(Complimentary Newsletter from Target Health Inc.)
July 15, 2001
Contents:
I. WHAT'S NEW
New Addition To Our Staff
II. HISTORY OF MEDICINE
James Parkinson - Child Advocate
III. SUMMER SAFETY TIPS
How to Avoid Stomach Distress
IV. ETHICS IN CLINICAL RESEARCH
Johns Hopkins Receives a 483 After a Death in a Clinical Trial
V. GENETICS
Familial Hemiplegic Migraine
VI. NEUROLOGY
Relapsing–Remitting Multiple Sclerosis (MS)
VII. MICROBIOLOGY
Drug Resistance and Duration and Intensity of Treatment
VII. FDA
Clinical Trials of Serious or Life-Threatening Conditions
TARGET HEALTH
New Addition To Our Staff
TARGET HEALTH is pleased to announce the appointment of Mr. Joonhyuk Choi as Data Analyst/Programmer to our growing Target e*CRF™ development team. Mr. Choi holds a degree in Electrical and Computer Engineering and will answer directly to our Chief Technology Officer, Joon You. Other members of the Target e*CRF™ team include Yong Joong Kim, Laura Suciu, and Kevin Kim. We know that we have the best and most user-friendly Internet-based data collection, retrieval and project management system in the Industry. For more information contact julesmitchel@targethealth.com. The strength of this premier group has taken its lead from our highly competent Clinical Research and Biostatistics and Data Management team which will produce its third NDA in three years.
James Parkinson - Child Advocate
James Parkinson (1755-1824), of Parkinson's disease fame, while well recognized as a pioneer of clinical neurology, was even more famous as a founder of modern paleontology. Parkinson’s writings, outreach and advocacy for children's health also characterized him as one whose influence was an important springboard from which evolved the modern specialty of pediatrics. Parkinson was one of the first to write on child-rearing practices and in this context antedated Benjamin Spock by 150 years. Parkinson was a pioneer of child safety and the prevention of childhood trauma. He wrote of the resuscitation of near-drowned children and of first aid for injured children. He also described child abuse and the development of post-abuse hydrocephalus. He described the pathophysiology and pathology of appendicitis in children, of fatal rabies in children and highlighted the risk of death even when a biting dog was not clinically rabid. His advocacy for social reform for children's welfare was pioneering.
The following will be part of a series of articles dealing with preventing summer illnesses. You will now know why, in every restaurant bathroom (WC), there is a sign that says Employees Must Wash Hands Before Returning To Work.
How to Avoid Stomach Distress
Viral gastroenteritis is one of the most common acute illnesses in the U.S., with more than 25 million cases reported annually. For some people, especially infants, older adults and those with compromised immune systems, gastroenteritis can be deadly. The disease claims the lives of more than 10,000 Americans each year. Viral gastroenteritis is usually contracted through eating or drinking contaminated food or water, or sharing utensils, towels or food with someone who's infected. Some shellfish, especially raw or undercooked oysters, can be quite dangerous if they're harvested from contaminated waters. Contaminated drinking water can also cause viral diarrhea. But in most cases, the virus is passed through the fecal-oral route. Although many different viruses can trigger intestinal problems, symptoms are usually the same: watery diarrhea, abdominal cramps, nausea, vomiting, pain, occasional muscle aches or headache and low-grade fever. There's no effective treatment for gastroenteritis, so prevention is key. In addition to avoiding food and water that may be contaminated, thorough and frequent hand washing is the best defense. Although commonly called stomach flu, gastroenteritis isn't the same as influenza which affects the respiratory system. Depending on the virus, symptoms may appear within a few hours to a few days after infection, and can last from 1 to 10 days. Because the symptoms are similar, it's easy to confuse viral diarrhea with the diarrhea caused by bacteria such as salmonella, E. coli, Staphylococcus aureus or by parasites such as Giardia and entameba. These days large-scale E. coli infections are a particular concern since they can cause serious illness and even death. Unlike stomach flu, these infections can be treated.
4. ETHICS IN CLINICAL RESEARCH
For the pharmaceutical industry, it is always a great tragedy when there is a death or serious injury in a clinical trial. All of us work diligently to assure patient/subject safety. Institutional Review Board (IRB/Ethics Committee) approval and oversight, appropriate informed consent and FDA clearance of studies of unapproved drugs are some of the many controls needed to assure safety. While we have no intention of prejudging what just occurred at Johns Hopkins, it is clear that we can never be too careful during human experimentation.
