share your love, share the holiday.

The Proposed NIH Framework for Clinical Trials Registration and Results Reporting: A Closer Look

By James E. Valentine* & Anne Marie Murphy

As we previously reported, last month the National Institutes of Health (“NIH”) published a Notice of Proposed Rulemaking on clinical trials registration and results submission (“NPRM”), and is requesting public comment by February 19, 2015.  The NPRM generally applies to “responsible parties” for “applicable clinical trials.”  In our previous post we took a first look at some of the key areas of expansion that are being considered as part of the rulemaking process, which includes NIH’s proposal to require disclosure of results information for trials of products that are not approved and limit the delay for disclosure of those results.  In addition to these high profile issues, there are a wide range of other clarifications and changes proposed in the 116-page NPRM.

Applicable Clinical Trials

The registration and results reporting requirements apply to all “applicable clinical trials.”  Section 801 of the Food and Drug Administration Amendments Act of 2007 (“FDAAA 801”) defined an “applicable clinical trial” as either an applicable device clinical trial or an applicable drug clinical trial.  An applicable drug clinical trial is defined as a controlled clinical investigation, other than a phase 1 clinical investigation of a drug subject to [the New Drug Application (“NDA”) or Biologics License Application (“BLA”) sections of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”).  An applicable device clinical trial is defined as either (1) a prospective clinical study of health outcomes comparing an intervention with a device subject to the 510(k), Premarket Approval (“PMA”), or Humanitarian Device Exemption (“HDE”) sections of the FD&C Act against a control in human subjects except for feasibility studies or (2) a pediatric postmarket surveillance as required under section 522 of the FD&C Act.

A key consideration in determining if a study meets the definition of an applicable clinical trial is if it is “controlled.”  The NPRM proposes to include both concurrent controls and non-concurrent controls, such as historical controls or comparisons to baseline data.  For single-arm trials, the NPRM would require that the control be specified in the protocol or statistical analysis plan, and for this to be identified as part of registration.  NIH invites comments specifically on this approach for identifying controlled single-arm trials.

Another key consideration is whether the drug is subject to U.S. Food and Drug Administration (“FDA”) regulation (as opposed to studies conducted entirely outside of the U.S.).  In general, studies are considered subject to FDA regulation if they meet one of the following criteria:

  • include one or more clinical study sites in the United States;
  • study a drug that is manufactured in the United States or its territories and is exported for use in a clinical trial outside the United States; or, 
  • conducted under an Investigational New Drug (“IND”).

Rather than continuing to have registrants indicate whether their trial is an applicable clinical trial, NIH proposes using a limited set of registration data elements on ClinicalTrials.gov to simplify the determination of whether a particular study meets the definition of an applicable clinical trial. 

Responsible Party

While not new information, the NPRM reiterates FDAAA 801’s definition for a “responsible party” with respect to a clinical trial of a drug or device as either (1) the sponsor of the clinical trial, or (2) the principal investigator of such clinical trial if designated by a sponsor, so long as the principal investigator is responsible for conducting the trial, has access to and control over the data from the trial, has the right to publish the results of the trial, and has the ability to meet all of the registration and reporting requirements.  If the trial is conducted under an IND or IDE, the IND/IDE holder is the sponsor; otherwise the sponsor is the person or entity who initiates the trial, by preparing and/or planning the trial, and who has authority and control over the trial.  For a pediatric postmarket surveillance of a device that is not a clinical trial, the responsible party is the entity whom FDA directs to conduct the surveillance of the device. 

Registration

In the NPRM also reiterates FDAAA 801’s general registration requirement: a responsible party must register an applicable clinical trial at ClinicalTrials.gov not later than 21 calendar days after enrolling the first participant.  The NPRM specifies requirements for registration, which include establishing structured data elements within four categories:

  • descriptive information (e.g., title, brief summary, primary purpose, study design, study phase, study type, primary disease or condition being studied, intervention name, study start date, completion date, enrollment);
  • recruitment information (e.g., eligibility criteria, gender, age limits, overall recruitment status, actual enrollment, individual site status);
  • location and contact information (e.g., name of sponsor, responsible party, facility information); and,
  • administrative information (e.g., unique protocol identification number, FDA IND number, human subjects protection review board status, record verification date, responsible party contact information).

