Horace Scudder’s 1915 “The Book of Fables and Folk Stories” includes a story, titled “The Arab and His Camel,” that ends with the moral “It is a wise rule to resist the beginnings of evil.”  This is, of course, a parable of the Middle Eastern metaphor for the situation where allowing a small act will lead to a larger undesirable circumstance: “Do not allow a camel to put his nose under the edge of your tent, for soon you will have a camel in your tent.”  In 1992, when Congress passed the Prescription Drug User Fee Act (“PDUFA”) establishing user fees for the review of “human drug applications,” the proverbial camel’s nose came under the tent.  Although it can be debated (particularly given the substantial decrease in NDA review times in the post-PDUFA era compared to the pre-PDUFA era) whether PDUFA signalled the “beginnings of evil” (as certainly some people both in and out of FDA would contend), PDUFA has clearly provided a blueprint for the creation other user fees.

In the almost 15 years since the passage of PDUFA, not only have human drug application user fees increased substantially (FDA’s interpretation of the law has also resulted in more user fee revenue), but Congress has created PDUFA-like user fee systems for medical devices (under the Medical Device User Fee and Modernization Act of 2002) and animal drugs (under the Animal Drug User Fee Act of 2003).  FDA has also proposed, and Congress is considering as part of omnibus FDA reform legislation, a PDUFA-like user fee system as part of PDUFA IV to fund the review of direct-to-consumer advertisements. 

The most recent user fee proposal was made earlier this month by Representative John Dingell (D-MI). (And you thought the whole camel already entered the tent.)  Rep. Dingell issued discussion draft legislation, titled the “Food and Drug Import Safety act of 2007,” that would amend the FDC Act to, among other things, permit the assessment of two new types of user fees: (1) imported food inspection user fees; and (2) imported drug inspection user fees.  According to a press release and “Dear Colleague” letter issued by Rep. Dingell “[r]ecent reports of tainted imports including pet food, seafood, and cough syrup, have highlighted the need for legislative action.”  A summary of the draft bill is available here.

Rep. Dingell’s draft bill, if enacted, would authorize food import fees totaling $500 million and drug import fees totaling $300 million in each of fiscal years 2008 through 2012.  A fee of up to $50 would be assessed for each line item of food, and a fee of up to $1000 would be assessed for each line item of drug.  FDA would need to issue regulations defining what constitutes a “line item” of food and drug.  The draft bill would also amend the FDC Act to enhance civil monetary penalties for food importers that violate the FDC Act.  Specifically, the bill would amend FDC Act § 303 to permit civil monetary penalties of $100,000 in the case of an individual and $500,000 in the case of a company (not to exceed $1 million for all adjudications in a single proceeding).    

Rep. Dingell’s user fee proposal, although it serves an admirable purpose, begs the questions of how much more room there is in the proverbial user fee tent, and whether Congress’ increasing reliance on user fees to fund FDA activities (instead of substantially increasing FDA appropriations) will eventually cause that tent to collapse. 

In two previous posts (here and here), we reported on a trend in Warning Letters issued by FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”) that focuses on ensuring that promotional pieces contain substantial evidence to support advertising claims and proper presentations of safety data.  In an August 10, 2007 article published by the Washington Legal Foundation, and titled “Recent Warning Letters for Ads Reflect FDA’s Fixation on ‘Substantial Evidence,’” former FDA Associate Chief Counsel Arnold I. Friede drives home the point that to avoid problems with DDMAC, companies need to pay attention to providing substantial evidence to support all advertising claims, and in particular comparative claims.  Mr. Friede comments that:

The recent DDMAC compliance correspondence should be studied closely by companies and practitioners to provide a first hand sense of how FDA applies the “substantial evidence” standard to specific advertising and promotional claims for prescription drugs. But the overall message is simple relatively straightforward: If you want to avoid problems with DDMAC, insure that claims in prescription drug advertising and promotion are supported by “substantial evidence,” no matter how competent and reliable the supporting evidence might otherwise be to the company and to leading experts in the field. To put it bluntly, DDMAC doesn’t really care.  What DDMAC cares about is like “location,” “location,” “location” in the real estate purchase context. It’s about “substantial evidence,” “substantial evidence,” “substantial evidence”.

So whether we like it or not, or whether we think it is unconstitutional or violates the [Administrative Procedure Act] or is otherwise illegal or not, for those who seek to avoid an unpleasant compliance confrontation with DDMAC, “substantial evidence” should be the watchword.

As if to reinforce this conclusion, on August 13, 2007, DDMAC posted a Warning Letter issued to Pfizer on July 16, 2007 concerning certain promotional materials for GEODON (ziprisadone mesylate) Injection.  GEODON is approved for the treatment of acute agitation in schizophrenic patients for whom treatment with ziprasidone is appropriate and who need intramuscular antipsychotic medication for rapid control of the agitation, and includes a black box warning concerning increased mortality in elderly patients with dementia-related psychosis.

DDMAC’s Warning Letter objects to Pfizer’s omission of important risk information (e.g., the failure to communicate certain warnings and precautions associated with Geodon) and to an unsubstantiated superiority claim.  Specifically, with respect Pfizer’s claim that there are “[p]roven advantages over haloperidol [intramuscular] ―twice the improvement as measured on the [Brief Psychiatric Rating Scale],” DDMAC comments that:

This presentation is misleading because it implies that Geodon for Injection is more effective than haloperidol [intramuscular] when this has not been demonstrated by substantial evidence or substantial clinical experience. The single study cited for this claim was an open-label study, which is not an appropriate study design to evaluate subjective endpoints, such as those measured by the Brief Psychiatric Rating Scale anchored version (BPRS), because of the potential for evaluator bias. In fact, FDA is not aware of any substantial evidence to support this claim. If you have data, please submit them to FDA for review. Of interest, in the clinical trials submitted to the NDA for Geodon for Injection, the BPRS was not used and there were no active comparators.

