Pharmacoligaclly Active : Clinical Trials and the Pharmaceuticals Industry

The global clinical trials industry is driven by the needs of pharmaceutical companies to bring new products to market; rapidly and in compliance with regulatory requirements. Many of the largest multinational pharmaceutical companies - the so-called 'pharmas' - are active in South Africa in importing and producing pharmaceuticals and in the conduct of clinical trials. This clinical trials industry now forms an important sub-sector of research and development (RetD) in the country. The release in August 2007 of the long-awaited Department of Trade and Industry national industrial policy framework designates four key value chains in the economy; one of which is chemicals; plastic fabrication and pharmaceuticals. This intention raises a key question: is South Africa to be a factory for the pharmas; or can it leverage its existing strengths in medical research and the conduct of clinical trials to develop a discovery-led local industry? This paper therefore offers an analytical and quantitative profile of the current state of the clinical trials industry in South Africa; to enquire as to its potential to grow a local pharmaceutical industry

Using standardized patients to teach end-of-life skills to clinical clerks.

BACKGROUND: This study examines the use of standardized patients to teach end-of-life skills to clinical clerks. METHODS: Forty-four third-year clinical medical students participated in a half-day standardized patient workshop that was precepted by faculty members. The students were asked to report on their perceived abilities prior to the workshop and these were compared with post-workshop responses. The students were also asked to provide an overall evaluation of the standardized patient workshop as a learning experience. RESULTS: The students uniformly found the workshop to be realistic, found the faculty facilitators to be helpful, and found the workshop effective in enhancing their end-of-life skills. Following participation in the workshop, students reported significant improvements in their perceived abilities to deal with pain, to appreciate cultural differences in the dying process, to deliver bad news, and to understand the legalities of do-not-resuscitate orders. CONCLUSIONS: Standardized patient workshops are useful for teaching end-of-life skills.

Residency program director evaluations do not correlate with performance on a required 4th-year objective structured clinical examination.

BACKGROUND: Assessment of resident performance is a complex task. PURPOSE: To correlate performance on a 4th-year objective structured clinical examination (OSCE) with residency program director assessment, class rank, and U.S. Medical Licensing Examination (USMLE) scores. METHODS: We surveyed program directors about the performance of 50 graduates from our medical school chosen to represent the highest (OSCEHI) and lowest (OSCELO) 25 performers on our required 4th-year OSCE. Program directors were unaware of the OSCE scores of the graduates. RESULTS: OSCE scores did not correlate with Likert scores for any survey parameter studied (r < .23, p > .13 for all comparisons). Similarly, program director evaluations did not correlate with class rank or USMLE scores (r < .26, p > .09 for all comparisons). CONCLUSIONS: We concluded that program director evaluations of resident performance do not appear to correlate with objective tests of either clinical skills or knowledge taken during medical school. These findings suggest that more structured and objective evaluative tools might improve postgraduate training program assessment of trainees.

Description of a combined internal medicine-pediatrics continuity clinic for combined program residents.

BACKGROUND: We sought to examine the ambulatory experience in our medicine-pediatrics clinic. METHODS: Data on patient visits were abstracted from the hospital's clinic utilization summary and charge sheets. A survey assessed resident satisfaction. RESULTS: Residents saw 63% adult and 37% pediatric patients, with an average of 3.5 patients per clinic. There was no significant difference in the mean number of patients seen by residents when compared by postgraduate year. Half of all visits were coded for 2 or more diagnoses. Hypertension and diabetes were the most common adult diagnoses, and well-child care and asthma were the most common pediatric diagnoses. Residents were satisfied with the clinic. CONCLUSIONS: The adult and pediatric patient visits were well balanced, with broad complexity. Residents rated their satisfaction with the clinic highly. Our experience may provide valuable information to programs that have a med-peds clinic or are considering creating one.

Postpartum acquired hemophilia (factor VIII inhibitors): a case report and review of the literature.

