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After compulsory licensing: coming issues in Canadian pharmaceutical policy and politics.

Bills C-22 and C-91 eliminated compulsory licensing for pharmaceutical products in Canada. However, in the wake of these bills there are pressing issues of pharmaceutical policy that need to be decided. The value of additional spending in pharmaceutical R and D has yet to be evaluated. There needs to be a public debate about how far government policy should go in encouraging pharmaceutical R and D as opposed to investing resources in other areas. There has been a continuing escalation in the cost of the average prescription, due to the introduction of newer, but not necessarily more effective, medications. So far government has not been willing to commit resources to promote cost-effective prescribing. Pharmaceutical companies are now lobbying for more rapid approval of products and an extension to the normal patent period to make up for the time that drugs spend in the regulatory process. The process that the government uses to resolve these issues will be just as important as the ultimate decisions.

Canada↗

A randomized trial of two acellular pertussis vaccines (dTpa and pa) and a licensed diphtheria-tetanus vaccine (Td) in adults.

A single blinded randomized controlled trial to compare the reactogenicity and immunogenicity of adult formulated dTpa and monovalent pa vaccines with a licensed Td vaccine. Five hundred and forty-eight healthy adults aged 19-70 years received a single injection of dTpa or separate injections of pa or Td (with the alternate vaccine 1 month later). Local and systemic reactions were monitored for 15 days after each vaccination. Serum antibody levels were measured immediately prior to and 1 month after vaccination. Antibody levels were measured 12 months after vaccination in 100 subjects. There was no difference in the total frequency of symptoms and signs between subjects receiving any of the three vaccines. There was a significantly lower incidence of local reactions following pa (60%) than dTpa (80%, P=0.002) or Td (93%, P=0.0008). The incidence of clinically significant (Grade 2 or 3) swelling (> or =20 mm) was higher for Td (20%, P=0.002) than for dTpa (11%) or for pa (2%), however, there were no other significant differences in the incidence of Grade 2 or 3 reactions between the vaccines. A high anti-pertussis seroconversion rate (>97%) against all the studied pertussis antigens was seen 1 month after vaccination with dTpa and pa. A total of 96 and 99% of subjects receiving dTpa and Td, respectively, had anti-diphtheria titres > or =0.01 IU/ml, and all but one subject had anti-tetanus titres > or =0.1 IU/ml after 1 month. Twelve months after vaccination the majority (90-100%) of the subjects were still seropositive for each antigen and although GMTs had decreased they were substantially higher than pre-vaccination levels. The dTpa vaccine was well tolerated and capable of eliciting an immune response against all the antigens in a broad spectrum of the adult population and could potentially replace Td for routine boosters in adults.

Adhesins, Bacterial↗

Comparative efficacy of a Coxiella burnetii chloroform:methanol residue (CMR) vaccine and a licensed cellular vaccine (Q-Vax) in rodents challenged by aerosol.

Q fever is an acute and self-limited febrile illness caused by the obligate intracellular bacterium Coxiella burnetii. While phase I cellular Q fever vaccines are efficacious in humans, vaccination of immune individuals may result in sterile abscesses and granulomas. The chloroform:methanol residue vaccine (CMR) was developed as a safer alternative. The efficacy of a licensed phase I cellular vaccine (Q-Vax) was compared with that of CMR vaccine in A/J mice and Hartley guinea pigs challenged with virulent phase I C. burnetii by aerosol. Both vaccines were efficacious. The CMR vaccine dose required to protect 50% of mice (PD50) against lethal aerosol challenge (11 LD50) was one-third of the Q-Vax dose. However, the PD50 for CMR was four times the Q-Vax dose in guinea pigs challenged by aerosol (60 LD50). It was concluded that CMR is an efficacious alternative to cellular Q fever vaccines for the prevention of Q fever.

Aerosols↗

Determination of CDT, a marker of chronic alcohol abuse, for driving license issuing: immunoassay versus capillary electrophoresis.