Certainly “substantial evidence” is the DDMAC watchword for now and for the foreseeable future. 

Indeed, as we were drafting this post, DDMAC updated its Warning Letter webpage with a yet another Warning Letter objecting to ubsubstantiated superiority claims.  The letter, issued to Novartis last week, cites certain statements in promotional materials for EXELON (rivastigmine tartrate) Capsules and Oral Solution that are misleading “because, on the basis of an inadequate study, it suggests that Exelon is superior to donepezil [(ARICEPT)] in patients with mild-to-moderate Alzheimer’s Disease who have not responded to donepezil.”

We previously reported on some of the highlights of the most notable provisions of the final rule issued by the Centers for Medicare & Medicaid Services (“CMS”) on the Medicaid Drug Rebate Program.  Today, Hyman, Phelps & McNamara, P.C. issued a detailed memorandum summarizing the July 17th final rule.  The memorandum, among other things, notes where the final rule differs from the proposed rule and prior CMS policy or guidance, and identifies issues that would benefit from further CMS clarification.

In December 1992, FDA promulgated final regulations under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments. These regulations, which are commonly referred to as “accelerated approval,” are located in Subpart H (21 C.F.R. § 314.500) of FDA’s drug regulations, and in Subpart E (21 C.F.R. § 601.40) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based: (1) on a demonstrated effect on a “surrogate endpoint” and a sponsor’s commitment to complete with “due diligence” the required postmarketing studies to demonstrate the product’s clinical benefits; or (2) on restrictions to assure safe use (that is, when FDA determines that a drug can be used safely only if distribution or use is modified or restricted, e.g., THALOMID (thalidomide)).  (In clinical trials, a “surrogate endpoint” is an alternative measurement of the symptoms of a disease or condition that are substituted for measurements of observable clinical symptoms.)   Importantly, FDA may expedite the withdrawal of approval of an application approved under the accelerated approval regulations if a sponsor “fails to perform the required postmarketing study with due diligence,” or if “[a] postmarketing clinical study fails to verify clinical benefit.”   

Since 1992, FDA has approved scores of applications under the Agency’s accelerated approval regulations –primarily for products with a demonstrated effect on a surrogate endpoint.  FDA has never, however, withdrawn approval of an application for a sponsor’s failure to complete a required postmarketing study with due diligence or because a postmarketing study failed to verify clinical benefit (under either Subpart H or Subpart E).  That may be changing.  (FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit.  Instead, FDA approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment.)   

FDA approved Shire’s PROAMATINE (midodrine hydrochloride) Tablets under the Agency’s Subpart H (surrogate endpoint) regulations in September 1996 for the treatment of symptomatic orthostatic hypotension.  FDA also subsequently approved several generic versions of the drug.  The labeling for PROAMATINE includes the following warning: 

The indication for use of ProAmatine® in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to carry out activities of daily living, have not been verified.

To verify the drug’s clinical benefit to conclude that the drug is safe and effective, FDA required the sponsor of PROAMATINE to conduct certain Phase 4 studies.  According to FDA’s Postmarketing Study Commitments Database, the official status of the required postmarketing studies is “delayed.”  This makes PROAMATINE the accelerated approval with the longest outstanding commitment. 

On August 7, 2007, FDA sent a letter to companies marketing approved versions of midodrine hydrochloride.  The letter states: “To date, the holder of the midodrine hydrochloride [NDA] has failed to obtain approval for the required phase 4 studies verifying clinical benefit.  If those studies are not approved in a timely manner, that NDA (and all ANDAs referencing that NDA) will be subject to withdrawal . . . .”  It is unclear whether Shire plans to complete and obtain FDA’s approval of those studies.  If not, then FDA’s letter raises the possibility that companies currently marketing generic versions of midodrine hydrochloride might conduct those studies.  FDA’s letter states that “several holders of approved [ANDAs] for midodrine hydrochloride have considered whether to conduct the requisite studies and have requested FDA advice regarding the availability and potential scope of 3-year new clinical studies exclusivity if holders of approved midodrine applications were to collaboratively or individually complete the required post-marketing studies to verify clinical benefit for midodrine hydrochloride.”  FDA requests comment on several questions related to 3-year exclusivity and withdrawal of approval of certain applications, because the proposals to conduct the required midodrine hydrochloride postmarketing studies “raise issues of first impression and will affect more than one midodrine application holder.”   

On August 7, 2007, the U.S. Court of Appeals for the District of Columbia Circuit held in Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach in an 8-2 opinion “that there is no fundamental right ‘deeply rooted in this Nation’s history and tradition’ of access to experimental drugs for the terminally ill.”  The decision affirmed an August 2004 opinion from the U.S. District Court for the District of Columbia.  In May 2006, however, a divided court of appeals ruled that where there are no other FDA-approved treatment options, a terminally ill patient’s access to investigational new drugs is a “fundamental right” protected under the Due Process Clause of the U.S. Constitution.  The appeals court remanded the case to the district court to determine whether FDA’s policy of restricting access to post-Phase 1 investigational new drugs under FDA’s Investigational New Drug (“IND”) regulations was “narrowly tailored” to serve a “compelling governmental interest.”  FDA appealed, and the D.C. Circuit agreed to hear the case en banc.

The case stems from a citizen petition Abigail Alliance and the Washington Legal Foundation submitted to FDA in June 2003 requesting that the Agency amend its IND regulations to create a policy “to grant Initial Approval for promising drugs, biologics, and devices intended to treat life-threatening diseases with unmet needs,” and to seek “regulatory changes to permit expanded availability of developmental lifesaving drugs following phase 1 clinical trials and at all subsequent stages of the trial and review process.”  Although FDA has not yet substantively responded to the petition, the Agency did respond to earlier Abigail Alliance submissions.  Specifically, in an April 2003 letter from FDA to Abigail Alliance, the Agency commented that accepting Abigail Alliance’s proposal “would upset the appropriate balance that [it is] seeking to maintain, by giving almost total weight to the goal of early availability and giving little recognition to the importance of marketing drugs with reasonable knowledge for patients and physicians of their likely clinical benefit and their toxicity.”

