Pharmaceutical Forced Degradation (Stress Testing) Endpoints: A Scientific Rationale and Industry Perspective.

Forced degradation (i.e., stress testing) of small molecule drug substances and products is a critical part of the drug development process, providing insight into the intrinsic stability of a drug that is foundational to the development and validation of stability-indicating analytical methods. There is a lack of clarity in the scientific literature and regulatory guidance as to what constitutes an "appropriate" endpoint to a set of stress experiments. That is, there is no clear agreement regarding how to determine if a sample has been sufficiently stressed. Notably, it is unclear what represents a suitable justification for declaring a drug substance (DS) or drug product (DP) "stable" to a specific forced degradation condition. To address these concerns and to ensure all pharmaceutically-relevant, potential degradation pathways have been suitably evaluated, we introduce a two-endpoint classification designation supported by experimental data. These two endpoints are 1) a % total degradation target outcome (e.g., for "reactive" drugs) or, 2) a specified amount of stress, even in the absence of any degradation (e.g., for "stable" drugs). These recommended endpoints are based on a review of the scientific literature, regulatory guidance, and a forced degradation data set from ten global pharmaceutical companies. The experimental data set, derived from the Campbell et al. (2022) benchmarking study,1 provides justification for the recommendations. Herein we provide a single source reference for small molecule DS and DP forced degradation stress conditions and endpoint best practices to support regulatory submissions (e.g., marketing applications). Application of these forced degradation conditions and endpoints, as part of a well-designed, comprehensive and a sufficiently rigorous study plan that includes both the DS and DP, provides comprehensive coverage of pharmaceutically-relevant degradation and avoids unreasonably extreme stress conditions and drastic endpoint recommendations sometimes found in the literature.

Assessing the Relevance of Solution Phase Stress Testing of Solid Dosage Form Drug Products: A Cross-Industry Benchmarking Study.

Stress testing (also known as forced degradation) of pharmaceutical products has long been recognized as a critical part of the drug development process, providing foundational information related to intrinsic stability characteristics and to the development of stability-indicating analytical methods. A benchmarking study was undertaken by nine pharmaceutical companies and the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, or ANVISA) with a goal of understanding the utility of various stress testing conditions for producing pharmaceutically-relevant chemical degradation of drugs. Special consideration was given to determining whether solution phase stress testing of solid drug products produced degradation products that were both unique when compared to other stress conditions and relevant to the formal drug product stability data. The results from studies of 62 solid dosage form drug products were compiled.  A total of 387 degradation products were reported as being observed in stress testing studies, along with 173 degradation products observed in accelerated and/or long-term stability studies for the 62 drug products.  Among these, 25 of the stress testing degradation products were unique to the solution phase stress testing of the drug products; however, none of these unique degradation products were relevant to the formal stability data. The relevant degradation products were sufficiently accounted for by stress testing studies that included only drug substance stressing (in solution and in the solid state) and drug product stressing (in the solid state). Based on these results, it is the opinion of the authors that for solid dosage form drug products, well-designed stress testing studies need not include solution phase stress testing of the drug product in order to be comprehensive.

The impact of California's full-service partnership program on mental health-related emergency department visits.

OBJECTIVE: This study examined the effects of California's 2005 Mental Health Services Act (MHSA) on the use of mental health-related emergency department visits. It focused on one MHSA program, the full-service partnership program, and hypothesized that individuals with public insurance who participate in the higher-quality full-service partnership program would have fewer emergency department visits compared with clients with public insurance who receive usual care. METHODS: Data were obtained from the Short-Doyle/Medi-Cal (Medicaid) file, the Data Collection and Reporting system, and the Consumer and Service Information System, all maintained by the California Department of Mental Health. The analytic sample covered 931,218 observations (155,203 adults) ages 18 and older from January 2007 to June 2008. The data represented clients from seven counties, which made up 48.5% of the California population. Fixed-effects logistic regression was used and included a continuous measure of time, in quarters, in the full-service partnership program; separate quarter indicators; and quarter-county interaction terms. The model thus controlled for both time-invariant personal characteristics (including personality as well as psychiatric and medical history as of entry into the study) and all time-varying county-level characteristics. RESULTS: Relative to persons receiving usual care, the odds of full-service partnership participants visiting the emergency department were 54% less after four quarters of treatment and 68% less after six quarters. CONCLUSIONS: The full-service partnership program was highly effective in reducing emergency visits. A statewide cost-effectiveness study should be conducted to determine the economic viability of the program.

Recovery in the USA: from politics to peer support.

