Orange Book Research Articles

Patent and Exclusivity Status of Essential Medicines for Non-Communicable Disease

ObjectiveThe threat of non-communicable diseases (“NCDs”) is increasingly becoming a global health crisis and are pervasive in high, middle, and low-income populations resulting in an estimated 36 million deaths per year. There is a need to assess intellectual property rights (“IPRs”) that may impede generic production and availability and affordability to essential NCD medicines.MethodsUsing the data sources listed below, the study design systematically eliminated NCD drugs that had no patent/exclusivity provisions on API, dosage, or administration route. The first step identified essential medicines that treat certain high disease burden NCDs. A second step examined the patent and exclusivity status of active ingredient, dosage and listed route of administration using exclusion criteria outlined in this study.MaterialsWe examined the patent and exclusivity status of medicines listed in the World Health Organization’s (“WHO”) Model List of Essential Drugs (Medicines) (“MLEM”) and other WHO sources for drugs treating certain NCDs. i.e., cardiovascular and respiratory disease, cancers, and diabetes. We utilized the USA Food and Drug Administration Orange Book and the USA Patent and Trademark Office databases as references given the predominant number of medicines registered in the USA.ResultsOf the 359 MLEM medicines identified, 22% (79/359) address targeted NCDs. Of these 79, only eight required in-depth patent or exclusivity assessment. Upon further review, no NCD MLEM medicines had study patent or exclusivity protection for reviewed criteria.ConclusionsWe find that ensuring availability and affordability of potential generic formulations of NCD MLEM medicines appears to be more complex than the presence of IPRs with API, dosage, or administration patent or exclusivity protection. Hence, more sophisticated analysis of NCD barriers to generic availability and affordability should be conducted in order to ensure equitable access to global populations for these essential medicines.

Competition in the pharmaceutical industry: How do quality differences shape advertising strategies?

We present a Hotelling model of price and advertising competition between prescription drugs that differ in quality/side effects. Promotional effort results in the endogenous formation of two consumer groups: brand loyal and non-brand loyal ones. We show that advertising intensities are strategic substitutes, with the better quality drugs being the ones that are most advertised. This positive association stems from the higher rents that firms can extract from consumers whose brand loyalty is endogenously determined by promotional effort. The model's main results on advertising and pricing strategies are taken to the data. The latter consists of product level data on prices and quantities, product level advertising data, as well as the qualitative information on drug quality contained in the Orange Book compiled by the Food and Drug Administration (FDA). The empirical results provide strong support to the model's predictions.

THE ORANGE BOOK, EDUCATION AND SOCIAL MOBILITY

Education policy was a vital theme of The Orange Book, even though there was no dedicated chapter. The book's commitment to using economically liberal means to deliver social liberal ends was the basis for a substantial repositioning of Liberal Democrat education policy ahead of the General Election, paving the way for agreement with the Conservatives on radical reform of educational delivery. At the same time, the Liberal commitment to education as the key driver of social justice, based on arguments of positive freedom, underpinned the party's election commitment to increasing resources for the most disadvantaged pupils through the Pupil Premium. This Liberal commitment to positive freedom and education distinguishes it from the welfarist bias of Fabianism; it was a key divide in progressive tradition in the 19th century and the division has endured to this day, reflected in the contrast between the welfarism of Gordon Brown and the social mobility agenda of the coalition.

THE ORANGE BOOK - TURNING RIGHT OR CHANGING GEARS?

The Liberal Democrats becoming kingmakers in 2010 did not depend solely on the numbers adding up on May 5th. Did The Orange Book pull the party to the right, making coalition with the Tories a meeting of minds? Or was it better viewed as an element in an overall strategic shift towards greater professionalism, making a deal with either of the major parties more likely?

THE ORANGE BOOK: EIGHT YEARS ON

The Orange Book had an important influence on Liberal Democrat thinking, particularly on economics, tax, and public service reform. Without the policy changes which the book and its authors anticipated, it is much more difficult to imagine the governing Liberal Democrat-Conservative coalition being formed and sustained. This paper examines the origins and impact of the book, and sketches out future directions for policy development.