The question Abigail Alliance presented to the D.C. Circuit for consideration was:

Whether the liberty protected by the Due Process Clause embraces the right of a terminally ill patient with no remaining approved treatment options to decide, in consultation with his or her own doctor, whether to seek access to investigational medications that the [FDA] concedes are safe and promising enough for substantial human testing.

The court reviewed the issue under the due process framework established in Washington v. Glucksberg, in which the Supreme Court described its “established method of substantive-due-process analysis” as having “two primary features:”

First, we have regularly observed that the Due Process Clause specially protects those fundamental rights and liberties which are, objectively, deeply rooted in this Nation’s history and tradition and implicit in the concept of ordered liberty, such that neither liberty nor justice would exist if they were sacrificed.  Second, we have required in substantive-due-process cases a careful description of the asserted fundamental liberty interest.

Assuming that Abigail Alliance’s description of its asserted right met the second Glucksberg feature, the court focused on Abigail Alliance’s arguments with respect to the first feature; namely that:

the concepts of self-defense, necessity, and interference with rescue are broad enough to demonstrate the existence of the fundamental right they seek —a right for “persons in mortal peril” to “try to save their own lives, even if the chosen means would otherwise be illegal or involve enormous risks.” (citations omitted).

The court dismissed Abigail Alliance’s arguments, noting that:

The Alliance argues that its right can be found in our history and legal traditions because “the government never interfered with the judgment of individual doctors about the medical efficacy of particular drugs until 1962,” i.e., when major amendments were made to the [FDC Act]. . . .  The Alliance has little to say, however, about our Nation’s history of regulating the safety of drugs. The Alliance’s effort to focus on efficacy regulation ignores one simple fact: it is unlawful for the Alliance to procure experimental drugs not only because they have not been proven effective, but because they have not been proven safe. Although the Alliance contends that it only wants drugs that “are safe and promising enough for substantial human testing,” i.e., drugs that have passed Phase I testing, current law bans access to an experimental drug on safety grounds until it has successfully completed all phases of testing. (citations omitted; emphasis in original).

With respect to Abigail Alliance’s arguments that barring access to experimental drugs for terminally ill patients is inconsistent with the common law doctrines of necessity, the tort of intentional interference with rescue, and the right to self-defense, the court again dismissed these arguments, relying, in part, on the Supreme Court’s decision in United States v. Oakland Cannabis Buyers’ Cooperative.  The court stated that “the common law doctrine of necessity provides little support to the Alliance’s proposed right,” that “we cannot agree that the tort of intentional interference with rescue evidences a right of access to experimental drugs,” and that “[b]ecause terminally ill patients cannot fairly be characterized as using reasonable force to defend themselves when they take unproven and possibly unsafe drugs, the Alliance’s desire that the terminally ill be free to assume the risk of experimental drugs cannot draw support from the doctrine of self-defense.”

The court also commented, citing, among other Supreme Court cases, the decision in United States v. Rutherford, that:

[W]e find it highly significant that the Supreme Court has rejected several similar challenges to the FDCA and related laws brought on statutory grounds . . . [a]nd other courts have rejected arguments that the Constitution provides an affirmative right of access to particular medical treatments reasonably prohibited by the Government.  In keeping with those decisions, we conclude that the Alliance has not provided evidence of a right to procure and use experimental drugs that is deeply rooted in our Nation’s history and traditions. To the contrary, our Nation’s history evidences increasing regulation of drugs as both the ability of government to address these risks has increased and the risks associated with drugs have become apparent. Similarly, our legal traditions of allowing a necessity defense, prohibiting intentional interference with rescue, and recognizing a right of self-defense cannot justify creating a constitutional right to assume any level of risk without regard to the scientific and medical judgment expressed through the clinical testing process.

In affirming the district court’s decision, the circuit court held that Abigail Alliance’s claim of a right of access to experimental drugs is subject to rational basis scrutiny and that:

Although terminally ill patients desperately need curative treatments, as Rutherford holds, their deaths can certainly be hastened by the use of a potentially toxic drug with no proven therapeutic benefit. Thus, we must conclude that, prior to distribution of a drug outside of controlled studies, the Government has a rational basis for ensuring that there is a scientifically and medically acceptable level of knowledge about the risks and benefits of such a drug. We therefore hold that the FDA’s policy of limiting access to investigational drugs is rationally related to the legitimate state interest of protecting patients, including the terminally ill, from potentially unsafe drugs with unknown therapeutic effects.

The two dissenting judges (Chief Judge Ginsberg and Judge Rogers) strongly rebuked the majority opinion in a 29-page dissent.  In sum, the judges contend that:

The court’s opinion reflects a flawed conception of the right claimed by the Abigail Alliance for Better Access to Developmental Drugs and a stunning misunderstanding of the stakes.  The court shifts the inquiry required by [Glucksberg], by changing the nature of the right, by conflating the right with the deprivation, and by prematurely advancing countervailing government interests.  The court fails to come to grips with the Nation’s history and traditions, which reflect deep respect and protection for the right to preserve life, a corollary to the right to life enshrined in the Constitution.  The court confuses this liberty interest with the manner in which the Alliance alleges that the liberty has been deprived, namely by denying terminally ill patients access to investigational medications under the narrow conditions described by the Alliance.  The court conflates the inquiry as to whether a fundamental right exists at all with whether the government has demonstrated a compelling interest, when strictly scrutinized, rendering its restrictive policy constitutional. . . .

