F.D.A. Deal Allows Amarin to Promote Drug for Off-Label Use

[garbon]

Here's further details I could find which seems to support my take on it.

http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2015/08/a-victory-for-amarin-further-erodes-fda-regulation-of-off-label-promotion.html

The case before Judge Engelmayer concerned Vascepa (icosapent ethyl), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid ("EPA") obtained from fish oil.  Vascepa is an approved drug indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.  Vascepa (icosapent ethyl), Label, NDA 202057 (June 23, 2015).

Vascepa's approval was based on a single phase 3 clinical trial (the MARINE trial), conducted in patients with "very high" triglycerides (≥ 500 mg/dL), pursuant to a Special Protocol Assessment ("SPA") agreement with FDA. Generally, a SPA indicates FDA agreement that a study will support the approval of a drug or biologic product's marketing application (or supplement to an approved application) if it is conducted according to the protocol and it achieves its agreed-upon objectives.  See FDCA § 505(b)(5)(B); see also FDA, Guidance for Industry: Special Protocol Assessment, 2 (May 2002).  Once FDA and a sponsor enter into a SPA agreement, there are only two narrow statutory bases for changes to the SPA – written agreement between FDA and the sponsor or where FDA finds a "substantial scientific issue essential to determining the safety or effectiveness of the drug" that is identified after the trial has begun.  FDCA § 505(b)(5)(C).

Similar to the Company's approach with the initial indication, Amarin designed a single phase 3 clinical trial to examine the effect of Vascepa on triglyceride levels among statin-treated patients with "persistently high" triglycerides (≥ 200 and ≤ 500 mg/dL), the ANCHOR trial, and entered into a separate SPA with FDA (the "ANCHOR SPA"). In connection with the ANCHOR SPA, Amarin also agreed to conduct a cardiovascular outcomes trial (the REDUCE-IT trial) to examine whether Vascepa would be effective in reducing cardiovascular events.  As a condition of the ANCHOR SPA, FDA required that the REDUCE-IT trial would need to be at least 50% enrolled before FDA would accept Amarin's supplemental new drug application ("sNDA") for use of Vascepa in patients with persistently high triglycerides.  When Amarin submitted its application for approval of the initial indication, FDA reviewed the ANCHOR data as a second, confirmatory trial and included the combined safety results from both trials in the first indication labeling.

Amarin believed it had satisfied all of FDA's requirements to obtain approval of Vascepa for persistently high triglycerides, per the ANCHOR SPA agreement.  The ANCHOR study achieved its primary endpoint demonstrating statistically significant reductions in triglyceride levels with Vascepa, compared to placebo. Vascepa achieved statistically significant results for its secondary endpoints in the ANCHOR study as well.  In addition, Amarin met its enrollment obligations with respect to the REDUCE-IT trial.  Thus, Amarin submitted its sNDA for the persistently high triglyceride indication in February 2013and anticipated a timely approval for this additional indication.

However, FDA convened an Advisory Committee during which the agency called into question the clinical validity of the ANCHOR study endpoint of triglyceride lowering, despite having agreed to that endpoint in the SPA. Data from several high-profile cardiovascular outcomes trials reported out after the ANCHOR SPA was entered into by FDA and Amarin and cast doubt on the clinical benefit of triglyceride lowering and whether a reduction in triglyceride levels would translate into a reduction in cardiovascular events, in general.  Upon reviewing these data, FDA asked the Advisory Committee to weigh in on whether Vascepa's triglyceride lowering effect was sufficient to approve the drug for use in patients with persistently high triglycerides. The Advisory Committee voted 9 to 2 against approval of Vascepa for that indication. Subsequently, FDA rescinded the ANCHOR SPA, something FDA has done only 10 times among approximately 1,000 SPAs, and issued a Complete Response Letter to Amarin indicating the need for data showing a reduction in cardiovascular events (i.e., data from the REDUCE-IT trial) prior to approval for persistently high triglycerides.  Amarin stated that FDA concluded the Complete Response Letter "with a warning that any effort by Amarin to market Vascepa for the proposed supplemental use could constitute 'misbrand[ing] under the Federal Food, Drug, and Cosmetic Act [("FDCA")].'"  Complaint at 27, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. May 7, 2015).

