The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs

BACKGROUND: For the purposes of drug approval, the interchangeability of a generic drug and the corresponding brand-name drug is based on the criterion of "essential similarity," which requires that the generic drug have the same amount and type of active principle, the same route of administration, and the same therapeutic effectiveness as the original drug, as demonstrated by a bioequivalence study. However, bioequivalence and therapeutic effectiveness are not necessarily the same. OBJECTIVE: This review summarizes available data comparing the bioequivalence and therapeutic efficacy of brand-name psychoactive drugs with those of the corresponding generic products. METHODS: Relevant information was identified through searches of MEDLINE, Current Contents/Clinical Medicine, and EMBASE for English-language articles and English abstracts of articles in other languages published between 1975 and the present. The search terms used were generic drug, branded drug, safety, toxicity, adverse events, clinical efficacy, bioequivalence, bioavailability, psychoactive drugs, and excipients. RESULTS: Few publications compared the bioequivalence and efficacy of brand-name and generic psychoactive drugs. Those that were identified revealed differences in the efficacy and tolerability of brand-name and generic psychoactive drugs that had not been noted in the original bioequivalence studies. Specifically, l study found that plasma levels of phenytoin were 31% lower after a switch from a brand-name to a generic product. Several controlled studies of carbamazepine showed a recurrence of convulsions after the shift to a generic formulation. After a sudden recurrence of seizures when generic valproic acid was substituted for the brand-name product, an investigation by the US Food and Drug Administration found a difference in bioavailability between the 2 formulations. Statistically significant differences in pharmacokinetic variables have been reported in favor of brand-name versus generic diazepam (P < 0.001). Finally, a case report involving paroxetine mesylate cast doubt on the tolerability and efficacy of the generic formulation. CONCLUSION: The essential-similarity requirement should be extended to include more rigorous analyses of tolerability and efficacy in actual patients as well as in healthy subjects.     

Cultural issues in palliative care

OBJECTIVES: To review the common issues at the end of life across cultures and the measures that can be taken to dress these issues. DATA SOURCES: Published articles and textbook chapters. CONCLUSION: Culture plays a critical role in how patients, families, and health care providers view the end of life. Cultural competence in end-of-life care includes knowledge and experience and working in cross-cultural situations. IMPLICATIONS FOR NURSING PRACTICE: Increased culture-specific knowledge will provide nurses with a basis for beginning exploration of individual or family beliefs.     

Solution‐driven approaches to generic substitution challenges – a survey among international experts

The main objective of this study was to explore the perception and understanding of economic, legal, and social barriers that may restrain generic uptake among recognized international experts in health care, and to identify and verify recommendations on how to streamline generic substitution (GS) at no expense of therapeutic safety. A questionnaire survey was devised, and experts with world‐renowned expertise in the field of generic medicinal products were selected. Almost 3/4 of respondents claimed that all drugs that satisfy bioequivalence criteria represent similar efficacy and adverse effects, and 1/4 of respondents believed that some differences could be reported. The majority of experts supported (i) the right of patients to refuse GS, (ii) the right of physicians to veto GS, and (iii) the introduction of a statutory obligation to provide patients with access to the cheapest generics available on the market. The main obstacles to more general uptake of generics were as follows: (i) perception of generics as lower quality products, (ii) absence of a transparent policy governing GS, and (iii) disincentives to pharmacists and physicians. Among the most popular recommendations were as follows: (i) introduction of various measures to aid physicians in generic prescribing, (ii) setting clear guidelines specifying when GS is not advisable, (iii) supporting competition on the generic market. The views of experts and the resulting recommendations were strongly affected by their opinion on the bioequivalence of generics. From this analysis, we have selected several principal recommendations which could help shape successful healthcare policies regarding GS.     

