Patenting genes and gene sequences: Analysis of public health implications and the law

At issue is whether or not isolated DNA is patent eligible under the U.S. Patent Law and the implications of that determination on public health. The U.S. Patent and Trademark Office has issued patents on DNA since the 1980s, and scientists and researchers have proceeded under that milieu since that time. Today, genetic research and testing related to the human breast cancer genes BRCA1 and BRCA2 is conducted within the framework of seven patents that were issued to Myriad Genetics and the University of Utah Research Foundation between 1997 and 2000. In 2009, suit was filed on behalf of multiple researchers, professional associations and others to invalidate fifteen of the claims underlying those patents. The Court of Appeals for the Federal Circuit, which hears patent cases, has invalidated claims for analyzing and comparing isolated DNA but has upheld claims to isolated DNA. The specific issue of whether isolated DNA is patent eligible is now before the Supreme Court, which is expected to decide the case by year's end. In this work, a systematic review was performed to determine the effects of DNA patents on various stakeholders and, ultimately, on public health; and to provide a legal analysis of the patent eligibility of isolated DNA and the likely outcome of the Supreme Court's decision. ^ A literature review was conducted to: first, identify principle stakeholders with an interest in patent eligibility of the isolated DNA sequences BRCA1 and BRCA2; and second, determine the effect of the case on those stakeholders. Published reports that addressed gene patents, the Myriad litigation, and implications of gene patents on stakeholders were included. Next, an in-depth legal analysis of the patent eligibility of isolated DNA and methods for analyzing it was performed pursuant to accepted methods of legal research and analysis based on legal briefs, federal law and jurisprudence, scholarly works and standard practice legal analysis. ^ Biotechnology, biomedical and clinical research, access to health care, and personalized medicine were identified as the principle stakeholders and interests herein. Many experts believe that the patent eligibility of isolated DNA will not greatly affect the biotechnology industry insofar as genetic testing is concerned; unlike for therapeutics, genetic testing does not require tremendous resources or lead time. The actual impact on biomedical researchers is uncertain, with greater impact expected for researchers whose work is intended for commercial purposes (versus basic science). The impact on access to health care has been surprisingly difficult to assess; while invalidating gene patents might be expected to decrease the cost of genetic testing and improve access to more laboratories and physicians' offices that provide the test, a 2010 study on the actual impact was inconclusive. As for personalized medicine, many experts believe that the availability of personalized medicine is ultimately a public policy issue for Congress, not the courts. ^ Based on the legal analysis performed in this work, this writer believes the Supreme Court is likely to invalidate patents on isolated DNA whose sequences are found in nature, because these gene sequences are a basic tool of scientific and technologic work and patents on isolated DNA would unduly inhibit their future use. Patents on complementary DNA (cDNA) are expected to stand, however, based on the human intervention required to craft cDNA and the product's distinction from the DNA found in nature. ^ In the end, the solution as to how to address gene patents may lie not in jurisprudence but in a fundamental change in business practices to provide expanded licenses to better address the interests of the several stakeholders. ^

Clinical trials, informed consent, & emergency medicine: A systematic literature review

Background: In the United States, the Food and Drug Administration (FDA) regulates clinical trials. These regulations address good clinical practices as well as human subject protection (FDA, 2012). One of the most important legal and ethical concerns in clinical trials is informed consent. 21 CFR 50 governs human subjects research. Part 50.24 provides an emergency research exception to the informed consent requirement. Research was conducted to determine the appropriateness of this exception, whether the benefit justifies the exception, and its public health significance.^ Methods: A systematic literature review was conducted and articles were identified from peer-reviewed journals.^ Results: There is some variance in opinions regarding the appropriateness of the exception, but the literature reviewed found the study results of these trials justified the waiver.^ Conclusion: The exception to the informed consent requirement is likely appropriate and justified in emergency research when implemented within the specified guidelines.^

Phase I clinical trials in 56 patients with thyroid cancer: the M. D. Anderson Cancer Center experience.

INTRODUCTION: Thyroid cancer is the most common endocrine malignancy. The outcomes of patients with relapsed thyroid cancer treated on early-phase clinical trials have not been systematically analyzed. PATIENTS AND METHODS: We reviewed the records of consecutive patients with metastatic thyroid cancer referred to the Phase I Clinical Trials Program from March 2006 to April 2008. Best response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: Fifty-six patients were identified. The median age was 55 yr (range 35-79 yr). Of 49 patients evaluable for response, nine (18.4%) had a partial response, and 16 (32.7%) had stable disease for 6 months or longer. The median progression-free survival was 1.12 yr. With a median follow-up of 15.6 months, the 1-yr survival rate was 81%. In univariate analysis, factors predicting shorter survival were anaplastic histology (P = 0.0002) and albumin levels less than 3.5 g/dl (P = 0.05). Among 26 patients with tumor decreases, none died (median follow-up 1.3 yr), whereas 52% of patients with any tumor increase died by 1 yr (P = 0.0001). The median time to failure in our phase I clinical trials was 11.5 months vs. 4.1 months for the previous treatment (P = 0.04). CONCLUSION: Patients with advanced thyroid cancer treated on phase I clinical trials had high rates of partial response and prolonged stable disease. Time to failure was significantly longer on the first phase I trial compared with the prior conventional treatment. Patients with any tumor decrease had significantly longer survival than those with any tumor increase.

Is paromomycin an effective and safe treatment against cutaneous leishmaniasis? A meta-analysis of 14 randomized controlled trials.

BACKGROUND: High cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26-1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54-0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56-1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV. CONCLUSIONS/SIGNIFICANCE: Topical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.

