By Wes Siegner –

The article “‘Medical Foods’ and Supplements for Brain Health Advance” that recently appeared in The Wall Street Journal provides important insights into a growing industry that is focused on offering a wider range of healthcare options.  However, the article contains common misconceptions about these products and the increasingly important role that they play in public health.

The article opens with the common misstatement that medical foods “aren't regulated by the Food and Drug Administration” and further demeans the category by implying that the data supporting efficacy is insufficient.   In fact, FDA regulates these products to assure that they are safe and manufactured in compliance with detailed “good manufacturing practice” regulations, and both the FTC and FDA regulate the claims for these products to assure that they are truthful and supported by competent and reliable scientific evidence.

The regulatory scheme for these products is appropriately less stringent than for drugs because the products, by their nature, are safe and therefore require less government oversight to permit more innovation and consumer choice.  Congress has appropriately authorized FDA to remove medical food and dietary supplement products from the market that are exceptions to the “inherently safe” rule and that do not meet FDA’s “good manufacturing practice” regulations.  As the article states, these products are not intended to cure diseases.  Such claims would make the product a “drug” requiring premarket approval.  The consequences of making illegal drug claims and violating the requirements intended to assure product safety can be severe, including criminal prosecution.

The article also misrepresents the amount and type of data that are required to support disease management claims for medical foods, stating that lab tests on cells are often the only basis cited.  While it is true that clinical testing of drugs is appropriately more stringent than for medical foods or dietary supplements, this does not mean that the claims for these products can be supported without clinical testing.  Disease management claims for medical foods are closely policed and, if found lacking in clinical support, are likely to be challenged by a wide range of groups, including the FDA, the FTC, the NAD (an industry self-regulatory arm of the BBB), state attorneys general, and plaintiffs' class action lawyers.  The potential penalties for failure to substantiate claims with well-controlled human studies include large financial penalties and prosecution. 

The level of FDA regulation of these products, as with other FDA-regulated products like drugs and devices, is based on a balance of risks and benefits to the public health.  Where the risks are low because the products are inherently safe, as with foods and dietary supplements, it is a waste of government resources and an unnecessary barrier to innovation to require premarket approval, as is required for most drugs.  The article’s discussion of medical foods for Alzheimer's illustrates how the more limited regulation for medical foods and dietary supplements opens the door to innovation and the development of important products that act as adjuncts to other treatments, thus providing a greater range of less expensive healthcare options to many patients who are affected by serious diseases.

By Karla L. Palmer & Larry K. Houck –

Drug Enforcement Administration (“DEA”) Administrator Michele M. Leonhart, accompanied by officials from Internal Revenue Service Criminal Investigations (Richard Weber), Immigration and Customs Office of Homeland Security (James Chaparro), and U.S. Postal Inspections, held a press conference yesterday announcing the results of “Operation Log Jam.”  This large-scale, synthetic drug enforcement operation that occurred on July 26, 2012, is the first nationwide federal, state and local multi-agency enforcement action against the synthetic drug industry.  Administrator Leonhart stated that the synthetic designer drug industry was responsible for producing and selling synthetic cathinones, which produce stimulant/hallucinogenic effects and are marketed as “bath salts” or “plant food,” and synthetic cannabinoids, which are easily available, more potent than marijuana and are marketed as “herbal incense,” “K2” and “Spice.”  The DEA’s press release is available here.

Administrator Leonhart explained that the takedown was a joint operation of DEA and ICE, with assistance from the Internal Revenue Service Criminal Investigations, U.S. Postal Inspection Service, U.S. Customs and Border Protection, FBI, Food and Drug Administration’s Office of Criminal Investigations, and “countless state and local law enforcement members in more than 109 cities.”  The operation also “targeted every level of the synthetic designer drug industry, including retailers, wholesalers, and manufacturers.”  Leonhart reported that the nationwide action resulted in the arrest of ninety individuals and the seizure of more than $36 million in cash.  The Administrator stated that the operation seized more than 4.8 million packets of synthetic cannabinoids (and products to produce another 13.6 million synthetic cannabinoid products), as well as 167,000 packets of synthetic cathinones (and products to produce an additional 392,000 cathinone products).

DEA explained in the accompanying press release that the products, sold in retail outlets, head shops and over the Internet, have become popular among teenagers and young adults.

Congress recently enacted the Synthetic Drug Abuse Prevention Act of 2012 as part of the Food and Drug Administration Safety and Innovation Act, which places twenty-six synthetic cathinones and synthetic cannabinoids into schedule I of the Federal Controlled Substances Act (“CSA”) (see our summary here).  Schedule I controlled substances have a high potential for abuse and no recognized medical use in the United States.  DEA had used its emergency scheduling authority to temporarily control those substances in schedule I to avoid an imminent hazard to the public health.

DEA acknowledged that several of the substances seized in Operation Log Jam are not, however, substances that are specifically prohibited by the CSA.  Leonhart noted that the Controlled Substance Analogue Enforcement Act of 1986 “specifically exists to combat these new and emerging designer drugs.”  The 1986 Act allows for the treatment of certain drugs and substances as controlled substances if they are chemically and pharmacologically similar to schedule I or II controlled substances; thus prosecutions could occur pursuant to the 1986 Act.  Ms. Leonhart stated that prosecutions might also occur under more strict state laws.  Of the joint effort, Leonhart added that “together with our federal, state, and local law enforcement partners, we are committed to targeting these new and emerging drugs with every scientific, legislative and investigative tool at our disposal.”

By John R. Fleder –

On July 27, 2012, the United States Court of Appeals for the D.C. Circuit issued its long-awaited ruling in Friedman v. Sebelius, No. 11-5028.  The case involves a challenge to a decision by the Secretary of Health and Human Services (“HHS”) to exclude three former executives of Purdue Frederick Company (“Purdue”) from participating in federal health care programs.  Although the D.C. Circuit affirmed HHS’s legal theories for excluding the Purdue executives, the Court remanded the case to the district court, ruling that HHS’s decision to exclude the three executives for twelve years was arbitrary and capricious.

The Court’s Opinion was authored by Judge Douglas H. Ginsburg.  Chief Judge David B. Sentelle concurred in part, dissented in part and dissented from the judgment.  Judge Stephen F. Williams concurred in part, dissented in part but concurred in the judgment.  Our prior blog posts on this case can be found here and here.

Michael Friedman, Paul Goldenheim, and Howard Udell (“the Purdue Executives”) were senior corporate officers at Purdue when the company marketed OxyContin.  In 2007, Purdue pleaded guilty to felony violations of the FDC Act involving the alleged misbranding of drugs.  The company was placed on probation, fined $500,000 and required to pay another $600 million, part of which was for restitution.  In contrast, the Purdue Executives each pleaded guilty to a misdemeanor violation of the FDC Act for failing to prevent Purdue’s alleged fraudulent marketing of OxyContin.  Each of the Purdue Executives was sentenced to do community service, fined $5000, placed on probation, and forced to disgorge compensation they had received at Purdue.

