Scientific and Regulatory Policy Committee Points to Consider*: Review of Scientific and Regulatory Policy Committee Points to Consider: Review of Current Practices for Ultrastructural Pathology Evaluations in Support of Nonclinical Toxicology Studies.

Anatomic pathology and clinical pathology end points are standard components of almost every nonclinical general toxicity study conducted during the risk assessment of novel pharmaceuticals and chemicals. On occasion, an ultrastructural pathology evaluation using transmission electron microscopy (TEM) may be included in nonclinical toxicity studies. Transmission electron microscopy is most commonly used when a light microscopic finding may require further characterization that could inform on the pathogenesis and/or mechanism of action. Regulatory guidance do not address the use of TEM in general study designs nor whether these assessments should be performed in laboratories conducted in compliance with Good Laboratory Practices. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current practices on the use of TEM in nonclinical toxicity studies. The Working Group constructed a survey sent to members of societies of toxicologic pathology in the United States, Europe, Britain, and Japan, and responses were collected through the STP for evaluation by the Working Group. The survey results and regulatory context are discussed, as are "points to consider" from the collective experience of the Working Group. This survey indicates that TEM remains an essential diagnostic option for complementing toxicologic pathology evaluations. *This Points to Consider article is a product of a Society of Toxicologic Pathology (STP) Working Group commissioned by the Scientific and Regulatory Policy Committee (SRPC) of the STP. It has been reviewed and approved by the SRPC and Executive Committee of the STP but it does not represent a formal Best Practice recommendation of the Society; rather, it is intended to provide key "points to consider" in designing nonclinical studies or interpreting data from toxicity and safety studies intended to support regulatory submissions. The points expressed in this document are those of the authors and do not reflect views or policies of the employing institutions. Readers of Toxicologic Pathology are encouraged to send their thoughts on these articles or ideas for new topics to the Editor.

Opinion: redefining the role of the physician in laboratory medicine in the context of emerging technologies, personalised medicine and patient autonomy ('4P medicine').

The role of clinical pathologists or laboratory-based physicians is being challenged on several fronts-exponential advances in technology, increasing patient autonomy exercised in the right to directly request tests and the use of non-medical specialists as substitutes. In response, clinical pathologists have focused their energies on the pre-analytical and postanalytical phases of Laboratory Medicine thus emphasising their essential role in individualised medical interpretation of complex laboratory results. Across the European Union, the role of medical doctors is enshrined in the Medical Act. This paper highlights the relevance of this act to patient welfare and the need to strengthen training programmes to prevent an erosion in the quality of Laboratory Medicine provided to patients and their physicians.

Investigation of pathology malpractice claims in China from 2002-2015.

OBJECTIVE: To examine pathology-related medical claims in China and identify the most common errors to result in such claims. METHOD: A retrospective analysis was performed of 71 forensic evaluation reports carried out in two Chinese institutes of forensic medicine between 2002 and 2015 due to suspicion of medical malpractice. The judicial outcomes of each case were also reviewed when available. RESULTS: Of 71 cases, 54 cases had judicial outcomes. The most frequently claimed events were false-negative diagnoses of skin cancer, invasive ductal carcinoma of the breast, and osteosarcoma; and false positive diagnoses of uterine cervical squamous cell carcinoma, gastric carcinoma, and soft tissue carcinoma. The most common cause of error (82%, 56 of 68) was pathological misinterpretation. Plaintiffs in most cases (89%, 48 of 54) received compensation. CONCLUSION: Our data are in agreement with other findings regarding the most frequent medical malpractice allegations related to pathology. Addressing the issues at the root of these claims would lead to a decline in the number of medical errors. Quality assurance programs and good pathologist-clinician communication may decrease the risk of litigation.

Legal responsibility of the pathologist in Tunisia.

The role of the pathologist has been highlighted by the medias since the recent years and the Tunisian law system suffers from a huge and there are no rules or jury verdicts concerning the e responsability  of the doctors in general with emphasis on pathologists. One might think that the lack of laws benefits to the pathologist, on the other hand, we can consider this as dangerous either for the patients or the pathologists. This lack of laws makes the judge dependant on the expert view. Other countries like European ones and the United States, has available data furnished by the insurance bodies that enrich the jury verdicts and the different laws that are available. Our aim was to help the pathologists understand their legal responsibilities and the law system. The latter may seem as complex for the pathologist as a pathologic report for a judge.