Pathologic inhibitors of blood coagulation as a cause of postpartum acquired hemostatic failure are rare. Since 1937, 96 cases of postpartum factor VIII (FVIII) inhibitors, including the current case, have been reported. Suspicion for the diagnosis of this condition is often low. We report a case of postpartum FVIII inhibitor formation in a 24-year-old woman who developed intermittent postpartum bleeding that resulted from the inhibitors she formed to FVIII. A unique form of therapy was used in treatment of her disorder. She did not respond to conventional surgical or medical management of her bleeding until Autoplex T (Baxter Healthcare, Glendale, CA), an activated prothrombin complex concentrate (aPCC) was used. The literature concerning acquired hemophilia is reviewed, and new therapeutic medical advances are emphasized.

Neuroacanthocytosis masquerading as Huntington's disease: CT/MRI findings.

Neuroacanthocytosis (NA) is a rare, degenerative, presumably autosomal-recessive disorder of the nervous system presenting in adulthood and is associated with acanthocytosis of the peripheral blood. The clinical spectrum of NA shares similarities with Huntington's disease (HD), including dyskinetic choreiform movements and degeneration of the caudate nucleus. A woman presented with choreiform movements and was given a presumed diagnosis of HD. Neuroimaging studies were consistent with HD. She lacked the genetic marker for HD, and further evaluation revealed acanthocytosis of the peripheral blood. The case illustrates the similarities and differences in the clinical presentations and neuroimaging studies of these two disease entities, emphasizing the need for a careful clinical evaluation.

Comparison of internal medicine, pediatric, and medicine/pediatrics applicants and factors influencing career choices.

BACKGROUND: A reemergence of medical students choosing primary care is occurring, with medicine/pediatrics as an increasingly popular option. We compared applicants to pediatrics, medicine, and medicine/pediatrics and the factors that influence career choice. METHODS: We designed a survey to gather objective data and information shown to influence career choices. Applicants interviewing in our three primary care programs completed the survey. RESULTS: Pediatric applicants were more likely to be women and to choose their career in the 2nd year of medical school. Medicine/Pediatrics applicants had the highest interest in practicing primary care and in pursuing an academic career. However, they had the smallest number of role models. The average education debt was the same. CONCLUSION: Differences in applicants applying to primary care programs may be used to target particular applicants and to counsel medical students on career choice.

Acute treatment-related diarrhea during postoperative adjuvant therapy for high-risk rectal carcinoma.

PURPOSE: The combination of pelvic radiotherapy and 5-fluorouracil-based chemotherapy is associated with an increase in acute gastrointestinal toxicity during rectal adjuvant therapy, most notably an increased incidence of diarrhea. Previous randomized, prospective studies have limited their analysis to presenting rates of severe and life-threatening diarrhea (Grade 3 or greater), and few data are available detailing the extent of mild to moderate diarrhea. To provide baseline data for future studies, we conducted a detailed analysis of diarrhea from a prior clinical trial of adjuvant therapy for rectal cancer. METHODS AND MATERIALS: In a multiinstitutional clinical trial, 204 eligible patients with rectal carcinoma that either was deeply invasive (T3-T4) or involved regional lymph nodes were randomized to receive either postoperative pelvic radiotherapy alone (45 to 50.4 Gy) or pelvic radiotherapy and bolus 5-fluorouracil-based chemotherapy. Toxicity was assessed prospectively. RESULTS: For the 99 eligible patients who received pelvic radiotherapy alone, rates of Grades 0, 1, 2, 3, and 4 diarrhea during treatment were 59, 20, 17, 4, and 0%, respectively. For the 96 eligible patients who received radiotherapy and 5-fluorouracil, the overall rates of grades 0, 1, 2, 3, and 4 diarrhea were 21, 34, 23, 20, and 2%, respectively. The increased rates of diarrhea during adjuvant rectal therapy were manifested across all toxicity levels for patients receiving chemotherapy and pelvic radiotherapy. Of primary clinical importance is the substantial increase in severe or life-threatening diarrhea (Grade 3 or more) (22 vs. 4%,p = 0.001) Additionally, increased rates of any diarrhea and also severe or life-threatening diarrhea were observed in patients who had a low anterior resection compared with those who had an abdominoperineal resection (p < 0.001 and p = 0.006, respectively). CONCLUSION: These results will be of value as a baseline for investigators who want to use treatment toxicity as an end point in cancer control or cancer therapy trials utilizing similar treatment techniques. Patients receiving 5-fluorouracil and pelvic radiotherapy compared with patients receiving pelvic radiotherapy alone and patients with a prior history of a low anterior resection compared with patients who had a prior history of an abdominoperineal resection experienced increased rates of Grades 1 through 4 acute treatment-related diarrhea, and the most important increase occurred as Grade 3 toxicity.