The felony provision of the FDC Act requires that a person (including a corporation) can be found guilty if that person acts with the intent to defraud or mislead.  In contrast, the misdemeanor provision of the FDC Act does not require any such intent.  Rather, an individual can be prosecuted under the “Park Doctrine” if that person was in a responsible position of authority to have prevented the FDC Act violation from occurring.  The Court’s Opinion states that the Purdue Executives admitted that they had the authority to prevent Purdue’s FDC Act violations from occurring, or could have promptly corrected misrepresentations that some other Purdue employees had made regarding OxyContin.  However, the Purdue Executives did not admit (nor did the Government allege) that they had intended to violate the FDC Act or had engaged in any type of fraudulent conduct.

The Purdue Executives quickly learned that their troubles with the government had not ended.  A few months after the convictions, HHS’s Office of the Inspector General (“OIG”) “determined” that the Purdue Executives should be excluded from participating in federal health care programs for 20 years.  The Purdue executives appealed this decision to an HHS Administrative Law Judge (“ALJ”), and then to HHS’s Departmental Appeals Board (DAB).  During the pendency of the appeal, the OIG reduced the exclusion period to 15 years because the Purdue Executives had assisted law enforcement authorities to combat abuse of OxyContin.  Thereafter, the ALJ affirmed the 15 year exclusion periods as being within a reasonable range.  However, the DAB reduced the exclusion periods to 12 years for a number of reasons.

The Purdue Executives sought review of the DAB’s decision in federal district court in Washington D.C.  That court upheld HHS’s exclusion decisions, including the length of the exclusions.  The Purdue Executives then appealed the District Court’s ruling to the D.C. Circuit.  They challenged the HHS decision in terms of whether there was any statutory basis for exclusion, and alternatively, the length of the exclusion.

HHS relied on 42 U.S.C. § 1320a-7(b)(1)(A) as the basis to exclude the Purdue Executives.  That provision provides in pertinent part that an individual can be excluded from participating in any federal health care program if that individual has been convicted “of a criminal offense consisting of a misdemeanor relating to fraud.”

The Purdue Executives did not deny that they had been convicted of a misdemeanor.  However, their principal argument on appeal was that their convictions were not “relating to fraud.”  Remember that they had pleaded guilty to a misdemeanor offense under the FDC Act which did not require any proof that they had engaged in fraud.  The Purdue Executives argued that because the violations to which they pleaded guilty were just “strict liability” offenses, the nexus to fraud was not present for purposes of the exclusion statute.  They claimed that for that exclusion provision to apply, the misdemeanor offense needed the core elements of fraud including scienter, something obviously missing from a misdemeanor charge and conviction under the FDC Act.

The Court posed the issue as being whether a “misdemeanor relating to fraud” refers to a generic criminal offense on one hand or to the facts underlying a particular defendant’s conviction.  The Court concluded that HHS’s decision to use a defendant circumstance-specific approach, rather than a generic approach, was correct.  In other words, HHS can exclude an individual under this provision based on a conviction which was for conduct factually related to fraud, even though the offense  to which the person pleaded guilty did not require a showing of fraud.

The Court ruled that the Purdue Executives’ “convictions under the responsible corporate officer doctrine were manifestly ‘related to’ a fraud.”  Slip Op. at 18.  It explained:

Finally, the Appellants and their amici argue, because the Secretary’s interpretation permits her to impose “career- ending disabilities” upon someone whose criminal conviction required no mens rea, it raises a serious question of validity under the Due Process Clause of the Fifth Amendment to the Constitution of the United States . . . . Section 1320a-7(b)(1), however, is not a criminal statute and, although exclusion may indeed have serious consequences, we do not think excluding an individual under 42 U.S.C. § 1320a-7(b) on the basis of his conviction for a strict liability offense raises any significant concern with due process. Exclusion effectively prohibits one from working for a government contractor or supplier. Surely the Government constitutionally may refuse to deal further with senior corporate officers who could have but failed to prevent a fraud against the Government on their watch. . . . [W]e hold section 1320a¬7(b)(1)(A) authorizes the Secretary to exclude from participation in Federal health care programs an individual convicted of a misdemeanor if the conduct underlying that conviction is factually related to fraud. The Appellants do not dispute they are excludable under this circumstance-specific approach: Their convictions for misdemeanor misbranding were predicated upon the company they led having pleaded guilty to fraudulently misbranding a drug and they admitted having “responsibility and authority either to prevent in the first instance or to promptly correct” that fraud; they did neither.

Next, the Court examined whether HHS acted arbitrarily and capriciously in excluding the Purdue Executives for 12 years.  They challenged the exclusion periods on a number of grounds, including that HHS had failed to justify the decisions as being consistent with exclusion decisions in other cases.  The Court did not find that prior HHS exclusion decisions were irrelevant to the length of exclusion that should be imposed on the Purdue Executives.

Using the arbitrary and capricious standard, the Court examined the length of prior HHS exclusion decisions.  HHS had cited a number of prior HHS exclusion rulings of individuals where the period exceeded ten years.  The Court found those decisions to be distinguishable.  Because these decisions involved mandatory exclusion, not permissive exclusion, as relevant here, or because the HHS cited cases involving either a felony conviction or a conviction for Medicare fraud involving imprisonment, the Court could not locate any analogous precedent.  The Court found that HHS had never excluded anyone for more than 10 years under the provision at issue in this case.  As a result, the Court remanded the case to allow HHS to justify its 12-year exclusion decision.

Judge Sentelle agreed with the Court’s analysis regarding whether the Purdue Executives were subject to exclusion.  However, he would have affirmed the 12 year exclusion period and not required a remand.  Judge Williams did not agree that HHS had justified the decision to exclude the Purdue Executives.  He would have remanded the case to HHS to require a better explanation of why the Purdue executives were even subject to exclusion.

The Purdue Executives can seek rehearing of the case before the same three judges and/or seek rehearing en banc by the entire D.C. Circuit.  They may also seek Supreme Court review of this decision.  Alternatively, they could just await a further decision by HHS regarding the length of the exclusion, and challenge that decision in court.

The decision certainly is not welcome news to the Purdue Executives and many others who have been tracking this case closely.  Exclusion is a government remedy that can threaten the livelihood of people in the health care industry.  This decision, if it stands, will add another weapon in the government’s enforcement arsenal, even when the government does not charge an executive with engaging in fraudulent conduct, let alone prove that such conduct occurred.

A very difficult issue posed by this decision relates to a person’s decision to plead, or not plead, guilty to a crime as a result of an FDA investigation.  It was traditionally thought that a misdemeanor plea to a violation of the FDC Act under the Park Doctrine would result in a small fine, no jail time, and perhaps a period of probation.  That would be all!