Assessing the psychosocial impact of the ICD: a national survey of implantable cardioverter defibrillator health care providers

The implantable cardioverter defibrillator (ICD) provides a survival advantage over antiarrhythmic medications for patients with life-threatening ventricular arrhythmias. However, the effect of ICD therapy on quality-of-life and psychosocial functioning are not as well understood. Health care providers (e.g., physicians, nurses) can serve as a valuable source of information related to these ICD outcomes. The purpose of this study was to investigate health care provider perceptions regarding: (1) the quality-of-life and psychosocial functioning of their ICD recipients, (2) the concerns or problems reported by ICD recipients, and (3) the degree of provider comfort in managing these concerns. The final sample of health care providers (n = 261) rated ICD recipients' global quality-of-life and psychosocial functioning, and specific concerns about health care, lifestyle, special population adjustment, marital and family adjustment, and emotional well-being. With regard to quality-of-life, health care providers reported that the majority of ICD recipients were functioning better (38%) or about the same (47%) than before implantation. However, health care providers reported that 15% of recipients experienced worse quality-of-life postimplantation. Similarly, health care providers indicated that 10%-20% of ICD recipients experienced worse emotional functioning and strained family relationships. Moreover, issues related to driving, dealing with ICD shocks, and depression were the most common ICD recipient concerns. Significant differences were noted between physicians and nurses/other health care professionals on a wide range of psychosocial issues. Health care providers generally reported the most comfort dealing with traditional medical issues (i.e., patient adherence), and the least comfort in managing emotional well-being issues (e.g., depression and anxiety). These results suggest that routine attention to ICD quality-of-life and psychosocial outcomes is indicated for health care providers who care for ICD recipients.     

Systematic review of the use of patients' own medications in acute care institutions

BACKGROUND: Patients' own medications (POM) are medications that patients have obtained in the community setting and bring to the hospital when admitted. The practice of using POMs has not been well studied. OBJECTIVE: To identify benefits, risks and other impacts on the use of POM in hospitals. Methods: A systematic search of the literature and internet was conducted for articles in the English language dated from 1984 to 2004. PubMed, CINAHL, IPA, and Embase databases were searched with combinations of the following text words: patient, own, drug, medication, medicine. References of relevant articles and specific journals were hand-searched. RESULTS: Nineteen primary studies that provided information on the benefits and risks of POMs were identified. Benefits included decreased wastage of POMs, improving the accuracy of admission orders, opportunities for patient counselling and continuity of care between acute and primary care. Hospitals must address liability and workload concerns but may benefit from savings to their drug budget. DISCUSSION: Only a limited number of studies were found that addressed the benefits, risks and costs of using POMs in hospitals. These studies had small sample sizes with limitations in the quality of the study design. Nevertheless, the literature contained examples of benefits to the patient and hospital, as well as assistance with practical issues. Further research is needed to evaluate the benefits and risks of using POMs. Hospital policies should describe identification, storage and documentation procedures to address liability and risk concerns. Implementation of policies to use POMs should include an evaluation component, which could include a comprehensive economic analysis of drug costs and staff workload.     

Pharmacy and generic substitution of antiepileptic drugs: missing in action?

Generic substitution of antiepileptic drugs is an issue that is gathering a lot of attention in the neurology community but is not receiving much attention within pharmacy. Several proposals have been drafted that restrict a pharmacist's decision-making in generic substitution. These proposals highlight concerns about the pharmacy community related to generic substitution. Careful consideration needs to be given to these issues by pharmacists and pharmacy professional organizations. Unless pharmacy as a profession takes strong positions in support of a pharmacist's ability to make decisions about pharmacotherapy and addresses many of the pharmacy-related problems of generic substitution, policies that negatively impact pharmacy will be established.     

