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Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV
Guidance for Industry 1
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact Debra B. Birnkrant 301-827-2330.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2004
Additional copies are available from:
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2004
|Page Number
|III. HIV Therapy and Resource Poor Settings
|IV. General Considerations
A. What Products Does this Guidance Apply To?
B. What Special Regulatory Procedures Are Available for FDC and Co-Packaged HIV Products?
C. What Are the Characteristics of Potential Regimens for FDC or Co-Packaged HIV Therapies?
|V. Clinical Considerations.
|VI. Clinical Pharmacology and Biopharmaceutics
A. Relative Bioavailability/Bioequivalence Study Design
B. Relevant Study Endpoints
C. Bioanalytical Method Validation
D. Data Analysis and Interpretation.
E. Food Effect.
F. Dissolution Testing
|VII. Chemistry, Manufacturing, and Controls
A. Applications Submitted for Co-Packaged Products
B. Applications Submitted for FDCs
1. Data showing lack of interaction between active ingredients
2. Appropriate quality standards for each active ingredient and for the dosage form
3. Assurance of reproducible drug release from the dosage form
4. Stability Data
5. References or data supporting safety of excipients
6. Demonstration that the manufacturing processes for active ingredients and dosage form are defined and understood
|VIII. Microbiology/Virology
|IX. Adverse Event Reporting
|X. Other Regulatory Considerations
A. Patents and Exclusivity
B. User Fees
C. Pediatric studies
This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
This guidance is intended to encourage sponsors to submit applications to the Food and Drug Administration (FDA) for approval of fixed dose combination (FDC) and co-packaged versions of previously approved antiretroviral therapies for the treatment of human immunodeficiency virus (HIV).2 The guidance seeks to clarify what regulatory requirements would be applied to such applications, what issues might be of concern, and how these should be addressed. Different considerations apply depending on whether (1) a sponsor owns or has a right of reference to all of the data required to support an application or (2) a sponsor plans to rely on literature or the FDA's findings of safety and effectiveness for an approved drug. Where appropriate, this guidance addresses the issues associated with these different scenarios.
For additional guidance, three attachments have been included: Attachment A contains some regulatory scenarios for approval of FDC or co-packaged products for the treatment of HIV. Attachment B contains examples of drug combinations supported by current clinical data and considered acceptable for FDC/co-packaging. Attachment C contains drug combinations not considered acceptable for FDC/co-packaging.
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
Combination therapy is essential for the treatment of HIV/AIDS. The goals of HIV therapy are to maximally and durably suppress virus to allow recovery of the immune system and reduce the emergence of HIV resistance. At least three active drugs, usually from two different classes, are required to suppress the virus, allow recovery of the immune system, and reduce the emergence of HIV resistance. In the United States and developing countries, simplified HIV regimens in the form of co-packaged drugs (such as blister packs) or FDCs may facilitate distribution and improve patient adherence.
For treatment-experienced patients, the choice of combination regimens is more complex and individualized. Therefore, triple FDCs or co-packaged products are probably most useful for treatment-naive patients; however, this may change as treatment guidelines for treatment-experienced patients evolve.
Although there are more than 20 unique antiretroviral drugs approved in the United States under § 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 355), only a few are approved for use as FDC products, and none is approved as a co-packaged product. Some antiretrovirals should not be combined due to overlapping toxicities and potential viral antagonism. Other antivirals should not be used in pregnant women and other special populations. It is important, therefore, that possible combinations of these products be evaluated for safety and efficacy in the various populations that may have need of them.
Recently, newer FDCs that have not been evaluated by the FDA have received attention, and some are being promoted for use in resource poor nations where HIV-1 has reached epidemic proportions.4. These FDCs may offer cost advantages and allow simplified dosing because two or three drugs are combined in one pill. However, the safety, efficacy, and quality of these products have not been evaluated by FDA. Products whose safety, efficacy, and quality do not conform to expected standards may pose a threat to individual patients by increasing the chances of substandard performance, which may lead not only to treatment failure, but also to the development and spread of resistant virus.
FDA believes that where adequate evidence of safety and efficacy already exists for the use of certain individually approved HIV drugs in combination, the path to regulatory approval of an FDC or co-packaged product is straightforward. FDA is prepared to move swiftly to evaluate such products when applications for them are submitted for approval.
FDA recognizes that FDC and co-packaged products may also be valuable in the treatment of other serious infectious diseases such as tuberculosis and malaria. This guidance is being written to address issues in HIV therapy, although many of the principles relied upon are more generally applicable. Sponsors with potential products for other serious infections such as those just mentioned are invited to contact the Division of Anti-Viral Drug Products to discuss these proposals.
III. HIV Therapy and Resource Poor Settings
In his State of the Union address on January 28, 2003, President Bush announced the President's Emergency Plan for AIDS Relief that would provide $15 billion over 5 years with the goal of preventing 7 million new infections, treating 2 million HIV infected people, and caring for 10 million HIV infected individuals and AIDS orphans. Drug treatment will play a major role in this relief plan, and it is important that resources spent on drug treatment be spent on treatments that have been demonstrated to be safe and effective.
On March 29 to 31, 2004, government officials and representatives of drug regulatory agencies from 23 nations, the research-based and generic pharmaceutical industries, public health leaders, healthcare providers, advocacy groups (including persons living with HIV/AIDS), academia, and members of nongovernmental organizations met to discuss the scientific and technical principles for FDC drug products for use in the treatment of AIDS, tuberculosis, and malaria, the most serious infectious disease threats facing the world today. On April 8, 2004, as a result of the meeting, the Southern African Development Community (SADC), the United Nations Joint Programme on HIV/AIDS (UNAIDS), HHS, and the World Health Organization (WHO) issued a joint statement titled Principles for Fixed-Dose Combination Drug Products.
The statement announced the development of a Principles Document addressing the development of FDCs and their potential benefits or disadvantages in treating these diseases. The Principles Document is to focus on aspects of the efficacy, safety, and quality of FDCs and provide points to consider when developing, evaluating, and/or considering FDC products for the treatment of these diseases. The document is not, however, intended to be a therapeutic or a regulatory guideline. A draft of the Principles Document was posted on the Internet on April 22, 2004,5 and comments were solicited. A final draft of the document is being developed.
The FDA has determined that it would be useful to describe in more detail the U.S. regulatory pathway for the development of antiretroviral FDCs and co-packaged products as a way to encourage the development and approval of such products so that they will be available for the treatment and prevention of the global spread of HIV/AIDS.
General Considerations
A. What Products Does this Guidance Apply To?
This guidance is aimed primarily at those combinations of individual drugs for antiretroviral therapy that have already been approved by the FDA for individual therapy and for which adequate evidence of safety and efficacy in combination already exists. We recommend that applicants contact the Division of Anti-Viral Drug Products with regard to combinations for which safety and effectiveness are not yet supported by currently available clinical data.
B. What Special Regulatory Procedures Are Available for FDC and Co-Packaged HIV Products?
Priority review and fast track designations are already available and likely would be applicable to these products. A priority review designation provides for the review of an application in 6 months or less.6 We expect, however, that the applications described in this guidance could be reviewed within even shorter time frames.
Fast track designation offers a number of advantages that can facilitate drug development and approval (see the guidance for industry Fast Track Drug Development Programs - Designation, Development, and Application Review, September 1998). Fast track designation encompasses programs that were already in existence prior to the creation of the fast track program, such as Subpart E - Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses (21 CFR 312.80 through 312.88); priority review; and accelerated approval (21 CFR 314.500). In addition, a fast track designation allows for parts of a marketing application to be accepted before submission of the complete application (i.e., rolling submission).
To facilitate rapid development and approval of combination HIV therapies, FDA is prepared to meet with sponsors in the early development stages of either a co-packaged or FDC product to discuss the appropriateness of the combination, the dosing strength, and the appropriate nonclinical data.
C. What Are the Characteristics of Potential Regimens for FDC or Co-Packaged HIV Therapies?
The goal of having FDC or co-packaged HIV products is to simplify regimens to allow for easier distribution and improved patient adherence, particularly in resource poor settings. Proposed combination products should be relatively well tolerated and easy to administer while providing potency and a sufficient barrier to the emergence of drug resistance. When developing FDCs or co-packaged products, we recommend that the products have the following important characteristics:
- Contain two or more components of a fully suppressive regimen
- Require a once or twice daily administration
- Be recommended as a preferred or alternate regimen (or regimen component) in treatment guidelines (see footnote 3)
- Have clinical efficacy and safety data that support use of the combination
- Be commonly used in treatment-naive patients
- Have drug interaction and toxicity profiles that allow for concomitant dosing
When considering proposed FDCs or co-packaged products, sponsors should take into account the required dosing frequency of each of the components. Each of the components of an FDC should have an identical dosing frequency and similar food instructions. Co-packaged products may include products with different dosing frequencies (once or twice daily), if the packaging design clearly delineates the dosing schedules in a user friendly format that facilitates adherence. Applicants should consider differences in food instructions between individual components when developing co-packaged products.
Pharmaceutical sponsors and other investigators have already conducted a substantial number of clinical studies of triple-combination regimens, particularly in treatment-naive patients. Based on these studies, several treatment guidelines7 recommend preferred and alternate HIV treatment regimens for initial therapy. In general, recommended triple-treatment regimens consist of two drugs from the nucleoside (or nucleotide) reverse transcriptase inhibitor (NRTI) class and one drug from either the nonnucleoside reverse transcriptase inhibitor (NNRTI) class or protease inhibitor class. One triple-nucleoside FDC has been approved; however, in treatment guidelines, this regimen is recommended as an alternate regimen when other preferred regimens are not suitable.
As stated above, a large collection of clinical trial data and other scientific data (e.g., in vitro studies of resistance) have shown that it takes three active antiretrovirals to adequately sustain virologic control of HIV over the long term. It has also been shown that each antiretroviral in the type of combination regimens mentioned above contributes to the overall efficacy and potency of a regimen. In fact, all approved antiretroviral agents are specifically indicated and labeled for use in combination with other antiretroviral agents. The combined use of antiretroviral drugs reduces the emergence of resistance and prolongs the usefulness of these drugs.
To encourage development of FDCs and co-packaged products, FDA has created a list of examples of regimens and regimen components (Attachment B) for which the clinical safety and efficacy of concomitant use have been evaluated and described in product labels or peer reviewed literature. FDA expects that developing FDCs or co-packaged products for combinations on this list could be accomplished without conducting new clinical efficacy and safety studies and that FDCs consisting of combinations on the attached list will satisfy the principles underpinning 21 CFR 300.50 with regard to their safe and effective use in combination.8
Inclusion criteria for this list are:
- Approved individual components
- Two-drug nucleoside analogue components9 (to be used with a protease inhibitors or NNRTI)
- Three-drug regimens, consisting of two NRTIs and a protease inhibitor or NNRTI
- Once or twice daily dosing
- Triple regimen (or two-drug component) studied for at least 48 weeks in trials evaluating changes in HIV-RNA and CD4 cells10
- Comparison of the regimen to appropriate controls
- Acceptable risk-benefit profile, particularly for treatment-naive patients
- Recommended as preferred or alternate regimens for initiating antiretroviral therapy.
This list is not meant to be comprehensive and will evolve over time as HIV clinical research continues.11 Applicants may have access to data supporting the efficacy and safety of combinations not included on this list. Sponsors should discuss with the Division of Anti-Viral Drug Products, in advance of an NDA submission, the available support for a FDC or a co-packaged product.
There are antiretroviral drugs that should not be combined due to viral antagonism and overlapping toxicities. In addition, there are triple-combination regimens that have shown poor virologic efficacy, likely due to an inadequate mutational barrier against the emergence of resistance.12 Drugs and regimens that would not be acceptable for FDCs or co-packaging because of known viral antagonism, poor virologic efficacy, or toxicity, are listed in Attachment C.
Combinations of two or more active antiretroviral drugs like those listed in Attachment B are not the only type of FDC product suitable for combinations. For example, Kaletra (lopinavir/ritonavir), an approved FDC, is an antiretroviral combined with a metabolic booster; a low dose of ritonavir (an inhibitor of cytochrome p450 3A) is used to increase plasma concentrations of lopinavir, the component responsible for the antiviral efficacy. Other HIV protease inhibitors are often administered with low doses of ritonavir and may be suitable for co-packaging or co-formulation. FDA encourages sponsors to develop FDCs for this type of drug combination to help in simplifying regimens.
V. Clinical Considerations
For many potential FDCs or co-packaged products (e.g., those in Attachment B), FDA believes adequate clinical studies confirming safety and efficacy of the combination have already been conducted, obviating the need for new clinical studies. Applicants for FDC or co-packaged products may provide clinical efficacy and safety information by one or more of the following mechanisms:
- Referencing their own relevant NDA or IND submission
- Cross-referencing another applicant's submission for which they have been given right of reference
- Submitting peer-reviewed literature describing relevant clinical studies and other scientific information and a summary that synthesizes the information and provides the rationale for the combination