Many of the registration data elements outlined in the NPRM are not required in the PHS Act but have been proposed by NIH under their statutory authority to modify requirements, mostly to aid in the determination of whether or not a clinical trial is an applicable clinical trial (some of these data elements have already been implemented, either prior to the enactment of FDAAA or as part of NIH’s implementation since 2007):

  • Single Arm Controlled? – a sub-element of Study Design that would enable the NIH to determine whether a registered clinical trial is an applicable clinical trial when such a determination cannot be made based on other submitted registration data elements.
  • Whether Study is a Pediatric Postmarket Surveillance of a Device – indicates if the study is a pediatric postmarket surveillance of a device to confirm that the study is an applicable device clinical trial.
  • Other Intervention Name(s) – a requirement if the sponsor has used more than one name publicly to identify the intervention under study in the clinical trial.
  • Intervention Description – to be submitted as clinical trial information to help distinguish between similar interventions.
  • Studies an FDA-regulated Device/Drug – to indicate whether or not a clinical trial studies an FDA-regulated device or drug to assist in determining whether or not a clinical trial is an applicable device or drug clinical trial.
  • U.S. FDA Approval, Licensure, or Clearance Status – to indicate whether any intervention regulated by FDA and studied in the clinical trial has been approved to help in assuring the data bank operates in compliance with statutory requirements (e.g., determining when clinical trial registration information submitted for an applicable device clinical trial may be posted publicly).
  • Product Manufactured in the U.S. – to assist determining whether a registered clinical trial is an applicable clinical trial.
  • Why Study Stopped? – when a trial is suspended, terminated, or withdrawn prior to its completion as anticipated by the protocol, in addition to updating the Overall Recruitment Status, a brief explanation of why the clinical trial was stopped (e.g., because of safety concerns, difficulties in recruitment, or for financial reasons) is required. 
  • Actual Enrollment – submission of the actual enrollment figure after enrollment is closed (i.e., when overall recruitment status is updated to “active, not recruiting” or “terminated”) to aid in tracking the subsequent progress of clinical trials.
  • Human Subjects Protection Review Board Status – to indicate whether a clinical trial registered is undergoing or has undergone human subjects protection review board review or is exempt from approval “to enhance patient enrollment.”  This data element is consistent with prior Agency practice of requiring this information.

Also, Section 402(j)(2)(A)(ii)(II)(gg) of the PHS Act specifies that for an applicable clinical trial of a drug that is not approved, the responsible party must specify whether or not there is expanded access for those who do not qualify for enrollment in the clinical trial and, if so, how to obtain information on such access.  In furtherance of making this information readily available, the NPRM proposes to create an Expanded Access record with its own NCT number. This record would consist of additional data elements describing the expanded access, including eligibility criteria for participation.

NIH invites comments on its proposed modifications and additions to the data elements of clinical trial registration information, including the benefits and burdens associated with structuring of certain registration data elements.

Posting of Registration Information – Drugs vs. Devices

Registration information for applicable drug clinical trials must be publicly posted by NIH no later than 30 calendar days after it is submitted.  The NPRM proposes to not make publicly available certain administration information, including the IND number and responsible party contact information.

By comparison, public posting of registration information for applicable device clinical trials is not so straightforward.  For trials of devices that were previously approved or cleared for any indication, registration information must be posted by NIH no later than 30 days after results information is required to be posted.  The NPRM proposes that, in practice, this registration information will be posted as soon as practicable after submission, but not later than 30 days after clinical trial results information is required to be posted. 