The court had acknowledged the lawful use of FDA-approved drugs for off-label uses by doctors and the inability of FDA to regulate doctors so using those drugs.  The court cited to numerous studies of off-label use that shows such use is ubiquitous in clinical medicine, noting in some areas that off-label use is "the norm rather than the exception."  Amarin at 5.  The court went on to say that the "therapeutic—indeed, sometimes life-saving—value of off-label uses of FDA-approved drugs has been widely recognized."  Id. at 6.

The court discussed how FDA has "long taken the position" that pharmaceutical manufacturers who market or promote off-label uses of approved drugs violate the FDCA.  Id. at 9.  The court described FDA's long-standing position that off-label promotion of drug products risks criminal misbranding under the FDCA.  FDCA § 301(b).  A drug is misbranded if its labeling is "false or misleading in any particular."  Id. § 502(a).  A drug is misbranded, according to the FDCA, if its labeling does not bear "adequate directions for use."  Id. § 502(f).  FDA regulations define adequate directions for use as those under which a lay person can "use a drug safely and for the purposes for which it was intended."  21 C.F.R. § 201.5.  The court, in its opinion, skipped a step, but it is important to note that labeling for prescription drugs, which are not safe for use except under supervision by a licensed health care provider, cannot bear adequate directions for use by a lay person, but can be subject to an exemption from this statutory requirement.  FDCA §§ 503(b), 502(f).  FDA regulations require that, to satisfy the conditions for this exemption, prescription drugs must have labeling that contains "adequate information for [] use . . . under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented."  21 C.F.R. § 201.100(d)(1) (emphasis added).  "Intended use" means the objective intent of the persons legally responsible for the labeling of drugs, which is determined by such persons' expressions or may be shown by the circumstances surrounding the distribution of the article.  This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives.  21 C.F.R. § 201.128.  Where the intended use of a prescription drug differs from the use approved by FDA (as indicated in the drug's approved labeling), FDA has asserted that the product is a "new drug" for which FDA approval is required.  Placing a new drug in interstate commerce without FDA approval is a violation of the FDCA.  FDCA § 505(a).

FDA has argued that misbranding actions against manufacturers who engage in off-label promotion furthers public safety.  Amarin at 12.  The court noted, "FDA has stated, its goal in pursuing misbranding charges against manufacturers based on the off-label promotion of drugs is to encourage use of the FDA's drug review and approval process."  Id.  Prosecutions therefore, act as a deterrent for manufacturers to evade FDA's drug approval process for new uses of approve drugs.  Id. at 13.

...

[Capetan Mihali]

The makers of Neurontin (the "everything" drug) got fined an incredible sum -- I want to say a billion dollars -- for marketing it off-label for neuropathic pain in the late 90s, IIRC.  Then a couple years later it was approved for diabetic neuropathy pain.

[Malthus]

Here's further details I could find which seems to support my take on it.

http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2015/08/a-victory-for-amarin-further-erodes-fda-regulation-of-off-label-promotion.html

The case before Judge Engelmayer concerned Vascepa (icosapent ethyl), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid ("EPA") obtained from fish oil.  Vascepa is an approved drug indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.  Vascepa (icosapent ethyl), Label, NDA 202057 (June 23, 2015).