THE ORANGE BOOK, THE LIBERAL DEMOCRATS AND ECONOMIC FREEDOM

Despite the Liberal Democrat's party heritage and despite the efforts of those who wroteThe Orange Book, the party still has difficulty embracing economic liberalism. The state is often seen as benign or even virtuous and there is huge caution when it comes to taxation, public service reform and deregulation which results from other priorities being put before economic growth. Indeed, even some ofThe Orange Bookauthors have produced mixed results when they have had opportunities in the coalition government.

The Illusion of Interchangeability: The Benefits and Dangers of Guidance-Plus Rulemaking in the FDA's Biosimilar Approval Process

On March 23, 2010, President Obama signed into law the ambitious Patient Protection and Affordable Care Act. While media attention focused largely on the sweeping changes the bill makes to the nation’s healthcare system, there was also a less-noticed rider to the bill, the Biologics Price Competition and Innovation Act of 2009 (Biosimilars Act). The Biosimilars Act grants the Food and Drug Administration (FDA) broad new authority to create an accelerated premarket approval pathway for generic competition to biologics in an attempt to drive biologic drug prices down and reduce the overall costs of health care.Traditionally, inventors of medical products such as drugs and devices obtain patent protection at the United States Patent and Trademark Office (USPTO) for a twenty-year exclusive term and simultaneously must seek FDA approval to market their invention and for a trademark for their brand name.Because of the complicated and thorough approval process the FDA conducts, it is often expensive and time-consuming for the initial innovator to bring a drug to market. Likewise, it is often prohibitively expensive for a generic follow-on company to bring an analogue to market, after patent protection has expired, through duplicative and costly reapproval of the innovator drug, and it would be unethical to subject further human subjects to unneeded clinical trials.To deal with these problems, in 1984 Congress enacted a law called the Price, Competition, and Patent Term Restoration Act, which is commonly referred to as the Hatch–Waxman Act. The Act allows generic follow-on drugs to seek accelerated approval by the FDA. In exchange, the law grants limited data exclusivity — and hence, often de facto market exclusivity — for the original brand-name innovator. The Act utilizes a preexisting compilation of all relevant drugs and their clinical indications, the Orange Book, to list generic analogues. Most importantly, Hatch–Waxman allows generic drug manufacturers to use the same FDA approval data as the brand-name manufacturers had in an abbreviated approval application (thus eliminating the need for duplicative human trials and reducing cost for generic manufacturers). The result has been a decrease in the cost of prescription drugs due to increased price competition after the expiration of the original drug’s patent term.By formulating the Hatch–Waxman Act broadly, Congress has given the FDA wide flexibility to regulate. It has mandated the use of guidance documents, a less costly and time-consuming form of regulating than formal or even informal rulemaking. This guidance mandate has the advantage of increased flexibility and a faster turnaround time than traditional notice-and-comment rulemaking. Nevertheless, if the FDA does not use that flexibility judiciously, the Biosimilars Act may not achieve actual reductions in the cost of prescription biological drugs or significantly affect the cost of health care.Part I of this Comment discusses the Hatch–Waxman amendments, analogous foreign biosimilars pathways, and the history of biologics approval. Part II discusses the new bill, compares the Hatch–Waxman pathway with the potential biosimilars pathway, and explores key differences between the two that could delay access to both innovator and generic drugs. Part III recommends using notice-and-comment procedures to establish product-class-specific guidance, while retaining flexibility within product classes for clinical requirements, and discourages the FDA from using two-sided biostatistical testing.