Meanwhile, the NPRM lays out the original statutory scheme to delay posting of registration information for applicable device clinical trials that have not previously been approved or cleared.  Registration information for these trials must be posted publicly no earlier than the date of approval or clearance of the device and no later than 30 days after such date.  NIH anticipates there will be a number of situations in which those who conduct this category of device clinical trials may prefer to make the registration information publicly available prior to this statutory mandated time frame (e.g., to meet ICMJE policy, assist in recruitment efforts).  The NPRM seeks input on potential mechanisms for addressing these situations.

Results Reporting

FDAAA 801 requires the submission of results information for each applicable drug clinical trial for a drug that is approved or licensed and each applicable device clinical trial for a device that is cleared or approved.  Following initial approval, clinical trial results information must be submitted no later than one year after the completion date or 30 calendar days after FDA approves the product, whichever is sooner. 

By contrast, for applicable clinical trials of drugs or devices that are not approved, licensed, or cleared, whether or not approval was sought, the statute provides that NIH determine through regulation whether results information must be submitted and, if they are, the date which such information shall be required to be submitted. Pursuant to this authority, NIH proposes to require submission of results information for applicable clinical trials that are not approved by FDA and to limit the delay for disclosure of those results. 

Generally, these results submissions for applicable clinical trials involving unapproved products are required no later than one year after the completion date of the clinical trial.  The exception to this proposed rule is that if initial approval is being sought, or may at a future date be sought, then the responsible party may delay submission by providing a certification prior to that deadline.  The allowable delay period for results information is now proposed in the NPRM to be limited to two years after the submission of a certification, and only one certification may be submitted for each clinical trial.  Therefore, the total delay in disclosure of results would be up to three years after the completion date of the trial.

If, instead, the sponsor of the applicable clinical trial is seeking approval of a new use for a previously approved drug or device, and has filed, or plans to file, with FDA within one year, the responsible party may submit a certification for delayed submission of results information.  This will delay the deadline for results submission to 30 calendar days after the earliest of the following events:

  • FDA approves the product for the use studied in the applicable clinical trial;
  • FDA issues a letter that ends the regulatory review cycle for the application, but does not approve the product for the use studied in the applicable clinical trial; or,
  • the application seeking approval of the new use is withdrawn without resubmission for not less than 210 calendar days.

Notwithstanding these deadlines, the responsible party must submit complete results no later than two years after the date that the certification was submitted, except in situations where the required clinical trial results information has not been collected.

The NPRM also proposes to allow submission of partial results where results for a secondary outcome measure have not been collected by the completion date, as well as extensions of results reporting for “good-cause.”

As proposed in the NPRM, drug clinical trial results information will be submitted through structured data entry, in an effort to ensure all required data elements are provided and to optimize the presentation of the submitted data.  The pre-specified fields for results reporting are proposed to consist of:

  • information documenting the progress of human subjects through the clinical trial by arm;
  • information on demographic and baseline measures and data collected by arm or comparison group and for the entire study population;
  • data for each primary and secondary outcome measure by arm or comparison group, including the results of scientifically appropriate statistical analysis performed on that data;
  • summarized adverse event information grouped, including (a) serious adverse events grouped by organ system and (b) all adverse events, other than serious adverse events, that exceed a frequency of five-percent within any arm of the clinical trial, grouped by organ system; and
  • certain administrative information (e.g., results point of contact).

At this time, NIH has not proposed requiring submission of either non-technical or technical summaries of trial results, or submission of the full protocol, but is considering whether to do so as part of the rulemaking.  To this end, NIH invites comments on methods to help determine if either type of summary or the full protocol should be required. 

NIH is required to publicly post this required results information no later than 30 calendar days after it is submitted.

Updates

In general, the NPRM provides that updates of clinical trial information must be provided every 12 months, unless there are no changes in that time frame.  A responsible party would have to submit updates until the final results information has been submitted for all primary and secondary outcome measures and all adverse events collected in accordance with the protocol. 