In the end, it is startling that the oft-limited rights to marry, to fornicate, to have children, to control the education and upbringing of children, to perform varied sexual acts in private, and to control one’s own body even if it results in one’s own death or the death of a fetus have all been deemed fundamental rights covered, although not always protected, by the Due Process Clause, but the right to try to save one’s life is left out in the cold despite its textual anchor in the right to life. This alone is reason the court should pause about refusing to put the FDA to its proof when it denies terminal patients with no alternative therapy the only option they have left, regardless of whether that option may be a long-shot with high risks. The court is on even weaker footing when it relies upon the risks entailed in medical procedures to wrest life-and-death decisions that once were vested in patients and their physicians. The court commits a logical error of dramatic consequence by concluding that the investigational drugs are somehow not “necessary.”  While the potential cures may not prove sufficient to save the life of a terminally ill patient, they are surely necessary if there is to be any possibility of preserving her life. (citation omitted; emphasis in original).

The immediate effect that this ruling might have on FDA’s plans to move forward with the Agency’s proposed treatment IND regulations and on Senator Sam Brownback’s (R-KS) efforts to pass legislation supported by Abigail Alliance is unclear at this time.  We will update you as we learn more information.   

Last week, the U.S. House of Representatives passed H.R. 3161, the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act for Fiscal Year 2008.  The bill, which, among other things, funds FDA’s discretionary spending for the upcoming fiscal year, “fully funds the [President’s request] for the FDA and provides targeted increases of $55 million,” according to the House report accompanying the bill.  These “targeted increases” are with respect to food safety activities, speeding up generic drug application reviews (with a $5 million increase to FDA’s Office of Generic Drugs), post-market drug safety reviews, and review of direct-to-consumer drug ads. 

The bill also includes a controversial provision that would allow the importation of certain prescription drugs into the United States.  Specifically, Section 726 of H.R. 3161 states:

None of the funds appropriated or otherwise made available by this Act for the [FDA] may be used under section 801 of the [FDC Act] to prevent an individual not in the business of importing a prescription drug within the meaning of section 801(g) of such Act, wholesalers, or pharmacists from importing a prescription drug (as defined in section 804(a)(3) of such Act) which complies with sections 501 [(adulteration)], 502 [(misbranding)], and 505 [(new drug approval)] of [the FDC Act].

Representative Jack Kingston (R-GA), who was unsuccessful in his attempt to get an amendment passed to strike the importation provision, commented in the House Report on H.R. 3161 that “[i]f this provision is going to remain in the bill, then there should be funding to ensure the safety and efficacy of those imported drugs.”

FDA explained its current importation policy in a February 2003 letter issued in response to inquiries about the liability of various parties involved in importing prescription drugs from Canada.  FDA’s letter states:

The reason that Canadian or other foreign versions of U.S.-approved drugs are generally considered unapproved in the U.S. is that FDA approvals are manufacturer-specific, product-specific, and include many requirements relating to the product, such as manufacturing location, formulation, source and specifications of active ingredients, processing methods, manufacturing controls, container/closure system, and appearance.  21 C.F.R. § 314.50.  Frequently, drugs sold outside of the U.S. are not manufactured by a firm that has FDA approval for that drug.  Moreover, even if the manufacturer has FDA approval for a drug, the version produced for foreign markets usually does not meet all of the requirements of the U.S. approval, and thus is considered to be unapproved.  21 U.S.C. § 355.

The U.S. Senate Appropriations Committee, which passed its version of the appropriations bill, S. 1859, on July 19, 2007, does not include a similar importation provision.  The Senate report accompanying the bill, however, includes an amendment, sponsored by Senator Byron Dorgan (D-ND) that would require FDA to:

issue a report, using available data sources, within 120 days of enactment of this act, that outlines the location of the manufacturer of all drugs approved since January 1, 2000; the location of the manufacturer of the active ingredient in each of those drugs, only as submitted in the original application; the extent to which drugs manufactured overseas and commercially distributed in the United States are subject to different regulation than drugs manufactured and distributed in the United States; and the procedures taken when a manufacturer changes the procurement of active ingredients for their drugs.  The Committee further directs that the FDA present this information in such as way as to not violate any commercial confidential, trade secret, or proprietary information.

Sen. Dorgan, who was unsuccessful in his attempt to add a provision to the FDA Revitalization Act (S. 1082) permitting prescription drug importation, issued a press release stating that the “action comes on the heels of an all out attack by the big drug makers on legislation sponsored by Dorgan and Senator Olympia Snowe to allow the importation of lower priced prescription drugs from other countries.  The drug makers argue prescription medicines imported from other countries are inherently dangerous and that there is no way to guarantee their safety.”  According to Sen. Dorgan, “I am not claiming that drugs made overseas are dangerous, but if that’s the argument drug manufacturers are going to make to block importation of lower priced medicines, then Americans have a right to know the origin of prescription medicines the drug companies are already selling here.”

The National Association of Manufacturers and the National Association of Chain Drug Stores, among other organizations, have voiced opposition to the inclusion of a provision permitting prescription drug importation in appropriations bills (and other legislation).  In addition, the White House has objected to the importation provision in H.R. 3161.  Specifically, the Office of Management and Budget (“OMB”) stated the following in a July 31, 2007 Statement of Administrative Policy:

The Administration strongly opposes the prescription drug importation provision, which does not include any protections to ensure that imported drugs are safe and effective and which will have a negative effect on incentives for beneficial innovation. In 2004, a Department of Health and Human Services Task Force found that there are significant safety and economic issues that must be addressed with respect to prescription drug re-importation. While the provision theoretically limits importation to only FDA-approved prescription drugs, it would be impossible for FDA to verify at the border that they are not counterfeit.

The White House has previously threatened to veto certain legislation permitting importation.  For example, OMB stated in a May 1, 2007 Statement of Administrative Policy with respect to Senate efforts to include an importation provision in S. 1082 that:

The Administration would also strongly oppose any provision that might be added on the Senate Floor regarding the importation of prescription drugs that does not address the serious safety concerns identified in the December 2004 Department of Health and Human Services Task Force Report on Prescription Drug Importation.  The Administration believes that allowing importation of drugs outside the current safety system established by the FDA without addressing these serious safety concerns would threaten public health and result in unsafe, unapproved, and counterfeit drugs being imported into the United States.  As a result, if any such importation provision were included in the final version of the bill presented to the President, the President’s senior advisors would recommend that he veto the bill.