Towards the improvement of UN N.5 test method for the characterization of substances which in contact with water emit flammable gases

This paper deals with a sensitivity analysis of main parameters affecting the measurement of the gas flowrate emitted during testing substances for their potential to emit flammables gases in dangerous quantities where in contact with water, according to the UN N.5 test procedure. UN N.5 is described in the Manual of Tests and Criteria of United Nations (part of the Orange Book) (ONU Manual of Test and Criteria, 2008), serving both applications of international transport regulations as well as classifications of dangerous substances according to Globally the Harmonized System (GHS) and the derived regulation applying in the EU known as “CLP” Regulation (Regulation (EC) No 1271/2008). The main reason that justifies the present research is that the measurement of emitted gases is highly critical in the final classification resulting from the interpretation of the test results. Moreover, that idea has been raised to adapt the UN N.5 test protocol for classifying, in the future, substances that by contact with water would emit dangerous quantities of toxic gases.Experiments have been carried out to cover the analysis of the influence of ambient temperature, overall volume of glassware, nature of aqueous media, mass sample and sample-to-liquid mass ratio, since such parameters are not fixed within any defined range in the UN N.5 test procedure. The influence of the flow rate measuring device was also considered. Results confirm that the above mentioned parameters may play a significant role to such an extent as to finally alter the final classification resulting from the testing. Guiding principles have also been derived from our measurements and observations towards an improved and more robust UN test protocol in the future.

Risk-Based Management Control in the Public Sector: A Live Experiment in Poland

Management control systems play a significant role in New Public Management reforms. This paper presents the case of Poland, where a small group of enthusiasts at the Ministry of Finance is attempting to enforce dramatic changes in control systems across the public sector. The changes are both technical and cultural. The new system is called 'management control' as opposed to 'internal financial control'. It is based on risk assessment and management, modeled on the British HM Treasury Orange Book standard. Moreover, the main sponsors of the new systems are internal auditors, a new professional group that is being developed since 2001 as an opposition to traditional control structures. The actor-network theory literature in management control systems predicts that the adoption of this innovation is contingent upon the sponsors ability to stimulate the translation process and to recruit allies who would support it. We document the developments of the reform to date and contribute two empirical studies: a survey of first reactions to the new system and a risk perception study. Both studies show that neither problematization nor interessment can be taken for granted. However, the new system has been embedded in national public finance law, which means that at least formally, it will persist. We discuss the potential for future research in the context presented.

Translating Research Into Policy: A Review of Pharmacovigilance Efforts From the Southern Network On Adverse Reactions (SONAR) Group

Abstract 4756 Introduction:SONAR, the only state-funded (South Carolina) pharmacovigilance initiative in the nation, focuses on identifying near fatal side effects of hematology and oncology therapeutics. Most safety findings are like “trees falling in the forest” – with no one hearing the noise. Our objective was to describe the outcomes from the findings of the pharmacovigilance efforts from the SONAR group. Methods:SONAR investigators reviewed practice and policy outcomes to our identification of adverse drug reactions with hematologic implications. Data sources used were PubMed, the Food and Drud Administration (FDA) files, and the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). Results:DrugSONAR findingConfirmationPeak at risk per year#pts/deaths% of ADR reports in the FDA databaseFDA ResponseMarket ActionGemtuzumab for AML patientsSinusoidal-obstructive syndrome- Leukemia Research 2007Biopsy findings50,00093/67100%Black BoxDrug WithdrawnTiclopidine, clopidogrel, prasugrel (antiplatelet agents)Thrombotic Thrombocytopenic Purpura (TTP)- NEJM 2000, Lancet 1998, JAMA 1998AntibodiesTiclopidine 1 million, Clopidogrel 5 millionTiclopidine 60/20, clopidogrel 37/5, prasugrel 9/060%, 90%, and 100% respectivelyBlack Box, WarningsTiclopidine market sales < $10 million (despite being generic)Rituximab- for lymphoma treatmentPML- Blood 2009WarningsNoneNevirapine for post-HIV-exposure following exposure to blood productsFulminant hepatitis in HCWs following needle-stick- Ann of Int Med 2002Biopsy findings30/020%Dear DoctorDrug not used in this setting. CD4 thresholds added for use among HIV-infected individuals.Thalidomide, lenalidomide for multiple myeloma patientsVenous thromboembolism (VTE)- JAMA 200617,00096/1271%Warning, Dear DrVTE prophylaxis is now routine – based on survey dataVoriconazole for anti-fungal prophylaxisBreakthrough Zygomycoses following stem cell transplantation for hematologic malignancies - BMT 2007Label changeNoneEprex-formulation of EpoetinPure red cell aplasia- NEJM 2000Neutralizing antibodies208/0100%Warning, Dear DrSQ use discontinuedEpoetin, darbepoetin- cancer ptsMortality, tumor progression- JAMA 2008Black Box, warningMarked decrease in ESA use- based on survey dataMegakaryocyte growth and development factor administration to healthy volunteersLymphoid malignancies - B J of Haematology 200613/00%NoneDrug development discontinuedGranulocyte colony-stimulating factor treated cancer patientsLeukemia/MDS - JNCI 2008, B J Haematol 2006NoneNoneGemcitabinePneumonitis150/52100%Label changeCYPHER stents for coronary artery diseaseHypersensitivity at the stent siteAutopsy findings1 million12/243%Dear DoctorEnoxaparin – following coronary artery stent proceduresSevere hemorrhage and pseudoaneurysm formationKnown toxicity5/00%None Conclusions:Most SONAR findings have been followed by FDA notifications and market responses. Identifying and reporting sADRs can have marked beneficial effects on medical care. Disclosures:No relevant conflicts of interest to declare.