Generics and substitution modalities: proposed methods for the evaluation of equivalence, traceability and pharmacovigilance reporting

The use of generics results in savings for the budget of the health insurance, and no player of health could question seriously the principle. The generic drug of a reference medicinal product defines itself as a drug having the same qualitative and quantitative composition in active ingredients, the same dosage form and the bioequivalence with this reference medicinal product was demonstrated by appropriate studies of bioavailability. It is the right to switch granted to the pharmacists in 1999 that is at the origin of the real development of these specialties on the French pharmaceutical market. Nevertheless, about 10 years later, it seems that the system in place does not offer all the necessary securities with regard to pharmacovigilance, notably for the products with narrow therapeutic margin. By strengthening and/or by completing the role played by the health care professionals and the public institutions concerned, it is highly possible to improve the robustness of the system. Also, the recent arrival in Europe of the biosimilars, similar molecules but not bioequivalent to biological products, cause an even more tricky specific situation than that of the generics because of their nature, of the difficulty to manufacture them, and of the risk of immunogenicity. If the substitution is not permitted in several European countries including France, the other issues can appear especially in case of interchangeability requiring also, the reinforcement of certain measures.The various aspects are described in this article with concrete proposals on how the current system can be made safer, both for the generics and the biosimilars.     

Symptoms affecting quality of life in women with gynecologic cancer

OBJECTIVES: To review quality-of-life issues in women diagnosed with gynecologic cancers. DATA SOURCES: Research studies, review articles, and medical and nursing text-books. CONCLUSIONS: Women diagnosed with gynecologic cancers carry a heavy physical and emotional burden because of surgical morbidity, chemotherapy toxicities, loss of fertility, changes in body image, sexual concerns, and altered relationships. IMPLICATIONS FOR NURSING PRACTICE: Health care providers play a key role in the identification and treatment of the complications of cancer therapy. Minimizing the effect of the symptoms of gynecologic cancer may positively impact the patient's quality of life.     

Generic substitution: issues for problematic drugs

The methodology and criteria for bioequivalence testing have been firmly established by the Food and Drug Administration (FDA). For certain drugs with a narrow therapeutic index (e.g., digoxin, levothyroxine, warfarin), generic substitution may not be advisable or even allowable, depending on the substitution laws of individual states. Digoxin and levothyroxine tablets are examples of drugs for which no New Drug Applications (NDAs) currently exist. However, commercially available generic products for both of these drugs have not been determined by the FDA to be therapeutically equivalent to the innovator products. Generic versions of warfarin have been approved by the FDA as being therapeutically equivalent to the innovator products, as have generic versions of the rescue inhaler albuterol. Yet, misinformation and myths persist regarding the adequacy and proven reliability of the FDA's determination of bioequivalence for these products.     

Substituting warfarin products: what's the source of the problem?

Many clinicians have expressed concerns about the bioequivalence of warfarin products, and data suggest that substituting warfarin products may increase the risk of major bleeding and thromboembolic complications. Anecdotal reports and some retrospective studies have reported differences in anticoagulation control after a warfarin product substitution. But the best available evidence-prospective, randomized, blinded clinical trials-has failed to validate these observations. Indeed, interpatient and intrapatient variability in anticoagulation control observed before and after warfarin product substitution is very similar. So, while differences in product standardization, bioavailability, and bioequivalence make a convenient explanation, the problem lies elsewhere. Perhaps poor communication, fractionated systems of care, and errors are the culprits.     

A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A. Berlin,Germany, November 19, 2001

A meeting of 14 transplant and pharmacokinetic specialists from Europe and North America was convened in November 2001 to evaluate scientific and clinical data regarding the use of different formulations of cyclosporin A (CsA). The following consensus was achieved. (1) CsA is a critical-dose drug with a narrow therapeutic window. Clinical outcomes after transplantation are affected by the pharmacokinetic properties of CsA, particularly by its bioavailability, and by intrapatient variability in CsA exposure. (2) Standard bioequivalence criteria do not address differences in CsA pharmacokinetics between transplant recipients and healthy volunteers, or between subpopulations of transplant recipients. (3) In some circumstances, currently available formulations of CsA that meet standard bioequivalence criteria are likely to be nonequivalent with respect to pharmacokinetic characteristics. (4) The choice of CsA formulation can affect the short- and long-term clinical outcome. Currently, there is a lack of clinical comparisons between generic CsA formulations and the Neoral formulation (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). Initial retrospective data from the Collaborative Transplant Study suggest that use of generic CsA formulations may result in reduced graft survival at 1 year. (5) Management of transplant recipients by monitoring Neoral concentrations 2 hours after dosing (C(2)) reduces the incidence and severity of acute rejection compared with monitoring of trough concentrations with no increase in toxicity. C(2) monitoring has been developed based on the pharmacokinetics of Neoral only and has not been evaluated or validated for generic formulations of CsA. (6) The major costs of care after transplantation relate to the management of poor clinical outcomes and toxicity. CsA formulations with different pharmacokinetic properties may be associated with varying clinical outcomes, which would be expected to affect total health care costs. (7) The transplant physician is responsible for selecting immunosuppressive agents and formulations for his or her patients. Any switch between CsA formulations in a particular patient should take place only in a controlled setting with adequate pharmacokinetic monitoring.     