Although drug importation legislation appears to be off the table as an item for consideration in pending omnibus FDA reform legislation, it appears that the House and Senate are headed for a showdown over the issue as a part of FDA appropriations legislation. 

Legislation that would permit the U.S. Patent and Trademark Office (“PTO”) to exercise discretion to accept untimely filed Patent Term Extension (“PTE”) applications has reportedly been added to the “Patent Reform Act of 2007” (S. 1145) by Senator Edward Kennedy (D-MA).  Representative William Delahunt (D-MA), who introduced a stand-alone bill earlier this year in the House, H.R. 1778, is trying to get the legislation added to the House version of the “Patent Reform Act of 2007” (H.R. 1908). 

The legislation, dubbed the “Dog Ate My Homework Act,” has been an agenda item for Massachusetts lawmakers for several years now, and is intended to help Massachusetts-based The Medicines Company, which submitted its PTE application for U.S. Patent #5,196,404 (“the ‘404 patent”) for ANGIOMAX (bivalirudin) 62 days after FDA approved its New Drug Application (“NDA”) .  The patent term extension law, 35 U.S.C. § 156, requires the submission of such an application “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use” (i.e., within 60-days of the date of NDA approval). 

FDA Approved ANGIOMAX on December 15, 2000.  On February 14, 2001, The Medicines Company submitted a PTE application to the PTO for the ‘404 patent, which is currently scheduled to expire in 2010.  After confirming the NDA approval date with FDA, the PTO dismissed the application in March 2002.  The Medicines Company subsequently requested reconsideration on the basis that the date of approval of the ANGIOMAX NDA was in fact first effective as of December 18, 2000, and in January 2007 requested a stay of action on its PTE application.  In April 2007, after permitting the company to amend and supplement its application, the PTO denied the extension request.  Among other things, the PTO cited Unimed, Inc. v. Quigg, 888 F2d 826; 12 USPQ2d 1644 (Fed. Cir. 1989), in which the Federal Circuit addressed the timeliness of a PTE application submission and observed that “section 156(d)(1) admits of no other meaning than that the sixty-day period begins on the FDA approval date.”  A copy of the file history of the ‘404 patent, including the April 2007 PTO decision, can be found on the PTO’s Patent Application Retrieval Database by searching by patent number. 

While the PTO was considering The Medicine Company’s PTE application and request for reconsideration, the company was, according to Securities and Exchange Commission filings made as early as March 2003, “exploring an alternative to extend the term of the patent.”  (The company’s most recent annual report reiterates this.)  This alternative took the form of lobbying Massachusetts lawmakers to push for legislation that would provide the PTO with discretion to consider PTE applications filed late unintentionally.  Until recently, the closest such legislation came to becoming law was on December 6, 2006, when the House passed the Senate version of the “Vessel Hull Design Protection Amendments of 2006’’ (S. 1785), which included language similar to H.R. 5120, a bill that had been introduced in April 2006 and that was vetted during a September 2006 House Judiciary Committee hearing. The Senate adjourned on December 9, 2006 without further considering S. 1785.

The issue did not remain dormant long.  In March 2007, Representative Delahunt introduced H.R. 1778, and in April, both the Senate and House began debating patent reform legislation, which offered one vehicle to which to attach such legislation.  Although the House Judiciary Committee passed H.R. 1908 (“Patent Reform Act of 2007”) on July 18, 2007 without the Delahunt PTE provision, Representative Delahunt will reportedly try to get it added when the full House considers the legislation.  In the Senate, Senator Kennedy reportedly was successful in his attempt to add language similar to the Delahunt House bill when the Senate Judiciary Committee considered S. 1145 (“Patent Reform Act of 2007”) during a mark-up session held on July 18, 2007.  The Senate Judiciary Committee is still considering the legislation.

UPDATE:

• A copy of Sen. Kennedy’s amendment agreed to at the Senate Judiciary Committee Executive Business Meeting is available here.

Last week, FDA announced the publication of a report by the Agency’s Nanotechnology Task Force (“NTF”) that recommends that FDA develop guidance and take other steps to address regulatory and scientific issues related to nanotechnology.  Nanotechnology is an emerging field of applied science and technology covering a broad range of topics in which the primary unifying theme is the control of matter on a scale 1/100,000th the thicknes of a sheet of paper (or one billionth of a meter).  FDA announced the creation of the NTF in August 2006 and charged it with “determining regulatory approaches that encourage the continued development of innovative, safe and effective FDA-regulated products that use nanotechnology materials.” In October 2006, the NTF held a public meeting to discuss some of the issues discussed in its report. 

The NTF report acknowledges that although products incorporating nanotechnology pose regulatory challenges similar to those posed by other FDA-regulated products using new technologies:

[t]hese challenges may be magnified both because nanotechnology can be used in, or to make, any FDA-regulated product, and because, at this scale, properties of a material relevant to the safety and (as applicable) effectiveness of FDA-regulated products might change repeatedly as size enters into or varies within the nanoscale range.  In addition, the emerging and uncertain nature of the science and potential for rapid development of applications for FDA-regulated products highlights the need for timely development of a transparent, consistent, and predictable regulatory pathway.

As such, the NTF report recommends that FDA take several actions.  First, with respect to scientific issues, the NTF “recommends strengthening FDA’s promotion of, and participation in, research and other efforts to increase scientific understanding, to facilitate assessment of data needs for regulated products,” for example, by “[a]ssessing data on general particle interactions with biological systems and on specific particles of concern to FDA,” and “[c]ollecting/collating/interpreting scientific information, including use of data calls for specific product review categories.”  Second, with respect to regulatory policy issues, the NTF recommends that FDA:

[i]ssue guidance to sponsors regarding identification of the particle size for:

• Products subject to premarket authorization, including OTC drugs (when a new monograph or amendment to a monograph is being proposed), and food and color additives (in petitions to approve new additives or to amend existing approvals); and

• Products not subject to premarket authorization but for which the sponsor is required to provide notice (such as dietary supplements containing certain new dietary ingredients), or may choose to provide notice (such as a GRAS notification).