- Relying on FDA's findings of safety and effectiveness for approved drug products, subject to U.S. intellectual property rights
We encourage sponsors to discuss with FDA their plans for providing such information before making a submission.
In general, clinical support for a FDC or co-packaged product should include efficacy and safety data from at least one well-controlled study for at least 48 weeks in duration evaluating changes in HIV-RNA and CD4 cell counts. Optimally, the study should have been designed to demonstrate statistical noninferiority, or superiority, of the regimen to an accepted control regimen (at the time the study was conducted). In addition, other clinical studies evaluating components of the proposed regimen used in various triple combinations may help to support the efficacy of the proposed triple regimen. In some cases, clinical support for a regimen may be based on a collection of well-controlled triple-combination studies that, when evaluated together, provide a convincing rationale for the proposed combination.
VI.Clinical Pharmacology and Biopharmaceutics
It is important to determine whether the rate and extent of absorption of each therapeutic moiety in a FDC product are the same as the rate and extent of absorption of each therapeutic moiety administered concurrently as separate single-ingredient products. This evaluation provides the link between the new combination drug product and the drug products whose safety, efficacy, and quality parameters are well established. It is unnecessary to provide new bioavailability information for co-packaged approved drug products. However, drug-drug interaction studies should be conducted between the therapeutic components of the FDC or co-packaged products, if the studies were not conducted previously and the potential for an interaction cannot be ruled out.
The following section describes considerations related to the relative bioavailability and bioequivalence evaluation of FDCs for HIV. For additional details, see the guidance for industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products- General Considerations (March 2003).
A. Relative Bioavailability/Bioequivalence Study Design
The optimal study design would be a randomized, single-dose, two-way crossover, in which subjects receive the FDC (test treatment) and the single entity products administered together (reference treatment), with an adequate washout between treatments.
The number of subjects would depend on the variability associated with the drug products to be studied. In most cases, 24 to 36 subjects should be adequate. However, there should not be fewer than 12 subjects. If feasible, we recommend that both male and female subjects be enrolled.
B. Relevant Study Endpoints
The rate and extent of drug absorption should be assessed by determining the following exposure measures: the area under the plasma concentration-time curve calculated to the last measured concentration (AUC0-t) and extrapolated to infinity (AUC∞), peak drug concentrations (Cmax), and time to achieve peak drug concentrations (Tmax).
C. Bioanalytical Method Validation
All bioanalytical methods should be well characterized, fully validated, and documented. In addition, assay precision and accuracy should be documented during analysis of samples collected during the relative bioavailability/bioequivalence study. For additional details, see the guidance for industry Bioanalytical Method Validation (May 2001).
D. Data Analysis and Interpretation
We recommend that the AUC and Cmax be analyzed statistically using the two one-sided tests procedure. Only descriptive statistics need to be determined for Tmax. The AUC and Cmax data are log-transformed prior to statistical testing. We recommend the statistical tests be implemented using the analysis of variance procedure (ANOVA). A point estimate and 90 percent confidence interval can be calculated for the test/reference ratio for AUC and Cmax. If the confidence intervals for AUC and Cmax values for all active moieties fall entirely within the 80 to 125 percent boundaries, bioequivalence can be concluded. For NDAs only, in cases when all confidence intervals do not fall within 80 to 125 percent, it may be acceptable to use exposure-response information to determine the clinical relevance of differences in exposure.
E. Food Effect
For NDAs, it may be necessary to determine the effect of food on the absorption of the active moieties included in the combination product. Sponsors can contact the review division to discuss the need for a food effect study.
For ANDA applications, it may be necessary to conduct separate fed and fasted bioequivalence studies.
For additional details about food-effect bioavailability studies and fed bioequivalence studies, see the guidance for industry Food-Effect Bioavailability and Fed Bioequivalence Studies (December 2002).
F. Dissolution Testing
A discriminating dissolution method should be developed, with limits set, for each active pharmaceutical ingredient in a drug product. The dissolution method should be incorporated into the stability and quality control programs. Dissolution testing should ensure that the presence of two or more drugs does not affect the dissolution performance testing. For additional details, see the guidance for industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms (August 1997).
VII. Chemistry, Manufacturing, and Controls
Developing a new FDC product poses formulation challenges, and it may be simpler from a development standpoint to co-package approved HIV drugs in blister packs, as long as the products have been shown to be safe and effective when used together. Although the principles for establishing the safety and efficacy of an FDC also apply to co-packaged products, the chemistry issues are different.
A. Applications Submitted for Co-Packaged Products
For products in integrated blister packaging (i.e., a blister strip or card containing multiple products), FDA expects that the individual products will have been already approved. In this situation, the needed chemistry, manufacturing, and controls (CMC) data would generally be available (by cross-referencing another application or a drug master file13) or could be generated readily.
The new information needed to support blister packaging would typically be limited to stability data (21 CFR 314.50 (d)(1)(ii)(a)). Data would typically include limited accelerated and available long-term stability data,14 plus short-term stress studies under high temperature and/or high-humidity conditions.15 Sponsors should evaluate the stability of the drug product in the actual dispensing package as well as in any bulk storage container and shipping container. Assessment of stability typically includes assaying each active ingredient to meet acceptance criteria of 90 to 110 percent of labeled strength, determining individual and total impurity levels, and measuring dissolution rates. Data on moisture uptake in the dosage form should be available and may be especially important if the product is to be packaged in a blister container, since polymer/foil blisters are not as impervious to moisture as high-density polyethylene bottles or foil/foil blisters. Justification should be provided for the proposed expiration dating period (e.g., supportive stability data, qualitative or statistical analysis of trends). The expiry period can generally be extended as additional stability data become available after approval.
B. Applications Submitted for FDCs
The application should generally include information covering the following aspects of product quality, safety, and performance.
1. Data showing lack of interaction between active ingredients
Typically, one-time stress studies should be performed to identify potential reaction products between active ingredients. We recommend that those degradants likely to be present during manufacturing and storage be monitored during stability studies.
2. Appropriate quality standards for each active ingredient and for the dosage form
Tests performed prior to release of each batch of drug substance and drug product (i.e., the specifications) and appropriate process controls during manufacture should be established.16 Validated analytical methods should be capable of distinguishing each active ingredient, synthesis (process) related impurities, and potential degradation products. If the active ingredients are poorly soluble, controls for particle size should be in place. If these active ingredients can exist in different solid-state polymorphic forms, additional controls may be needed. Acceptance criteria for process impurities and degradants should be set based on manufacturing experience and toxicological considerations. If impurities exceed the recommended qualification thresholds,17 additional toxicological justification may be necessary.
3. Assurance of reproducible drug release from the dosage form
It is important to establish that each manufactured lot of drug product will release all active ingredients at an appropriate rate. This is typically monitored by a dissolution test performed as part of the drug product specification. This test should use a physiologically relevant medium, one that can be correlated to an in vivo study, or a scientific justification for the dissolution medium (e.g., pH, composition) should be provided in the application.
4. Stability Data
Stability of the combination drug product needs to be demonstrated (21 CFR 314.50 (d)(1)(ii)(a)). Data would typically include accelerated and available long-term stability data,18 plus short-term stress studies under high temperature and/or high humidity conditions (see ICH Q1F guidance). Sponsors should evaluate the stability of the drug product in the actual dispensing package as well as in any bulk storage container and shipping container. Assessment of stability typically includes assaying each active ingredient to meet acceptance criteria of 90 to 110 percent of labeled strength, determining individual and total impurity levels, and measuring dissolution rates. Data on moisture uptake in the dosage form should be available and may be especially important if the product is to be packaged in a blister container, since polymer/foil blisters are not as impervious to moisture as high-density polyethylene bottles or foil/foil blisters. Justification should be provided for the proposed expiration dating period (e.g., supportive stability data, qualitative or statistical analysis of trends). The expiry period can generally be extended as additional stability data become available after approval.
5. References or data supporting safety of excipients
We recommend that the products be formulated using excipients that are described in internationally recognized compendia and meet these compendial standards. Justification for any novel excipients should be provided, including animal toxicity data if necessary.
6. Demonstration that the manufacturing processes for active ingredients and dosage form are defined and understood
The manufacturing processes, including appropriate controls, should be described in the application for each drug substance and for the drug product (or provided by cross-referencing another application or a drug master file19).
All applications, whether for integrated blister packaging or FDCs, should identify the manufacturing facilities where the active ingredients and the dosage form(s) are produced, packaged, and tested so that the FDA can verify that good manufacturing practices are followed appropriately.20, 21
FDA will work with applicants on rapid evaluation of anti-counterfeit technologies.22
VIII. Microbiology/Virology
In general, FDCs and co-packaged products containing approved antiretrovirals will require few, if any, additional nonclinical studies. Data from the following types of studies should usually be available from existing IND or NDA submissions, from literature references, or by reliance on the FDA's findings for a previously approved drug. Any studies providing this type of data should have been conducted in accordance with accepted standards of good laboratory practices.
Applicants can submit virology data by:
- Referencing their own relevant NDA or IND submission
- Cross-referencing another applicant's submission for which they have been given right of reference
- Submitting peer-reviewed literature of relevant nonclinical studies, although this approach should be discussed in advance with the Division of Anti-Viral Drug Products.
- Relying on the FDA's findings of safety and effectiveness for an approved drug
Specifically, the types of information that should be included or referenced to support an FDC are listed below. However, for drug combinations already supported by adequate clinical data, such as those mentioned in attachment B, additional in vitro studies will not be needed.
- Mechanism of action of the individual components
- Antiviral activity in vitro against standard laboratory strains and clinical isolates (including a variety of the most common HIV clades from diverse geographic regions), and effects of serum protein binding on antiviral activity
- Cytotoxicity for dividing cells, including mitochondrial toxicity
- In vitro combination activity studies of the antiviral components to rule out antagonistic effects
- In vitro selection of resistant virus and phenotypic/genotypic characterization of the isolates. When components of the combination have the same target protein, selection of resistant virus in vitro should be carried out in the presence of the combination at concentrations equivalent to the in vivo concentrations. The genotypic and phenotypic nature of the resultant resistant isolates should be characterized to identify common resistance pathways.
FDCs and co-packaged products should contain drugs that together impose a significant mutational barrier for the development of resistance. In clinical studies, some triple-nucleoside regimens have been shown to have high virologic failure rates associated with high rates of drug resistance (see Attachment C). The cause of the high failure rates appears to be associated with the emergence of single or dual cross-resistant mutations that confer resistance to all three components.
IX. Adverse Event Reporting
Applicants are expected to comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81) (i.e., reports of serious and unexpected adverse events within 15 days of receipt of the information by the applicant or its affiliates). If the combination product is to be mass distributed in developing countries, a system of collecting and reporting adverse drug reactions by the distributor would be desirable (e.g., through governmental or nongovernmental agencies distributing the products).
X. Other Regulatory Considerations
A. Patents and Exclusivity
If these FDC and co-packaged products are to be developed by sponsors who either own or can obtain a right of reference to the underlying data, patents and exclusivity should not be a bar to the review and approval of such products. If these products are not developed by sponsors who either own or can obtain a right of reference to the underlying data, the regulations that govern the submission and approval of 505(j) and 505(b)(2) applications would apply. In these situations, the FDA encourages the applicant to contact the review division to discuss possible approaches to the development of their product(s).
B. User Fees
By law, FDA must assess user fees on applications, products, and establishments that meet the legal criteria for fees (section 736(a) of the FD&C Act, 21 U.S.C. 379h(a)).23 However, the law provides that under certain circumstances FDA can grant a waiver or reduction in fees.
The waiver criteria provide that FDA may grant a waiver or reduction in fees for any of the following reasons:
- A waiver or reduction is necessary to protect the public health.
- Assessment of the fee would present a significant barrier to innovation because of limited resources available to such person or other circumstances.
- The fees to be paid by such person will exceed the anticipated present and future costs incurred by the Secretary in conducting the process for the review of human drug applications for such person.24
- The applicant involved is a small business submitting its first human drug application to the Secretary for review.25
FDA is evaluating the circumstances under which it may grant user fee waivers or reductions for sponsors developing products under this guidance.
For information about how to request a waiver or reduction, please contact the User Fee Team in the Office of Regulatory Policy at 301-594-2041. More information on user fees is available on the Internet at http://www.fda.gov/cder/pdufa/default.htm.
C. Pediatric studies