A systematic review of community-based colorectal cancer screening randomized controlled trials with multi-ethnic groups

Background. The CDC estimates that 40% of adults 50 years of age or older do not receive time-appropriate colorectal cancer screening. Sixty percent of colorectal cancer deaths could be prevented by regular screening of adults 50 years of age and older. Yet, in 2000 only 42.5% of adults age 50 or older in the U.S. had received recommended screening. Disparities by health care, nativity status, socioeconomic status, and race/ethnicity are evident. Disparities in minority, underserved populations prevent us from attaining Goal 2 of Healthy People 2010 to “eliminate health disparities.” This review focuses on community-based screening research among underserved populations that includes multiple ethnic groups for appropriate disparities analysis. There is a gap in the colorectal cancer screening literature describing the effectiveness of community-based randomized controlled trials. ^ Objective. To critically review the literature describing community-based colorectal cancer screening strategies that are randomized controlled trials, and that include multiple racial/ethnic groups. ^ Methods. The review includes a preliminary disparities analysis to assess whether interventions were appropriately targeted in communities to those groups experiencing the greatest health disparities. Review articles are from an original search using Ovid Medline and a cross-matching search in Pubmed, both from January 2001 to June 2009. The Ovid Medline literature review is divided into eight exclusionary stages, seven electronic, and the last stage consisting of final manual review. ^ Results. The final studies (n=15) are categorized into four categories: Patient mailings (n=3), Telephone outreach (n=3), Electronic/multimedia (n=4), and Counseling/community education (n=5). Of 15 studies, 11 (73%) demonstrated that screening rates increased for the intervention group compared to controls, including all studies (100%) from the Patient mailings and Telephone outreach groups, 4 of 5 (80%) Counseling/community education studies, and 1 of 4 (25%) Electronic/multimedia interventions. ^ Conclusions. Patient choice and tailoring education and/or messages to individuals have proven to be two important factors in improving colorectal cancer screening adherence rates. Technological strategies have not been overly successful with underserved populations in community-based trials. Based on limited findings to date, future community-based colorectal cancer screening trials should include diverse populations who are experiencing incidence, survival, mortality and screening disparities. ^

A systematic review of the evidence for use of herbal medicine for the treatment of acute diarrhea

Background. Acute diarrhea (AD) is an important cause of morbidity and mortality among both children and adults. An ideal antidiarrheal treatment should be safe, effective, compatible with Oral Rehydration Solution, and inexpensive. Herbal medicines, if effective, should fit these criteria as well or better than standard treatment. ^ Objective. The objective of the present study was to assess the effectiveness of plant preparations in patients with AD in reports of randomized and non-randomized controlled trials. ^ Aims. The aims of the present study were to identify effective antidiarrheal herbs and to identify potential antidiarrheal herbs for future studies of efficacy through well designed clinical trials in human populations. ^ Methods. Nineteen published studies of herbal management of AD were examined to identify effective plant preparations. Ten plant preparations including Berberine (Berberis aristata), tormentil root ( Potentialla tormentilla), baohauhau (from the baobaosan plant), carob (Ceratonia siliqua), pectin (Malus domestica), wood creosote (Creosote bush), guava (Psidium guajava L.), belladonna (Atropa belladonna), white bean (Phaseolis vulgaris), and wheat (Triticum aestivum) were identified. ^ Results. Qualitative data analysis of nineteen clinical trials indicated berberine’s potentially valuable antisecretory effects against diarrhea caused by Vibrio cholerae and enterotoxigenic Escherichia coli. Tormentil root showed significant efficacy against rotavirus-induced diarrhea; carob exhibited antidiarrheal properties not only by acting to detoxify and constipate but by providing a rich source of calories; guava and belladonna are antispasmodics and have been shown to relieve the symptoms of AD. Finally, white bean and wheat yielded favorable clinical and dietary outcomes in children with diarrhea. ^ Conclusion. The present study is the first to review the evidence for use of herbal compounds for treatment of AD. Future randomized controlled trials are needed to evaluate their efficacy and safety.^

A systematic review of personalized therapy in patients with advanced cancer

Background: An increased understanding of the pathogenesis of cancer at the molecular level has led to the development of personalized cancer therapy based on the mutation status of the tumor. Tailoring treatments to genetic signatures has improved treatment outcomes in patients with advanced cancer. We conducted a meta-analysis to provide a quantitative summary of the response to treatment on a phase I clinical trial matched to molecular aberration in patients with advanced solid tumors. ^ Methods: Original studies that reported the results of phase I clinical trials in patients with advanced cancer treated with matched anti-cancer therapies between January 2006 and November 2011 were identified through an extensive search of Medline, Embase, Web of Science and Cochrane Library databases. Odds Ratio (OR) with 95% confidence interval (CI) was estimated for each study to assess the strength of an association between objective response rate (ORR) and mutation status. Random effects model was used to estimate the pooled OR and their 95% CI was derived. Funnel plot was used to assess publication bias. ^ Results: Thirteen studies published between January 2006 and November 2011that reported on responses to matched phase I clinical trials in patients with advanced cancer were included in the meta-analysis. Nine studies reported on the responses seen in 538 of the 835 patients with driver mutations responsive to therapy and seven studies on the responses observed in 234 of the 306 patients with mutation predictive for negative response. Random effects model was used to estimate pooled OR, which was 7.767(95% CI = 4.199 − 14.366; p-value=0.000) in patients with activating mutations that were responsive to therapy and 0.287 (95% CI = 0.119 − 0.694; p-value=0.009) in patients with mutation predictive of negative response. ^ Conclusion: It is evident from the meta-analysis that somatic mutations present in tumor tissue of patients are predictive of responses to therapy in patients with advanced cancer in phase I setting. Plethora of research and growing evidence base indicate that selection of patients based on mutation analysis of the tumor and personalizing therapy is a step forward in the war against cancer.^