In addition, although several comments were submitted to the FDA docket established for the October 2006 NTF meeting urging the disclosure (in labeling) of the presence of nanoscale materials in FDA-regulated products, the NTF recommends otherwise:

Because the current science does not support a finding that classes of products with nanoscale materials necessarily present greater safety concerns than classes of products without nanoscale materials, the [NTF] does not believe there is a basis for saying that, as a general matter, a product containing nanoscale materials must be labeled as such.

In May 2006, prior to the creation of the NTF, the International Center for Technology Assessment (“CTA”) submitted a citizen petition to FDA requesting that the Agency create a new regulatory framework to address nanoscale particles –one that treats all nanoparticles as new substances subject to nano-specific paradigms of health and safety testing, and labeling requirements. In addition, CTA requests, among other things, a product recall and development moratorium for sunscreens and cosmetics using nanoscale materials.  Although FDA has not substantively responded to the petition, clearly the NTF report is urging a more tempered FDA approach to nanotech products at this time.

RELATED READING:

• National Nanotechnology Institute
• FDA Consumer Article on Nanotechnology
• FDA Nanotechnology FAQ

Every so often something comes across our desk that is so comical that we feel compelled to share it with others in the food and drug community who will also appreciate it.  One such story comes from a case involving Biovail and FDA in the U.S. District Court for the District of Maryland concerning certain Hatch-Waxman issues.  The following is an excerpt from the transcript of a December 21, 2006 oral argument before Judge Roger W. Titus in that case.  Gerald C. Kell from the Department of Justice argued the case for FDA.

THE COURT:  The [Federal Food, Drug, and Cosmetic Act] itself uses the term “strength.”  It references the drug with respect to which the certification is made.  The certification will mention the listed drug which includes the strength; correct?

MR. KELL:  That’s correct, Your Honor.

THE COURT:  All right.  There’s a special place in Hell where they torture people who write things like this.  For 14 years I was on the Rules Committee of Maryland’s Court of Appeals that didn’t have as many subsections as this, so I would flunk the person who gave me this as a draft rule.  I would say this is 50 rules.

Anyway, I wanted to wander into the right place of this endless section.  When I first went to Westlaw and said, just give me section 355, it had to tell me it was going to be 85 pages.  I said, no, no, no, no.  Let’s try (j), and I get this huge thing here.

MR. KELL:  Well I hope that our brief lays out the precise subsections, Your Honor.  I believe it does.  But that is the sum of my argument, unless the court has any further questions.

THE COURT:  No.  You’ve been very helpful.  I’m glad to have somebody here who knows what they’re talking about.

MR. KELL:  So am I, Your Honor.  It’s just not me.  Thank you.

THE COURT:  Thank you.

If so, the Department of Health and Human Services (“DHHS”) is convening a four day stakeholders workshop in Washington, D.C. beginning on July 31, 2007.  The purpose of the workshop is to enable stakeholders from government, industry, and academia to discuss the government’s plans to implement the legal authorities granted to DHHS and other federal agencies by the Project BioShield Act of 2004 and the Pandemic and All-Hazards Preparedness Act of 2006 to develop medical responses to chemical, biological, radiological, and nuclear (“CBRN”) attacks and to the possible outbreak of influenza or other pandemics.  Information regarding the stakeholders workshop, portions of which will be webcast, can be found here and here.

An article written by Hyman, Phelps & McNamara attorney Paul Ferrari that appears in the July/August 2007 edition of the Food and Drug Law Institute’s (“FDLI’s”) Update magazine provides an analysis of the government’s current efforts to develop and procure CBRN countermeasures and updates a similar article that appeared in an earlier edition of the FDLI publication.

FDA has released a new draft guidance for In Vitro Diagnostic Multivariate Index Assays (“IVDMIAs”).  The first version, which was released on September 7, 2006, attracted many critical comments.  The new draft seeks to address some (but not all) of those concerns.

Creating a new classification of devices called IVDMIAs, FDA is seeking to regulate a subset of laboratory developed tests.   Even though they would not be sold outside of a single laboratory, IVDMIAs would be subject to the full device regulatory scheme, including the need for FDA clearance or approval.

One of the major criticisms of the first draft was that the definition of an IVDMIA was not clear.  The proposed definition has been modified.  An IVDMIA is now defined as a device that:

1)  Combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g., a “classification,” “score,” “index,” etc.), that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, and

2)  Provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.

The second prong of the definition is likely to attract the most attention, since it will not always be clear whether a result is “non-transparent” or how the phrase “cannot be independently derived or verified” will be applied.  FDA has given some examples of tests that are IVDMIAs, and some that are not.  These illustrations provide some greater clarity, but even so there will almost certainly be controversy over whether a particular test falls inside or outside the IVDMIA definition.

Another area of concern for commenters related to the scope of the IVDMIA “device.”  Was the device the algorithm; the algorithm and software; the algorithm, software, and laboratory tests; or something else?  FDA has definitively answered that question, although not in a way that will satisfy those who proposed a narrow definition.  The new draft guidance states:

FDA believes that any safety and effectiveness determinations that are part of the premarket review process should include review of the performance of the entire system, including the accurate measurement of the input variables, directions for use, and expected analytical or clinical performance, rather than a review of only certain subcomponents of the test.