The Pediatric Research Equity Act of 2003 (PREA) requires that pediatric studies be conducted for any new application (NDA, BLA, or supplement) that provides for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration, unless the requirement is waived or deferred. Under PREA, pediatric studies may be deferred if (1) the drug is ready for approval in adults before pediatric studies are complete, (2) additional safety or effectiveness data need to be collected, or (3) there is another appropriate reason for the deferral, and the applicant submits appropriate information to support the deferral. Pediatric studies may be fully waived if (1) the studies are impossible or impracticable, (2) there is evidence that the drug would be ineffective or unsafe in the pediatric population, or (3) the drug does not represent a meaningful therapeutic benefit over existing therapies and it is not likely to be used in a substantial number of pediatric patients. FDA encourages sponsors to consult with FDA at the earliest possible time regarding their pediatric drug development plans and the availability of a waiver or deferral.
FDA also encourages sponsors to consult with the FDA regarding the availability of pediatric exclusivity under § 505A of the FD&C Act if sponsors conduct studies requested by FDA that are needed to label the drug product for use in pediatric populations.
Scenario 1: Two or more innovator companies agree to jointly develop a new drug application (NDA) for a two- or three-drug FDC or co-packaged product. Each of the individual component drug products is currently separately approved, and there are studies owned by one or more of the innovator sponsors showing that the drugs can be safely and effectively used together.
- Application would be a stand alone NDA under section 505(b)(1) of the FD&C Act, because the sponsors of the FDC or co-packaged product would own or have a right of reference to the underlying preclinical and safety and efficacy data for each of the individual component drug products and for the combination use on which the approval of the FDC or co-packaged product would be based.
- Because each of the products already is separately approved and there are studies owned by one or more of the innovator sponsors showing that the products can be safely and effectively used together, no new preclinical or safety and efficacy data would be needed for the application.
- Bioavailability data would be needed for FDCs to show that the combination product would produce blood levels for each of the active ingredients adequate to achieve efficacy.
- The application would contain chemistry data per the guidance, labeling, and other routine information.
- Approval would not be delayed by patents or most exclusivity. Approval of a stand alone NDA could be delayed only by orphan exclusivity.26
- If the sponsor needs data or information from literature to support the safe and effective use of the combination, the application would not be a stand alone NDA (see scenario 2).
Scenario 2: A noninnovator company wants to submit an application for approval of a new two- or three-drug fixed dose combination or co-packaged product with combined labeling showing how the drugs should be used together. Each of the individual drug components is currently separately approved.
- The application would be an NDA described in section 505(b)(2) of the FD&C Act (a 505(b)(2) application) if the noninnovator company does not own or have a right of reference to all preclinical and safety and efficacy data on the individual active ingredients and on the combination product. It cannot be an abbreviated new drug application (ANDA) under section 505(j) because an ANDA would require the previous approval of a reference listed drug ( i.e., an approved product containing the same components for the combination use).
- The application does not need to contain preclinical data or safety and efficacy data for the individual ingredients, but would have to provide safety and efficacy data for the combination, either from studies the noninnovator conducted or from the literature, to support approval of the combination.
- Bioavailability data would be needed to show that the combination product will produce blood levels for each of the active ingredients adequate to achieve efficacy.
- The application would contain chemistry data per the guidance, labeling, and other routine information.
- Approval could be delayed by applicable exclusivity (e.g., pediatric, three-year, orphan), but the application could receive tentative approval (which recognizes that, at the time the tentative approval action is taken, the application meets the technical and scientific requirements for approval, but final approval is blocked by patent or exclusivity). If one or more of the already-approved drugs has new chemical entity exclusivity; however, acceptance for review could be delayed.
- If one or more of the approved drug components is covered by a patent, the FDA could not approve the 505(b)(2) application until the patent expires or, if the patent is challenged by the 505(b)(2) applicant and the applicant is sued, for 30 months or until the patents are declared invalid or not infringed by a court, whichever is first. However, the application could be tentatively approved.
Scenario 3: A noninnovator applicant wants to submit an ANDA under section 505(j) of the FD&C Act for approval of an already approved single-ingredient or two- or three-drug FDC product, such as the drug combinations approved in Combivir (zidovudine and lamivudine) or Trizivir (zidovudine, lamivudine, and abacavir).
- An ANDA would have to demonstrate that the proposed product is the same as the approved single-ingredient or FDC product. If the noninnovator wants to substitute one ingredient for another in a FDC, it can submit a suitability petition requesting authorization to do so.
- An ANDA does not need to contain any preclinical data or clinical safety and efficacy data.
- The applicant must demonstrate that the proposed product is bioequivalent to the reference listed drug (i.e., that the rate and extent of absorption of the active ingredient, or ingredients, are the same as that of the reference drug in accordance with certain statistical criteria).
- The application would contain chemistry data, labeling, and other routine information.
- Approval could be delayed by applicable exclusivity (e.g., pediatric, three-year orphan), but the ANDA could receive tentative approval (which recognizes that, at the time the tentative approval action is taken, the application meets the technical and scientific requirements for approval, but final approval is blocked by patent or exclusivity). If the already-approved drug has new chemical entity exclusivity; however, acceptance for review could be delayed.
- If the approved listed drug is covered by a patent, we could not approve the application until the patent expired or, if the patent is challenged by the ANDA applicant and the applicant is sued, for 30 months or until the patent is declared invalid or not infringed by a court, whichever is first. However, the application could be tentatively approved.
Scenario 4: An innovator company wants to give another company a license to obtain approval to market a single ingredient, FDC, or co-packaged product.
- The application would be a stand alone NDA under 505(b)(1) if the innovator provided a right of reference to all of the preclinical data and safety and efficacy data necessary for approval (see scenario 1).
- The application would be an ANDA under section 505(j) if there is a reference listed drug (i.e., an approved product containing either the single ingredient or the same combination approved for the combination use), and the innovator does not provide a right of reference to the data (see scenario 3).
- The application would be a 505(b)(2) application if the data provided by the innovator are not adequate to support approval of the specific combination and application must be supplemented with literature (see scenario 2).
- Bioavailability or bioequivalence data would be needed, either to show that the single ingredient or fixed combination product will produce blood levels for each of the active ingredients adequate to achieve efficacy (a stand alone NDA or 505(b)(2) application) or that the rate and extent of absorption of the active ingredients are the same as that of the reference drug in accordance with certain statistical criteria (an ANDA).
- Patent rights and most exclusivity will not delay approval of a stand alone NDA under 505(b)(1). Only orphan exclusivity could delay approval of a stand alone NDA.
- As part of the patent certification process for an ANDA or 505(b)(2) application, the applicant would provide evidence that the innovator company has provided a license and has agreed not to exercise its patent rights and that the innovator has agreed to waive exclusivity.
- The application would contain chemistry data, labeling, and other routine information.
Two-drug combinations (to be used in combination with a third drug)<
abacavir + lamivudine
didanosine27 + lamivudine
didanosine27 + emtricitabine
stavudine + lamivudine
tenofovir + emtricitabine
tenofovir + lamivudine
zidovudine + lamivudine (approved FDC, trade name Combivir)
Three-drug regimens
abacavir + lamivudine + lopinavir/ritonavir
abacavir +lamivudine + nevirapine28
abacavir + lamivudine + efavirenz
didanosine27 + emtricitabine + efavirenz
didanosine27 + lamivudine + efavirenz
stavudine + lamivudine + efavirenz
stavudine + lamivudine + lopinavir/ritonavir
stavudine + lamividine + nelfinavir29
stavudine + lamivudine + nevirapine28
tenofovir + emtricitabine + efavirenz
tenofovir + lamivudine + efavirenz
zidovudine + lamivudine + abacavir30 (approved FDC, trade name Trizivir)
zidovudine + lamivudine + efavirenz31
zidovudine + lamivudine + lopinavir/ritonavir
zidovudine + lamivudine + nelfinavir
zidovudine + lamivudine + nevirapine28
Combinations with Viral Antagonism or Overlapping Toxicity32
stavudine + zidovudine
stavudine + zalcitabine
Combinations with Inadequate Efficacy32
abacavir + lamivudine (or emtricitabine) + tenofovir
didanosine + lamivudine (or emtricitabine) + tenofovir
1 This guidance has been prepared by the Division of Anti-Viral Drug Products in the Center for Drug Evaluation and Research (CDER) in cooperation with the Office of Regulatory Policy, CDER.
2 For the purposes of this guidance, a co-packaged product consists of two or more separate drug products in their final dosage form, packaged together with appropriate labeling to support the combination use. A fixed-dose combination product is one in which two or more separate drug ingredients are combined in a single dosage form.
3 See Department of Health and Human Services (HHS) Panel on Clinical Practice for the Treatment of HIV Infection, Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents, http://www.aidsinfo.nih.gov/;Yeni PG, SM Hammer, CC Carpenter, et al., Antiretroviral Treatment for Adult HIV Infection in 2002: Updated Recommendations of the International AIDS Society-USA Panel, JAMA, 2002 Jul 10;288(2):222-35.
4 Although there are two types of HIV virus (HIV-1 and HIV- 2), most of the AIDS pandemic is due to infection with HIV-1. HIV-2 is less prevalent, particularly outside of West Africa; HIV-2 also appears to be less pathogenic and less efficiently transmitted compared to HIV-1. Clinical studies of antiretroviral drugs for the treatment of HIV infected patients have thus far focused primarily on the treatment of the HIV-1 virus. In fact, some of the drugs and drug combinations referred to in this guidance are clearly not effective (i.e., lack activity against HIV-2 in in vitro studies) or have not been shown to be effective in the treatment of HIV/AIDS caused by HIV- 2. This guidance addresses FDC or co-packaged products to treat patients with HIV/AIDS caused by the HIV-1 virus.
5 See http://www.globalhealth.gov/fdc.shtml.
6 FDA procedures have been established to address these designations (e.g., CDER MAPP 6020.3, Priority Review Policy).
8 21 CFR 300.50 describes FDA's policy for the approval of fixed combination prescription drugs for humans. The rule states in pertinent part, "Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug." 21 CFR 300.50(a). This has been interpreted to require a factorial analysis of proposed combination ingredients that demonstrates that the combination is more effective than each component of the combination alone. For HIV drugs, however, it would not be feasible, or ethical, to study the efficacy of an FDC in a clinical study with a factorial design in which the entire combination would be compared to its individual components. This type of study design would require HIV-infected individuals to be exposed to suboptimal regimens that could quickly result in drug resistance not only to the drug or drugs under study, but in many cases to other antiretroviral drugs from within the same class. Suboptimal therapy may jeopardize the success of future therapeutic options for those patients exposed to single or dual antiretroviral treatment. See section V for further information on showing efficacy of these combinations.
9 This list contains one triple-nucleoside analogue regimen.
10 Given the large number of potential combinations, it is not possible to study every possible regimen. For some combinations, extrapolated data from studies of similar combinations are considered to be supportive (although not necessarily sufficient). For example, stavudine + lamivudine is considered to offer similar potency as zidovudine + lamivudine in the setting of triple combinations with a protease inhibitor or NNRTI. Prior to submitting an application, applicants should discuss with the Division of Anti-Viral Drug Products the clinical rationale and evidence to support a particular co-packaged product or FDC.
11 At this time, the list is limited to two- and three-component combinations. Several additional protease inhibitor-based regimens may be suitable for co-packaging or FDCs. However, since some of the protease inhibitor regimens require the addition of low-dose ritonavir, a fourth drug component would be required and may add complexity.
14 Guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products; International Conference on Harmonization, November 2003.
15 Guidance on Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV; International Conference on Harmonization, November 2003.
16 Guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances; International Conference on Harmonization, Deccember 2000.
17 Guidance for industry Q3B(R) Impurities in New Drug Products; International Conference on Harmonization, November 2003.
20 FD&C Act § 501(a)(2)(B) (21 USC § 351(a)(2)(B); 21 CFR Part 210 and Part 211.
21 Guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; International Conference on Harmonization, August 2001.
22 Combating Counterfeit Drugs: A Report of the Food and Drug Administration; February 2004; http://www.fda.gov/oc/initiatives/counterfeit/report02_04.pdf.
23 The application fee, which must be paid at the time an application is submitted, is the most significant of the fees, representing over $500,000.
24 For a complete discussion of the fees-exceed-the-costs waiver provision, see FDA's guidance document entitled Fees-Exceed-the-Costs Waivers Under the Prescription Drug User Fee Act.
25 See section 736(d)(3), 21 U.S.C. 379h(d)(3), of the Act for the rules for small business waivers.
26 For information on the Orphan Drug program, see http://www.fda.gov/cder/handbook/orphan.htm.
27 A once-daily formulation would facilitate dosing.
28 Nevirapine is administered once daily for the first two weeks followed by twice daily. Therefore, for the first two weeks, one could not administer the triple-regimen as a single FDC.
29 Nelfinavir-based regimens are inferior to some other triple-drug regimens, but may have a role in treating pregnant women (Walmsley S, B Bernstein, M King, et al., Lopinavir-Ritonavir Versus Nelfinavir for the Initial Treatment of HIV Infection., N Engl J Med., 2002 Jun 27;346(26):2039-46. HHS Panel on Clinical Practice for the Treatment of HIV Infection, Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents, http://www.aidsinfo.nih.gov/; Yeni PG, SM Hammer, CC Carpenter, et al., Antiretroviral Treatment for Adult HIV Infection in 2002: Updated Recommendations of the International AIDS Society-USA Panel, JAMA, 2002 Jul 10;288(2):222-35).
30 Reported to be less potent than efavirenz-based HAART regimen (Gulick RM, HJ Ribaudo, CM Shikuma, et al., Triple-Nucleoside Regimens Versus Efavirenz-Containing Regimens for the Initial Treatment of HIV-1 Infection, N Engl J Med., 2004 Apr 29;350(18):1850-61).
31 Because of different dosing schudules, this would be more suitable for co-packaging.