STP Best Practices for Evaluating Clinical Pathology in Pharmaceutical Recovery Studies.

The Society of Toxicologic Pathology formed a working group in collaboration with the American Society for Veterinary Clinical Pathology to provide recommendations for the appropriate inclusion of clinical pathology evaluation in recovery arms of nonclinical toxicity studies but not on when to perform recovery studies. Evaluation of the recovery of clinical pathology findings is not required routinely but provides useful information on risk assessment in nonclinical toxicity studies and is recommended when the ability of the organ to recover is uncertain. The study design generally requires inclusion of concurrent controls to separate procedure-related changes from test article-related changes, but return of clinical pathology values toward baseline may be sufficient in some cases. Evaluation of either a select or full panel of standard hematology, coagulation, and serum and urine chemistry biomarkers can be scientifically justified. It is also acceptable to redesignate dosing phase animals to the recovery phase or vice versa to optimize data interpretation. Assessment of delayed toxicity during the recovery phase is not required but may be appropriate in development programs with unique concerns. Evaluation of the recovery of clinical pathology data for vaccine development is required and, for efficacy markers, is recommended if it furthers pharmacologic understanding.

[Management of Ethical Problems in the Japanese Society of Laboratory Medicine].

The Ethics Committee of the Japanese Society of Laboratory Medicine published "Opinions of Japanese Society of Laboratory Medicine about utilization of specimens after laboratory examinations for laboratory work, education and clinical studies" in 2002, and amended it in 2008. The Ethics Committee, Committee for Conflict of Interest, Compliance Committee, and Editorial Committee for Rinsho Byori, the official journal of the Japanese Society of Laboratory Medicine, cooperate to solve ethical problems in laboratory medicine. The management of ethical problems in the Japanese Society of Laboratory Medicine is discussed.

[Laboratory management fee in national health insurance; what is required from clinical laboratory physicians? --message from Chairpersons].

The laboratory management fee (LMF) in national health insurance ("Kentai-Kensa-Kanri-Kasan" in Japanese) has had a major impact on Japanese clinical laboratories, especially in recent years. In 2012, the fee was raised to approximately 5,000 yen per admitted patient. In order to address this national support, clinical pathologists are required to increase their knowledge and skills. On the other hand, there are insufficient clinical pathologists in Japan. In order to solve this problem, the Japanese Society of Laboratory Medicine (JSLM) approved a new license for Qualified Clinical Laboratory Managing Physicians (CLMPs), in addition to Certified Clinical Laboratory Physicians (CCLPs). The requirements to become a CLMP are less strict than for CCLP. There are approximately 500 CLMPs and 600 CCLPs in this country. The aim of this symposium was to offer opportunities to increase attendees' clinical skills, especially CLMPs and young clinical pathologists. Four CCLPs were chosen as speakers from a university hospital, a major city hospital, a medium-sized acute care hospital, and a university hospital anatomical pathologist, together with a chief medical technologist from a university hospital. All the speakers presented their ideal role models of clinical pathologists matching LMF requirements. JSLM together with the Japanese Association of Clinical Laboratory Physicians (JACLaP) sponsored this symposium. It was a successful meeting with more than two hundred attendees.

Placental release or disposal? Experiences of perinatal pathologists.

Placentas have been often considered medical waste in hospitals. This view is particularly held by the patients themselves, who may not understand the importance of placental examination. Hospitals have been receiving requests for placental release to patients and need to be prepared to handle these requests. Therefore, a survey was conducted to explore the experiences and practices of perinatal pathologists with respect to placental release. Utilizing SurveyMonkey, we emailed a survey to 192 practicing perinatal pathologists in the United States and Canada. Questions were asked about policies in force at their particular institution, conditions of release, and the purpose of release, ie, what the disposition of the placenta was after release to the family. Thirty-six responses were received; 22 (61.1%) of respondents did allow release of placentas, and those who did not release usually reported that they had not received requests for release. In most cases, specific policies were in place, with multiple departments within the hospital having input on the creation of the policy. Parental signature was required in most cases. The most common reason for patient request was to bury the placenta, although some placental release was for consumption and/or encapsulation. Although there are no specific religious requirements for use or burial of the placenta after delivery, there are many cultural reasons for requests. Hospitals and specific providers need to be aware of this interest and have a specific policy in place so that they are prepared when a request is received.

