FDA Lawyers Blog

by Dan Constantinescu, Ph.D.

The Federal Circuit handed down its opinion in Association for Molecular Pathology v. Myriad July 29, 2011, reversing, in large part, the district court's holding that the claims are not directed to patent eligible subject matter as required by 35 U.S.C Section 101. The Court made the following holdings with respect to patent eligibility:

(1) Myriad's composition claims to BRCA1 and BRCA2 DNA sequences and to certain alterations associated with a predisposition to breast and ovarian cancers are patent eligible subject matter.

(2) Myriad's process claims for analyzing or comparing a subject's BRCA1 and BRCA2 DNA sequences with wild-type sequences to identify cancer-associated alterations are not patent eligible subject matter.

(3) Myriad's process claim for screening potential cancer therapeutics using transformed cell lines expressing altered BRCA1 and BRCA2 DNA sequences is patent eligible subject matter.

The Court concluded that the composition claims to isolated DNA sequences are patent eligible because the claims "cover molecules that are markedly different--have a distinctive chemical identity and nature--from molecules that exist in nature." The Court observed that isolated DNA is different from native DNA as found in a cell because "[i]solated DNA has been cleaved (i.e., had covalent bonds in its backbone chemically severed) or synthesized to consist of just a fraction of a naturally occurring DNA molecule." The Court also distinguished isolated DNA from the lines of cases dealing with purified natural elements, noting that "isolated DNA is not purified DNA. Purification makes pure what was the same material, but was previously impure. Although isolated DNA must be removed from its native cellular and chromosomal environment, it has also been manipulated chemically so as to produce a molecule that is markedly different from that which exists in the body."

"Revisiting the Debate on an Orange Book for the Biologics Price Competition and Innovation Act" by Andrew S. Wasson was published in the latest edition of FDLI Update. In comparing the Biologics Price Competition and Innovation Act ("BPCIA") to the Hatch-Waxman Amendments, commentators are quick to point out that the laws differ in many ways. Commentators often cite that the BPCIA lacks the patent information machinery contained Hatch-Waxman which would eventually lead to the Orange Book. In the article, Mr. Wasson hoped to carefully think through the role of patent information in Hatch-Waxman, understand the relationship between the original statutory language and the Orange Book in its present form, and evaluate whether the exclusion of patent information from the workings of the BPCIA would have any effect.

Wasson Associates Corner

Mr. Wasson concluded that patent information does play an important role in Hatch-Waxman. He hypothesized that a legislative scheme lacking a central repository of patent information may discourage competition, insofar as potential biosimilar manufacturers might be less likely to invest without some upfront certainty to the relevant patents. He also concluded that some of the initial concerns that militated against an Orange Book-like publication might be unfounded. For example, worries about gaming the system have less force where publication of patent information is separated from any effect on stay of approval. Further, proponents of a regime without an Orange Book made several critical assumptions about patenting patterns (i.e., that biologic products are subject many more extensive layers of patents compared to small molecule drugs). This may or may not be true.
His goal remains to gather statistics on patents per product for both drug products as well as biologic products. Because of the Orange Book, it would be relatively straightforward (albeit tedious) to gather the data on small molecule drugs. It appears less straightforward to gather the data on biologic products. Thus, it does not seem that such an empirical comparison will be forthcoming in the near future.

by Howard E. Rosenberg, Ph.D.

Case C-195/09 Synthon v Merz Pharma
Case C‑427/09 Generics [UK] v Synaptech

On July 28, the Court of Justice of the European Union ("CJEU") handed down decisions on two cases. The first between Synthon and Merz concerning the medicinal product, memantine and a second similar issue concerning galantamine. The CJEU followed the Attorney General's opinions and decided that the Supplementary Protection Certificate ("SPC") for both memantine and galantamine were invalid.

Memantine had been on the market in Germany (and approved in Luxembourg) without going through the now currently accepted safety and efficacy testing as required by the European Union ("EU") Directive 65/65. However a new marketing authorization was submitted for a second medical use and approved. This new authorization contained the safety and efficacy data required by the Directive. Subsequently the original product was withdrawn, the new product launched and an SPC applied for based on this new authorization.