ACCF/AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Purpose of This Document . . . . . . . . . . . . . . .1291 2. Document Development Process . . . . . . . . . .1291 3. Definitions, Terminology, and Regulations . . .1292 1. Terminology . . . . . . . . . . . . . . . . . . . .1292 2. Generics . . . . . . . . . . . . . . . . . . . . . . . .1293 3. Bioequivalence . . . . . . . . . . . . . . . . . .1293 4. Biologics and Biosimilars. . . . . . . . . . .1294 2. Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . .1295 3. Federal Regulations and State Laws . . . . . . . . . . .1296 4. Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . .1296 1. Therapeutic Interchange . . . . . . . . . . . . . . . . .1296 2. Therapeutic Substitution . . . . . . . . . . . . . . . . .1297 3. Generic Substitution . . . . . . . . . . . …

US Solicitor General's Opinion Sought on Permissible Breadth of Orange Book Entries

Biotechnology Law ReportVol. 30, No. 4 PatentsUS Solicitor General's Opinion Sought on Permissible Breadth of Orange Book EntriesPublished Online:21 Jul 2011https://doi.org/10.1089/blr.2011.9833AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetails Volume 30Issue 4Aug 2011 InformationCopyright 2011, Mary Ann Liebert, Inc.To cite this article:US Solicitor General's Opinion Sought on Permissible Breadth of Orange Book Entries.Biotechnology Law Report.Aug 2011.472-473.http://doi.org/10.1089/blr.2011.9833Published in Volume: 30 Issue 4: July 21, 2011PDF download

Applying the Essential Medicines Concept to US Preferred Drug Lists

We assessed whether state Medicaid preferred drug lists are concordant with the World Health Organization's 2009 16th Essential Medicines List and with each other. We also characterized listed medicines by generic availability and appearance on treatment guidelines. We derived generic availability and first-line treatment status from the US Food and Drug Administration's Orange Book and the 2004-2009 National Health Service National Institute for Clinical Excellence guidelines. We report characteristics of Essential Medicines List and preferred drug list (PDL)-only medicines and describe differences between medicines that are frequently and infrequently listed on PDLs. Only 6 of 120 Essential Medicines List medicines appeared on fewer than 50% of PDLs. PDL-only medicines (n = 249) were less likely than were Essential Medicines List medicines (n = 120) to have generic versions available (56% vs 76%) and to be first-line treatments (21% vs 41%). The content of PDLs was variable: 33% of medicines appeared on 80% to 100% of PDLs. Application of the essential medicines concept to Medicaid PDLs could reduce costs and provide more equitable and evidence-based health care to low-income patients in the United States.