However, the NPRM identifies several data elements that would be required to be updated more quickly:

  • No later than 30 days after the change occurs: study start date, intervention name(s),  availability of expanded access, overall recruitment status, individual site status, human subjects protection review board status, completion date, responsible party, responsible party contact information, and if the protocol is amended in a manner that changes are communicated to human subjects.
  • No later than 15 days after the change occurs: U.S. FDA approval, licensure, or clearance status.

Providing Comment

Comments can be submitted no later than February 19, 2015 to docket number NIH-2011-0003 at Regulations.gov.  NIH also announced, in conjunction with the NPRM, a draft policy that would extend similar registration and reporting requirements to all clinical trials funded by NIH, regardless of whether they are subject to FDAAA.

*Not admitted to practice law. Working under the supervision of the Firm’s attorneys.

The Opioid Dependence Big Picture

First Posted 1/16/2014

Below, internet colleague Paul Dessauer shares his extensive knowledge of opioids in comments about my naltrexone post. His comments were particularly interesting in that they provide evidence that at least someone is aware of the big picture about addiction to heroin and pain pills.

In my post about naltrexone, I described how some people favored the drug over buprenorphine because of its lack of opioid effects. Unlike buprenorphine, naltrexone is an antagonist that has no abuse potential.  But I wondered… at a time when so many young people are dying, shouldn’t the primary issue be whether naltrexone saves lives?  Sure, it is ‘safe’– but does it work?

Paul provided references to answer my question.  While everyone is focused on the fact that naltrexone can block opioid receptors, Paul’s data shows that when naltrexone is used in the real world, people die.  I’m excited that someone, somewhere, has the courage to investigate the one thing that is never addressed in discussions about addiction, whether related to residential treatment, counseling, or medication: Does it work?

Paul’s comments:

You wrote;

<<< If ‘success’ consists of moving to naltrexone—a medication that many real-world addicts reject– how long is naltrexone continued, and what happens when it is stopped? Do people go back to heroin again? If not, why not? The cycle of ‘use, treat, cease treatment, use, and repeat’ should be a black box warning on naltrexone >>>

The other “black box” issue is dropped tolerance overdose when someone exits naltrexone treatment and relapses to illicit opioid use.

You asked; <<< How many people will die in their quest—or their doctor’s quest—for ‘abstinent recovery’ with or without naltrexone? >>>

This study used Australian coronial records to compare mortality rates amongst patients in methadone treatment, buprenorphine treatment, and naltrexone treatment. The authors make it clear that they believe the mortality rates for naltrexone calculated here are significant underestimates, as coronial data does not record such deaths consistently, and they found the majority of known naltrexone-related deaths did not appear in this data.

<<< When expressed as deaths per number of treatment episodes, it was estimated that naltrexone had a mortality rate of 10.1 per 1000 treatment episodes. If the mean treatment retention in naltrexone treatment was estimated at 3 months (rather than two months, as assumed in the above estimate), the mortality rate for naltrexone treatment increased to 15.2 deaths per 1000 treatment episodes.

Naltrexone was associated with a mortality rate of 22.1 per 100 person years during the period of high risk (2 weeks post-treatment), and 1 per 100 person years during the period of low risk (during treatment)…. >>>

<<< …The estimated mortality rate was 0.02 per 1000 treatment episodes for buprenorphine and 2.7 per 1000 episodes for methadone.

The mortality rate for naltrexone was four times higher than for methadone when calculated as deaths per number of episodes of treatment, and substantially higher than for buprenorphine.