Johns Hopkins Receives a 483 After a Death in a Clinical Trial
The FDA said that researchers at Johns Hopkins University who conducted an asthma experiment that led to a healthy volunteer's death last month had not sought or received FDA approval to use the unlicenced drug. In Form 483, which is available online at www.fda.gov, the FDA stated that the sponsor/clinical investigator failed to submit an IND to the FDA prior to conducting this clinical investigation, which involved the administration of hexamethonium bromide by inhalation to three human subjects. The FDA added that there was also a failure to report an unanticipated adverse event to the IRB. The first subject in the study was administered hexamethonium bromide on 4/23/01. She developed an unexpected persistent cough from 4/25/01 till 5/3/01. The IRB was not notified of this event. The clinical investigator also failed to follow the protocol in that the protocol stated that hexamethonium bromide would be administered by inhalation. What actually happened was that hexamethonium bromide with sodium bicarbonate were administered to the second and third subjects. The clinical investigator made changes to the approved protocol without notifying the IRB and without IRB approval. There also were no records available for review to determine how much sodium bicarbonate was added. The protocol approved by the IRB stated that the subjects would be premedicated with either hexamethonium bromide, or its vehicle (normal saline), by inhalation. The clinical investigator administered 4.5% hyperosmolar saline instead of the normal saline. The FDA concluded that there was failure to obtain effective informed consent, in that the clinical investigator failed to disclose that inhalation administration of hexamethonium bromide was an experimental use of the drug.
Familial Hemiplegic Migraine
Familial hemiplegic migraine is an autosomal dominant disorder characterized by attacks of transient hemiparesis (paralysis on one side of the body) followed by a migraine headache. It is divided into pure familial hemiplegic migraine (affecting 80% of families) and familial hemiplegic migraine with permanent cerebellar signs (affecting 20% of families). Mutations in CACNA1A, which encodes a neuronal calcium channel, are present in 50% of families with hemiplegic migraine, including all those with cerebellar signs. According to an article published in the New England Journal of Medicine (NEJM 2001; 345:17-24), hemiplegic migraine in subjects with mutations in CACNA1A has a broad clinical spectrum and that this variability is partially associated with the various types of mutations. For the study, the various clinical manifestations associated with mutations in CACNA1A in 28 families with hemiplegic migraine with and without cerebellar signs were evaluated. Nine mutations were detected in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. Genotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. Results showed that 89% of the subjects with mutations had attacks of hemiplegic migraine. One third had severe attacks with coma, prolonged hemiplegia, or both, with full recovery. All nine mutations, including five newly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83% of the subjects with these six mutations had nystagmus (rapid oscillation of the eyeball), ataxia (loss of muscle coordination), or both. Three mutations were associated with pure hemiplegic migraine.
Relapsing–Remitting Multiple Sclerosis (MS)
According to an article published in the journal Neurology (2001;56:1628-1636), the PRISMS study has now demonstrated significant clinical and MRI benefit at 2 years for interferon-ß-1a compared with placebo, in relapsing–remitting MS. For the study, patients initially receiving placebo were randomized to blinded interferon-ß-1a, (doses of 22 or 44 µg 3x daily (n = 172; crossover group), while others continued blinded treatment with their originally assigned dose (Rx22 or Rx44; n = 167 per group). Patients had 3- to 6-month clinical and annual MRI assessments. Results showed that relapse rates for 4 years were 1.02 (crossover), 0.80 (Rx22, p < 0.001), and 0.72 (Rx44, p < 0.001). The dose effect approached significance (p = 0.069; risk ratio, 0.88; 95% CI, 0.76–1.01). Crossover groups showed reductions in relapse count, MRI activity, and lesion-burden accumulation with interferon-ß-1a compared with their placebo period (p < 0.001 both doses). Time to sustained disability progression was prolonged by 18 months in the Rx44 group compared with the crossover group (p = 0.047). Rx22 and Rx44 reduced new T2 lesion number and lesion burden compared with crossover (p < 0.001). Rx44 was superior to Rx22 on several clinical and MRI outcomes. Persistent neutralizing antibodies developed in 14.3% (Rx44) and 23.7% (Rx22) of patients and were associated with reduced efficacy. It was concluded that clinical and MRI benefits continued for both doses up to 4 years, with evidence of dose response. Outcomes were consistently better for patients treated for 4 years than for patients in crossover groups and efficacy decreased with neutralizing antibody formation.
