Tutorial on How the US Food and Drug Administration Regulates Parenteral Nutrition Products.

Parenteral nutrition (PN) products are regulated in the United States by the Food and Drug Administration (FDA). The FDA regulates PN products as "drugs," and the approval of a new product depends on there being "substantial evidence" of safety and efficacy obtained from "adequate and well-controlled studies." The processes by which the FDA approves PN products in the United States are designed to protect patients from unsafe or ineffective products, but they may also contribute to delaying and preventing access to certain valuable new products. This tutorial is designed to inform the PN community about FDA processes with regard to PN products, including the structure of FDA review teams, requirements for investigational studies, applications for marketing approval, postapproval clinical trial requirements, and requirements for studies in pediatric populations. Knowledge of how the FDA process works and how the FDA regulates PN products can help the PN community work together in advancing the development of new products.

Food and Drug Administration Requirements for Clinical Studies in Pediatric Patients.

Many drugs approved by the US Food and Drug Administration (FDA) for use in adults lack adequate data on safety and efficacy in pediatric patients, a potential source of unintended harm to pediatric patients. Through a series of laws, regulations, and guidance documents, the US Congress and FDA have created a program both to encourage and mandate clinical studies in pediatric patients to develop evidence-based dosing, safety, and efficacy information. A "Pediatric Study Plan" (PSP) is required for every new drug. FDA provides incentives for the voluntary conduct of clinical trials in pediatric patients, including opportunities for added marketing exclusivity and for obtaining a "priority review voucher." FDA also mandates that clinical studies for new drugs be conducted in each pediatric age group (newborns, infants, children, and adolescents), except in circumstances where a waiver or a deferral of studies can be justified. Sometimes this mandate can be met by extrapolation from studies in adults, or from patients in one pediatric age group to another, for evidence of efficacy. However, separate studies of safety and dosing are usually required for each pediatric age group. The package insert for each new drug now must address the use in pediatric patients. In addition, the FDA website displays all changes in drug labeling related to pediatric patients (excerpted from the labels for easy access), summaries of all pediatric studies that have led to labeling changes, links to FDA medical reviews of pediatric studies, summaries of all pediatric safety issues presented to the FDA Pediatric Advisory Committee (with links to the meeting materials and transcripts), and details of deferred pediatric studies with their timelines and progress. These measures reflect the increasing attention by FDA and the medical community to the importance of clinical studies in pediatric patients.

Pathogenesis of hepatitis B virus-associated hepatocellular carcinoma.

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) remains the most common form of HCC in large areas of Asia and Africa. It remains common even in some countries where hepatitis C virus (HCV)-associated HCC has become the predominant form, such as Japan. Integration of HBV in HCC DNA is found at random sites in the host genome in nearly all patients with HBV-associated HCC. It is not clear how often this integration results in insertional mutagenesis, but previously unknown growth regulating genes and cancer-associated genes have been found frequently near HBV integration sites in HCC in recent studies. In addition, HBV encodes a transactivating protein, the X protein, which could enable the randomly integrated HBV to alter the function of host genes that are not near the integration site. Mutations at two adjacent codons in HBV (1762(T)/1764(A) mutations) within the X gene are frequently found in HCC patients, and may play a role in the mutagenic or transactivational role of HBV in HCC. The presence of cirrhosis in most patients with HBV-associated HCC, and the presence of mutations in tumor suppressor genes in many, suggests that these are also factors in hepatocarcinogenesis. Few studies have examined the mutations of more than one gene in the same HCC patients. Fewstudies have evaluated the interactions between HBV mutations, host gene mutations, cirrhosis, and other potentially mutagenic stresses at the cellular level, with progression to HCC, and few studies have been conducted to determine whether these changes must accumulate in succession to lead to HCC. The recent availability of rapid sequencing methods and DNA microarray technologies has permitted expression profiling and permutation analysis of an array of genes to explore the pattern and succession of molecular changes leading to HBV-associated HCC. To date, these methods have been used to show patterns of molecular changes that differ in HBV-associated HCC (compared to HCV-associated HCC or to HCC in patients lacking either virus) and patterns that can predict survival (and hence may directly indicate different mechanisms of disease), and may soon make possible a universally accepted clinical classification scheme for HCC.

Infections by hepatitis B surface antigen gene mutants in Europe and North America.

Hepatitis B virus (HBV) mutants have usually been studied in patients in Asia because of the wider use of HBV immunization there and the resultant emergence of viral mutants. Nevertheless, HBV surface antigen (S) gene mutants also are found in Europe and North America. In Europe and North America, HBV with mutations in the portion of the S gene coding the "a" determinant of the hepatitis B surface antigen (HBsAg) have been documented in small numbers of infants born to HBV-infected mothers following post-natal HBV vaccine and hepatitis B immune globulin (HBIG) prophylaxis and in many liver transplant recipients who develop HBV re-infection despite HBIG prophylaxis. In some cases, these mutations have included a glycine to arginine substitution at position 145 (G145R), which results in a conformational change and different reactivity to monoclonal antibody reagents than that of the wild-type virus. Mutations in the a determinant (but not G145R) also have been reported in European patients with chronic HBV infection who have not received HBV vaccine or HBIG. However, it appears that such mutations are only responsible for a small proportion of "occult" or "silent" HBV infections, which are characterized by the presence of HBV DNA in serum in the absence of detectable HBsAg. However, some of these mutant forms of HBV in cases of occult HBV may theoretically escape detection and could present a risk to blood safety.