When considering deaths per periods of high and low risk, the mortality related to naltrexone was approximately seven times that of methadone during the period of high risk and three times the rate during the period of low risk. Naltrexone treatment was associated with a mortality rate of 22.1 per 100 person years during the period of high risk (two weeks following treatment cessation) and 1 per 100 person years during the period of low risk (during treatment). Buprenorphine mortality rates were not expressed in terms of periods of high and low risk due to the low number of deaths detected with this search method. >>>

<<< In comparing mortality rates associated with these pharmacotherapies, it is important to draw the reader’s attention to the rates of mortality for active heroin users. It has been estimated that mortality rates for heroin-dependent persons not in treatment are in the vicinity of 0.9 per 100 person years of risk, very similar to the mortality rate of a person in naltrexone treatment (during the period of low risk) calculated in this study. >>>

Actually, this is slightly less than the risk of naltrexone-associated death calculated in the study, which is believed to be an underestimate.

And the risk of naltrexone-related death calculated for the “high risk” period (the two weeks immediately following cessation of naltrexone) is more than TWENTY TWO TIMES higher than the risk of death estimated for someone using street heroin who is not in any form of treatment at all.

<<< While maintained in methadone or buprenorphine treatment after the initial induction stages, opioid-dependent people are at lower risk of dying. Clearly, an important aspect of methadone and buprenorphine treatment for opioid dependence is the improvement of treatment retention rates.

The mortality risks associated with oral naltrexone treatment, particularly following treatment cessation, warrant serious attention. This is especially the case considering that the majority of unselected opioid-dependent persons will return to opioid use soon after leaving naltrexone treatment. It is recommended that future trials of all treatments for opioid dependence include monitoring of post-treatment mortality risk >>>

Gibson, A. and Degenhardt, L. (2005) Mortality related to naltrexone in the treatment of opioid dependence: A comparative analysis, Sydney: National Drug and Alcohol Research Centre

How does hope help our alcoholic or addicted children?

Spiritual Practice Aids RecoveryI’ve thought a lot about hope because it is such an essential part of recovery for all. I first felt a stirring of hope when our son cried out for rehab. Finally, a glimmer of light leading out of the madness.  I began to tally up the days of his sobriety, mistakenly believing that we’d reach a magic number at some point and our son would be miraculously and permanently healed.  The nightmare would be over.
I don’t know if that was hope or ignorance, but it kept me going through some very dark days. The truth is that relapses– which may be a part of this disease—tends to occur further and further apart as time goes by. One year without relapse, then three years without relapse.  But there are no guarantees.  Still, each day of recovery gave me a larger sliver of hope.

At the same time, misplaced hope can impede recovery because it drives us to take unreasonable action. Because we hope against hope that our children are “cured,” we write the check for the apartment instead of Sober Living. We hope they have seen the error of their ways and will resolve to change course this time, once and for all.  This time they really really really mean it, so we lend them money again, or lend them the car. We hope, above all, that the sheer force of our love for them will give them the strength and conviction to resist drugs or alcohol. If only it were that simple.

Our hope for their recovery leads us to make mistakes– to rent that apartment for them, to pay their bills “until they get back on their feet.” Misplaced hope can make it easier for our kids to stay sick than to get healthy.
Most of all, our children need hope for brighter days. We give them that gift when we honestly and realistically take action that support their recovery instead of their substance abuse. When believe in them and give them the reigns to their lives and let them know that we won’t be dragged through the mud again. Only then can they believe in themselves.

Fourth Circuit Rolls Back District Court Decision on Pre-MMA 180-Day Exclusivity for Generic CELEBREX

By Kurt R. Karst

December 16th was a good day for Hyman, Phelps & McNamara, P.C. We learned that the U.S. Court of Appeals for the Fourth Circuit handed our client, Mylan Pharmaceuticals, Inc. (“Mylan”), a significant victory. In a 3-0 panel decision (Circuit Judges Wilkinson, Shedd, and Wynn), the Court reversed and remanded by unpublished opinion a June 2014 decision from the U.S. District Court for the Northern District of West Virginia concerning 180-day exclusivity for generic versions of GD Searle LLC’s (now Pfizer Inc.’s) CELEBREX (celecoxib) Capsules, 100 mg, 200 mg, and 400 mg. The Court’s decision also puts the kibosh on FDA’s “bundle of rights” theory, under which an original patent and a reissued patent are treated as a single bundle of rights for 180-day exclusivity purposes. FDA first publicly articulated that interpretation of the law in an April 2014 Letter Decision, just before ruling on 180-day exclusivity for generic CELEBREX; however, as we previously posted (and as discussed in FDA’s Letter Decision), the Agency has applied that interpretation in other instances going back several years.