The High Court of Justice (England and Wales) had doubts as to both the scope of Regulation No 1768/92 and the definition of 'first authorisation to place ... on the market in the Community', within the meaning of Articles 13 and 19 of that regulation, and referred questions to the Court of Justice for a preliminary ruling:

(1) For the purposes of Articles 13 and 19 of [Regulation No 1768/92], is an authorisation a "first authorisation to place ... on the market in the Community" if it is granted in pursuance of a national law which is compliant with [Directive 65/65], or is it necessary that it be established in addition that, in granting the authorisation in question, the national authority followed an assessment of data as required by the administrative procedure laid down in that directive?

(2) For the purposes of Articles 13 and 19 of [Regulation No 1768/92], does the expression "first authorisation to place ... on the market in the Community" include authorisations which had been permitted by national law to co-exist with an authorisation regime which complies with [Directive 65/65]?

(3) Is a product which is authorised to be placed on the market for the first time in the EEC without going through the administrative procedure laid down in [Directive 65/65] within the scope of [Regulation No 1768/92] as defined by Article 2?

(4) If not, is an SPC granted in respect of such a product invalid?

by Andrew M. Nason

On July 28, Cetero Research ("Cetero"), a contract research organization ("CRO"), responded to FDA's allegations of "a pattern of misconduct" at Cetero's bioanalytics laboratory in Houston, Texas. FDA says it uncovered the wrongdoing during two inspections of the Houston facility. Cetero performs early-phase bioequivalence and pharmacokinetic testing for a number of pharmaceutical companies, which then may use those studies as supporting evidence in drug approval applications to FDA. FDA notified affected pharmaceutical companies via a posting on the FDA website on Wednesday that bioanalytical studies performed at Cetero's Houston laboratory between April 2005 and June 2010 in support of marketing applications may need to be confirmed or repeated.

Specifically, FDA found 1,900 instances over a five-year period from 2005 to 2010 in which laboratory technicians cited for doing research work were not even present at the facility. FDA concluded that Cetero may have fixed its work, omitting any data that it did not like and always delivering desired results to its customers. FDA did say, however, in its public announcement: "It is unlikely that these concerns relating to data integrity affect the overall safety and efficacy of drugs already on the market and, at this time, there is no evidence of problems with the safety, quality, purity or potency of drugs already approved." Thus, claims Cetero, FDA has not questioned the safety or efficacy of drugs approved based on data generated from its Houston laboratory.

According to Cetero, the company did not engage in any routine falsification of trial data, but rather the discrepancies resulted from six chemists misreporting the date samples were extracted prior to analysis to seek additional compensation through weekend pay and for hours when they did not actually work. Additionally, Cetero initiated an internal investigation over two years ago, and contacted FDA to self-report its preliminary findings regarding these six chemists. At the time it reported its findings to FDA in 2009, Cetero requested feedback from FDA on the nature and scope of Cetero's own investigation plan. FDA did not respond to the request, however, until it sent a letter to Cetero on July 26, 2011 and posted its notification on its website the next day. Due to this lack of communication, Cetero has said it is pleased that it will finally have the opportunity to meet with FDA decision-makers to seek to resolve this issue appropriately.

Cetero maintains that all processes in use at its facilities are state-of-the-art and in full compliance with FDA regulations and bioanalytical industry standards and that all research conducted on behalf of its pharmaceutical sponsors can be, and has been, properly validated. Cetero has also indicated it will continue to cooperate fully with the FDA and with its clients to support them through the process of resolving this issue.

by Rachael P. McClure

On July 21, FDA issued a draft guidance setting forth proposed regulatory policies for mobile medical applications. These applications are software programs that run on smart phones, tablets, and other mobile communications devices, allowing consumers to monitor and manage their own health. They are also used by health care professionals to facilitate patient care. Examples include applications that calculate an individual's calorie needs for healthy weight loss or allow doctors to view patient test results on their mobile devices. A recent study estimated that 500 million people will be using mobile healthcare applications four years from now. While FDA supports development of mobile medical apps, it has "a public health responsibility to oversee the safety and effectiveness of a small subset of mobile medical applications that present a potential risk to patients if they do not work as intended."

In the draft guidance, FDA proposes regulation of a subset of mobile medical apps that meet two requirements. First, an application must be intended for use to: (a) diagnose a disease or other condition; (b) cure, mitigate, treat, or prevent a disease; or (c) affect the structure or any function of the human body. Second, it must either be used as an accessory to a regulated medical device or transform a mobile platform into a regulated medical device. Transformation may occur via use of attachments, display screens, or sensors, for example attachment of a blood glucose strip reader to a mobile platform to function as a glucose meter. Displaying, analyzing, storing, or transmitting patient-specific medical device data, and controlling the operation, function, or energy source of a medical device qualify as accessory uses. An example of the former is remote display of patient data from bedside monitors; an example of the latter is mobile app that controls the delivery of insulin on an insulin pump by transmitting control signals to the pumps from the mobile platform.