Today, this is no longer true.  A defendant pleading guilty to a Park offense is more likely to go to jail than was true in the 1970s and 1980s, even though the person is not charged with, and does not admit to, intending to violate the law, let alone committing fraud.  See our blog posting in the Synthes case here.  In addition, the Friedman case shows that an individual can be subject to exclusion by HHS.  Not to be forgotten is FDA’s separate authority to debar someone, particularly for offenses relating to drugs.  For a recent blog entry regarding FDA debarments, look here.

Thus, what is a person threatened with criminal charges under the FDC Act to do?  Going to trial is costly and the outcome is uncertain.  However, the Friedman case shows that a decision to plead guilty leads to an eventual outcome that is equally uncertain.  A court may or may not accept a guilty plea.  Although, a person negotiating a plea may seek to reach a global resolution, is that possible in the debarment/exclusion area?  Whom does the individual bargain with on this issue?  DOJ? HHS? FDA? How about the VA and the Defense Department, which have their own debarment/exclusion authorities when federal funds are involved?

Reaching a plea bargain that brings certainty to whether an individual will be debarred or excluded may well be difficult if not impossible.  Assuming someone considering pleading guilty is not ready to retire, this uncertainty alone may lead to more individuals simply saying “no” to plea bargains and taking a case to trial.

By Douglas B. Farquhar – 

In a rare request for a court to review FDA’s failure to clear a medical device for market distribution, arguments have been finalized, briefs have been filed, and oral argument has been scheduled for September 21, 2012.

The case, filed in the U.S. Court of Appeals for the D.C. Circuit (appeal no. 11-1268),  relates to two medical devices for which Cytori Therapeutics, Inc., of San Diego, California, sought clearance.  The first device is called the Celution 700/LAB device, which Cytori’s brief describes as, in layman’s terms, “a liposuction device which allows a physician to access a patient’s stem cells from the body fat in which the cells are stored, and then to study those cells in a clinical laboratory.”  Cytori argues in its brief and in its reply brief that it first became aware of the reason FDA refused to clear the device when FDA filed in court the administrative record on FDA’s decision, and that FDA is apparently concerned that the device will be used to process stromal (or stem) cells to be transfused back into the donor’s body.  In other words, while the indications for the device’s use listed in the labeling are for analytical use, FDA voiced a concern that the device would be put to therapeutic use.   Cytori argues that it is wrong for FDA to refuse to clear a device because of potential off-label uses.

The second device is called the StemSource 900/MB.  Cytori says in its opening brief that “the two devices have similar physical attributes,” but that Cytori “submitted them separately to the FDA to be approved for different intended uses and indications.”  Cytori further states that, while “the 700/LAB device was submitted to be approved for laboratory use, the 900/MB Processor System was submitted for use in banking/cryopreservation.”  Cytori admits in its brief that the StemSource 900/MB was intended to be used to remove and process stem cells at the point of care (in other words, the patient’s bedside) for potential reinsertion in the donor’s body.  But Cytori argues that FDA inaccurately declined clearance because Cytori requested a Class 1 classification for the device, that FDA believed that the Class 1 classification was inappropriate for bedside use, and, as Cytori puts it, “whether a device is used in the operating room has nothing to do with whether it may be classified as Class I.”

Cytori claims that FDA’s refusal to clear the devices for distribution in the United States is thus arbitrary and capricious.

The parties agree that the standard for market clearance (under what is commonly referred to as the “510(k) process” after the relevant statutory section of the Federal Food, Drug, and Cosmetic Act) is whether the devices are “substantially equivalent” to “a legally marketed predicate device” (generally, a previously approved or cleared device).  A detailed discussion of the arguments advanced by Cytori and FDA is beyond the scope of this blogpost (and, to the uninitiated, would likely be soporific).

But FDA counters in its brief that the StemSource/900 MB device is not “substantially equivalent” to the predicate devices, because the Cytori proposed device is intended to process cells from adipose (or fatty) tissue, whereas the predicate devices are intended to process cells from “cord blood” (that is, blood from an umbilical cord or placenta).  One of the FDA brief’s sentences encapsulates its arguments thusly: “Fat is not blood.”

Likewise, FDA argues that the devices cited by Cytori as predicates for the Celution 700/Lab System are not predicates, because they were not cleared for processing stem cells derived from adipose tissue.  FDA also argues that an enzyme Cytori proposed to process the cells is a "new technology that raises new questions of safety.”

FDA earlier asked the court to dismiss Cytori’s petition seeking review of FDA’s decisions by the appellate court, but a panel of the court denied the motion late last year and required the parties to address, in their main briefs, whether the court has jurisdiction to review the matter.  FDA argues that the appellate court has primary jurisdiction to review only a decision to clear a device (not a refusal to clear a device); Cytori, of course, disagrees.

The decision issued in this case (generally, in cases of this complexity, two to ten months after the argument) could well determine two important issues: first, whether the Court of Appeals has primary jurisdiction to review an FDA decision not to clear a device for distribution (or whether the issue must first be presented to a U.S. District Court); and, second, if the court decides to issue a decision on the substance of the case, how thoroughly an appellate court will scrutinize the manner in which FDA applies the substantial equivalence criteria to a proposed medical device.

By Larry K. Houck –
 
Senators Orrin Hatch (R-UT) and Sheldon Whitehorse (D-RI) introduced legislation on July 25, 2012, that would amend the definition of “anabolic steroid” under the Federal Controlled Substances Act (“CSA”) and expressly add twenty-seven additional anabolic steroids to schedule III.  The proposed “Designer Anabolic Steroid Control Act of 2012” (S. 3431) (“2012 Act”) would significantly increase Drug Enforcement Administration (“DEA”) control over drugs and substances that meet anabolic steroid criteria.  If enacted, the 2012 Act would be the third major federal legislative action impacting anabolic steroids since 1990.  Congress passed the Anabolic Steroid Control Acts of 1990 and 2004 that placed certain anabolic steroids into schedule III of the CSA, expanding DEA’s authority to regulate such substances. 
 
Passage of the 2012 Act would similarly add twenty-seven anabolic steroids, their salts and esters, to schedule III of the CSA.  Placement of anabolic steroids in schedule III subjects manufacturers, distributors, dispensers such as pharmacies and physicians, importers, exporters, and anyone in possession of the scheduled anabolic steroids to the applicable provisions of the CSA and its implementing regulations that establish registration, recordkeeping/reporting and security requirements as well as administrative, civil and criminal sanctions.
 
The 2012 Act would expand the definition of anabolic steroids to include a drug or hormonal substance (other than estrogens, progestins, corticosteroids and dehydroepiandrosterone) “derived from, or has a chemical structure substantially similar to” anabolic steroids listed under the CSA if:  the drug or substance has been created or manufactured with the intent of producing a drug or other substance that promotes muscle growth or causes a pharmacological effect similar to that of testosterone; or the drug or substance has been, or is intended to be marketed or otherwise promoted in a manner suggesting that consumption will promote muscle growth or any pharmacological effect similar to that of testosterone.  The 2012 Act would exclude herbs and other botanicals, “a concentrate, metabolite, or extract of, or a constituent isolated directly from” herbs or botanicals that are dietary ingredients for purposes of the Federal Food, Drug and Cosmetic Act. 
 