There is no Orange Book: the coming wave of biological therapeutics

Widespread therapeutic use of biological pharmaceutical products is inevitable. The law governing approval of biosimilar products in the United States is developing, along with scientific advances. This article discusses recent developments in United States patent law and newly enacted statutory provisons relating to approval of biosimilar and interchangeable biologic pharmaceutical products. It places those developments in the context of developments in synthetic biology, especially the disclosure by Craig Venter's team of the first self-replicating synthetic bacterium.

Tracking R&amp;D behavior: bibliometric analysis of drug patents in the Orange Book

The Publication Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book) identifies drug products approved by the United States Food and Drug Administration (USFDA) for safety and effectiveness, and provides substantial information on new drug applications (NDAs) with patent data. To explore the patterns among drug patents in the Orange Book, this study used patent bibliometric analysis. The productivity and impact are presented at the assignee level and applicant level, respectively, and the applicant's patent portfolio is further discussed. 2,033 drug patents are identified in this current study. Our findings indicate that the applicant's patent portfolio in the Orange Book is helpful in revealing the technological capability and patent strategy of the pharmaceutical incumbents. By linking drug data and patent information, this current study sheds light on patent research in the pharmaceutical industry.

The failure to show bioequivalence is not evidence against generics

I read with interest the paper by Del Tacca et al. [1]. I agree that verification of the bioavailability of marketed pharmaceutical products is an interesting topic, since not all marketed products have been shown to be bioequivalent to the reference product. It is only possible to believe naively that all products on the market are bioequivalent with the reference product from the complete ignorance of the pharmaceutical legislation of the European Union [2]. Therefore, a list similar to the FDA Orange Book [3], which identifies the (bio)equivalent products and its reference product, is essential for prescribers. Interestingly, the legislation allowing the authorization of products with unknown bioavailability (e.g. bibliographical applications), but with the dosage instructions of the reference product, or the absence of a ‘European Orange Book’ are not criticized. On the contrary, the criticism is motivated by the substitution policies, which affect economically the reference products and prescribers, and are focused on the second-entry products that assure best the safety and efficacy profile and interchangeability with the reference product. Average bioequivalence is not only a surrogate of therapeutic equivalence but also of equivalent biopharmaceutical quality, which assures that generic and reference products will behave in the same way in all individual patients, irrespective of their demographics, concomitant medication or illnesses. From my point of view, this failed bioequivalence study has been used as an excuse to criticize the authorized generic pharmaceutical products and the substitution policies, but this is not scientifically correct for the following reasons. First, it would be convenient to distinguish between bioequivalence (i.e. 90% CI within the acceptance limits), bioinequivalence (90% CI completely outside of the acceptance limits) and non-equivalence (90% CI with some part inside and some part outside of the acceptance limits). In practical terms, it is necessary to conclude inequivalence in order to conclude that a generic is not similar to the reference product, since non-equivalence is inconclusive and another study with more statistical power (i.e. a lower variability or a higher sample size) might be able to conclude equivalence. In statistical terms, it is incorrect to conclude that one of the generic products is not equivalent simply because the authors were unable to conclude equivalence (90% CI for Cmax 0.7921, 1.0134). The inability to reject the null hypothesis does not support the validity of the null hypothesis. Only the alternative hypothesis can be proved in a test of hypothesis. In bioequivalence studies the null hypothesis is that the products are inequivalent and the alternative hypothesis is that the products are equivalent. In other words, absence of evidence (of bioequivalence) is not evidence of absence (of bioequivalence). On the contrary, the study results suggest that a study with lower variability or higher sample size would be able to show bioequivalence since the lower boundary of the 90% CI is very close to the acceptance range. Therefore, it is reasonable to believe that the marketing authorization holder will have sponsored a bioequivalence study that was able to conclude equivalence. In this respect, it is surprising that this paper was accepted without requiring the identification of the products under investigation. Presently, the study cannot be replicated, the Marketing Authorization Holders cannot defend themselves by submitting evidence of the bioequivalence of the products in another bioequivalence study and it is not possible to verify if they are products approved based on bioequivalence or not. Second, the authors claim that the reference product showed 8.5 and 5.4% greater AUC, but it is not statistically appropriate to give validity to a difference in point estimates that was not able to reach statistical significance. As all 90% confidence intervals included 100%, this study was not able to find any statistically significant difference between products, which, at the same time, is not enough to conclude equivalence because a large variability makes the study inconclusive. In addition, the study results show some inconsistencies that cast doubt on its correctness. According to the authors the AUC CV was 27.4% and the Cmax CV was 27.6%, which illustrates that the statistical analysis has been performed on the combined data from the three formulations. If this were the case, the width of the 90% CI would be the same for all three comparisons. However, the width of all three comparisons is different, which shows that the three comparisons have been calculated with a different CV, some of them higher than 30% in contrast to the authors' claim. Many other statements from the authors deserve a comment, but there is no room for more. In my opinion, this is enough to illustrate that the paper by Del Tacca et al. [1] describes an inconclusive study and only adds noise to the debate on the validity of bioequivalence as demonstration of therapeutic equivalence and interchangeability in case of generic substitution.