The present work is aimed at a validation of the carbohydrate-deficient transferrin (CDT) determination in real cases by comparison between the a commercial immunometric method and a method based on capillary electrophoresis. Overall, 650 serum samples from subjects applying to re-obtain their driving license, previously withdrawn for "drunk driving", were investigated. A highly significant correlation (P < 0.001) was found between the results from immunoassay and capillary electrophoresis. However, particularly in the samples with CDT values around the cut-off or moderately elevated, a wide dispersion of the correlation data was found. This finding stresses the need to confirm by alternative techniques all the results from CDT immunoassays. For this purpose, capillary electrophoresis, because of its inherent characteristics of high selectivity, easy operation, high productivity and low operative costs looks well-suited for becoming the method of choice.

Adult↗

Simultaneous hair testing for opiates, cocaine, and metabolites by GC-MS: a survey of applicants for driving licenses with a history of drug use.

A sensitive GC-MS method for the simultaneous determination of opiates, cocaine, and metabolites in hair at a cut-off level of 0.1 ng/mg was adopted to assess past exposure to these drugs in applicants for driving licenses with a history of drug use. The sampling protocol consisted of collection of one hair (sample A, 5-cm length) and one urine sample. When hair and urine (EMIT Syva, cut-off levels: 0.3 mg/l for opiates, 0.15 mg/l for cocaine, GC-MS confirmation of positives) were both positive or negative the protocol was concluded. In the other cases, the assessment of 'current exposure' to drugs was carried out, in order to avoid seriated random urinalysis, by collecting a second hair sample (sample B) 6 weeks later and analysing the proximal 1-cm segment. Out of the 214 'A' hair samples analyzed, 14 (6.5%) tested positive for morphine and/or 6-acetylmorphine (6AM), and 26 (12%) for cocaine and/or benzoylecgonine (BE), whereas none of the samples tested positive for both drugs. Levels between 0.1 and 1 ng/mg of the single analytes were found in eight out of the 14 morphine-6AM positives (57%) and in 18 out of the 26 cocaine-BE positives (69%). The time course of positive cases showed a progressive decrease of morphine-6AM positives and a corresponding increase of cocaine-BE positives within the study period September 1995-February 1999. No cases with positive urine and negative hair were observed. Among the 40 positive cases, seven (four and three for opiates and cocaine, respectively) were found to be 'currently exposed to drug', four by urinalysis (three and one) and three by analysis of the hair sample B (1 and 2).

Automobile Driving↗

Licensing new antibacterial agents - a European perspective.

There are two procedures by which new antibacterial agents may be granted marketing authorisation in the EU. The Centralised Procedure involves a single application through the European Agency for the Evaluation of Medicinal Products (EMEA). If a positive opinion is advised by the Committee on Proprietary Medicinal Products (CPMP), the European Commission grants a marketing authorisation in all EU Member States (MS). In the Mutual Recognition Procedure, the first EU country to license the drug becomes the Reference MS (RMS) and the company then requests some or all of the other MS to recognise this first authorisation. Both Centralised and Decentralised Procedures result in a Summary of Product Characteristics (SPC) which is identical in all EU MS. These EU-wide procedures have made possible the development of CPMP guidance regarding the clinical development of antibacterial agents, the presentation of data on in-vitro activity in SPCs, and the exploration of the pharmacokinetic-pharmacodynamic relationship. In addition, many CPMP guidelines that are applicable to a wide range of drugs, such as that regarding drug development in children, are pertinent to antibacterial agents.

Anti-Bacterial Agents↗

Analysis of a coded panel of licensed vaccines by polymerase chain reaction-based reverse transcriptase assays: a collaborative study [seecomments].

BACKGROUND: A recent publication reporting the presence of low levels of reverse transcriptase (RT) activity in certain vaccines for human use necessitated that regulatory agencies address the issue of whether this RT activity presented a risk to humans. Detection of low levels of RT activity corresponding to fewer than ten virions became possible with the development of highly-sensitive polymerase chain reaction (PCR)-based RT (PBRT) assays. Variations of the PBRT assay were developed in three laboratories. These assays were reported as being at least one million-fold more sensitive than conventional RT assays. OBJECTIVE: To ascertain the sensitivity and reliability of PBRT assays in different laboratories and to determine which vaccine samples possessed RT activity. STUDY DESIGN: Coded panels of licensed vaccines together with positive and negative controls was assembled at the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA) and distributed to five cooperating laboratories as well as to our laboratory at CBER. Each laboratory carried out their version of the PBRT assay and submitted the results to the coordinator at CBER. RESULTS: Results of the PBRT analyses carried out in the six laboratories are presented. Five of the six laboratories reported results that were highly consistent. RT activity was detected in live attenuated vaccines that were prepared in chick embryo cells (mumps, measles and yellow fever), but very low or undetectable RT activity was found in vaccines produced in mammalian cells (rabies and rubella). Influenza vaccines from several manufacturers included in the panel displayed the most variability, with different products of this inactivated vaccine having differing amounts of RT activity. CONCLUSIONS: Only vaccines produced in chick embryo cells had significant RT activity. Because RT activity was present in the allantoic fluid of uninfected chick embryos and culture medium from chick embryo fibroblasts, the RT activity arises from the cell substrate used for vaccine production. The PBRT assays were reliably able to detect the low levels of RT activity in chicken-derived vaccines.