The 2012 Act would also authorize DEA to issue a temporary order for up to two years (that could be extended six additional months) adding a drug or other substance to the list of anabolic steroids in schedule III if it finds that the drug or substance satisfies the Act’s criteria as an anabolic steroid.  Adding the drug or substance to the list of anabolic steroids “will assist in preventing the unlawful importation, manufacture, distribution, or dispensing of such drug or other substance.”  The Act would also consider a drug or other substance not temporarily or permanently listed as an anabolic steroid in any criminal, civil or administrative proceeding arising under the CSA that satisfies the anabolic steroid criteria.  This could occur if, for example, such product was promoted for muscle growth.  The Act would also require anabolic steroids and products containing anabolic steroids to bear a label identifying such contents.  Lastly, the Act would also subject violators to specific civil and/or criminal penalties including up to $500,000 per violation and imprisonment of up to ten years.
 
DEA Deputy Assistant Administrator Joseph Rannazzisi, stated in testimony before the Senate Judiciary Committee Subcommittee on Crime and Drugs, “[t]he use of anabolic steroids or dietary supplements that contain anabolic steroids or designer steroids, in high doses that boost, alter or derive from testosterone may trigger numerous adverse health effects in the human body including liver toxicity, baldness, uncontrolled rage and heart attacks.” 
 
The Council for Responsible Nutrition and American Herbal Products Association have issued statements endorsing the measure (here and here).
 
The 2012 Act has been referred to the Senate Committee on the Judiciary.

By William T. Koustas –

We have been following the litigation between Regenerative Sciences, LLC (“Regenerative”) and FDA for over two years (see here, here, here, here, and here.  On Monday, the United State District Court for the District of Columbia ruled in favor of FDA and granted its motion for summary judgment and issued a permanent injunction against the use of the Regenexx Procedure.  We will not be surprised if the case ends up in the D.C. Circuit. 

As you may recall from prior blog posts, Regenerative is a Colorado company that owns a procedure known as the Regenexx Procedure.  It is a non-surgical procedure by which physicians take bone marrow and blood samples from a patient, culture the stem cells, and inject them back into that patient in order to treat joint, muscle, tendon, or bone pain.  Regenerative states that the Regenexx Procedure is exclusively licensed for use by a particular Colorado clinic where its inventors practice. 

While explained in more depth in our prior blog posts, FDA essentially argued that the Regenexx Procedure is a drug under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and must therefore only be performed pursuant to a New Drug Application and under current Good Manufacturing Practices (“cGMP”).  By contrast, Regenerative argued that the Regenexx Procedure is the practice of medicine, which is outside of FDA’s jurisdiction and is not introduced or delivered for introduction into interstate commerce since the entire Regenexx Procedure is performed within the borders of Colorado.  FDA countered that this procedure was introduced into interstate commerce because one or more of its components is shipped via interstate commerce and because it substantially affects interstate commerce by depressing the market for FDA-approved out-of-state drugs by encouraging individuals to travel to Colorado to have the Regenexx Procedure performed instead.

The Court ultimately sided with FDA, although it called the decision a “close question.”  Among other things, the Court found that the Regenexx Procedure is a drug as defined under the FDCA as it determined the procedure is an article intended to treat a condition (i.e., orthopedic pain). 

More importantly, the Court ruled that the FDCA provides FDA with jurisdiction over the Regenexx Procedure despite the fact that it is done entirely in Colorado.  The Court held that, “because a component of the [Regenexx Procedure] shipped through interstate commerce prior to its administration to the patient,” the interstate commerce FDCA requirement had been satisfied.  Memorandum Opinion at 15.  The component the Court referred to is a prescription drug used to process a patient’s stem cells.  Therefore, the Court found that the Regenexx Procedure is a drug that is held for sale and introduced into interstate commerce. 

It should be noted that the Court only found that the Regenexx Procedure was introduced into interstate commerce because a component used in the procedure moved through interstate commerce.  As discussed in a prior blog post, FDA also contended that the Regenexx Procedure substantially affected interstate commerce under the Constitution because individuals traveling to Colorado for the procedure would depress the market for out-of-state drugs.  We noted that such an interpretation of the interstate commerce requirement was highly unusual to say the least and would significantly expand FDA’s authority.  It is interesting that the Court’s opinion did not even mention that constitutional argument.

Following the interstate commerce ruling, the Court ruled that the Regenexx Procedure is an adulterated and misbranded drug.  It is adulterated because it is not “manufactured” in conformance with cGMP requirements and misbranded because the information on the “label” on the syringe that contained the processed stem cells did not include the statutory or regulatory disclosure requirements.  The Court also ruled that FDA is not interfering with the practice of medicine by regulating the Regenexx Procedure because FDA is merely attempting to control the availability of a “drug” rather than controlling which approved drug a physician uses.

All of Regenerative’s counter claims were also dismissed by the Court.

By Kurt R. Karst –      

Last week, Representative William Keating (D-MA) announced the introduction of new legislation – the Stop Tampering of Prescription Pills Act of 2012, or STOPP Act (H.R. 6160) – that is intended to direct companies “to invest in research and production to formulate tamper resistant drugs in order to compete with drugs of a similar nature that already employ tamper resistant technologies.”  Although Congress has, over the years, encouraged companies to develop drug products with tamper- or abuse-resistant characteristics and has issued certain directives to FDA with respect to such products (see here, page 142; here, page 102; and here, page 81), including directing FDA to issue guidance on the development of abuse-deterrent drug products as part of the recently enacted FDA Safety and Innovation Act (§ 1122), the STOPP Act goes much further.

The STOPP Act would amend the FDC Act to, among other things, establish new requirements for the approval of brand-name and generic drugs that are otherwise available in a tamper-resistant formulation.  Specifically, under the STOPP Act:

• If a pharmaceutical manufacturer submits an [ANDA] to [FDA] that refers to a listed drug that utilizes a tamper resistant formulation, the application must include data demonstrating that the new drug is tamper resistant to a degree comparable to the listed drug.  If the ANDA does not make such a showing, FDA must refuse approval of the application.

• FDA must refuse approval of a [NDA] for a new drug, which is an oral dosage form, that contains a controlled substance as an active ingredient and does not utilize a tamper resistant or abuse deterrent formulation, where FDA has previously approved a drug that: (1) is an oral dosage form, (2) contains the same controlled substance as an active ingredient, (3) utilizes a tamper resistant or abuse deterrent formulation, and (4) has not been discontinued from marketing.

• If a listed drug begins to utilize a tamper resistant formulation, any drug previously approved under an ANDA that refers to such listed drug must be deemed not therapeutically equivalent – and thus not substitutable – to the listed drug, unless and until the generic also begins to utilize a tamper resistant formulation.