text: Satellite Data Research Group wrote: > Dear all > > I am trying to get numpy working with MacOSX 10.4 on an intel > processor. I had it working for Python2.3.5, but after installing > Python 2.4 it didn't work on either python version. > > After inputing: > sudo python setup.py build > and then > sudo python setup.py install > > and also trying to load up a basic array, I get the following errors. > The errors that I get repeatedly during the installation process seem > to mainly be (without showing you the entire massive output, unless you > need to see it): > > > building extension "numpy.core.umath" sources > adding 'build/src.darwin-8.7.1-i386-2.3/numpy/core/config.h' to sources. > adding 'build/src.darwin-8.7.1-i386-2.3/numpy/core/__ufunc_api.h' to sources. > adding 'build/src.darwin-8.7.1-i386-2.3/numpy/core/src' to include_dirs. > numpy.core - nothing done with h_files= > ['build/src.darwin-8.7.1-i386-2.3/numpy/core/config.h', > 'build/src.darwin-8.7.1-i386-2.3/numpy/core/__multiarray_api.h', > 'build/src.darwin-8.7.1-i386-2.3/numpy/core/__ufunc_api.h'] > > building extension "numpy.core._dotblas" sources > adding 'numpy/core/blasdot/_dotblas.c' to sources. > building extension "numpy.lib._compiled_base" sources > building extension "numpy.dft.fftpack_lite" sources > building extension "numpy.linalg.lapack_lite" sources > adding 'numpy/linalg/lapack_litemodule.c' to sources. > building extension "numpy.random.mtrand" sources > customize NAGFCompiler > customize AbsoftFCompiler > customize IbmFCompiler > Could not locate executable g77 > Could not locate executable f77 > Could not locate executable gfortran > Could not locate executable f95 > > customize GnuFCompiler > customize Gnu95FCompiler > customize G95FCompiler > customize GnuFCompiler > customize Gnu95FCompiler > customize NAGFCompiler > customize NAGFCompiler using config > gcc options: '-fno-strict-aliasing -Wno-long-double -no-cpp-precomp > -mno-fused-madd -fno-common -dynamic -DNDEBUG -g -O3 -Wall > -Wstrict-prototypes' > compile options: '-Inumpy/core/src -Inumpy/core/include > -I/System/Library/Frameworks/Python.framework/Versions/2.3/include/python2.3 > -c' > gcc: _configtest.c > > _configtest.c:7:2: error: #error No _WIN32 > _configtest.c:7:2: error: #error No _WIN32 > > The above lines of output are repeated a few times. If it makes any > difference, which I am sure that it does, I am running on an intel chip. > > This is not a problem. These are "configuration" "error" that the system uses to incorporate platform-specific code. > In Python, when typing > >>>> from numpy import * >>>> > I get: > Running from numpy source directory. > > This is the problem. The error is telling you that you can't import numpy from the directory where numpy was built (the import mechanism gets confused between the system-installed numpy and the directory structure underneath). Just exit Python and cd to another directory. Then numpy should work fine. -Travis