Satisfying regulatory and accreditation requirements for quality control.

The Clinical Laboratory Improvement Amendments of 1988 (CLIA) requires all US clinical laboratories that test "materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease..." to be regulated. The CLIA mandates are site neutral; based on test complexity; and focus on the three phases of the testing process (preanalytical, analytical, and postanalytical). Many testing sites choose to meet the CLIA requirements by following the testing standards of a professional accreditation organization deemed by the Centers for Medicare and Medicaid Services. The three principal organizations are The Joint Commission, the College of American Pathologists, and COLA.

Guidelines for biomarker testing in colorectal carcinoma (CRC): a national consensus of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM).

This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology and the Spanish Society of Medical Oncology, makes diagnostic and treatment recommendations for the management of patients with hereditary, localised and advanced CRC based on the current scientific evidence on biomarker use. This consensus statement thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the currently available data on this subject, this expert group recommends testing for microsatellite instability (MSI) in patients with localised CRC, as this is a strong predictive factor for deciding on adjuvant treatment. However, although the ColoPrint(®) and Oncotype Dx(®) gene expression signatures have been shown to have prognostic value, no consensus yet exists concerning their use in clinical practice. For advanced CRC, it is essential to test for KRAS mutation status before administering an anti-EGFR treatment, such as cetuximab or panitumumab. However, testing for other biomarkers, such as BRAF, EGFR, PI3K and PTEN mutations, should not be done routinely, because this does not influence treatment planning at the present time. Other important issues addressed include organisational requirements and the quality controls needed for proper testing of these biomarkers as well as the legal implications to be borne in mind when testing some biomarkers.

[Development of targeted indicators of quality in postmortem examination].

The indicators of quality for impartial quantitative assessment of postmortem examination have been suggested. These indicators were based on ratio of achievement and target indexes of pathologicoanatomic activity. The indicators are necessary for decision making for enhancement of pathologicoanatomic service quality in the health-care agencies.

Pretransfusion testing practices in North America, 2005-2010: an analysis of the College Of American Pathologists Interlaboratory Comparison Program J-survey data, 2005-2010.

CONTEXT: Data collection and analysis of the College of American Pathologists (CAP) Interlaboratory Comparison Program (Proficiency Testing) J-Survey results provide insights into North American pretransfusion compatibility testing practices and trends. OBJECTIVES: To assess current North American manual testing practices for ABO grouping, rhesus (Rh) typing, antibody screening, and crossmatching using CAP proficiency testing data. DESIGN: Analysis of the CAP Interlaboratory Comparison Program J-Survey data (2005-2010) to identify laboratory methods used for ABO grouping, Rh typing, antibody screening, and crossmatching. Data were analyzed by test method using Microsoft (Redmond, Washington) Excel software. RESULTS: The method used most often in ABO grouping and Rh typing was tube testing. Many laboratories also used tube testing for antibody detection and crossmatching, but during the study period, the proportion of laboratories using gel-based methodologies increased considerably. CONCLUSIONS: Most North American CAP laboratories continue to use tube methods for ABO/Rh testing. Use of gel-based methodologies increased during the past 5 years for antibody screening and crossmatching.

Trends in pathology malpractice claims.

Previously reported analyses of pathology malpractice claims reported to The Doctors Company from 1995 through 2003 uncovered repetitive patterns of specimen type and diagnostic category that contributed to claims. To determine whether these patterns had changed, 276 pathology malpractice claims from 2004 through 2010 were reviewed and are the subject of this report. Claims involving melanoma, breast (specimens and fine needle aspiration), system error, gynecologic cytology, and fine needle aspiration (excluding breast) accounted for 49% of the total claims. There has been a significant decline in the number of claims involving melanoma, breast, and gynecologic cytology, and the factors contributing to this decline are discussed.

Legal issues for pathologists.

For better or for worse, the practice of pathology has evolved rapidly in the last decade, particularly the last several years. The dominance of certain national and regional pathology providers and the in-sourcing of pathology services as a revenue stream by nonpathology specialists have transformed pathology services into a commodity in many market, rather than a professional medical service. Despite significant health care reform and a myriad of compliance laws and regulations, it is unlikely that pathology practice will return to "the good old days." As a result, it is important for pathologists to become familiar with the trends in their specialty and have familiarity with the legal issues presented by these trends.