Vascepa's approval was based on a single phase 3 clinical trial (the MARINE trial), conducted in patients with "very high" triglycerides (≥ 500 mg/dL), pursuant to a Special Protocol Assessment ("SPA") agreement with FDA. Generally, a SPA indicates FDA agreement that a study will support the approval of a drug or biologic product's marketing application (or supplement to an approved application) if it is conducted according to the protocol and it achieves its agreed-upon objectives.  See FDCA § 505(b)(5)(B); see also FDA, Guidance for Industry: Special Protocol Assessment, 2 (May 2002).  Once FDA and a sponsor enter into a SPA agreement, there are only two narrow statutory bases for changes to the SPA – written agreement between FDA and the sponsor or where FDA finds a "substantial scientific issue essential to determining the safety or effectiveness of the drug" that is identified after the trial has begun.  FDCA § 505(b)(5)(C).

Similar to the Company's approach with the initial indication, Amarin designed a single phase 3 clinical trial to examine the effect of Vascepa on triglyceride levels among statin-treated patients with "persistently high" triglycerides (≥ 200 and ≤ 500 mg/dL), the ANCHOR trial, and entered into a separate SPA with FDA (the "ANCHOR SPA"). In connection with the ANCHOR SPA, Amarin also agreed to conduct a cardiovascular outcomes trial (the REDUCE-IT trial) to examine whether Vascepa would be effective in reducing cardiovascular events.  As a condition of the ANCHOR SPA, FDA required that the REDUCE-IT trial would need to be at least 50% enrolled before FDA would accept Amarin's supplemental new drug application ("sNDA") for use of Vascepa in patients with persistently high triglycerides.  When Amarin submitted its application for approval of the initial indication, FDA reviewed the ANCHOR data as a second, confirmatory trial and included the combined safety results from both trials in the first indication labeling.

Amarin believed it had satisfied all of FDA's requirements to obtain approval of Vascepa for persistently high triglycerides, per the ANCHOR SPA agreement.  The ANCHOR study achieved its primary endpoint demonstrating statistically significant reductions in triglyceride levels with Vascepa, compared to placebo. Vascepa achieved statistically significant results for its secondary endpoints in the ANCHOR study as well.  In addition, Amarin met its enrollment obligations with respect to the REDUCE-IT trial.  Thus, Amarin submitted its sNDA for the persistently high triglyceride indication in February 2013and anticipated a timely approval for this additional indication.

However, FDA convened an Advisory Committee during which the agency called into question the clinical validity of the ANCHOR study endpoint of triglyceride lowering, despite having agreed to that endpoint in the SPA. Data from several high-profile cardiovascular outcomes trials reported out after the ANCHOR SPA was entered into by FDA and Amarin and cast doubt on the clinical benefit of triglyceride lowering and whether a reduction in triglyceride levels would translate into a reduction in cardiovascular events, in general.  Upon reviewing these data, FDA asked the Advisory Committee to weigh in on whether Vascepa's triglyceride lowering effect was sufficient to approve the drug for use in patients with persistently high triglycerides. The Advisory Committee voted 9 to 2 against approval of Vascepa for that indication. Subsequently, FDA rescinded the ANCHOR SPA, something FDA has done only 10 times among approximately 1,000 SPAs, and issued a Complete Response Letter to Amarin indicating the need for data showing a reduction in cardiovascular events (i.e., data from the REDUCE-IT trial) prior to approval for persistently high triglycerides.  Amarin stated that FDA concluded the Complete Response Letter "with a warning that any effort by Amarin to market Vascepa for the proposed supplemental use could constitute 'misbrand[ing] under the Federal Food, Drug, and Cosmetic Act [("FDCA")].'"  Complaint at 27, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. May 7, 2015).

The court had acknowledged the lawful use of FDA-approved drugs for off-label uses by doctors and the inability of FDA to regulate doctors so using those drugs.  The court cited to numerous studies of off-label use that shows such use is ubiquitous in clinical medicine, noting in some areas that off-label use is "the norm rather than the exception."  Amarin at 5.  The court went on to say that the "therapeutic—indeed, sometimes life-saving—value of off-label uses of FDA-approved drugs has been widely recognized."  Id. at 6.