Drug Resistance and Duration and Intensity of Treatment
According to an article published in the Journal of the American Medical Association (JAMA 2001;286:49-56), emerging drug resistance threatens the effectiveness of existing antibiotic therapies for pneumococcal infections, but modifying the dose and duration of therapy may limit the spread of resistant pneumococci. The objective of the study was to determine whether short-course, high-dose amoxicillin therapy reduces risk of posttreatment resistant pneumococcal carriage (load) among children with respiratory tract infections. The study was a randomized trial conducted in an outpatient clinic in Santo Domingo, Dominican Republic, between October 1999 and July 2000. Study participants included 795 children aged 6 to 59 months who were receiving antibiotic prescriptions for respiratory tract illness. Children were randomly assigned to receive 1 of 2 twice-daily regimens of amoxicillin: 90 mg/kg per day for 5 days (n = 398) or 40 mg/kg per day for 10 days (n = 397). The endpoints were 1) penicillin-nonsusceptible Streptococcus pneumoniae carriage, assessed in nasopharyngeal specimens collected at days 0, 5, 10, and 28; 2) baseline risk factors for nonsusceptible pneumococcal carriage; and 3) treatment compliance. Results showed that at the day 28 visit, risk of penicillin-nonsusceptible pneumococcal carriage was significantly lower in the short-course, high-dose group (24%) compared with the standard-course group (32%); relative risk (RR), 0.77; 95% confidence interval (CI), 0.60-0.97; P = .03. The risk of trimethoprim-sulfamethoxazole nonsusceptibility was also lower in the short-course, high-dose group (RR, 0.77; 95% CI, 0.58-1.03; P = .08). The protective effect of short-course, high-dose therapy was stronger in households with thee or more children (RR, 0.72; 95% CI, 0.52-0.98). Adherence to treatment was higher in the short-course, high-dose group (82% vs 74%; P = .02). It was concluded that short-course, high-dose outpatient antibiotic therapy appears promising as an intervention to minimize the impact of antibiotic use on drug-resistant pneumococci.
TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.
Clinical Trials of Serious or Life-Threatening Conditions
Section 113 of the FDA Modernization Act provides for the public availability of specified information on studies of drugs for serious or life-threatening diseases conducted under FDA’s IND regulations (21 CFR part 312). The Clinical Trials Data Bank is intended to be a central resource, providing current information on clinical trials to individuals with serious or life-threatening diseases, to other members of the public, and to health care providers and researchers. Specifically, the Clinical Trials Data Bank contains (1) information about clinical trials, both federally and privately funded; (2) a description of the purpose of the experimental drug; (3) patient eligibility criteria; (4) the location of clinical trials sites; and (5) a point of contact for patients. The National Institutes of Health (NIH), through its National Library of Medicine (NLM) and with input from the FDA and others, developed the Clinical Trials Data Bank and is implementing it in a phased approach. The first version of the Clinical Trials Data Bank was made available to the public on February 29, 2000, on the Internet at http://clinicaltrials.gov. A March 23, 2001, Federal Register notice announced OMB approval of Agency information collection activities for the program (66 FR 16251). The March 29, 2000, draft guidance provided recommendations for industry on the submission of protocol information to the Clinical Trials Data Bank. It included information on the types of clinical trials for which submissions will be required as well as the types of information to be submitted.
TARGET HEALTH INC. is a full service CRO with full-time staff dedicated to all aspects of Regulatory Affairs, including IND, IDE, NDA, 510(k) and PMA submissions, Clinical Research Management, Medical Writing, Internet-based Data Capture and Project Management (Target e*CRF), Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEATH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic planning from discovery to market launch. Let us help you on your next project.
TARGET HEALTH INC.
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Dr. Jules T. Mitchel, President (julesmitchel@targethealth.com)
Ms. Joyce Hays, CEO, TARGET HEALTH INC. (joycehays@targethealth.com)
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