Chronic thrombotic thrombocytopenic purpura masquerading as other disease entities.

A 37-year-old woman with a chief complaint of nausea, headache and, prolonged menses was diagnosed with thrombotic thrombocytopenic purpura based on a peripheral smear with active microangiopathic hemolytic anemia and a platelet count of 4,000/mm3. Her past medical history was significant for several conditions including multiple sclerosis, Bell's palsy, Raynaud's syndrome and HELLP syndrome. In retrospect, it appears that this patient's clinical history was most consistent with one unifying diagnosis, chronic thrombotic thrombocytopenic purpura. Physicians should search for the elusive clinical and laboratory clues for chronic thrombotic thrombocytopenic purpura that can masquerade as other disease entities.

Chemoprevention for colorectal carcinoma.

The literature on chemoprevention for colorectal carcinoma can be summarized as follows: (1) Aspirin and NSAIDs usage can decrease polyp formation and promote polyp regression and have a strong epidemiologic link to colorectal cancer prevention. (2) Fiber intake is strongly associated with a decreased incidence of colorectal carcinoma. Whether supplemental fiber can prevent colorectal neoplasia is not yet clear. (3) Calcium and vitamin D intake is inversely proportional to the risk of developing colorectal carcinoma. Prospective trials make the role of supplemental calcium as a chemoprotective agent unclear: (4) Chemoprevention is an exciting area of research. More work needs to be done to establish the precise steps necessary for neoplastic transformation of cells so that pharmaceuticals can be developed to target carcinogenesis at several levels.

An enhanced prognostic system for clinically localized carcinoma of the prostate.

BACKGROUND: This investigation was conducted to develop an enhanced prognostic system based on readily available and independently predictive tumor-related factors for patients with clinically localized prostate carcinoma. METHODS: The outcome of 500 patients treated solely with irradiation for clinical TNM classifications T1-4, NO or NX, MO prostate carcinoma was used to identify factors independently associated with disease relapse. Logistic regression constructed a risk score equation, and optimized cutoff points to characterize patient groups with low, intermediate, or high risks for relapse were established with receiver operating characteristic curve analysis. RESULTS: Clinical tumor stage (P < 0.00001), Gleason score (P = 0.0002), and pretherapy serum prostate specific antigen (P < 0.00001) were independently associated with clinical or biochemical relapse. These factors were included in a risk score equation that defined patient groups with a distinctly different outcome. For the low, intermediate, and high risk groups, the relapse-free probabilities at 5 years after irradiation were 92%, 67%, and 24%, respectively (P < 0.00001). CONCLUSIONS: Readily available, pretherapy disease-related characteristics formed the basis of an enhanced prognostic system for patients with clinically localized prostate carcinoma. A multivariate prognostic system of this nature estimated patient prognosis in a more exacting fashion than a system exclusively based on anatomic factors.

Hepatosplenic gammadelta T-cell lymphoma: ultrastructural, immunophenotypic, and functional evidence for cytotoxic T lymphocyte differentiation.