By way of background, CELEBREX (approved under NDA 020998) is currently listed in the Orange Book with two unexpired patents: U.S. Patent Nos. 5,760,068 (“the ‘068 patent) and RE44,048 (“the ‘048 patent”). Both patents expire on the same date – i.e., June 2, 2015 (and are subject to a period of pediatric exclusivity that expires on December 2, 2015) – because the ‘048 patent is a reissue of the ‘068 patent.

The first ANDA for a generic version of Celecoxib Capsules, 100 mg, 200 mg, and 400 mg, containing a certification to an Orange Book-listed patent was submitted to FDA prior to the December 2003 enactment of the Medicare Modernization Act (“MMA”). As such, 180-day exclusivity for the drug is governed by the pre-MMA version of the law. Pre-MMA 180-day exclusivity is patent-based, such that an ANDA applicant is (or different applicants are) eligible for 180-day exclusivity with respect to different Orange Book-listed patents covering the Reference Listed Drug if such applicant submitted the first ANDA to FDA containing a Paragraph IV certification to a particular patent. Pre-MMA 180-day exclusivity is triggered by the earlier of either the first commercial marketing (for all patents certified to as Paragraph IV by a first-filer), or by a court decision favorable to an ANDA applicant (with respect to a particular patent). Although the list of pre-MMA drugs is fixed (see our previous post here), disputes under the pre-MMA version of the law continue to come up – and may for years to come.

TEVA Pharmaceuticals USA, Inc. (“Teva”) was the first company to submit an ANDA (ANDA 076898) for generic CELEBREX containing Paragraph IV certifications to certain Orange Book-listed patents, including the ‘068 patent. An initial district court decision held that the CELEBREX patents were valid; however, the Federal Circuit revered in part, ruling that many of the claims of the ‘068 patent were invalid. The Federal Circuit issued its mandate on May 13, 2008.

Fast-forward to March 5, 2013, when the U.S. Patent and Trademark Office reissued the invalidated ‘068 patent as the ‘048 patent. The ‘048 patent was promptly listed in the Orange Book and several companies, including Teva and Mylan, certified Paragraph IV to the patent. In March 2014, a district court deemed the ‘048 patent invalid, and the decision was appealed to the Federal Circuit where the case remains pending.

After some ANDA applicants inquired with FDA as to how the Agency would apply, in the case of Celecoxib Capsules, 100 mg, 200 mg, and 400 mg, the pre-MMA provisions of the FDC Act concerning 180-day exclusivity, the Agency issued a Letter Decision on April 24, 2014 addressing situations involving a reissued patent. FDA concluded that:

for purposes of 180-day exclusivity, upon the listing of a reissued patent, a prior court decision on the original patent is not regarded as having triggered 180-day exclusivity for the single bundle of patent rights represented by the original and reissued patent. In such a case, eligibility for 180-day exclusivity is only available to the applicant that first filed a paragraph IV certification to the original patent, and that applicant must make a timely submission of a paragraph IV certification to the reissued patent to remain eligible for 180-day exclusivity.

In other words, FDA ruled that only Teva was eligible for 180-day exclusivity because only Teva certified Paragraph IV first to both the ‘068 and ‘048 patents, and that the Federal Circuit’s decision with respect to the ‘068 patent did not trigger 180-day exclusivity because the ‘068 patent and the reissued ‘048 patent are considered by the Agency as a single bundle of patent rights. FDA approved Teva ANDA 076898 on May 30, 2014 after the expiration of a period of pediatric exclusivity on another patent that the Federal Circuit upheld in 2008.