Practitioner ethics and managed care

Mental health services provided through a managed care company cause some serious ethical concerns for providers and potentially for licensing boards. Confidentiality, record keeping, abandonment of patients, and informed consent are a few of the major issues confronting providers and the patients with whom they work. The importance of these issues for providers and the need for managed care companies and their employees to pay more attention to these ethical problems are covered in this article.     

A model of survivorship in cancer genetic care

OBJECTIVES: To propose a shift in the paradigm of survivorship in genetic cancer care. DATA SOURCES: Published articles and, studies. CONCLUSION: Previous models of survivorship are insufficient to address the evolving needs of patients and families with heritable cancers. The construction of a new model of survivorship is needed to address the unique concerns of individuals who have undergone hereditary cancer risk assessment and counseling. IMPLICATIONS FOR NURSING PRACTICE: Health care providers must be familiar with the recommendations for treatment, surveillance, and follow-up care for individuals and families with heritable cancers to maximize their quantity and quality of life.     

The impact of genetic information on policy and clinical practice

This article discusses genetics-related policy issues that have an impact on health care systems, health care providers, and their patients: privacy, mass screening, family screening, and knowledge dissemination. Access, cost, and ethical implications are important discussant points for each of these genetic-related policy issues. Embedded in the issue of privacy are concerns of insurability, confidentiality, and discrimination. The public health policy implications related to mass screening programs include efficacy of the screening tests, availability of primary and secondary interventions, access, costs, and program evaluation. Policy issues for family screening are similar to mass screening, with added concerns about privacy and availability of adequate resources, including health care providers and counselors trained in genetics. Knowledge dissemination is critical to maintaining currency of clinical information and applications of genetic technologies and treatments. As genetic information expands, the need for knowledge dissemination will increase. The importance of advanced practice nurses' involvement in these policy issues is discussed.     

It just didn't work: the realities of quality assessment in the English health care context

AIMS: Assessment of care quality is integral to health and palliative care provision and there is a need to develop and implement outcome measures to assess quality. This study aimed to: (1) describe the implementation of a palliative care outcome measure in non-specialist palliative care settings and (2) to understand the implementation of the measure. METHOD: Twenty-five non-specialist palliative care settings were purposely sampled and invited to implement a palliative care outcome measure. Fifteen settings agreed to take part. The research team provided training and support in the use of the measure. Data were collected on actual use of the measure and, via interviews with patients and nurses, on their experiences. RESULTS: The number of assessments was low (21 patients assessed against an anticipated minimum of 240). The analysis of nurses' accounts identified important considerations in understanding the low response. Although nurses saw the implementation of the outcome measure as bringing opportunities for themselves, including their own professional development, and for the organisations they represent, including raising organisational profiles, there were a number of factors that acted as impediments. These include: perceived time to administer the paperwork; competence and confidence in recruiting patients and proceeding with informed consent; concerns about the effects of completing the measure with very ill patients; and the effects of nurses raising palliative care issues on their relationships with patients. CONCLUSIONS: It is difficult to integrate outcome measures into routine clinical practice. Future interventions should consider how to tailor the implementation of outcome measures within existing working structures and provide education and training to enable nurses to deal with potentially sensitive palliative care issues.     