subset: commoncrawl


text:
Has the rivalry between the Pittsburgh Penguins and Washington Capitals cooled? Debatable.
And if it had, according to Arron Asham, the is heat is back.
Asham on Friday called out Capitals star Alex Ovechkin for Ovechkin's reaction to a fight between Asham and Jay Beagle on Thursday.
The night before, Asham apologized for what he called "classless" gestures after knocking out Beagle, a significantly less experienced fighter, with two punches.
Ovechkin echoed those sentiments, saying they were "not respectful."
Asham didn't appreciate that, calling back to Ovechkin's infamous "hot stick" celebration in 2009.
"I don't know what Ovi's talking about, disrespectful," Asham said on Friday, according to the Pittsburgh Tribune-Review. "A guy who throws his stick down and warms his hands over it. He is being a hypocrite himself. The rivalry is back. I'm sure the next game is going to have a lot of fireworks."
— MORE ON THE FIGHT: Laich: Players can't be "babysat"
On Thursday night, Asham bloodied Beagle, who was on the ice for several minutes and appeared to pull out a tooth on his way out, and gestured that he was "asleep" on the way to the penalty box. Immediately after, Asham tapped his stick in the penalty box as a sign respect for Beagle.
"My gestures after it was done, I was into the game, it was uncalled for. Classless on my part," Asham told reporters after the game. "You know, I think those guys over there know that I'm not the kind of guy to be going off. It was a big game, I wanted to get my bench going—classless move on my part."
Ovechkin, who was shown on the TV broadcast screaming at Asham after the fight, didn't disagree.
"It's a fight. It's hockey game, but again it was pretty tough but Beagle, like, he's just first-year NHL," the former NHL MVP said. "Asham, I don't know if he knows that or not, but just put him on the ice. He's not a fighter, it's not his job to fight. I don't know, it looked kind of not respectful for players on different team. I don't know what people think but I think it's not respectful."
The fight came after Beagle hit Penguins defenseman Kris Letang in the face moments before. At the time, it was assumed that Asham challenged Beagle. Not so, he said on Friday.
"The thing is, I didn't go up and ask (Beagle) to fight. I told him to settle down. He challenged me. He wanted to fight me," said Asham, who reiterated that he felt the gestures were classless and wanted to put the incident behind him and apologized to Beagle through Capitals winger Mike Knuble.
"I talked to Mike Knuble last night and made sure the kid was all right and told him I apologized for the stupid antics I did afterward," Asham said. "He knows the kind of guy I am."
Knuble defended Asham, calling him an "honest" player.
"Arron was just doing his job," Knuble said. "I've played with Arron, he's an honest player, he's tremendous at what he does and he's doing what he had to do. Jay did what he felt what he had to do. It's a little bit more experience against someone who doesn't have a lot and that's the result."
Capitals coach Bruce Boudreau also implied Beagle, who missed practice on Friday but according to Boudreau showed no signs of a concussion, made a mistake in challenging Asham.
After Thursday's 3-2 win, Washington is 12-1-2 in its last 15 regular-season meetings with Pittsburgh, including eight straight wins on the road, though Pittsburgh has knocked Washington out of the Stanley Cup playoffs seven times in eight chances, including during its run to the Stanley Cup in 2009.
As for the "fireworks" Asham predicted: the teams next play on Dec. 1 in Washington.


text:
Catalyst 9.10 Now Avalable Page: 1
ATI Release new Catalyst 9.10 Drivers
Well it's happened again, another month, another driver update from AMD/ATI.
As many of you may know, regularly updating your graphics drivers can improve the performance and stability of your card, while also fixing problems in games and videos. ATI have just released their latest Catalyst 9.10 drivers to the general public, the new drivers include bugfixes and improved features for all Windows versions, including:
• The flickering issue while playing back Blu-Ray DVD H.264/VC-1 content is no longer present
• The DTV (HDMI) Pixel Format settings will now be restored when a HDMI display is hotplugged back after a DVI display is hotplugged
• The "Force maximum performance clocks" option in Catalyst Control Center is now available for the second GPU when two R700 cards are connected.
• GPU acceleration for the Windows 7 Drag and Drop video converting application on Radeon 4000 and 5000 Series Cards.
• Super Sample Anti-Aliasing for the ATI Radeon HD 5800 Series
This last new feature should be great news for those of you lucky enough to own one of the new 5800 series cards. According to ATI, "Users can now experience the high level of anti-aliasing image quality using Super Sampling anti-aliasing while maintaining good performance levels." Sounds good to me, this should just be a taste of things to come!
What are you waiting for? If you're on the red team,
get them here
! You can discuss this further in our


text: Ready to turn some heads at your next event? This luscious frock will surely do the trick. Pair with towering heels for a complete look. This bandage dress features crisscross front, two tone, sleeveless style, t-strap back and finished off with a curve hugging fit. 90% Polyester 10% Spandex Style: clothing-bandage-r6-b2495yellowblack Brand: WOW Couture


text:
Xzbit - the man who is as comfortable in the booth as he is in front of camera, is to tour the UK this coming October, it has been announced.
A platinum recording artist first and foremost, X first came to the attention of hip-hop listeners as part of rap collective The Likwit Crew, before releasing his 1996 debut At The Speed Of Life that housed West Coast classic "Paparazzi".
Mainstream success came courtesy of an appearance on Snoop Dogg's "B Please" - I'd imagine I don't have to tell you what the 'B' stands for - and a spot on Dr. Dre's 'Up In Smoke' tour beckoned.
A household name, X has never forgotten his roots. "I still love it as much as I did when I first burst through the door," confirms X, "And I'm going to keep spitting like I'm that unsigned kid desperate to showcase himself."
Xzibit kicks off his UK tour on October 19th in Glasgow, with dates in Bristol, Birmingham, Manchester and London following. More information can be found by following this link.