SEN virus: epidemiology and characteristics of a transfusion-transmitted virus.

SEN virus (SEN-V) is a blood-borne, single-stranded, nonenveloped DNA virus. Although its prevalence varies by geographic region, it has been detected in as many as 30 percent of postoperative transfusion recipients, compared to 3 percent of postoperative patients who did not receive transfusions. A significant association has been observed between transfusion volume and the occurrence of SEN-V infection. Transmission by transfusion also has been confirmed by the detection of greater than 99 percent homology between SEN-V in donor and recipient sera. Concurrent infections with SEN-V and hepatitis B virus, hepatitis C virus, or human immunodeficiency virus type 1 have been documented, and these observations probably reflect the blood-borne transmission of these viruses as well as SEN-V. Although SEN-V was discovered as part of a search for causes of posttransfusion hepatitis, there is no firm evidence so far that SEN-V infection either causes hepatitis or worsens the course of coexistent liver disease. Nevertheless, SEN-V appears to be transmitted by transfusion, and further studies may reveal more about its role in the future.

Truncated hepatitis C virus core protein encoded in hepatocellular carcinomas.

Studies have suggested that a truncated form of the hepatitis C virus (HCV) core protein can enter hepatocyte nuclei and might play a role in HCV-associated hepato-carcinogenesis. In the present study, the HCV core gene from hepatocellular carcinomas (HCC) and/or adjacent non-tumorous liver tissues from eight patients was amplified by nested RT-PCR and sequenced. Mutations in the HCV core gene that would encode a truncated core protein were found in 4 of the 8 patients. Since truncated core proteins have been shown to be capable of entry into the hepatocyte nucleus (unlike HCV itself, which is an exclusively cytoplasmic virus), the detection of mutated sequences encoding them in these four HCC patients suggests that these mutations may have played a role in the development of these HCCs.

Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection.

BACKGROUND: A study was designed to estimate relative analytic sensitivity and window-period (WP) closure and to project incremental yield of newer HBsAg tests, pooled-sample NAT, and single-sample NAT, compared to currently licensed HBsAg tests. STUDY DESIGN AND METHODS: HBV DNA and HBsAg test results for 23 HBV seroconversion (SC) panels were first analyzed to construct a model of primary HBV viremia. One-hundred representative samples were then selected from 10 panels and coded with 28 analytical controls. All 128 samples were tested by seven HBsAg tests and by four pooled-sample and three single-sample NAT assay formats. Results were analyzed to obtain differential times to HBV detection and combined with HBV incidence rates to project comparative yields. RESULTS: HBV doubling time during the ramp-up phase was estimated at 2.56 days. HBsAg concentrations at cutoff for new tests ranged from 0.07 to 0.12 ng per mL, compared with 0.13 to 0.62 ng per mL for licensed tests. Estimated viral load at cutoff ranged from 102 to 267 IU per mL for new tests and from 363 to 1069 IU per mL for licensed tests. HBsAg tests detected 31 to 63 percent of early ramp-up phase samples in the 100-member seroconversion panel study, while pooled-sample NAT detected 55 to 71 percent and single-sample NAT, 82 to 99 percent. Compared with currently licensed HBsAg assays, newer HBsAg assays would reduce the WP by 2 to 9 days; pooled-sample NAT would reduce the WP by 9 to 11 days; and single-sample NAT would reduce the WP by 25 to 36 days. CONCLUSION: Newer HBsAg tests would be expected to detect an additional 15 to 21 infected units per 107 donations, compared to licensed HBsAg tests. Sensitivity, WP closure, and yield projections for newer HBsAg assays and pooled-sample NAT are comparable. Single-sample NAT would increase yield by 13 to 15 units per 107 donations over pooled-sample NAT and newer HBsAg assays and by 35 to 50 units per 107 donations over currently licensed HBsAg assays.

Drift in the hypervariable region of the hepatitis C virus during 27 years in two patients.

Serial serum samples were obtained over a 27-year period from a hepatitis C virus (HCV)-infected patient and from a nurse who appeared to become infected by this patient. The hypervariable region 1 (HVR1) and 5'noncoding region (5'NCR) of the HCV genome were amplified from each serum sample by polymerase chain reaction (PCR) and cloned. In the first serum specimen from the patient and the first two serum specimens from the nurse, most of the 20 clones from each serum sample had one common sequence in the HVR1 gene. All later serum samples contained a heterogeneous mixture of HCV quasispecies. The uniformity of the HVR1 sequence in the early samples and the emergence of greater diversity in later serum samples is consistent with the apparent transmission of HCV between the patient and nurse and the eventual emergence of other quasispecies as the virus replicated in the new host. In addition, the immune globulin given to the nurse may have been responsible for some of the HCV quasispecies changes observed in her serum.