How can osteoporosis patients benefit more from their therapy? Adherence issues with bisphosphonate therapy

OBJECTIVE: To review the evidence on adherence with bisphosphonates and evolving dosing strategies for osteoporosis treatment. DATA SOURCES: Articles were identified by searching MEDLINE (1975-December 2005) using the following terms: osteoporosis, postmenopausal, fracture, adherence, compliance, persistence, drug therapy, bisphosphonates, alendronate, risedronate, ibandronate, and zoledronate. Additional data included bibliographies from identified articles. STUDY SELECTION AND DATA EXTRACTION: All pertinent English-language articles that discussed adherence issues in patients with osteoporosis were included. Both those that reviewed overall issues of medication adherence in osteoporosis and those that focused specifically on adherence to bisphosphonates were included, as were articles that addressed strategies for overcoming nonadherence. DATA SYNTHESIS: Inadequate diagnosis and treatment of osteoporosis result in a higher risk of fractures than is necessary. Even patients who are diagnosed and beginning treatment often do not persist with their osteoporosis medication because they perceive their fracture risk to be low and, given the asymptomatic nature of osteoporosis, do not experience the benefit of symptom reduction after taking the drugs. Factors that affect adherence to osteoporosis therapy include drug costs, adverse effects, dosing frequency, disease education, patient follow-up, and patient involvement in treatment decisions. CONCLUSIONS: By considering and implementing strategies that can improve adherence and persistence, primary care providers and pharmacists (via counseling) may enhance long-term outcomes for patients with osteoporosis.     

Assessing the methodological quality of nonrandomized intervention studies

In many areas of health care, randomized controlled trials (the best evidence regarding the effectiveness of health care interventions) are lacking and decision-makers have to rely on evidence from nonrandomized studies (NRS). We conducted a Medline search to identify English-language articles describing instruments for assessing the quality of NRS of health care interventions. These instruments varied greatly in scope, in the number and types of items and in developmental rigor. Items commonly included were those related to specification of study questions, allocation method, comparability of groups, and blinding of outcome assessment. We do not support the development of a generic scale to evaluate the methodological quality of nonrandomized intervention studies. Instead, further study should be directed to investigate the degree to which, and the circumstances under which, different methodological characteristics are associated with bias. This information will assist researchers in identifying a priori which methodological characteristics need careful evaluation in particular studies.     

Generic substitution of antihypertensive drugs: does it affect adherence?

BACKGROUND: Generic substitution is an important opportunity to reduce the costs of pharmaceutical care. However, pharmacists and physicians often find that patients and brand-name manufacturers have doubt about the equivalence of the substituted drug. This may be reflected by decreased adherence to therapy. OBJECTIVE: To assess the association between generic substitution and nonadherence to antihypertensive drugs. METHODS: We conducted a matched cohort study between January 1, 1999, and December 31, 2002. Data were obtained from PHARMO, a record linkage system containing drug-dispensing records from community pharmacies and linked hospital discharge records of approximately 950,000 people in The Netherlands. Residents of 30 medium-sized cities who initiated antihypertensive drug therapy were potential subjects. Refill adherence with antihypertensive drugs after substitution was determined; those with refill adherence below 80% were considered nonadherent. RESULTS: Four hundred sixty-three patients with a substitution in therapy and 565 controls, matched on age, gender, therapy start date, duration of use, and generic product code, were identified. Of the patients who switched from brand-name to generic formulations ("substituted"), 13.6% were nonadherent, and of the non-substituted patients (those who did not switch to generic), 18.7% were nonadherent (OR 0.68; 95% CI 0.48 to 0.96). The association was absent in males. None of the patients discontinued the medication. No differences in hospitalizations for cardiovascular disease in the 6 months after the substitution were observed. CONCLUSIONS: Generic substitution of antihypertensive drugs does not lead to lower adherence or more discontinuation and cardiovascular disease-related hospitalizations compared with brand-name therapy. When a less-expensive antihypertensive generic equivalent becomes available, generic substitution should be considered to achieve economic benefits.