• If approval of a listed drug has been withdrawn, or if such drug is withdrawn from sale, after a tamper resistant version of that drug has been approved under another NDA, then such drug shall be considered withdrawn from sale for a safety reason.

• FDA must refuse a suitability petition where the petition references a listed drug that utilizes an abuse deterrent formulation, and the new drug contains any active ingredient(s) that differ in any respect from those contained in the listed drug.  As a result, any such new drug must be approved under an NDA rather than an ANDA.

One example cited by Rep. Keating as a basis for the STOPP Act is the tamper-resistant version of Purdue Pharma L.P.’s OxyContin (oxycodone hydrochloride) Controlled-Release Tablets that FDA approved in April 2010 under NDA No. 022272 and that replaced the original and now discontinued non-tamper-resistant version of the drug FDA approved in December 1995 under NDA No. 020553.  FDA has already received several citizen petitions (Docket Nos. FDA-2011-P-0473, FDA-2010-P-0540, and FDA-2010-P-0526) requesting that the Agency determine whether the discontinued version of OxyContin was voluntarily withdrawn for safety or effectiveness reasons.  FDA’s decision on the issue will determine whether the agency can approve any pending ANDAs for the discontinued formulation. 

More recenty, and just a week prior to the introduction of the STOPP Act, Purdue submitted a 75-page citizen petition to FDA (Docket No. FDA-2012-P-0760) requesting that the Agency, among other things, issue guidance detailing the in vitro and in vivo tests that must be performed by the sponsor of an ANDA for a generic version of the tamper-resistant version of OxyContin “to characterize the physicochemical properties of the proposed generic product and to assess the release of oxycodone when the product is manipulated in order to simulate attempts to tamper with the product for purposes of abuse or misuse,” and to refuse to approve any ANDA that does not meet such standards.  In July 2010, FDA issued draft guidance specifying the types of bioequivalence studies the Agency recommends for generic versions of the tamper-resistant version of OxyContin; however, the draft guidance makes no mention of studies taking into account tamper resistance.  More recently, FDA issued draft bioequivalence guidance with respect to generic versions of EMBEDA (morphine sulfate and naltrexone hydrochloride) Extended-Release Capsules that includes a crush study that “allows for the assessment of Naltrexone bioequivalence in a potential abuse situation.”

By Jennifer D. Newberger –

The pre-Investigational Device Exemption ("IDE") program, established in 1995, was originally intended as a way for sponsors to obtain FDA feedback on future IDE applications. 

Over time, the program expanded to include feedback on other submissions, such as premarket approval ("PMA") applications, humanitarian device exemption ("HDE") applications, and premarket notification (510(k)) submissions.  To update the pre IDE program to account for its expansion, on July 13, 2012, FDA issued a draft guidance titled, “Medical Devices: The Pre-Submission Program and Meetings with FDA Staff,” which renames the pre-IDE program the Pre-Submission ("Pre-Sub") program and also broadens the program to include devices regulated by the Center for Biologics Evaluation and Research ("CBER").

As with pre-IDEs, Pre-Subs are voluntary, and it is up to the sponsor to decide whether one is necessary.  FDA encourages early interaction between it and the sponsor to “improve the quality of subsequent submissions and facilitate the development process for new devices.”  The draft guidance also states that FDA will attempt to maintain continuity between various Pre-Subs related to the same topic by tracking as supplement submissions subsequent to the original submission. If the sponsor anticipates more than one Pre-Sub for the same device/ indication, FDA asks that the sponsor submit an overview of the expected submissions in the original Pre-Sub.

The draft guidance provides examples of circumstances in which FDA believes it is particularly useful to submit a Pre-Sub.  For example, it may be useful when the new device involves novel technology; the proposed indication will cause the device to be a “first of a kind” device; or the sponsor desires FDA input on specific issues related to planned clinical studies. 

In an appendix, FDA provides recommendations for the information that should be included in specific types of Pre-Subs (PMA, 510(k), IDE, HDE).  The draft guidance also discusses informational meetings, in which FDA does not provide feedback to a sponsor, and submission issue meetings, which a sponsor can request to discuss deficiencies identified during review of a 510(k) notification, PMA, HDE, IDE, or de novo submission. 

One of industry’s primary concerns about the pre-IDE program has been that FDA often provides advice and guidance in a pre-IDE meeting and then subsequently changes its position.  The sponsor then must decide whether it has sufficient resources to address FDA’s newly stated concerns, or if it must abandon its efforts due to FDA’s new approach. 

Though the draft guidance clearly states that advice provided in a Pre-Sub is “not decisional or binding on the agency or the applicant,” it also states that FDA intends to commit to the advice provided in a Pre-Sub, “unless the circumstances sufficiently change such that [the] advice is no longer applicable, such as when a sponsor changes the intended use of [its] device after [FDA] provide[s] feedback.” 

Later, the draft guidance further limits when FDA may change the advice given in a Pre-Sub:  “Modifications to FDA’s feedback will be limited to situations in which FDA concludes that the feedback given previously does not adequately address important new issues materially relevant to a determination of safety or effectiveness that have emerged since the time of the Pre-Sub.”  This is not exactly an iron clad guarantee, but if FDA adheres to this approach, it will help provide greater certainty in the product review process.  It is fair to say, then, that this draft guidance is a step in the right direction. 

By Ricardo Carvajal –

FDA published a Federal Register notice announcing the filing of Rep. Edward J. Markey’s food additive petition asking the agency to amend its regulations “to no longer provide for the use of Bisphenol A (BPA)-based epoxy resins as coatings in packaging for infant formula.”  The petition contends that those uses “have been intentionally and permanently abandoned.”  If granted, the amendment would not be based on safety; therefore, FDA is not asking for comments on the safety of BPA.

Concurrently, FDA published a final rule amending its food additive regulations “to no longer provide for the use of polycarbonate (PC) resins” (which are made with BPA) in baby bottles and sippy cups because those uses  have been abandoned.  That action was taken in response to a petition submitted by the American Chemistry Council.  Because the action was based on abandonment, the preamble to the final rule does not address safety issues.

Not long ago, FDA denied a petition submitted by the Natural Resources Defense Council ("NRDC") to ban BPA in food packaging (see our previous post here).  The steady march away from BPA in a range of consumer food contact articles may help soothe NRDC’s disappointment.

By JP Ellison –
 
In a July 3, 2012 memorandum opinion out of the Eastern District of Pennsylvania, the court granted in part and denied in part the defendants’ motion to dismiss the plaintiff’s claims for failure to state a claim.  The case, United States of America ex rel Streck v. Allergan Inc., is a qui tam alleging federal and state false claims action violations arising out of average manufacturer price (“AMP”) reporting.  The relator alleged that various drug manufacturers violated the false claims acts through their treatment of service fees paid by manufacturers to wholesalers.  Hyman Phelps represented two of the defendants in the case.  The relator divided the defendants into two groups, so-called “Discount Defendants” and “Service Fee Defendants.”
 