text: Rugged cotton crewneck sweater in multistripe Item F7901 Color: HTHR IVORY Size: SMALL MEDIUM LARGE X-LARGE Size Charts Quantity: 1 2 3 4 5 6 7 8 9 Add to Bag Wishlist Add to Bag Add To Wishlist share: Find In Store Please select a size above. size & fit Product Details You don't have to own a sailboat to look good in stripes. Case in point: this cotton sweater, which will keep you warm without overheating. It's perfect for transitional weather, chilly offices and, yes, even trips on a boat. Cotton. Machine wash. Import. Select stores. Item F7901.


text:
Canadian company Viking Air and Moscow-based Vityaz Avia Corp. have signed a memorandum of understanding for the potential development of a final assembly facility in eastern Russia for the new Twin Otter 400.
Viking would establish quality, maintenance and training procedures and the facility would also potentially become a factory endorsed service center (FESC) and Series 400 training complex, once the type has been introduced in the territory. Viking Air launched the DHC-6 Twin Otter Series 400 production program in 2007.
Here at the Farnborough show yesterday, Viking received the Canadian type certificate for the new Twin Otter. The first example is being delivered to Zimex Aviation.
Viking Air has also entered into a multi-year agreement with Avtrak of Colorado, for the use of the Avtrak Globalnet platform to assist operators with their maintenance management needs. The program, known as Viking MX, will be managed by Aircraft Technical Liaison and Support (ATLAS), Viking's customer support division.
The International Civil Aviation Organization, acting on behalf of the government of Argentina and the Argentine Aeronautic Administration (AAA), has awarded Viking Air the maintenance contract for overhaul of the second of eight DHC-6 Twin Otter Series 200 operated by the AAA. The work will be carried out at the Argentine air force base at Quilmes (Buenos Aires) and will encompass a heavy maintenance visit, including completion of C-check, installation of uprated engines and a new avionics suite, and incorporation of applicable Airworthiness Directives and Service Bulletins. Viking's representatives will supervise, instruct and train Argentine air force personnel to carry out the work.


text: This phone is excellent for the money i paid. 150 bucks from walmart, straight talk variant. Monthly bill is nice and cheap at 45 bucks. I noticed the textured back as soon as i took it out of the box. Definately makes the phone more grippy. I turned it on and was greeted by a nice bright, clear display with no fuzziness whatsoever. Screen is perfectly responsive. All menus scroll buttery smooth. So far so good. Plugged the phone into my laptop to root. At this point i was nervous. Ive been through some real nightmares recently with rooting. My beloved Optimus Net took me six hours to root. I tried for a full day to root a Hero without success. But i was delighted to get the Proclaim rooted in about twenty minutes without hassle using the odin method. There is a bug in my phone now that makes it act as a cd drive when plugged into a pc via usb, but this is a very minor nuisance. The sd slot is on the side of the phone and easy to access so popping it in and out of a reader is no problem After activating the phone with a straight talk card, i tested the data speed. I found that youtube videos loaded around three times as fast on this phone and more reliably than they did on the Optimus Net (net ten on Sprint towers). Data speed on the stock browser was very fast, search results from google popped up in about two to two and a half seconds. Phone holds 3G at all times that data is enabled and having had it active for a week it has yet to drop 3G and aquire 1x, something my Optimus did regularly. Email messages came through reliabley. I popped the sd card from my Optimus into the Proclaim and tested videos that the Optimus had played at glitched, unsynced, terrible quality and was delighted when mx player handled them flawlessly. I underclocked the processor by 20 percent to 800 mhz and still got perfect quality. Sound quality from videos and mp3 files was also quite good. Phone still operated smoothly and with no lag. Underclocked to 400mhz with same results. Videos glitched at this speed but just barely. The gps locks on quickly and reliabley even inside a vehicle. Maps load quickly and voice commands are reliable and accurate. On to software. The phone came with a bunch of manufacturer crap on it. Two music players (not sure why they put two in this thing but w/e), google books (useless) some crap called share all, facebook (useless since i dont network socially), some other nonsense. Removed all the garbage with gemini and nobloat so now there is oodles of storage for apps. A couple minor things Im not pleasd about: The tip on how to organize the menu pops up whenever I optimize ram and then press menu and it is slightly annoying. Also the phone came with a 2gb sd card. Samsung couldve given us a four. Oh well. I suppose they couldve included a free pony too but profit margin is profit margin. Overall I give the Straight Talk Samsung Galaxy Proclaim four and a half out of five stars. I had thought the Lg Optimus Net would have to be pried from my lifeless fingers but now that I have the Proclaim I dont even miss it. I hope you enjoyed my poorly written and badly organized review. Wrote the whole thing on the Proclaim using the Phandroid app. Like a boss.


text:
Presence as a statement
In keeping with its calm yet imposing presence, the Audi RS 6 conveys its superb performance with subtlety. Together with 18?inch or 19-inch alloy wheels, modifications to the nose and tail ends and the sills of the Audi RS 6 lend it a dynamic but restrained note.
Three large air intake apertures - the centre one for cooling the water and oil and the two outer ones for intercooling - determine the appearance of the RS 6 front end. The decorative grilles for the air intake apertures have a honeycomb design. Xenon Plus headlights behind clear-glass covers and fog lights in the right and left air intake shafts complete the "face" of the Audi RS 6.
Two vertical flaps on these air intake apertures improve the air routing to the intercoolers. The aerodynamically shaped spoiler lip also contributes to this effect, providing additional negative lift at the front axle.
The rear apron echoes the design principle of the front end with its three smaller but visually identical grille inserts. The two oval exhaust tailpipes add a further visual note.
Aerodynamically shaped sills in the body colour and a discreet separation edge on the saloon's luggage compartment lid accentuate the sporty styling of the Audi RS 6.
The names of the five exclusive paint finishes for the Audi RS 6 reflect its proximity to the world of motor sport. Customers can choose from the pearl effect colours Mugello Blue, Daytona Grey, Avus Silver, Misano Red and Goodwood Green - all named after racing circuits. The Audi RS 6 is also available in Ebony Black.
The roof surround strips, window capping strips, door mirrors, radiator grille frame and also the roof rails on the Avant are in matt aluminium. Like the RS 6 logo with laser red rhombus on the rear lid, radiator grille and sill strips, they are among the more restrained external distinguishing features of this car.
Sports appeal and individuality also characterise the exclusive interior equipment of the Audi RS 6. The distinctive ambience created by choice materials and carefully selected components has a particularly harmonious feel to it.
The Recaro sports seats with special upholstery and embossed RS 6 logo provide stability, optimum lateral support and ample comfort however long the journey may be. The steering wheel rim and selector lever knob are trimmed with perforated leather which affords a particularly good grip.
The gearbox gate has a matt brushed aluminium surround, the inside door handles are coated with matt black anodised material.
The RS 6 customer has a basic choice of two interior colours: Black or Silver. The Black specification includes a choice of three different types of seat upholstery: silk nappa leather with silver piping on the seat contours, a leather/cloth combination or, as an option, natural leather.
In the case of the leather/cloth combination, the side sections and head restraints are upholstered in black pearl nappa leather, whereas the seat centre section is of cloth incorporating an aluminium thread. The headlining stretching over the generous interior is in black Alcantara.
The other colour alternative includes seats with silver-coloured silk nappa leather upholstery and black piping on the contours, a headlining in silver-grey Alcantara and silver-coloured seat belts.
The door panel inserts are in leather to match the colour of the seat upholstery. The trim strips in the doors and on the instrument panel and centre console are available in a choice of black piano finish, agate-coloured poplar wood or carbon fibre, at no extra charge.


text:
Macklemore & Ryan Lewis: Exclusive GRAMMY.com Interview
Rising hip-hop duo Macklemore & Ryan Lewis recently visited the GRAMMY Museum in Los Angeles to participate in an exclusive GRAMMY.com interview. The pair discussed the impact and the tolerance message of their hit "Same Love," their views on the music industry and their latest album, The Heist, among other topics.
"'Same Love' has had many different moments," said Macklemore. "It's timed very well with what's happening in the nation and what's happening on the forefront of civil rights in America. It's not telling anybody to think one way or another way — it's hoping that people engage in discussion around this issue."
Seattle-based rapper Macklemore and DJ/producer Lewis have been making music fans take notice since they released their 2009 debut EP, The VS. EP. They followed with VS. Redux, which reached No. 7 on the iTunes Hip-Hop chart. The duo made waves in 2011 with the release of their hit single "Can't Hold Us" featuring Ray Dalton. The next year Macklemore was featured on the cover of XXL Magazine's coveted Freshman Class issue, and Rolling Stone dubbed the duo an "indie rags-to-riches" success story.
Released in 2012, Macklemore & Ryan Lewis' debut studio album, The Heist, reached No. 2 on the Billboard 200, propelled by the No. 1 hits "Can't Hold Us" and "Thrift Shop," the latter of which reached multi-platinum status and remained on top of the charts for six weeks. The duo's Top 20 hit "Same Love" featuring Mary Lambert has been adopted by some as a pro-equality anthem. The video for the track recently picked up Best Video with a Message honors at the 2013 MTV Video Music Awards.
Macklemore & Ryan Lewis will kick off a North American tour beginning Oct. 22 in Portland, Ore., with dates scheduled through December.