Animals↗

[The incidence of prescriptions without marketing product license in a neonatal intensive care unit].

UNLABELLED: Most of the drugs prescribed in pediatric units have no product licence. The lack of clinical studies in children and appropriate drug formulations decrease their safety. The lack of a legal framework makes the prescriber insecure. Even if the debate is not recent, few studies have been carried out in this field. The aim of the present study was to evaluate the rate of prescriptions of unlicensed and off-label drugs in a neonatal intensive care unit. PATIENTS AND METHODS: The present study was carried out in our neonatal intensive care unit, from January 12 to February 12, 1998. Forty babies aged 0 to 128 days were included (90% newborns), with a gestational age between 25 to 40 weeks (88% were premature, with a birth weight lower than 1000 g). RESULTS: Two hundred and fifty-seven prescriptions were administered with 55 different types of drugs during this period. Ten percent of the prescribed drugs had no product licence. Sixty-two percent were off-label for premature infants and 64% for newborns: 90% due to age, 9.3% due to dose and 0.7% to method of administration. No therapeutic alternatives to these prescriptions were found among the few available licensed drugs. CONCLUSION: The prescriptions of unlicensed and off-label drugs in neonatal intensive care units are daily and repeated events. The prescribers are usually not aware of the exact status of the drug and do not realize neither he importance of the problem nor the legal and potential consequences. The lack of pediatric clinical studies is to a large extent responsible for the absence of drug registration in pediatrics. The pharmaceutical industry has few incentives to develop the pediatric product licences.

Age Factors↗

The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1).

G(1) cell cycle regulators are often mutated in cancer, but how this causes genomic instability is unclear. Here we show that yeast lacking the CDK inhibitor Sic1 initiate DNA replication from fewer origins, have an extended S phase, and inefficiently separate sister chromatids during anaphase. This leads to double-strand breaks (DSBs) in a fraction of sic1 cells as evidenced by the accumulation of Ddc1 foci and a 575-fold increase in gross chromosomal rearrangements. Both S and M phase defects are rescued by delaying S-CDK activation, indicating that Sic1 promotes origin licensing in late G(1) by preventing the untimely activation of CDKs. We propose that precocious CDK activation causes genomic instability by altering the dynamics of S phase, which then hinders normal chromosome segregation.

Cell Cycle Proteins↗

Using the biologic license application or new drug application as a basis for the common technical document.

With the introduction of the common technical document (CTD), many writers in the biotech and pharmaceutical industries are now required to submit dossiers in this format. The format of the CTD is not extremely difficult from the familiar documents of the Biologic License Application (BLA) or New Drug Application (NDA). The CTD can be mapped to existing areas of the BLA or NDA. The components of the CTD are discussed and references to the current guidance worldwide are provided to assist the writer.

Documentation↗

A license to kill: transcriptional activation and enhanced turnover of Myc by the SCF(kp2) ubiquitin ligase.

Understanding the mechanisms through which the abundance and activity of the Myc oncoprotein is regulated has been a major preoccupation of the cancer and transcription communities. New work, published in the May issue of Molecular Cell, reveals that ubiquitination of Myc by the oncogenic SCF(Skp2) complex not only promotes Myc turnover but is also required for Myc transcriptional activation, suggesting that Myc activity is "licensed" by ubiquitination.

Humans↗

Do parent-imposed delayed licensure and restricted driving reduce risky driving behaviors among newly licensed teens?