The impact of that broad definition may be partially softened (at least in the short term) by FDA’s acknowledgement that the Clinical Laboratory Improvement Amendments (“CLIA”) “requirements may partially fulfill corresponding” Quality System (“QS”) requirements.  FDA states that it will issue guidance to help laboratories comply with QS requirements.  Furthermore, FDA will “exercise enforcement discretion” (i.e., presumably not apply QS requirements until the final guidance has been issued).  How FDA will ultimately minimize the overlapping requirements of CLIA and the QS regulations is not discussed in the document.

FDA also adopted the suggestion offered by many commenters that there be a transition period.  The grace period will be 12 months from the date of the final guidance document “for currently marketed” IVDMIAs, and then six more months if a 510(k) or premarket approval application is submitted.  These transition periods are certainly better than requiring immediate compliance, but they are significantly shorter than some commenters had proposed.

While FDA did adopt the concept of a transition period, it rejected the many comments that requested the agency to proceed through notice and comment rulemaking.  FDA’s decision to use the guidance document process instead of rulemaking may result in a legal challenge over whether FDA violated the Administrative Procedure Act.  Even more fundamentally, FDA continued to assert that IVDMIAs are devices that are subject to FDA regulation.  This position, too, has been sharply questioned.

The comment period is a rather short 30 days.  After the first draft guidance was issued, FDA extended the initial 90-day comment period by 90 days.  It remains to be seen whether FDA will extend the comment period again in light of the significant impact that would follow adoption of an IVDMIA category.

By Jeffrey N. Gibbs 

After a highly anticipated revision of Medicare’s Clinical Trial Policy (“CTP”) that was issued in a July 9, 2007 Decision Memorandum (“Proposed Decision”) left many scratching their heads, the Centers for Medicare & Medicaid Services (“CMS”) issued a Proposed Decision Memorandum for Second Reconsideration of the CTP (“Second Reconsideration of the Proposed Decision”) on July 19, 2007.  A Proposed Decision Memorandum was issued on April 10, 2007 to clarify and expand Medicare coverage of items and services in clinical research.  The April 10, 2007 proposed policy generated many public comments from providers and industry.  Based in part on significant concerns raised in public comments, including the apparent confusion among Medicare contractors on interpretation of the CTP, CMS decided to “preserve the status quo” and made just two changes, including addition of Coverage with Evidence Development (“CED”) to Medicare clinical research policy.  CMS explained that based on several important issues raised in public comments on the Proposed Decision, the agency would reopen reconsideration of the CTP and issue a new proposed National Coverage Determination (“NCD”), which CMS did on July 19th.

The Second Reconsideration of the Proposed Decision is intended to clarify many of the issues that were identified in public comments on the Proposed Decision, renames the CTP to “Clinical Research Policy,” and expands the policy’s scope to cover a broad range of clinical research.  The Second Reconsideration of the Proposed Decision addresses many issues raised in comments on the Proposed Decision and defines new terms, including:

1. Explaining the scope of the policy by defining “clinical research” and renaming the overall NCD to clearly include all clinical research.
2. Replacing the requirements and other necessary characteristics for qualifying clinical trials under the CTP with scientific and technical standards for certified clinical research studies.
3. Preserving CMS authority to permit CED when appropriate.
4. Redefining coverage for qualifying clinical research studies or CED to avoid confusion with terms used in other contexts, using the term “usual patient care.”
5. Defining “routine clinical services” that are included in “usual patient care.”
6. Clarifying the extent to which “investigational clinical services” are included in “usual patient care.”
7. Clarifying that coverage does not include “administrative services” required to carry out studies but not required to furnish usual patient care.
8. Establishing a process that clinical research study sponsors/principal investigators must use to certify to CMS that their study meets the standards described in the policy, including registration with ClinicalTrials.gov.
9. Enumerating the types of clinical research studies that are excluded from the policy.
10. Clarifying the relationship between coverage under the policy and local coverage determinations.
11. No change in Medicare coverage policy for category A and B Investigational Device Exemptions (“IDEs”) (e.g., IDE category B devices remain eligible for coverage).
12. No change in contractor discretion to cover humanitarian use devices.
13. No effect on Medicare Part D policy.
14. No effect on any clinical research study that was covered under any previous policy that began enrollment prior to the effective date of the policy.

Medicare has covered routine costs incurred by Medicare beneficiaries in clinical trials since 2000.  However, CMS guidance on “routine costs” has been confusing and interpreted differently by various Medicare contractors.  CMS explained in the Proposed Decision that several comments showed there is significant confusion about the 2000 CTP, including the fact that Medicare contractors have been paying claims for items and services outside the terms of the CTP. 

The Proposed Decision added language intended to clarify when routine costs in clinical trials are covered.  Specifically, routine costs of a clinical trial include all items and services that are otherwise covered by Medicare that are provided in either the experimental or the control arms of a clinical trial, except the investigational item or service itself, unless otherwise covered outside of the clinical trial.  CMS added the phrase “unless otherwise covered outside of the clinical trial” to clarify that investigational items that are already covered by Medicare may also be covered when they are an investigational item in a clinical trial.

CMS also added to the CTP Medicare coverage of certain items and services under CED.  CMS uses CED to impose Medicare coverage with conditions — Medicare coverage is conditioned on the collection of additional evidence on appropriateness or effectiveness using either data submission to registries or data developed in further clinical research.  The CED policy was discussed in a December 13, 2006 meeting of the Medicare Coverage with Evidence Development & Coverage Advisory Committee and was supported by the committee.  Based on that support and the support of a federal panel convened by the Agency for Healthcare Research and Quality, CMS decided to adopt the policy as part of CTP coverage.  Although public comment highlighted the burden and additional expense that may be imposed on beneficiaries, providers, and sponsors/investigators under CED, CMS chose not provide funding for the additional data collection.  CMS explained that it appreciates the additional burden that further clinical research adds to patient care, but CED allows Medicare coverage for items and services that would not otherwise be covered.  Therefore, according to CMS, the benefits of covering additional items and services under CED outweigh the burden.  CMS includes the addition of CED policy in the Second Reconsideration of the Proposed Decision.