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There are some who might call Young Adult, the latest feature from Juno collaborators Jason Reitman and Diablo Cody, a daring film. It's centered on a sadistic train wreck of a protagonist who seeks to destroy the lives of others in order to justify her own life decisions, whose only character arc involves feeling better about her decision to do so. If this were an early Neil LaBute film, perhaps I would agree, since that particular brand of sociopathic storytelling came from a clinical storyteller, who sought not to judge his characters' behavior but instead merely depict it, and allow the audience to come to their own conclusions. But Young Adult wallows in its protagonist's pain so much, and comes to such trite conclusions about her nature, that I couldn't shake the feeling that the film is merely indulgent. It defies convention only as a last minute switcheroo, and feels remarkably inconsequential as a result. It's neither objective enough to play as elaborate ruse, nor empathetic enough to stand on its own as a dark character study. I cannot recommend it with a good conscience.
Charlize Theron plays Mavis Gary, a former prom queen turned minor hometown celebrity, who left for the big city – Minneapolis – and became a ghost writer for a popular series of "young adult" books along the lines of Sweet Valley High. But despite her "success," she's a miserable alcoholic with no personal ties to speak of. Her already bleak world is further sullied when her high school beau, Buddy, played by Patrick Wilson, e-mail bombs an announcement that he is a new father. Under the guise of pitying his suburban shackles, Mavis treks back home to intentionally wreck Buddy's marriage and tear him away from his newborn so he can join her in an urban, "superior" lifestyle.
Reitman tells the story of Young Adult in a particularly bleak visual style, full of weakened colors and specifically subdued camera angles, which give the film the appearance of dramatic heft. It's a clever disguise. Charlize Theron gives an excellent performance but the rest of the film can't seem to find the right angle through which to view her experiences. Sometimes Mavis is a sad, tortured soul, and we want to sympathize with her plight. But these moments contrast badly with her coping mechanism, selfishly trying to destroy Buddy's marriage, and her clearly deluded justifications for her own behavior. The snippets of her latest teen novel we hear in voice-over are clearly the voice of degenerative madness, as her ego struggles to defend her own perceived greatness over the perceived failures of those she left behind, who settled for simple, family-oriented pleasures.
On paper, that's a compelling psychological struggle, but it's all undone by a last-minute revelation: that her insecurity and depression stems from a single defining moment that's as simplistic as it is arguably sexist. Much like another recent cinematic attempt to justify non-conventional female behavior, namely Natalie Portman's polyamory in No Strings Attached, it all boils down to a woman who is lesser for not having a traditional female role in society, which doesn't seem like much of a message. I've heard it argued that the previous Reitman/Cody effort, Juno, adds up to a similarly staunch, conservative value judgment, but at the very least Juno buried it under an avalanche of twee likability. Young Adult's pensive affectations boost its troublesome themes right to the surface. The result is unpleasant.
In the end Young Adult tries to deny this ugly message by telling Mavis that she was perfectly okay the way she was; which might be acceptable, if at the very least her cruelty had abated even slightly by the end of the film. But her last mean-spirited, condescending exchange with a rather sad character indicates otherwise. The message the filmmakers tried to subvert ends up reaffirmed: she's a broken human being for a very conventional reason, and only conning herself into thinking otherwise. Adding insult to injury, the last minute refusal to give Mavis a hint of personal growth negates the very existence of Patton Oswalt's character, who was splendidly acted (if a little too perfect for Mavis's needs), but ultimately turns out to be one sad Jiminy Cricket (who really wants to f**k Pinocchio) whose reasoned, conscientious objections to the hero's self-destructive tendencies are completely written off by the film's end.
I suspect Young Adult was made with the best intentions, but it doesn't seem to have been made very well. The message comes across as disturbingly conformist, if indeed it even has one. If I'm reading too much into a mere character study, then I am forced to throw up my hands and say that the character isn't likable enough to spend an hour and a half my time with. That it is splendidly acted and occasionally rather funny is damning with moderate praise, since both complimentary aspects are in service of a narrative which amounts to an unremarkable, albeit atypically melodramatic episode of Seinfeld that lacks the wisdom to run only 22 minutes long.


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Quadring is a small village and civil parish in the South Holland district of Lincolnshire, England. It lies on the A152, north-east from Gosberton, and 2 miles south-east from Donington.
The village includes the community of Barholme to its south-west. To the east of Quadring is Quadring Eaudike, and to the west is Quadring Fen. Nearby to the west is the Peterborough to Lincoln Line. The A152 (as Main Road within the village) transects Quadring and provides links to Spalding, Boston, Donington and Gosberton.
The village name is derived from the Old English "cwead+haefer+ingas" (Muddy settlement of Haefer), and is recorded in the Domesday Book as Quadheveringe and Quedhaveringe.
The Grade I listed village church, dedicated to St Margaret of Antioch, lies north of, and separate from, the village. Mainly an example of Perpendicular architecture, it was rebuilt in 1872.
Other listed buildings include a Grade II cottage, house, granary, coaching house, farm, and farm house.
Research Tips
Lincolnshire is very low-lying and land had to be drained for agriculture to be successful. The larger drainage channels, many of which are parallel to each other, became boundaries between parishes. Many parishes are long and thin for this reason.
There is much fenland in Lincolnshire, particularly in the Boston and Horncastle areas. Fenlands tended to be extraparochial before the mid 1850s, and although many sections were identified with names and given the title "civil parish", little information has been found about them. Many appear to be abolished in 1906, but the parish which adopts them is not given in A Vision of Britain through Time. Note the WR category Lincolnshire Fenland Settlements which is an attempt to organize them into one list.
From 1889 until 1974 Lincolnshire was divided into three administrative counties: Parts of Holland, Parts of Kesteven and Parts of Lindsey. These formal names do not fit with modern grammatical usage, but that is what they were, nonetheless. In 1974 the northern section of Lindsey, along with the East Riding of Yorkshire, became the short-lived county of Humberside. In 1996 Humberside was abolished and the area previously in Lincolnshire was made into the two "unitary authorities" of North Lincolnshire and North East Lincolnshire. The remainder of Lincolnshire was divided into "non-metropolitan districts" or "district municipalities" in 1974. Towns, villages and parishes are all listed under Lincolnshire, but the present-day districts are also given so that places in this large county can more easily be located and linked to their wider neighbourhoods. See the WR placepage Lincolnshire, England and the smaller divisions for further explanation.


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Simulating an Edge Shape in Android
Tinniam V Ganesh 270004Y158 Visits (2994)
Here is a small post on how I managed to simulate an Edge Shape in Android. I wanted to do this after I saw the Java demo of Box2D in JBox
Since it is a cosine curve I place a ball shape for every point on a cosine function, close to each other to seem continuous and create a body from the Sprite with physical properties.
for (int i = 0; i < nBodies; ++i)
float angle = (float) ((10.0 * PI * i)/180.0);
float y1 = 300 + (flo
circles[i] = new Sprite(x1, y1,
circlesBody[i] = Phys
x1 = (float) (x1 + 0.5);
So this can be done for every mathematical curve. I also intended to create other curves like the Archimedes Spiral and the Lemniscate. Maybe I will leave that for a rainy day!! :-)
However, I am not sure how to create a irregular edge shape. I will probably figure that out.
The egde shape is made to be a STATIC_BODY. I then took code of creating Animated Sprites at the point where I touch from AndEngine examples (Phy
face =
body = Phys
The effect is better if the phone is horizontal to the ground and not so great if the phone is kept vertical and the bodies do not seem to shoot off.
The simulation can be seen at Simulating an Edge Shape
You can clone the entire project from Github at EdgeShape.
Disclaimer: "