Motor vehicle crashes are the leading cause of death and injury to teenagers. Crash risks result from their age, inexperience, and risky driving. The purpose of this study was to determine whether parent-imposed delayed licensure and restricted driving are related to fewer teenage risky driving behaviors. At baseline, 275 teenagers with a learner's permit and one of their parents were interviewed about driving attitudes and teenage behaviors. One year later, 161 of the teenagers had since obtained a provisional license and were reinterviewed about time of licensure, parental restrictions on driving, and driving attitudes and behaviors. The results indicated that parents delayed licensure until teens were "ready," and limited their driving in terms of trip and risk conditions. Higher levels of risky driving behaviors were predicted by younger ages at licensure and fewer limits on driving in the first month, in addition to male gender, higher conflict over driving, lower perceptions of dangers related to driving, more problem behaviors at baseline, and more high-risk driving (e.g., at night, teenage passengers). Overall, the results indicate that a combination of being older at licensure and restricting driving under high-risk conditions at licensure may be an effective way to curb teens' risky driving behaviors.

Adolescent↗

Web-based strategies to disseminate a sun safety curriculum to public elementary schools and state-licensed child-care facilities.

The Sunny Days, Healthy Ways curriculum, which has been effective in previous trials, was disseminated to public elementary schools (n=2,030) and state-licensed child-care facilities (n=3,755) in 4 states. Two Web sites were created, varying in the amount and type of information. Mailings referred principals and directors to the sites. Overall 117 unique users made 172 visits to the sites. More repeat visits were made to the enhanced than to the basic site (p=.04). In a survey, 20.0% of principals and directors recalled receiving the mailings and 80.9% of these read them. Web-based strategies were weak, but the low response rate may be typical for such marketing. They will require supplementation by more personal approaches.

Adolescent↗

Depletion of licensing inhibitor geminin causes centrosome overduplication and mitotic defects.

Metazoans limit origin firing to once per cell cycle by oscillations in cyclin-dependent kinases and the replication licensing inhibitor geminin. Geminin inhibits pre-replication complex assembly by preventing Cdt1 from recruiting the minichromosome maintenance proteins to chromatin. Geminin depletion results in genomic over-replication in Drosophila and human cell lines. Here, we show that loss of geminin affects other cell cycle-dependent events in addition to DNA replication. Geminin inactivation causes centrosome overduplication without passage through mitosis in human normal and cancer cells. Centrosomes are microtubule-organizing centres that are duplicated during S phase and have an important role in the fidelity of chromosome transmission by nucleating the mitotic spindle. Consistent with this, geminin-depleted cells show multiple mitotic defects, including multipolar spindles, when driven into mitosis by checkpoint abrogation. These results show that the consequences of geminin loss exceed its immediate role in DNA replication and extend to promoting chromosome mis-segregation in mitosis.

Caffeine↗

Accuracy of self-reported pesticide use duration information from licensed pesticide applicators in the Agricultural Health Study.

Epidemiologists frequently rely on self-reported information regarding a variety of exposures including smoking history, medication use, and occupational exposure because other sources of information are either unavailable or difficult to obtain. One way to evaluate the accuracy of self-reported information is through logic checks using other sources. To assess the quality of the self-reported pesticide product use history of 57,311 licensed pesticide applicators in the Agricultural Health Study (AHS), we compared the self-reported decade of first use and total years of use to the year the pesticide active ingredient was first registered for use. We obtained pesticide active ingredient registration information from the United States Environmental Protection Agency (USEPA) and other publicly available sources for the 52 pesticides on the AHS initial questionnaires administered from 1994 to 1997. Based on the registration year, we assessed 19 pesticides for potential inaccuracies regarding duration of use or decade of first use. When calculating potential total years of use, we did not consider the impact of chemicals being removed from the market, since the possibility for continued use existed. The majority of respondents provided plausible responses for both decade of first use and total duration of use. On average, 1% of the subjects overestimated total possible duration of use, ranging from less than 1% for carbofuran and chlorpyrifos to 5% for imazethapyr. Decade of first use was also reasonably reported, although more subjects did not report decade of first use than duration of use, with an average of 6% of subjects missing decade information for an individual chemical. For subjects who reported a decade of first use, 98% gave plausible responses on average, with overestimates highest for cyanazine, introduced in 1971 (6% reported earlier use), and chlorimuron ethyl, introduced in 1985 (7% reported earlier use). This analysis provided the opportunity to consider only one source of potential overreporting of exposure, and while underreporting may have also occurred, we cannot evaluate its role nor the balance between these potential inaccuracies. While we are unable to validate directly the accuracy of a respondent's use of pesticides, this analysis suggests that participants provide plausible information regarding their pesticide use.