The Second Reconsideration of the Proposed Decision is intended to “[build] upon the input from the previous reconsideration.”  At the outset, CMS explains its authority for making coverage decisions under § 1862(a)(1)(A) of the Social Security Act when evaluating evidence to whether items and services meet the reasonable and necessary standard.  However, evidence-based review is not feasible for the broad range of items and services used in clinical research.  As a result, CMS relies on the integrity of clinical research protocols to gain assurance that research interventions are reasonable and necessary, expose participating beneficiaries to the least amount of risk, and maximize health outcomes.

In an apparent effort to clarify Medicare coverage policy on items and services already covered outside the clinical research context, CMS proposes Medicare coverage of “usual patient care” in qualified clinical research.  “Usual patient care” is defined as routine clinical services and investigational clinical services in clinical research when the investigational clinical services would be covered outside of the clinical research and the clinical research meets the standards for a clinical research study. 

CMS defines “clinical research,” and proposes standards that it believes exposes beneficiaries to the least amount of risk and maximizes the potential for improvement of health outcomes.  Clinical research is defined as “any systematic investigation involving human participants which is designed to contribute to generalizable knowledge and which involves a clinical intervention, care delivery strategy, or diagnostic technique designed to potentially improve predefined health outcomes.”  CMS identifies 13 scientific and technical standards for clinical research that would be required for providers, practitioners, or suppliers who request payment for usual patient care furnished to Medicare beneficiaries participating in clinical research. 

Medicare secondary payer concerns have been a lingering cloud of disquiet for sponsors and principal investigators.  The Second Reconsideration of the Proposed Decision appears to shed some light on these concerns by explaining that Medicare does not cover usual patient care when the care is provided free to the Medicare beneficiary, or when the study sponsor agreement with the investigator sites or the informed consent documents provided to the patient specify that the care will be provided free to participants.  In other words, if a study sponsor or agreement states that routine or investigation clinical services otherwise covered by Medicare are free, Medicare will not pay for the services.

Interested stakeholders have 30 days to comment on the Second Reconsideration of the Proposed Decision.

By Kirk L. Dobbins 

Support for legislation that would create a biogenerics approval path is reportedly crumbling.  Last month, the Senate Health, Education, Labor, and Pensions (“HELP”) Committee passed S. 1695, “the Biologics Price Competition and Innovation Act of 2007.”  Although neither the full Senate, nor the House Energy and Commerce Committee have passed similar legislation, it was widely speculated that S. 1695 (or similar legislation) would be considered in the conference committee established to iron out differences between the House- and Senate-passed versions of FDA reform legislation.  S. 1695 would amend the Public Health Service Act to add § 351(k) to provide for an approval pathway for “biosimilar” and “interchangeable” biologics that rely, in part, on FDA’s previous licensure of an innovator’s product.  In addition, the bill would provide a 12-year period of innovator marketing exclusivity, limited “generic” exclusivity under certain circumstances, and patent resolution provisions. 

Over the past several days, a provision of that legislation providing brand name sponsors with additional exclusivity periods for certain product improvements, such as new indications and structural modifications, has been questioned by the generics industry.  A similar two-tier exclusivity paradigm is currently in place for drug products approved under the FDC Act, where innovators can obtain 5-year new chemical entity exclusivity and 3-year exclusivity for certain product improvements. Generic supporters have reportedly suggested lowering the 12-year exclusivity period in S. 1695 in exchange for providing a period of “new use” exclusivity.  Innovator companies want to stick with the 12-year period agreed to under S. 1695.

In addition, some House Members have signed a letter sent to the chairmen and ranking members of the House Energy and Commerce Committee and the Senate HELP Committee opposing the current consideration of biogenerics legislation.  According to the letter’s signatories:

We believe the establishment of a pathway for biosimilars is appropriate for Congress to consider, but only after consideration of the views of all stakeholders and full deliberation, hearings, and markup by the appropriations committees.  Until such time, we oppose inclusion of biosimilar legislation in the context of unrelated FDA reauthorizations.  We are also deeply concerned that efforts to resolve differences over biosimilars will endanger prompt enactment of legislation which provides necessary funding for vital FDA functions such as drug and medical device approval and safety monitoring. 

Finally, we have learned that the Congressional Budget Office (“CBO”) is drafting a report and a score of biogenerics legislation (that could be published in the next few weeks) that would reportedly place economic savings of biogenerics over the next 10 years at an amount significantly less than the estimates of some biogeneric proponents.  CBO is reportedly taking a hard look at reports by Avalere Health and Duke University Fuqua School of Business Professor Henry Grabowski.  The Avalere report pegs government savings around only $3.6 billion over the next 10 years. 

Because some of the momentum for biogenerics legislation has been the belief that it will create significant economic savings, a CBO report to the contrary, coupled with innovator/generic and House member disagreements, could destroy the fragile support for biogenerics legislation that had led to the Senate HELP Committee’s passage of S. 1695.

RELATED READING:

• FTC Commissioner Pamela Jones Harbour BioGenerics Speech

Before you do, be sure to become familiar with the Federal Trade Commission’s (“FTC’s”) regulation of the advertising of such products.  Hyman, Phelps & McNamara attorneys Cassandra Soltis and John Fleder noted in an article for the Food and Drug Law Institute’s Update magazine that the FTC has stepped up its enforcement activity against weight-loss and diet products.  They warn that companies can expect that trend to continue as they market an increasing number of products to help consumers combat excess weight and obesity. 

ADDITIONAL READING:

• FTC Diet & Fitness Homepage

On Tuesday, July 17th, Hyman, Phelps & McNamara attorneys Michelle Butler and Jeff Wasserstein gave a teleconference, titled “False Claims Act Compliance Strategies: Don’t Lose Access to Medicare and Medicaid Reimbursement.”  Audio copies of the teleconference, along with a transcript of the witty, yet thoughtful, presentation can be obtained here.