As to the Discount Defendants, the plaintiff alleged that these defendants improperly treated the service fees paid to wholesalers as discounts, resulting in lower and allegedly false AMPs.  As to the Service Fee Defendants, the plaintiff alleged that these defendants had contracts with wholesalers pursuant to which any service fees owed by manufacturers to wholesalers were offset by price increases that occurred after the wholesaler had been invoiced by the manufacturer.  The plaintiff further alleged that this offset—a “price appreciation credit” hid these price increases and similarly resulted in lower and allegedly false AMPs.
 
The defendants made several arguments in support of their motion to dismiss including the argument that the plaintiff failed to plead sufficient facts to allow the court to conclude that it was plausible that the defendants had acted with the intent necessary to commit a false claims act violation.  Under the federal false claims act, a defendant must act “knowingly” which is defined to include both deliberate ignorance of and reckless disregard for the truth or falsity of the information—in this case the reported AMPs. 

After a review of the statutory and regulatory history of the AMP statute and regulatory guidance , the court concluded that the absence of relevant guidance was fatal to all of plaintiff’s claims prior to January 1, 2007, when Congress changed—and in the court’s view clarified–the statutory definition of AMP.  From that date forward, the court ruled that there was sufficient guidance that plaintiff’s claims against the Discount Defendants were plausible, and thus could survive a motion to dismiss.  At a later stage in the case, the Discount Defendants will be able to present evidence that even after January 1, 2007, their AMP calculations did not violate the false claims act, but at this juncture, the court only considered the plaintiff’s allegations and was required by law to accept them as true.
 
As to the Service Fee Defendants, the court noted that the absence of guidance continued until much more recently, specifically February 2, 2012, when CMS, in the preamble to a proposed rule opined that price appreciation credits did not meet the definition of bona fide service fees.  Because that guidance post-dated the plaintiff’s complaint, it was of no help in establishing a “knowing” violation by the Service Fee Defendants.  Consequently, the court dismissed the claims against those defendants in their entirety.

By Benjamin K. Wolf* & John R. Fleder –

Dr. Glen R. Justice, a 67 year old oncologist and hematologist, pleaded guilty to defrauding government, public and private insurers out of at least $400,000.  The government alleged that Dr. Justice billed for treatments either not given or which were for more expensive medications than were provided.  According to news articles here and here and a July 2011 press release issued by the Department of Justice here, DOJ originally planned to recommend that Dr. Justice receive probation as part of his plea to the five counts of health care fraud, each a felony punishable by up to ten years in jail.  Dr. Justice instead received a sentence of 18 months in jail plus he was ordered to make restitution of slightly over $1 million after the prosecutor recommended jail time.  Why the change of heart?  Dr. Justice allegedly continued these billing practices after he had signed the plea deal.  As a result of his conviction, the California Medical Board suspended Dr. Justice’s license to practice medicine.

Our astute readers might be asking: what does this have to do with the FDA?  We wondered the same thing when we saw the notice in the Federal Register last week in which FDA announced that it was debarring Dr. Justice for 25 years.

The relevant FDA debarment provision provides for “permissive” debarment when (1) FDA finds that an individual has been convicted of a felony which involves fraud; and (2) FDA finds that such individual has demonstrated a pattern of conduct sufficient to find that there is reason to believe that such individual may violate the FDCA relating to drug products.  21 U.S.C. § 335a(b)(2)(B)(ii)(I).  Debarment under § 335a(b)(2)(B)(ii) is not to exceed five years per count.  §335a(c)(2)(A)(iii).  A debarred individual may not provide services to anyone who has an approved or pending drug product application.  § 335a(c)(1)(B).  A more complete explanation and history of the FDA debarment statute may be found here.

In this case, the Agency found that Dr. Justice had demonstrated a pattern of conduct sufficient to find that FDA had reason to believe that he may violate the FDCA relating to drug products.  This was based on FDA’s conclusion that (1) Dr. Justice shirked his legal and professional obligations to bill honestly and treat his patients with appropriate medications for their conditions and (2) because the drugs he billed for were “FDA-regulated.”  FDA did not explain how such conduct would violate the FDCA.

We are aware of only one other instance when a FDA debarment was based on the rationale underlying Dr. Justice’s debarment.  Dr. Ehigiator O. Akhigbe’s 25-year FDA debarment was announced in a Federal Register notice on December 17, 2010.  Dr. Akhigbe was debarred after he was convicted of one count of health care fraud and 16 counts of false statements in health care matters.  Like Dr. Justice, he allegedly submitted claims for procedures and treatment he did not perform.

It is difficult to discern the reasoning behind the length of Dr. Justice’s debarment where FDA seemed to determine the period of debarment by simply multiplying the number of counts as to which Dr. Justice pleaded guilty (five) by the maximum length of the debarment period for each offense (also five).  In contrast, the Federal Sentencing Guidelines urges federal judges to impose sentences for convicted persons by grouping the counts as to which a person has pleaded guilty, rather than impose a sentence based solely or largely on the number of counts as to which that person has pleaded guilty.  For FDA debarment, the opposite seems to be true.  We are left to wonder why Dr. Justice, who will be 92 when he can once again provide services to drug companies, essentially got a lifetime debarment?

Unfortunately, we also can not answer an even more puzzling question raised by the Dr. Justice debarment.  Why did FDA debar Dr. Justice for health care fraud, for conduct that seems unrelated to violations of the FDCA, when FDA has obviously chosen not to debar a multitude of other persons convicted of health care fraud every year for offenses unrelated to the FDCA?

We certainly are supportive of FDA exercising prosecutorial discretion when the Agency chooses not to debar certain people.  However, FDA’s decision in the Justice case, both in terms of the decision to debar him and the length of the debarment period suggests that FDA may be arbitrarily singling out one or two people for an extensive period of debarment without any clearly articulated rational and legal basis for doing so.

We expect to be soon reporting on the outcome of the D.C. Circuit’s long-awaited decision in the HHS debarment proceedings involving former executives in the Purdue Frederick Co., Inc. case.  That case was argued in December 2011, and we expect a decision will be rendered soon.  Our earlier blog post can be found here.

* Summer Associate

By Riëtte van Laack –

As we anticipated, both the FTC Staff and POM Wonderful appealed the May 17, 2012 Initial Decision by the FTC’s Administrative Law Judge (ALJ).  Among other things, the FTC Staff appealed the ALJ’s conclusion that substantiation of disease efficacy claims does not require well-designed, well-conducted, double-blind, randomized, controlled clinical trials (RCTs) and the ALJ’s denial of FTC Staff’s proposed remedy to require FDA approval for all future claims that any POM product is effective in the diagnosis, cure, mitigation, treatment or prevention of a disease.  POM has also appealed the ALJ’s findings that POM contends were erroneous.