The day after FDA issued its Letter Decision, Mylan filed an action against FDA in the U.S. District Court for the Northern District of West Virginia seeking injunctive and declaratory relief. Other ANDA applicants, including Teva, Watson Laboratories, Inc. (“Watson”), and Lupin Pharmaceuticals, Inc. (“Lupin”) entered the lawsuit. The District Court denied Mylan’s Motion for Preliminary Injunction in a May 29, 2014 decision and subsequently entered a final judgment on June 16, 2014.

Mylan (and other ANDA sponsors with tentative approval) appealed the decision to the Fourth Circuit. In a joint brief, Mylan and Watson asked the court to address two issues:

  1. Whether the FDA Decision was unlawful, arbitrary, and capricious because it determined, contrary to the clear statutory language of the Hatch-Waxman Amendments, that a final court decision invalidating an original patent is not a court decision trigger for 180-day generic drug marketing exclusivity if the invalid patent is later replaced by a reissue patent.
  2. Whether the FDA Decision to deny eligible generic drug manufacturing companies a period of shared exclusivity tied to the reissue patent was arbitrary, capricious, or otherwise not in accordance with law.

Lupin filed a separate brief arguing that first-filers to the ‘048 patent are not entitled to shared 180-day exclusivity.

After briefing the case (briefs available here, here, here, here, here, and here) and holding Oral Argument in September 2014, the Fourth Circuit issued its decsion on December 16, 2014.  

Analyzing this issues under the familiar two-step Chevron analysis, the Court was able end its analysis at Chevron Step One. “Here, Congress has spoken directly regarding the court decision trigger,” wrote the Court. “The statute makes plain that the 180-day exclusivity runs from ‘the date of a decision of a court in an action . . . holding the patent which is the subject of the certification to be invalid or not infringed.’ 21 U.S.C. § 355(j)(5)(B)(iv).”  Applying that language to the case at hand, the Court wrote that “[a]s to generic celecoxib, such a decision was reached by the Federal Circuit in 2008. . . . Teva’s 180-day exclusivity period as to the ‘068 patent began to run from the date the Federal Circuit issued its mandate in May 2008. And the exclusivity period expired on November 9, 2008, i.e., 180 days later.”

Moving on to FDA’s treatment of a patent and a reissue of that patent as a “bundle of rights,” the Court said that FDA’s interpretation is contrary to the statutory text, and that a reissue patent is a separate and distinct patent that can yield a separate period of 180-day exclusivity:

Hatch-Waxman does not define “patent” nor does it specifically speak to reissued patents. This does not, however, render the statute ambiguous. The “court-decision trigger” speaks of “the patent which is the subject of the certification.” 21 U.S.C. §355(j)(5)(B)(iv) (emphasis added). FDA’s interpretation of this language treats the original patent and the reissued patent as a single “bundle of rights” which can only be the subject of one Paragraph IV certification and therefore provides only a single 180-day exclusivity period. However, this interpretation is contrary to the plain statutory
language. . . .

The plain language of the statute indicates that each patent that is the subject of a certification may trigger exclusivity. The Hatch-Waxman Act required [ANDA] applicants to certify as to both the original and reissued patents; each could be “the patent which is the subject of the certification.” 21 U.S.C. §355(j)(5)(B)(iv).

Setting aside FDA’s interpretation, the Court reversed the West Virginia District Court decision and remanded the case with instructions for the District Court to proceed with adjudicating the rights of ANDA applicants consistent with the Court’s opinion.

Last week, several ANDA applicants whose approvals were blocked as a result of FDA’s now-invalidated Letter Decision announced (here, here, and here) the launch of authorized generic versions of Celecoxib Capsules, 100 mg, 200 mg and 400 mg. Teva also announced the launch of its Celecoxib drug products. As a result, any 180-day exclusivity associated with the drug has been triggered.