Epidemiologic Studies↗

Alcohol licensing system changes and alcohol consumption: introduction of wine into New Zealand grocery stores.

New Zealand permitted grocery stores to sell table wine products beginning April 1990 with the implementation of a new Sale of Liquor Act. The number of licensed outlets for retail sales of wine for consumption off-premises increased substantially. Using an interrupted multiple time-series design with nation-wide quarterly alcohol sales data from 1983 to 1993, we assessed the effects of the policy change on sales of wine. Results from Box-Jenkins time-series models revealed a 17% increase in wine sales associated with the introduction of wine grocery stores. Increased sales were limited to the specific category of alcoholic beverages permitted in grocery stores--table wine. Sales of fortified wine, distilled spirits and beer did not increase. We conclude that expansion in retail availability of wine is associated with increased sales and consumption.

Alcohol Drinking↗

Use of IgM monoclonal reagents licensed for tube tests in column agglutination technology.

BACKGROUND: Red cell (RBC) phenotyping using column agglutination technology (CAT) is currently limited by the reagents formulated in the system. To overcome this limitation, it was investigated whether monoclonal IgM reagents licensed for use with tube tests produced valid results with CAT. STUDY DESIGN AND METHODS: Commercial CAT, does not contain antisera, was used to evaluate Procedures A (40 microL of reagent and 10 microL of 4% RBCs) and B (50 microL of reagent and 50 microL of 0.8% RBCs) with or without incubation at room temperature. In Study 1, reagents were tested to determine whether potentiators inhibit the passage of antigen-negative RBCs through the column. In Study 2, CAT sensitivity was measured by the use of potency titrations to define a procedure for each reagent that matched or exceeded that of the tube method. In Study 3, the specificity of each reagent was determined in parallel with the CAT and tube tests. Typing of 1644 samples was performed. RESULTS: Study 1: Free passage was obtained with all reagents. Study 2: Immediate-spin methods using CAT produced the same results as the tube method. Study 3: With 8048 comparisons made, discrepant results were found in 32 transfused patients and in 6 cord blood samples, mainly with Lewis reagents. With comparison of CAT and the standard tube method, complete agreement was obtained with Kell reagents, 99.9-percent agreement with Kidd reagents, and 98.9-percent and 99.4-percent agreement with Lewis reagents. CONCLUSION: Most examined reagents seem suitable for use with CAT.

Aged↗

[Driving behavior of patients before cataract operation--is an unlimited driver's license justifiable? Results of an analysis of 1,124 patients of the ophthalmology department of a central hospital].

BACKGROUND: The aim of the study was to evaluate the driving habits and patterns of those patients, who underwent cataract-surgery during a one year period at the Landesaugenklinik Salzburg and to compare the preoperative visual acuity with the legal requirements in effect in Austria. MATERIALS AND METHODS: The best-corrected visual acuity prior to surgery and the individual driving customs were noted on a detailed questionnaire. RESULTS: A minimum of 5.6% of the overall number of patients with cataract (not taking visual field defects into account) were driving a motor vehicle with a visual acuity not sufficient to meet current legal requirements. Considering only those drivers licence holders that admitted to still driving a motor vehicle it can be concluded that 26% have a legally unsatisfactory visual acuity. As between 28,000 and 31,000 cataract-operations are performed yearly in Austria, this study seems to clearly indicate that at least 1,600 of these persons--regardless of an additional visual field defect--are illegally driving a motor vehicle. It can be additionally concluded that the number of undetected cases is significantly higher. CONCLUSIONS: It therefore seems appropriate to call for a mandatory eye exam by a qualified ophthalmologist of all persons holding a driving licence, possibly beginning at the age of 60. The license issued thereafter should be valid for an age-related period of time only.

Accidents, Traffic↗