The court discussed how FDA has "long taken the position" that pharmaceutical manufacturers who market or promote off-label uses of approved drugs violate the FDCA.  Id. at 9.  The court described FDA's long-standing position that off-label promotion of drug products risks criminal misbranding under the FDCA.  FDCA § 301(b).  A drug is misbranded if its labeling is "false or misleading in any particular."  Id. § 502(a).  A drug is misbranded, according to the FDCA, if its labeling does not bear "adequate directions for use."  Id. § 502(f).  FDA regulations define adequate directions for use as those under which a lay person can "use a drug safely and for the purposes for which it was intended."  21 C.F.R. § 201.5.  The court, in its opinion, skipped a step, but it is important to note that labeling for prescription drugs, which are not safe for use except under supervision by a licensed health care provider, cannot bear adequate directions for use by a lay person, but can be subject to an exemption from this statutory requirement.  FDCA §§ 503(b), 502(f).  FDA regulations require that, to satisfy the conditions for this exemption, prescription drugs must have labeling that contains "adequate information for [] use . . . under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented."  21 C.F.R. § 201.100(d)(1) (emphasis added).  "Intended use" means the objective intent of the persons legally responsible for the labeling of drugs, which is determined by such persons' expressions or may be shown by the circumstances surrounding the distribution of the article.  This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives.  21 C.F.R. § 201.128.  Where the intended use of a prescription drug differs from the use approved by FDA (as indicated in the drug's approved labeling), FDA has asserted that the product is a "new drug" for which FDA approval is required.  Placing a new drug in interstate commerce without FDA approval is a violation of the FDCA.  FDCA § 505(a).

FDA has argued that misbranding actions against manufacturers who engage in off-label promotion furthers public safety.  Amarin at 12.  The court noted, "FDA has stated, its goal in pursuing misbranding charges against manufacturers based on the off-label promotion of drugs is to encourage use of the FDA's drug review and approval process."  Id.  Prosecutions therefore, act as a deterrent for manufacturers to evade FDA's drug approval process for new uses of approve drugs.  Id. at 13.

...

Well, in this case the maker had a drug that they were able to demonstrate lowers triglycerides, but the agency eventually ruled that this wasn't a strong enough indicator to demonstrate clinical efficacy - despite having agreed to it before the trial was started (via the SPA). I have no idea if the agency was correct in that assessment or not.   

That sucks for the manufacturer and it is easy to see why they were pissed off. Obviously, the maker was of the opinion that the users or prescribers of the drug would disagree with the agency, and knowing that it lowered triglycerides, would prescribe it because THEY think that's a good enough indicator of efficacy.

However, ultimately, it is the agency's job to ensure that drugs are effective, and that makers only promote drugs for indications where efficacy has been proved. Or at least, that's how they look at it.

[garbon]

Yeah from things I've heard over the years this is a pretty typical thing for the FDA to do, sort of a bait and switch, randomly at whims they can decide to change what endpoints they want you to match - which leads to long delays.

I can totally see both sides here. Just when looking at the deeper details, I'm less concerned from a 'why run reasonable trials stand front' though clearly with this ruling the gov't and its agencies will need to be more vigilant on companies.

[grumbler]

While I agree with this statement, in substance and in sentiment, in this case it is more a problem with the reporting and not with the judge's decision.  The decision in this was based on an earlier appeals court opinion from 2012 (Caronia) - which concerned an attempted prosecution of a pharma rep for giving truthful off-label info about a drug.  Neither this case nor Caronia either rely on or even cited to Citizen's United.  They both relied on the Supreme Court's old Central Gas case that set forth the standards for evaluating commercial speech.  The rights that are at stake are the speech rights for speech made by company representatives on behalf of the company.  There is no need to import legal fictions like "corporate speech rights" to decide the case; that was just imprecise reporting from the NYT.

Thanks for the correction.  I'll still rage about CU, though.  I just won't have the facts to support the raging!