Hepatosplenic gammadelta T cell lymphoma (TCL) is a rare, aggressive subset of peripheral TCL that presents with hepatosplenomegaly and cytopenias. Detailed clinicopathological, ultrastructural, and cytogenetic analyses of these lymphomas are limited; functional characteristics of these lymphomas are unknown. We have undertaken a clinicopathological, immunophenotypic, ultrastructural, cytogenetic, and functional analysis of three hepatosplenic gammadelta TCLs. All patients presented with massive hepatosplenomegaly and anemia, thrombocytopenia, or severe neutropenia; terminal blastlike transformation occurred in one patient. Combination chemotherapy had no response in two patients, but induced complete remission in one. gammadelta T cell receptor (TCR) expression and clonal TCRdelta gene rearrangements were documented in each case. Two different subsets of gammadelta TCL were identified based on delta chain variable region usage; two lymphomas were Vdelta1+, whereas the third was negative for both Vdelta1 and Vdelta2. Cytogenetic analysis was performed on two lymphomas; isochromosome 7q and probable trisomy 8 was shown in one of the Vdelta1+ lymphomas, whereas the Vdelta1 negative lymphoma had 14p+ with t(1;14)(q21;p13). NK cell-associated antigens (CD11c, CD16, or CD56) and cytotoxic T lymphocyte (CTL) effector proteins (perforin, granzyme B, TIA-1, and Fas ligand) were expressed by each lymphoma; dense core cytolytic granules were observed by electron microscopy in both lymphomas studied. Functional studies performed in two cases showed TCR-mediated cytolysis of P815 x 2 FcR+ cells induced by anti-CD3 in a redirected cytolysis assay in one of the CD56+, Vdelta1+ lymphomas, whereas IFNgamma secretion was induced by anti-CD3 in the CD56-, Vdelta1 negative lymphoma. These studies show that hepatosplenic gammadelta TCLs have CTL differentiation, retain functional activity in vitro, and are derived from at least two gammadelta T cell subsets.

Genetic testing for susceptibility to adult-onset cancer. The process and content of informed consent.

OBJECTIVE: To provide guidance on informed consent to clinicians offering cancer susceptibility testing. PARTICIPANTS: The Task Force on Informed Consent is part of the Cancer Genetics Studies Consortium (CGSC), whose members were recipients of National Institutes of Health grants to assess the implications of cancer susceptibility testing. The 10 task force members represent a range of relevant backgrounds, including various medical specialties, social science, genetic counseling, and consumer advocacy. EVIDENCE: The CGSC held 3 public meetings from 1994 to 1996. At its first meeting, the task force jointly established a list of topics. The cochairs (G.G. and J.R.B) then developed an outline and assigned each topic to an appropriate writer and reviewer. Writers summarized the literature on their topics and drafted recommendations, which were then revised by the reviewers. The cochairs compiled and edited the entire manuscript. All members were involved in writing this report. CONSENSUS PROCESS: The first draft was distributed to task force members, after which a meeting was held to discuss its content and organization. Consensus was reached by voting. A subsequent draft was presented to the entire CGSC at its third meeting, and comments were incorporated. CONCLUSIONS: The task force recommends that informed consent for cancer susceptibility testing be an ongoing process of education and counseling in which (1) providers elicit participant, family, and community values and disclose their own, (2) decision making is shared, (3) the style of information disclosure is individualized, and (4) specific content areas are discussed.

Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium.

OBJECTIVE: To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations associated with hereditary nonpolyposis colon cancer (HNPCC). PARTICIPANTS: A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by the National Human Genome Research Institute (previously the National Center for Human Genome Research). EVIDENCE: Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to colon cancer were identified using MEDLINE and bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "colon cancer," and "screening" in combination with "cancer family" and "HNPCC." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. CONSENSUS PROCESS: The task force developed recommendations through discussions over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on observational studies, colonoscopy every 1 to 3 years starting at age 25 years is recommended for individuals known to have HNPCC-associated mutations. Endometrial cancer screening is also recommended, based on expert opinion concerning presumptive benefit. No recommendation is made for or against prophylactic surgery (ie, colectomy, hysterectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.

Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium.

OBJECTIVE: To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations in the BRCA1 or BRCA2 genes. PARTICIPANTS: A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by National Human Genome Research Institute (previously the National Center for Human Genome Research). EVIDENCE: Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to breast and ovarian cancer were identified using MEDLINE (National Library of Medicine) and from bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "breast cancer," "ovarian cancer," and "screening," or "surveillance" in combination with "cancer family" and "BRCA1" and "BRCA2." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. CONSENSUS PROCESS: The task force developed recommendations through discussions over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on expert opinion concerning presumptive benefit, early breast cancer and ovarian cancer screening are recommended for individuals with BRCA1 mutations and early breast cancer screening for those with BRCA2 mutations. No recommendation is made for or against prophylactic surgery (eg, mastectomy, oophorectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking, and case reports have documented the occurrence of cancer following prophylactic surgery. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.