Evaluating the Bioavailability and Bioequivalence of Generic Medications

By law, the U.S. Food and Drug Administration (FDA) is permitted to approve generic versions of brand-name medications without necessarily requiring that research be conducted to prove them safe and effective, provided that a number of criteria are met. The most important criterion is bioequivalence. Bioavailability refers to the rate and extent to which the active ingredient is absorbed from a drug product. Maximum drug concentration (Cmax) is the parameter used to characterize the absorption rate. The area under the plasma drug concentration-time curve (AUC) is the parameter used to characterize the extent of drug absorption. Bioequivalence means that there is an equivalent rate and extent of absorption of the same active ingredient from two or more drug products. For a generic drug to be approved, both Cmax and AUC must vary only within a certain limited range compared with those for the brand name medication. Information about generic and pharmaceutical alternative drugs can be found in the Orange Book and via Drugs@FDA.

Radioanalytical Chemistry–Revision of the Orange Book Chapter

Radioanalytical Chemistry–Revision of the Orange Book Chapter

Effects of Paddle-Shaft Position and Inclination of Dissolution Apparatus on the Dissolution Rate of Carbamazepine Tablets and the Equivalence Assessment of Generic Drugs

Dissolution testing is useful for controlling the quality of an oral generic equivalent (GE) drug and rejecting a bioinequivalent GE. However, several sources of variability in dissolution tests can affect evaluations of drug quality. Recently, we reported that shifting the paddle shaft off-center significantly changed the dissolution rate of sodium diclofenac tablets, with the result that some GE tablets did not meet the criteria for equivalence. The aim of this study was to confirm the effect of paddle position and to investigate the effect of inclining the dissolution apparatus on the dissolution rates, quality assessment, and equivalence assessment of rapid-release carbamazepine tablets using a brand product (BR) and three GE products. Dissolution tests were carried out on the basis of the Japanese Pharmacopoeia (JP) 15 and Japanese Orange Book paddle methods. The paddle was shifted 5 mm from the center of the vessel, and the dissolution apparatus was inclined backward approximately 4° from the horizontal position. The percentage of drug that dissolved was then calculated. Shifting the paddle significantly increased the dissolution rate for all tablets, whereas inclining the apparatus reduced the dissolution rate for some tablets. All carbamazepine tablets passed the quality evaluation, and all GE products were judged equivalent to the BR product when the paddle was positioned centrally and the apparatus was horizontal. However, the BR product did not meet the criteria of the quality evaluation, and one GE product was judged not equivalent to the BR product in the 5-mm-off-center experiment, suggesting that the position of the paddle affects the quality and equivalence assessment of the rapid-release carbamazepine tablets. In conclusion, offsetting the paddle position from the center could affect the equivalence, as well as the quality assessment, of GEs by enhancing the dissolution rate. Inclining the apparatus reduced the dissolution rate but did not affect the equivalence assessment of GEs.

Focus on magnetics and electromagnetism

Focus on magnetics and electromagnetism