FDA's proposed framework will require manufacturers of applications that convert a mobile platform into a regulated medical device to satisfy the obligations associated with that device classification, i.e., Class I general controls, Class II general and special controls, or Class III premarket approval. General controls include registration and medical device listing, quality regulation, and labeling requirements. The future is less clear for manufacturers of mobile medical apps that serve as accessories to other medical devices, for which FDA is seeking comment on how it best assure safety and effectiveness.

by Michael W. Harkness

Last Thursday, the Senate Judiciary Committee cleared for debate a Bill (S. 27) designed to eliminate so-called "pay-for-delay" settlements between brand and generic pharmaceutical manufacturers. The Bill, introduced in February by Senator Herb Kohl (D-WI), can now be presented to the entire Senate floor for debate and amendment. "Pay-for-delay" settlements, also called "reverse payment" settlements, are intended to keep generic versions of patented drugs off the market for a particular amount of time, although never beyond the exclusionary life of the patent. Under the Bill, any patent infringement settlement that (1) involves the would-be generic manufacturer receiving something of value (e.g. a licensing payment), and (2) involves the generic manufacturer "foregoing research, development, manufacturing, marketing or sales of the generic product for any period of time" would be presumed unlawful.

Senator Orrin Hatch (R-UT), a co-sponsor of the Hatch-Waxman Act, released a statement after the Judiciary Committee vote, stating that he is opposed to the legislation as it would "stifle[] innovation and would make both name brand and generic drugs much more expensive." As a sponsor and major advocate of the Hatch-Waxman Act, Senator Hatch made it clear that he has been a "longtime proponent of allowing businesses to settle patent-infringement cases out of court," and his objections to Senator Kohl's proposed legislation also stems from the Bill's plan to allow "unelected Washington bureaucrats" from the Federal Trade Commission ("FTC") to control settlement negotiations between private businesses.

The Generic Pharmaceutical Association ("GPhA") issued a statement after the Committee's decision, particularly worried about the fact that "the bill includes a provision that would retroactively extend the ban on pro-consumer patent settlements to products already on the market. That means patients who today rely on safe, affordable generic medications for their treatment could potentially lose access to these medications, leaving them with only one, more expensive product as an option." Additionally, the GPhA noted in its statement that "patent settlements have never prevented competition beyond a patent's expiration, and in many cases have resulted in making lower-cost generics available months and even years before patents have expired."

by Erin A. Lawrence

On July 13, FDA denied Purdue Pharma L.P.'s ("Purdue's") Citizen Petition, which requested that FDA refuse to approve King Pharmaceuticals, Inc.'s ("King") new drug application ("NDA") for extended-release oxycodone, Remoxy®, until King certifies to all patents listed in the Orange Book and serves Paragraph IV notice letters stating the basis for why these patents are invalid, unenforceable, or not infringed. Purdue's Citizen Petition also alleged that King's application did not contain an "appropriate reference to OxyContin."

In June 2008, Pain Therapeutics Inc. ("PTI") submitted an NDA under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act("FD&C Act") for Remoxy®. Remoxy® is an extended-release, oral formulation of oxycodone for the relief of moderate to severe pain requiring continuous, around-the-clock opioid treatment. It is designed to discourage tampering and abuse. King took over the Remoxy® NDA in March 2009.

Purdue argues that, under FD&C Act Section 505(b)(2), King is required to reference the "most similar" drug product in the absence of a pharmaceutical equivalent and must certify to the Orange Book-listed patents for that drug. Purdue also argues that King's application is defective because it "plainly relies" on the findings found in Purdue's Oxycontin® related to the safety and efficacy of oxycodone. Purdue concludes that, since King did not reference OxyContin®, the most similar drug, King should be required to withdraw its NDA, because it is deficient and King is precluded by the FD&C Act from amending or supplementing its application to rely on a different drug.

by Elizabeth Murphy

In the past several years, some cities have begun to take a more active role in the regulation of restaurants and other food establishments. In 2006, New York City banned the use of trans fats in restaurants and mandated caloric content labeling in certain chain establishments. Last year, San Francisco did away with "Happy Meals," prohibiting the sale of fat- and calorie-laden meals sold with toys and marketed to children. Even more recently, Cleveland attempted to ban trans fats in its restaurants and eating establishments as part of its "Healthy Cleveland" initiative.