Efforts to transform the mental health service delivery system to a more consumer-driven and recovery-orientated approach has its roots in a somewhat radical anti-psychiatry and civil-rights movement dating back to the 1970s. This grass-roots effort gained momentum and credibility with Harding's landmark study published in 1988 followed by the work of Anthony et al. from Boston University in beginning to define the term 'recovery'. In 1998 the Office of the US Surgeon General issued its first report on mental health, and this critical view of the shortcomings of the existing service system set the stage for the 2003 President's New Freedom Commission and its recommendations for recovery-orientated systems transformation. The recovery movement has evolved from a more radical view in the early days, to participatory involvement in systems, to returning to alternative models of care that are more independent. Now as more peer specialists work in systems, there is an increased emphasis on non-medical alternatives and the cycle continues. Regardless, recovery, self-determination, choice, etc. are always at the centre. This paper notes the interesting cycles of recovery-orientation and how they spin around the values/tenets of the movement's early roots.

The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation.

Ablation of mouse occipital cortex induces precisely timed and uniform p53-modulated and Bax-dependent apoptosis of thalamocortical projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 d after lesion. We tested the hypothesis that this neuronal apoptosis is initiated by oxidative stress and the mitochondrial permeability transition pore (mPTP). Preapoptotic LGN neurons accumulate mitochondria, Zn(2+) and Ca(2+), and generate higher levels of reactive oxygen species (ROS), including superoxide, nitric oxide (NO), and peroxynitrite, than LGN neurons with an intact cortical target. Preapoptosis of LGN neurons is associated with increased formation of protein carbonyls, protein nitration, and protein S-nitrosylation. Genetic deletion of nitric oxide synthase 1 (nos1) and inhibition of NOS1 with nitroindazole protected LGN neurons from apoptosis, revealing NO as a mediator. Putative components of the mPTP are expressed in mouse LGN, including the voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT), and cyclophilin D (CyPD). Nitration of CyPD and ANT in LGN mitochondria occurs by 2 d after cortical injury. Chemical cross-linking showed that LGN neuron preapoptosis is associated with formation of CyPD and VDAC oligomers, consistent with mPTP formation. Mice without CyPD are rescued from neuron apoptosis as are mice treated with the mPTP inhibitors TRO-19622 (cholest-4-en-3-one oxime) and TAT-Bcl-X(L)-BH4. Manipulation of the mPTP markedly attenuated the early preapoptotic production of reactive oxygen/nitrogen species in target-deprived neurons. Our results demonstrate in adult mouse brain neurons that the mPTP functions to enhance ROS production and the mPTP and NO trigger apoptosis; thus, the mPTP is a target for neuroprotection in vivo.

Involuntary civil commitments after the implementation of California's Mental Health Services Act.

OBJECTIVE: As of fiscal year 2008-2009, California's Mental Health Services Act (MHSA) has distributed $3.2 billion in new tax revenues to county mental health systems. This voter-approved act attempts to address the needs of unserved and underserved consumers with severe mental illness by implementing a "whatever it takes" approach. The research literature indicates that the incidence of involuntary treatment may gauge the overall functioning of the public mental health system. Consistent with the notion that the MHSA may facilitate effective treatment of severe mental illness, the authors tested the hypothesis that the incidence of two types of involuntary treatment-72-hour holds and 14-day psychiatric civil commitments--declines as the enhancement of service access and quality is supported by MHSA funds. METHODS: The investigators obtained quarterly counts of involuntary 72-hour holds (N=593,751) and 14-day psychiatric hospitalizations (N=202,554) for 28 counties, with over 22 million inhabitants, from July 2000 to June 2007. A fixed-effects regression approach adjusted for temporal patterns in treatment. RESULTS: The petitions for involuntary 14-day hospitalizations, but not involuntary 72-hour holds, fell below expected values after disbursement of MHSA funds. In these counties, 3,073 fewer involuntary 14-day treatments-approximately 10% below expected levels-could be attributed to disbursement of MHSA funds. Results remained robust to alternative regression specifications. CONCLUSIONS: Fewer than expected involuntary 14-day holds for continued hospitalization may indicate an important shift in service delivery. MHSA funds may have facilitated the discharge of clients from the hospital by providing enhanced resources and access to a range of less-restrictive community-based treatment alternatives.

What predicts recovery orientation in county departments of mental health? A pilot study.

In this pilot study we examined the determinants of recovery orientation among employees and influential stakeholders in a sample of 12 county departments of mental health in California. A two-level hierarchical linear model with random intercepts was estimated. Analyses show that recovery orientation has a U-shaped relationship with the age of staff/influential stakeholders and is negatively related to the difference between the desired level of adhocracy and the current level of adhocracy. Recovery orientation is positively related to the education level of staff/influential stakeholders, satisfying transformational leadership outcomes, and larger mental health budgets per capita. Policy implications are discussed.

Scales to evaluate quality of medication management: development and psychometric properties.