In general, the FTC has historically proclaimed that the standard of substantiation is “Competent and Reliable Scientific Evidence,” a standard that the FTC has stated is flexible.  Although consent decrees suggested otherwise, the Agency has been unwilling to specify that, with regard to health benefit claims, this standard always requires RCTs.  However, in its appeal in In Re POM Wonderful, the FTC Staff  unequivocally asserts that for so-called establishment claims, i.e., claims about the amount and type of evidence about the products specific health benefit, only RCTs are sufficiently reliable to establish a causal link between the product and the reduced risk of a disease.  In fact, according to the FTC Staff, it is “axiomatic that only [RCTs] can establish that a product is proven to treat, prevent or reduce the risk of a specific disease.”  Although it applies a different analysis, FTC Staff also concludes that for non-establishment disease efficacy claims, i.e., claims that a product treats, prevents or reduces the risk of diseases, only RCTs will do.  The FTC Staff stresses that the requirement for RCTs applies to disease efficacy claims and its statements should not be interpreted to mean that RCTs are automatically required for any health efficacy claims. 

The FTC Staff also again argues that its proposed remedy requiring FDA pre-approval for future disease efficacy claims is justified in light of POM’s past conduct, the complexity of the scientific issues, the expertise of FDA to evaluate this type of claims, and the FTC’s interest in harmonizing with FDA.  The FTC Staff asserts that this requirement provides a bright line and will protect the FTC from disputes of the kind it has encountered in previous litigated cases (e.g., Lane Labs, Inc. and Garden of Life, Inc.).

Now that the FTC Staff and POM have made their written arguments, the next step in the process is for the five FTC Commissioners to hear oral argument and make a final decision regarding whether to adopt, in whole or in part, or not at all, the ALJ’s Initial Decision.  Oral argument before the Commission is scheduled for August 23, 2012.

By Nisha P. Shah –

On July 8, 2012, Massachusetts Governor Deval Patrick signed H. 4200, which, in part, relaxes: (1) the state anti-kickback law to permit the offering of coupons for prescription drug and biological products, and (2) the marketing laws to allow prescription drug and medical device manufacturers to provide meals to health care practitioners (HCPs) consumed outside of a health care setting.   

All-Payor Anti-Kickback Law

Massachusetts is one of a few states to have an all-payor anti-kickback statute that prohibits, in part, a person from offering any remuneration (including rebates) to induce the purchase or order of any good, facility, service, or item that is paid in whole or in part by a health care insurer.  Mass. Gen. Laws ch. 175H, sec. 3.  Under this law, manufacturers have been prohibited from providing coupons or rebates that are offered by manufacturers to patients insured by any health care plan (not just Medicare, Medicaid, or other government health care program) to offset the costs or co-payments associated with prescription drug or biological products.  Manufacturers offering such coupon programs typically have excluded all residents of Massachusetts from benefiting from the coupon program.

Sections 128 to 130 of H. 4200 add an exception to the all-payor anti-kickback statute to allow, among other things, pharmaceutical manufacturing companies (as defined in the marketing law, Mass. Gen. Laws ch. 111N) to provide a discount, rebate, voucher, or other reduction in a patient’s out-of-pocket expenses (including co-payments and deductibles) on a biological product or prescription drug.  However, the law specifically prohibits a pharmaceutical manufacturer from offering such coupons for a prescription drug that has an AB rated generic equivalent as determined by FDA.  Additionally, the coupon must be given to a patient directly or electronically or through a point of sale or mail-in rebate, or through similar means.  The phrase “similar means” was not defined, and it is not clear how broadly this should be construed (for example, whether coupons could be provided to HCPs to give to patients).  This coupon exception will not apply if a pharmaceutical manufacturer excludes or favors any pharmacy in the redemption of such coupon. 

Sections 128 to 130 went into effect immediately and are scheduled to sunset on July 1, 2015.  By December 31, 2014, the Division of Health Care Finance and Policy (Division), in consultation with the Department of Public Health (DPH), must complete an analysis of the impact on health care costs of the use of such coupons for biological products and prescription drugs from August 1, 2012 to July 31, 2014.  The statute authorizes the Division to require manufacturers of biological products and prescription drugs to report on the number and types of coupons that the manufacturers have issued and that have been redeemed in Massachusetts.

Marketing Law

In H. 4200, the Massachusetts legislature also relaxed the marketing laws that prohibit the provision of meals outside of the hospital or medical office setting.  In 2008, Massachusetts enacted a law that imposes compliance and reporting requirements on pharmaceutical and medical device companies that employ a person to sell or market prescription drugs or medical devices in Massachusetts (see our blog post here).  See generally, Mass. Gen. Laws ch. 111N.  The original law prohibited a company from providing meals to HCPs that are part of a recreational event, offered without an informational presentation, consumed outside of a health care setting, or for a HCP’s spouse or other guest. 

According to Section 111 of H. 4200, manufacturers are now permitted to provide or pay for “modest meals and refreshments” in connection with non-continuing medical education (CME) presentations for the purpose of educating HCPs about the benefits, risks and appropriate uses of prescription drugs or medical devices, disease states or other scientific information, as long as the presentation occurs “in a venue that is conducive to informational communications.”  DPH must define in regulation what constitutes “modest meals and refreshments” and also determine whether companies must pay a fee to pay for the costs of administering the new requirements.  Companies must file quarterly reports detailing all non-CME educational presentations at which such meals or refreshments are provided.  The reports must include the following information: (1) the location of the non-CME presentation; (2) a description of any pharmaceutical products, medical devices or other products discussed at the presentation; and (3) the total amount spent on the presentation and an estimate of the amount spent per participant. 

Additionally, Section 111 of H. 4200 also permits the payment of reasonable expenses for the technical training on the use of a medical device.  Section 113 of H. 4200 instructs DPH to no longer require reporting by pharmaceutical and medical device manufacturers of any information that has been disclosed to the federal government that may be obtained by DPH.  This follows the federal preemption requirement under section 6002 of the Patient Protection and Affordable Care Act (PPACA) (see our blog posts here and here).  Finally, DPH will be required to make data submitted by companies in annual reports publicly available and in a searchable format on DPH’s web site not later than 90 days following receipt of the information.

By Kurt R. Karst –

FDA’s Office of Generic Drugs (“OGD”) will have a new leader beginning next week.  On July 13th, Helen Winkle, Director of the Office of Pharmaceutical Science in the Center for Drug Evaluation and Research, in which OGD is housed, announced that Gregory P. Geba, M.D., M.P.H. has been named OGD Director.  Dr. Geba will replace Dr. Keith Webber, who has served as OGD’s Acting Director since the departure of Gary Buehler in 2010.  During that time, Dr. Webber has also served as Deputy Director of the Office of Pharmaceutical Science. 

The announcement comes just days after the enactment of the Generic Drug User Fee Amendments of 2012 (“GDUFA”) as part of the FDA Safety and Innovation Act (see here).  GDUFA significantly revamps the generic drug approval process and will have wide-ranging effects on industry and on OGD.  Below is the correspondence from Ms. Winkle announcing Dr. Geba’s selection.