Some state legislatures are not on board with the new health-conscious measures and are, in a few instances, retaliating. The Ohio state legislature, for one, thwarted Cleveland's trans fat ban by adding an amendment to its 2012-2013 budget curtailing the authority of municipalities to impose restrictions on restaurant and food establishments. Other states, such as Florida, Arizona and Alabama have acted preemptively by introducing legislation that would similarly limit city and municipality authority.

Whether laws that attempt to proscribe healthy eating should even be enacted is a topic of some debate. Proponents of such measures as the trans fat bans and labeling laws argue that they are easily implemented, common-sense solutions to real public health concerns. Further, proponents argue, allowing local municipalities the authority to enact these measures provides a sort of testing ground before large-scale implementation. On the other hand, opponents of such laws cite the danger of creating a "nanny state" and emphasize the importance of personal choice in healthy eating decisions as well as state-wide uniformity in regulation of business.

The debate as to the appropriate level of government participation in healthy eating choices is likely to continue. At a federal level, FDA is currently reviewing comments on its proposed labeling regulations, which will require certain "chain" food establishments to prominently and conspicuously display nutritional information. See our previous posts regarding FDA's food labeling regulations here, here and here.

by Russell A. Garman, Ph.D.

The world of drugs, medical devices, and food products has changed substantially over the past 30 years, and now, FDA is changing with it. In an e-mail memorandum sent to FDA employees, Commissioner Margaret A. Hamburg, M.D. announced that the FDA is realigning its management structure from a system that has been in place since 1970. Aimed to "more accurately reflect the agency's responsibilities, subject-matter expertise and mandates in an ever more complex world, where products and services do not fit into a single category," the realignment involves the division of the FDA's programs into "directorates" that "reflect the core functions and responsibilities of the [FDA]."

The first directorate will be led by the newly-created Deputy Commissioner for Medical Products and Tobacco, who will "provide high-level coordination and leadership across the Centers for drug, biologics, medical devices, and tobacco products" and "will oversee [the FDA's] Special Medical programs." To fill this position, Commissioner Hamburg has brought in Dr. Steven Spielberg, former Dean of Dartmouth Medical School and currently Director of the Center for Personalized Medicine and Therapeutic Innovation at Children's Mercy Hospital in Kansas City.

The second directorate will be lead by the newly-created Deputy Commissioner for Global Regulatory Operations and Policy, who will oversee the transformation of FDA from "being a regulator of domestic products to one overseeing a worldwide enterprise" to handle the global nature of food and drug production and supply. This position will have a specific mandate to make import safety a top priority. This position will be filled by Deborah Autor, an attorney who now is Director of the Center for Drug Evaluation & Research.

by Jason Kanter

A recent article in the New England Journal of Medicine suggests that pills produced by generic manufacturers should look like their brand-name counterparts. In the article, Harvard Medical School researcher's Jeremy Greene and Aaron Kesselheim advocate for a more uniform system of pharmaceutical appearance and argue that differences between brand and generic drugs may negatively impact consumer well-being.

Specifically, the article contends that differences in generic pill appearance may result in patient confusion, which could lead to patients failing to take prescribed medicine. In an interview with The New York Times, Greene noted: "Everyone has seen a patient who has gone off of a medication because it changed color. It can lead to disastrous outcomes."

Greene and Kesselheim also address concerns that promoting conformity in generic and brand appearance might lead to confusion about whether a particular pill contains the brand or generic drug. In the article, they argue that such concerns stem from the inadequate testing and regulation of drugs that occurred prior to the 1960's. They explain that the lack of sufficient regulation gave rise to fears that counterfeit versions of popular drugs might make their way into the market and endanger consumers. As a result, courts were willing to recognize manufacturers' rights in the appearance of their drugs. However, these concerns have largely been obviated by the subsequent amendments to the Federal Food, Drug, and Cosmetic Act, requiring drug manufacturers to demonstrate pre-marketing safety and efficacy.

by Rachael P. McClure

On July 14, FDA issued a draft Guidance explaining and soliciting comments on its proposed policies for regulation of in vitro companion diagnostics devices ("companion diagnostics"). The Guidance is intended to help facilitate development and review of companion diagnostics. Most notably, it recommends that a companion diagnostic which is "essential for the safe and effective use of a therapeutic product" be reviewed at the same time as that product.