This paper describes the psychometric properties of two fidelity scales created as part of the Substance Abuse and Mental Health Services Administration (SAMHSA) sponsored medication management toolkit and their metric properties when used in 26 public mental health clinics with 50 prescribers. A 23-item scale, based on chart reviews, was developed to assess whether prescribers are following good medication practices, in conjunction with a 17-item scale to assess organizational support for and evaluation of prescriber adherence to recommended medication-related practices. Fundamental gaps in routine practice, including poor documentation of medication history and infrequent monitoring of symptoms and side effects were found.

Transformation of the California mental health system: stakeholder-driven planning as a transformational activity.

OBJECTIVE: This study describes strategies developed by California counties to transform their mental health systems under the 2004 Mental Health Services Act (MHSA). This voter initiative places a 1% tax on annual incomes over $1 million; tax monies are earmarked to transform county-operated mental health services into systems that are oriented more toward recovery. MHSA implementation itself can be considered "transformational" by balancing greater standardization of mental health service delivery in the state with a locally driven planning process. METHODS: A qualitative content analysis of the three-year plans submitted by 12 counties to receive funds under MHSA was conducted to identify common themes, as well as innovative approaches. These 12 (out of 58) counties were chosen to represent both small and large counties, as well as geographic diversity, and they represent 62.3% of the state population. RESULTS: This analysis showed that the state guidelines and local planning process generated consistency across counties in establishing full-service partnerships with a "whatever it takes" approach to providing goal-directed services and supports to consumers and their families. There was, however, little convergence around the specific strategies to achieve this vision, reflecting both the local planning process and a relative lack of clear policy and guidance on evidence-based practices. CONCLUSIONS: There are many obstacles to the successful implementation of these ambitious plans. However, the state-guided, but stakeholder-driven, transformation in California appears to generate innovative approaches to recovery-oriented services, involve consumers and family members in service planning and delivery, and build community partnerships that create new opportunities for consumers to meet their recovery goals.

Safety of intravitreal ketorolac and diclofenac: an electroretinographic and histopathologic study.

OBJECTIVE: To determine the clinical, histologic, and electroretinographic effects in the rabbit retina of escalating doses of two intravitreally delivered nonsteroidal anti-inflammatory drugs (NSAIDs): ketorolac and diclofenac. METHODS: Right eyes received a single 0.1 mL injection of either ketorolac (500-6000 microg/0.1 mL) or diclofenac (300-1500 microg/0.1 mL) prepared in balanced salt solution (BSS). Left eyes served as controls and received BSS. Dark- and light-adapted electroretinograms (ERG) were obtained at baseline and 4 and 8 weeks postinjection. Enucleated eyes were examined histologically. RESULTS: Ophthalmic examinations demonstrated no signs of intraocular inflammation or retinal toxicity. Intraocular pressure measurements remained similar between NSAID injected and control eyes. Histologic and ERG studies of eyes injected with 6000 microg ketorolac and >or=500 microg diclofenac demonstrated toxicity. In contrast, doses up to 3000 microg ketorolac demonstrated enhanced b-wave amplitude responses. Delayed drug toxicity was observed for the highest doses of both NSAIDs. CONCLUSIONS: Intravitreal 3000 microg ketorolac and 300 microg diclofenac were nontoxic in this animal study, and may offer an effective and safer alternative to intravitreal corticosteroids.

Report of recommendations: the Annapolis Coalition Conference on Behavioral Health Work Force Competencies.

In May 2004, the Annapolis Coalition on Behavioral Health Workforce Education convened a national meeting on the identification and assessment of competencies. The Conference on Behavioral Health Workforce Competencies brought leading consumer and family advocates together with other experts on competencies from diverse disciplines and specialties in the fields of both mental health care and substance use disorders treatment. Aided by experts on competency development in business and medicine, conference participants have generated 10 consensus recommendations to guide the future development of workforce competencies in behavioral health. This article outlines those recommendations. A collaborative effort to identify a set of core or common competencies is envisioned as a key strategy for advancing behavioral health education, training, and other workforce development initiatives.

Millionaires and mental health: Proposition 63 in California.

In November 2004 California passed Proposition 63, a landmark piece of mental health and fiscal legislation. This initiative places a 1 percent tax on adjusted gross income over dollar 1 million, affecting about 30,000 taxpayers and raising dollar 1.8 billion (a 31 percent increase) in new revenues over the first three years to support county-operated mental health systems. Our analysis suggests that Proposition 63 passed with strong support from Democrats, urban dwellers, and social workers and in counties with high rates of homelessness. Proposition 63 faces challenges in implementation and provides unprecedented opportunities for transformation and change.

Sometimes a great notion ... a common agenda for change.

In the midst of a sea of change in the behavioral health care field, there is emerging a common agenda regarding critical issues and challenges. This article briefly examines the implications for education and training as we pursue this common agenda. Understanding the process of social change helps to chart a course for addressing the identified challenges.