The Office of Pharmaceutical Science (OPS) is proud to announce the selection of Gregory P. Geba, M.D., M.P.H., as Director of the Office of Generic Drugs (OGD) effective July 15, 2012.
 
Dr. Geba has served in senior-level clinical/managerial positions in the pharmaceutical industry for the past 15 years. He most recently served as Deputy Chief Medical Officer for Sanofi US, where he provided medical and scientific leadership and managerial direction to a staff of approximately 500 multidisciplinary scientific and regulatory professionals engaged in drug development activities across all therapeutic areas, as well as to the company’s field medical group.
 
He has contributed to the registration of more than 20 currently marketed drugs or devices across multiple therapeutic areas. In so doing, he successfully employed his working knowledge and demonstrated practical application of drug manufacturing processes, current quality and risk management processes, and standards relevant to FDA’s laws and regulations. He brings extensive clinical research experience, including leading or serving as the key point in filing new drug applications, biologic license applications, and promotional studies comparing efficacy and effectiveness of novel biopharmaceuticals versus standard of care (including regimens containing branded or generic drugs), and has provided or supervised key safety updates and presentations to FDA Advisory Committees. Dr. Geba’s experience also includes leading medical affairs activities while serving in a variety of senior-level positions. His scope of responsibility in those activities included contribution to the design of experimental protocols and assessment of data from pre-clinical, animal, and first-in-human studies; design, implementation, analysis, and interpretation of phase 2a proof-of-concept and 2b dose ranging studies; and production of important comparative effectiveness and safety data when assessing benefit-risk relationships during phase 3, phase 3b, and phase 4 studies.
 
Dr. Geba received his medical degree from the University of Navarre and his M.P.H. from the Johns Hopkins Bloomberg School of Public Health. He joins OGD at an opportune time to lead our expanding generic program into a reorganization of both structure and process to improve coordination, communication, and efficiency, as well as enhance the Office’s ability to ensure that all generic drugs—which make up nearly 80 percent of prescriptions filled in the United States—are safe, effective, of high quality, and interchangeable with the brand name drug product/reference listed drug.
 
Please join me in welcoming Dr. Geba to this important position. We welcome the wealth of knowledge and experience that he will bring to the organization.

By Alexander J. Varond –

After more than three years, FDA approved a class-wide Risk Evaluation and Mitigation Strategy (“REMS”) for extended-release and long-acting (“ER/LA”) opioid analgesics on July 9, 2012.  The ER/LA opioid REMS applies to more than 20 companies and 30 products, and while it includes a shared implementation program, each opioid product REMS is to be written and approved as an individual document.

In this post, we first briefly discuss the history of the program’s development and then explain the implications of the new class-wide REMS.

A long road for a rather dull REMS.  On February 6, 2009, FDA sent letters of ER/LA opioid analgesics detailing the need for a new REMS.  During a media briefing on February 9, 2009, FDA officials expressed the agency’s ambitious plan to develop a class-wide opioids REMS and further expressed that the program was “going to be the largest risk management effort [FDA had ever] undertaken.”  Rightly so, FDA announced it was taking on an effort aimed at addressing the nation’s growing prescription drug abuse epidemic.  During the media briefing, FDA also intimated that it was actively exploring requiring mandatory training for prescribers and developing a more restrictive distribution system. 

In February 2009, FDA felt it had a “pretty good outline” of what the REMS should include but took steps to consult with stakeholders, health professionals, and patient advocacy groups about the new REMS.  After collecting information from these groups, FDA planned to write letters to manufacturers and explain the requirements for the new REMS.  Within six months of the letters’ issuance, FDA expected companies to implement the REMS.

More than two years later, in April 2011, FDA finally sent letters to manufacturers of ER/LA opioids detailing its requirements for a new REMS program.  We discussed those requirements here.

Now, more than three years after beginning the opioid REM process, the final REMS is completed and amounts to essentially a mere education and monitoring program.  Additionally, despite FDA’s statement in 2009 that “voluntary programs have not been successful in getting us where we need to go with maintaining access to legitimate patients and dramatically decreasing the serious adverse event reports,” the healthcare professional education provided by the REMS is in fact voluntary. 

It is clear that, in 2009, the agency underestimated both (1) the complexity of creating a program that did not adversely affect patients in need of pain management and (2) the difficulty associated in creating a class-wide REMS program with many manufacturers.  FDA also miscalculated its authority to create a mandatory training program (FDA later considered its ability to create a mandatory training system but decided that it would need a grant of legislative power to create such a system).

Moreover, FDA did not anticipate the resistance (here and here) it would receive from healthcare professionals and patient advocacy groups against mandatory training or restrictive distribution systems.  These groups urged the agency not to require a REMS that was overly burdensome or jeopardized patient access to ER/LA opioid analgesics.

FDA’s decision not to impose mandatory education on prescribers or patients highlights the agency’s “step-wise approach” and emphasizes the difficulty it faces in reducing prescription drug abuse while maintaining access to patients with legitimate needs.  Moreover, the approximately 41-month timeframe it took to develop the LA/ER opioid analgesics REMS program reveals the difficulty FDA faces in coordinating class-wide and shared REMS programs of this nature.

FDA’s Blueprint for a house it’s not completely satisfied with.  Under the approved REMS, drug manufacturers are required to pay accredited continuing education ("CE") companies to independently develop and provide voluntary 2-3 hour ER/LA opioid training programs to prescribers in accordance with FDA’s “Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.”

The training will focus on developing prescriber knowledge about ER/LA opioid analgesic therapy in the following categories: assessing patients for treatment; initiating therapy, modifying dosing, and discontinuing use; managing therapy; counseling patients and caregivers about safe use; general drug information about ER/LA opioid analgesics; and specific drug information.  Additionally, prescribers will be counseled on how to recognize evidence of and potential for opioid misuse, abuse, and addiction.

Manufacturers will also be expected to provide a patient counseling document for prescribers to give to patients, helping prescribers to properly counsel patients on their responsibilities for using ER/LA opioid analgesics safely and an updated one-page Medication Guide that pharmacists will include when dispensing the drug that contains consumer-friendly information on the safe use and disposal of the medicines.

The first CE programs must be offered to prescribers by March 1, 2013.  FDA also expects 25% of the nation’s estimated 320,000 prescribers to be educated by year one, 50% by year two, and 60% within three years.  The REMS includes additional assessment metrics which include the number of grants awarded to CE providers, the number of prescribers trained, patient knowledge of risk information, and the effect on access to patients with legitimate needs for ER/LA opioid analgesics.

During the announcement of the REMS, Margaret Hamburg, Commissioner of FDA, and R. Gil Kerlikowske, Director of National Drug Control Policy, expressed a desire that these efforts to curb prescription drug abuse would be bolstered by future legislation to make opioid analgesic training mandatory.