Companion diagnostic are tests that assist health care professionals in determining whether a particular patient should receive a certain therapy and, if so, what dosage he should receive. For example, new technologies are able to delineate patient populations that are more or less likely to respond to a given treatment or exhibit a particular side effect. Such devices are vital to the 'personalized medicine' model, a "rapidly advancing field of healthcare that is informed by each person's unique clinical, genetic, genomic, and environmental information."

As the Guidance explains, more and more therapies require such tests to meet the safety and effectiveness claims on their labels. Because the reliability of the results of companion diagnostics is essential to these therapies, FDA believes they two should be considered for approval simultaneously, and the Guidance emphasizes collaboration between producers of drug therapies and producers of diagnostic devices. Further, it recommends that, in most cases, approval of a companion diagnostic device be a general prerequisite for approval of a therapeutic product that relies on that device for its safe and effective use.

by Leann M. Clymer

As the use of genetically engineered varieties of soybeans and corn increased in the United States this year, the European Parliament recently agreed to allow member states to ban the cultivation of genetically-modified crops based on environmental concerns. The U.S. Department of Agriculture ("USDA") earlier this month released the "Adoption of Genetically Engineered Crops in the U.S." report which indicates that nine out of ten farmers in America chose to plant biotech seeds in 2011.

But on the other side of the pond, citizens of the European Union ("EU") member states generally oppose genetically-modified crops. Accordingly, the European Parliament voted to strengthen proposed legislation that would allow each country's government to decide whether to ban or to allow the use of genetically-modified seeds. The original proposal would not have allowed environmental or health grounds to be the basis of a country's ban of the use of biotech seeds. This piece of the proposed rules was modified, and now governments in the EU may cite to environmental concerns as a justification for the ban of genetically modified seeds, which is more likely to survive a legal challenge in the World Trade Organization ("WTO").

In addition to allowing the protection of biodiversity or prevention of the spread of so-called "super weeds" that are resistant to herbicides, the draft legislation also includes a requirement that all EU countries would need to adopt rules to prevent contamination by biotech seeds of conventional and organically-grown crops. This draft legislation still must be approved by the EU member states before it becomes final.

by Andrew S. Wasson

Prevor, a French company specializing in chemical risk management, recently sued FDA in the District Court of the District of Columbia for allegedly misclassifying its proposed product Diphoterine® Skin Wash ("DSW") as a drug-device combination with a "drug" primary mode of action. FDA's classification determines the standards for approval and which Center at FDA regulates (and ultimately controls the approval of) the proposed product. FDA's Center for Drug Evaluation and Research ("CDER") as a rule has jurisdiction over drugs and all combination products where the drug provides the primary mode of action. On the other hand, the Center for Devices and Radiological Health ("CDRH") reviews all device products and all combination products where the device provides the primary mode of action. Generally speaking, drug standards of approval are more rigorous than device standards, thus regulated industry will often attempt to characterize a product as a device rather than a drug if a choice is available.

Here, DSW is intended for use as a "first response" to accidental chemical burns occurring in an industrial setting. DSW comprises 96% water and 4% diphoterine in variously-sized canisters wherein the contents are propelled by pressurized gasses. The complaint avers that the primary mode of action is to "physically and mechanically remove or wash away" the offensive chemical. According to the complaint, this comprises 90% of the intended use. The complaint does acknowledge that DSW has a "chemical" effect as well (neutralizing acidic or basic chemicals residing on the skin), but that this chemical effect comprises only 10% of its intended use.

The complaint requests injunctive relief and a declaratory judgment: (1) vacating FDA's finding that DSW is a drug and not a device, (2) vacating FDA's determination that DSW is a combination product with a drug primary mode of action, (3) declaring that FDA's determination was arbitrary, capricious, or an abuse of discretion, and (4) declaring that DSW is a device, or at least a combination product with a device primary mode of action.

by Andrew M. Nason

On July 5, 2011, Ropes & Gray LLP ("Ropes") submitted a citizen petition on behalf of seven medical product manufacturers asking the FDA Commissioner, Margaret A. Hamburg, M.D., to clarify FDA regulations and policies governing certain communications and activities relating to new or off-label use of marketed products. Ropes submitted the Petition on behalf of Allergan, Inc., Eli Lilly and Company; Johnson & Johnson, Novartis Pharmaceuticals Corporation, Novo Nordisk, Inc., Pfizer, Inc., and Sanofi-Aventis U.S. LLC. According to the Petition, the vagueness regarding permissible manufacturer speech regarding off-label use has significant consequences to manufacturers, the government, physicians, and patients.