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The Pakistan government does not believe Taliban or al-Qaida officials have moved from the tribal border region to Pakistan's southwestern-most province and would oppose expanding U.S. drone strikes there, a government official said Wednesday.
The Pakistani reaction followed a New York Times report Tuesday that the Obama administration is considering proposals to expand air strikes into the province of Baluchistan to target al-Qaida and Taliban officials.
U.S. intelligence officials believe some militant leaders have fled there to avoid the U.S. drone attacks in the lawless tribal region to the north. The proposals are part of an ongoing larger review of U.S strategy in Pakistan and Afghanistan to counter terrorist organizations and help stabilize both countries, according to the Times.
"As far as we're concerned we do not think Taliban leadership or al-Qaida are present in Baluchistan or Quetta as some suggest," said a Pakistan embassy official, who asked for anonymity to discuss the sensitive intelligence issue.
"If there is any evidence of Taliban or al-Qaida, we are available for intelligence sharing and we will take immediate action," the official said."
Pakistan has repeatedly objected to Predator drone strikes in the Federal Administered Tribal Areas along Pakistan's northwest frontier with Afghanistan, believed by U.S. intelligence to be home to al-Qaida leaders. The Hellfire missile strikes sometimes kill innocent bystanders and Pakistani officials say they inflame anti-American sentiment.
Pakistani Foreign Minister Shah Mahmood Qureshi declined to comment specifically on the possibility of expanding the covert war into Baluchistan, but reiterated Wednesday that the U.S. had agreed to review the overall policy of drone strikes.
"We have made them agree to think over it," he said. "In the next interaction, there is a chance to put this issue up for further discussion."
Asked about reports that Pakistan has allowed the U.S. to use bases on its soil to land and launch the unmanned drones behind the missile strikes, Qureshi said the country "has not given uses of its bases for kinetic strikes."
He declined to elaborate further, although the statement left open the possibility that Pakistan hosts drones that simply conduct surveillance. Sen. Dianne Feinstein, D-Calif., who chairs the Senate Intelligence Committee, said at a hearing last month that Pakistan allowed the aircraft to operate from Pakistani air bases.
The White House's Afghan war strategy review is expected to place an onus on Pakistan to contain extremism, according to defense and administration officials who said it could be completed as early as this week.
The in-house review coordinated by the White House National Security Council lays out objectives over three to five years, although that doesn't necessarily mean the U.S. military could leave in that time, defense officials said.
The White House objectives were expected to roughly parallel 15 goals contained in a 20-page classified report to the White House from the Joint Chiefs of Staff. Among them were getting rid of terrorist safe havens in Pakistan and adopting a regional approach to reducing the threat of terrorism and extremism in both countries.
The U.S. goal in Afghanistan must be to protect Kabul's fragile government from collapsing under pressure from the Taliban, which can only be achieved by securing Pakistan's cooperation, increasing substantially the size of Afghanistan's national security forces and boosting economic aid in the region, according to senior military and intelligence officials.
Associated Press Writer Munir Ahmad in Islamabad contributed to this report.


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Options and Accessories (View All)
Marketing Information
The CyberPower RMCARD203 is a full-featured network UPS management device that remotely manages, monitors, and controls CyberPower UPS products. The internal card allows remote monitoring and control of a UPS via Web Browser or NMS connection. By utilizing the auto-shutdown software, servers and workstations stay protected from data loss due to power failure. An optional Environmental Sensor (model #: ENVIROSENSOR) can be added to monitor a server room / datacenter's temperature and humidity. Event logging tracks the UPS operational history. Automated event notifications via email or SNMP Trap can be setup to insure real time status of changes to the UPS and its input voltages. Firmware can be updated by users to insure you have the latest features and updates. MD5 security management is also provided to protect the integrity of the UPS and network. A Three-Year Warranty ensures the RMCARD203 has passed our highest quality standards in design, assembly, material and workmanship.
General Information
|Product Type
|Remote Power Management Adapter
|Manufacturer Part Number
|Manufacturer Website Address
|CyberPower Systems, Inc
|Product Model
|Product Name
|RMCARD203 Remote Management Card - SNMP/HTTP/NMS and ENVIROSENSOR Port
|Brand Name
Technical Information
|1 x RJ-45 Female 10/100Base-TX
|1 x RJ-45 Serial
|Package Contents
|Standard Warranty
|3 Year Limited
This product is shipped only within Canada and Warranty valid for Canada only.
Computer Valley makes every effort to provide accurate specifications, descriptions, images and price on all products that are found on www.computervalley.ca
However for complete and updated descriptions, compatibilities, specifications and actual photo we recommend our clients to consult with manufacturer's websites or simply call us for proper clarifications. Computer Valley is not responsible and will not accept returns for items purchased that are not compatible with your system. Please ensure that you have verified compatibility and actual photo with your system by visiting the manufacturer's web site prior to purchase or give us a call to make sure what you are purchasing.
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Welcome to Randy3011
Posted 11-02-2009 at 05:28 PM by Randy3011
I've been interested in Linux since 2004 with Suse 9.0 (actually paid for it at Best Buy). Tried Mandrake LE2005, various Mandriva's, openSUSE up to 11.1, but have been with Ubuntu seriously since Dapper. Have tried KDE's in various distros but I have been using Gnome since Heron.
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Permanent Count Program
A permanent counter is an automated device in place 24 hours per day, 365 days per year. Its purpose is to gather a continuous record of how bicycling and walking changes over time. Permanent counters provide a record that allows us to understand how volumes change with weather and season.
If cyclist and pedestrian travel patterns were the same everywhere, we could get by with just one permanent counter for the whole country! But in reality, many factors affect our travel patterns, from climate to culture. For this reason, a permanent count program of multiple bicycle and pedestrian counters is needed to help us understand the time-related patterns of bicycling and walking in a region, county, city or state.
If your region has no permanent counters, consider installing one as soon as possible. Without this, one cannot compute seasonal adjustment factors, and without those one cannot estimate Annual Average Daily Bicycle and Pedestrian Traffic (AADBP) from shorter duration counts.
Creating a permanent count program is an iterative process. At least once a year review the data, look for patterns, group the sites, compute factors and evaluate if and where additional counters are needed. This series of web pages will discuss the steps in setting up a bicycle and pedestrian count program, following the general outline in the Traffic Monitoring Guide, Chapter 4. If you have no permanent counters, start with the Select Sites & Install page. If you have counters, start with Look for Patterns.
This is an area of ongoing research and the field is still working on answering some of the questions. We'll update this website as new information and resources become available, so check back for the latest.
The process for collecting continuous non-motorized traffic data should follow the steps already outlined for motorized traffic in Chapter 3, as follows:
14. Review the existing continuous count program;
The following sections provide additional detail for implementing these steps.
In this edition of the Traffic Monitoring Guide, pedestrians and bicyclists are grouped together as non-motorized traffic. There will be differences in these two types of facility users that may affect the monitoring approach. However, the known distinctions and differences between pedestrian and bicyclist traffic will be pointed out in each combined section. As ongoing research identifies the best approach for each, future editions of the Guide may provide additional information for separate monitoring of pedestrian traffic and bicyclist traffic.


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UNDER INVESTIGATION: Fire inspectors examine the scene.
HISTORY DESTROYED: The Billens building.
SPARKS FLY: A massive fire in central Christchurch on Friday night.
Firefighters work to contain the blaze on the corner of High St and Tuam St, near the McKenzie & Willis site.
WATCHFUL: A firefighter near the scene of a large fire in central Christchurch.
ABLAZE: A massive fire broke out in a three-storey building next to Christchurch's McKenzie & Willis building at the corner of Tuam and High St about 9.20pm.
HELPING HANDS: Emergency services at the scene of a large fire in central Christchurch.


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A Girl's Childhoodby Stephen Lassonde Deborah Weinstein Dr Linda C. Mayes
Sixty years ago, a group of prominent psychoanalysts, developmentalists, pediatricians, and educators at the Yale Child Study Center joined together with the purpose of formulating a general psychoanalytic theory of children's early development. The group's members composed detailed narratives about their work with the study's children, interviewed families regularly and visited them in their homes, and over the course of a decade met monthly for discussion. The contributors to this volume consider the significance of the Child Study Center's landmark study from various perspectives, focusing particularly on one child's unfolding sense of herself, her gender, and her relationships.
The Pathological Familyby Deborah Weinstein
While iconic popular images celebrated family life during the 1950s and 1960s, American families were simultaneously regarded as potentially menacing sources of social disruption. The history of family therapy makes the complicated power of the family at midcentury vividly apparent. Clinicians developed a new approach to psychotherapy that claimed to locate the cause and treatment of mental illness in observable patterns of family interaction and communication rather than in individual psyches. Drawing on cybernetics, systems theory, and the social and behavioral sciences, they ambitiously aimed to cure schizophrenia and stop juvenile delinquency. With particular sensitivity to the importance of scientific observation and visual technologies such as one-way mirrors and training films in shaping the young field, The Pathological Family examines how family therapy developed against the intellectual and cultural landscape of postwar America. As Deborah Weinstein shows, the midcentury expansion of America's therapeutic culture and the postwar fixation on family life profoundly affected one another. Family therapists and other postwar commentators alike framed the promotion of democracy in the language of personality formation and psychological health forged in the crucible of the family. As therapists in this era shifted their clinical gaze to whole families, they nevertheless grappled in particular with the role played by mothers in the onset of their children's aberrant behavior. Although attitudes toward family therapy have shifted during intervening generations, the relations between family and therapeutic culture remain salient today.
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Aged Brackenridge Man dies At Walnut Street Home
Stephen Kurn, aged 74 years, died Sunday at 12:10 pm, at his home on Walnut street. Brackenridge. He was one of the oldest and best known residents of the borough. (PA Death Certificate states age as 72 years, 8 or 9 months, 12 days.)
Surviving are his widow and the following children: William, Brackenridge; Harvey, Tarentum; Harry, Brackenridge; Mrs. Margaret E???? (Ewalt)?, Pittsburgh; Mrs. Oliver Smith?, Brackenridge; Mrs. Bertha Schemmler?, Jackson, Tenn.; one sister, Miss? Mary Kurn of Pittsburgh; and ?? grandchildren.
Funeral services will be conducted Tuesday at 2:30 pm from Brackenridge M.E. church by D.L. Myers. Interment will follow at Prospect Cemetery.
NOTE that there is no mention of his daughter Bessie Virginia Kurn (Schutzler). But there is a daughter in Jackson Tennessee, where my mother Virginia Wilhelmena Schutzler (Smith) lived with her family when she was a girl. Perhaps they were visiting an aunt?
SOURCE: Obituary for Stephen Kurn, published in the Valley Daily
Monday Evening, 11 March 1918.
Obtained from Community Library of Allegheny Valley,
315 East 6th Avenue, Tarentum PA 15084
Submitted by Edward L. Smith, email: firstname.lastname@example.com 15-March-1999.
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