While FDA has explicitly recognized important mechanisms for the sharing of truthful and non-misleading scientific information, the Petition argues there is a lack of clarity as to what practices these mechanisms permit. Manufacturers, lawyers, and prosecutors infer operative law from FDA's letters and other agency materials, and develop guidelines based on their interpretation of the documents. As a result, each individual manufacturer's sales representatives, field medical personnel, and other employees may over- or under-communicate clinically relevant information, with significant consequences to the public health, Petitioners argue. The Petition asks FDA to clarify the contours of its policies on the dissemination of information on off-label uses to give medical product manufacturers comprehensive guidance consistent with FDA's mission to protect the public health. Specifically, the Petition asks FDA to clarify rules regarding manufacturer responses to unsolicited requests, the boundaries of "scientific exchange," permitted communications with formulary committees, payors, and similar entities, and dissemination of third-party clinical practice guidelines.

The Petition notes: "We have long understood that manufacturers may provide new use information in response to unsolicited requests, but no law states this rule or defines the boundaries of the safe harbor." The Petition goes on to list Petitioners understanding how FDA's policy has developed over time. In 1982, FDA first expressed in a guidance letter to the industry that responses to unsolicited requests for information about marketed drugs did not constitute labeling, but were personal communications between the manufacturer and requester. It reiterated its policy in 1994, but required companies to maintain documentation concerning the nature of the request, and avoid a pattern of repeated dissemination of materials. FDA further revised its policy in a 1994 notice published in the Federal Register, reiterating that companies could provide responsive, non-promotional, balanced scientific information when such information is requested, but the notice did not identify conduct that could qualify as solicitation. A 2006 guidance document confirmed that the 1994 Federal Register notice governs responses to unsolicited requests. The 2006 guidance also referred to a 1997 guidance document that stated that manufacturers could provide "technical support" for a scientific or educational activity in response to an unsolicited request, and that whether a statement made in the context of such activity qualified as "promotional" could depend on whether it had been disseminated after an initial program. The petition asks FDA to embody its policy in binding regulations, and in doing so to clearly distinguish a non-promotional response to an unsolicited request from product promotion, so that manufacturers have a meaningful "safe harbor."

by Rachael P. McClure

A recent publication in the Orphanet Journal of Rare Diseases calls for FDA to improve access to its accelerated approval pathway for orphan drugs. The Orphan Drug Act, passed in January 1983, defines orphan drugs as products used for the diagnosis, treatment, or prevention of diseases and conditions that affect fewer than 200,000 people in the United States. It was intended, in part, to encourage pharmaceutical companies to develop drugs directed towards small patient populations. FDA's Office of Orphan Products Development ("OOPD") is tasked with advancing evaluation and development of such products by providing incentives, including tax incentives for clinical research, exemption from filing fees, and grant funding, to sponsors of orphan drug projects.

The accelerated approval ("AA") pathway, available to orphan drugs and drugs for other serious illnesses, was created in 1992 to help deliver treatments to patients with rare life-threatening diseases as soon as possible. It allows new drug applications ("NDAs") to be approved using "surrogate endpoints" before traditional indicators of effectiveness are available. Surrogate endpoints are laboratory measurements, such as blood or urine tests, or physical signs that predict that a drug will improve a patient's condition. To gain accelerated approval, applicants must demonstrate that surrogate endpoints are "reasonably likely" to provide a clinical benefit. FDA then continues to monitor AA-approved drugs until their efficacy is confirmed in post-approval trials.

The Orphanet paper, written by Brigitta Miyamoto and Emil Kakkis of the Kakkis EveryLife Foundation, says that while twenty-six new cancer drugs and twenty-nine new human immunodeficiency virus ("HIV") drugs have been approved under the AA pathway since its creation, only one orphan drug has passed muster. They attribute this to the complicated nature of orphan drug development--the lack of understanding of a rare disease and insufficient patient data can make it very difficult to support surrogate endpoints as predictors of benefit.