Each issue of the CoramClick provides an in-depth focus on timely and practical solutions. In this issue of the Click, we are focusing on clinical trials. Full, printable issues of the Click are available in the CoramClick archive for easy reference!

	A Brief Overview of Clinical Trials Clinical trials are required before the FDA will approve marketing of a new or changed drug or device. One of the biggest challenges sponsor companies face is finding ways to improve overall recruitment and retention rates of clinical trial patients.		Bug of the Month: Lyme Disease Lyme disease is the most common vector-borne disease in the U.S., with greater than 20,000 cases reported annually.
	The Ambulatory Infusion Suite (AIS) Model The AIS model allows for the administration of newly approved medications in a safe, controlled environment, meeting the needs of specific patient populations.		Do You Know? Based on the pre-clinical time, and the four phases of clinical trials, the FDA reports that the new drug development timeline averages how many years to complete? a) 4 years b) 6.5 years c) 7.5 years d) 9 years
	Common ICD-9 Codes An example list of diagnoses associated with treatment infusions typically driven to an AIS setting.		Resource Center Featuring the Drug Information Association, Coram Clinical Trials, CoramAIS.com, the National Institutes of Health and the American Lyme Disease Foundation.
	Subscribe to the CoramClick. Please include your email, first and last name, company, city and state.

A Brief Overview of Clinical Trials

Clinical trials are required before the U.S. Food and Drug Administration (FDA) will approve marketing of a new or changed drug or device. During clinical trials, an investigational compound is administered to humans and is evaluated for its safety and effectiveness in treating, preventing or diagnosing a specific disease or condition. The results of the testing will comprise the single most important factor in the approval or disapproval of a new drug.

The FDA monitors the study design and conduct of clinical trials to ensure that people in the trials are not exposed to unnecessary risks. The trials can only commence once satisfactory information has been gathered on the quality of the investigational product and its non-clinical safety through toxicity and animal studies.

There are four primary phases of trials, and as products show promising results in one phase, they typically move to the next.

• Phase I is the initial introduction of the investigational article into humans. These studies are usually designed to determine the metabolism and pharmacological actions of the investigational article in humans, any side-effects associated with increasing doses and early evidence of efficacy.
• Phase II studies are primarily short-term, controlled, dose-ranging clinical studies conducted to evaluate the efficacy of the drug for a particular indication(s) and to determine the common short-term side-effects and risks associated with the drug.
• Phase III studies are expanded controlled and uncontrolled trials. The studies are usually intended to gather additional information about the efficacy and long-term safety of the article needed to evaluate the overall benefit/risk relationship.
• Phase IV studies or post-marketing studies collect long-term safety and adverse event data. They often involve direct comparisons with competitive drugs and are usually undertaken to obtain data needed to support a desired revision in labeling.

Based on the pre-clinical time, and the four phases of clinical trials, the FDA reports that the new drug development timeline is anywhere from 3–17 years, with an average of 7.5 years. With these types of timelines, the recruitment and retention of study patients is critical to help reduce and maintain the development timeline.

According to an article in the June 2007 issue of Abstract from Business Insights, “almost half of all trial delays are caused by patient recruitment problems. These delays cost makers of specialty products more than $500,000 in lost sales and they result in losses of over $8 million for blockbusters.”

With this high-dollar value impact from delays, sponsor companies are looking for ways to help improve overall patient recruitment and retention rates. A unique solution to recruitment and retention issues offered by Coram Clinical Trials is to bring the trial to the patient. By providing both pharmacy and nursing services in the patient’s home for all stages of trials and therapeutic areas, patient access barriers are reduced.

The Ambulatory Infusion Suite Model

As new medications are introduced to the market, pharmaceutical companies look for sites of care that can meet the needs of specific patient populations. The ambulatory infusion suite (AIS) model allows administration of newly approved medications in a safe, controlled environment. For instance, patients receiving treatment in an infusion suite are typically offered flexible hours and days in order for patients to maintain normal work and family schedules. Additional benefits of the AIS include the chance for patients of similar diseases to meet and discuss the needs and challenges associated with their disease. A national network of infusion suites allows patients who are traveling the chance to do so without missing a single dose of medication.

For these reasons, Coram has established a reputation among pharmaceutical companies as an organization dedicated to providing quality care and meeting the unique needs of patients for high-tech infused medications. The treatments for Paroxysmal Nocturnal Hemoglobulinuria (PNH), plaque psoriasis and Crohn’s disease are examples utilizing a typical AIS setting.

Paroxysmal Nocturnal Hemoglobulinuria (PNH)
Soliris^® is provided to individuals with Paroxysmal Nocturnal Hemoglobulinuria (PNH), a rare disorder causing chronic hemolysis of red blood cells. PNH usually strikes middle-aged adults between the ages of 35–55 and the mortality rate for this disease is 50% within 10–15 years of diagnosis due to a thrombotic event. The continual hemolysis of red blood cells leads to debilitating fatigue, poor concentration, palpitations, shortness of breath, difficulty swallowing and blood in the urine. Diagnosis of the disease usually takes five to seven years due to the fact that symptoms of PNH mimic many other types of diseases.

Treatment with Soliris begins with five induction doses, once a week for five weeks, and continues with maintenance doses every two weeks for life. Coram began working with the manufacturer of Soliris prior to approval in order to gain an understanding of the unique needs of this patient population and to develop a program to meet the customer’s expectations. Once the drug was approved in 2007, Coram had the clinical knowledge and expertise needed to provide Soliris in its network of infusion suites, offering a safe, cost-effective environment for PNH patients.

Plaque Psoriasis
Plaque psoriasis belongs to a group of diseases known as immune mediated inflammatory disease (IMID). Other IMIDs include rheumatoid arthritis, inflammatory bowel disease and psoriatic arthritis. All of these diseases lack a definitive etiology, but they are characterized by common inflammatory pathways leading to inflammation or triggering an abnormal immune system response. All IMIDs, if not treated, lead to end-stage organ damage and are associated with increased morbidity and mortality. Psoriasis is a non-contagious, chronic skin disease. Normally dead skin cells are shed every seven days, but in individuals with plaque psoriasis, skin cell shedding is accelerated to every three days causing raised, red patches covered with a silvery build-up of dead skin cells.

Remicade^® was FDA approved for its seventh indication in 2006 with the addition of plaque psoriasis. Treatment for psoriasis with Remicade begins with three induction doses over a six week period and maintenance therapy every eight weeks. As common pathways are identified among disease processes, one medication can be used for treatment of multiple disease states.

Crohn’s Disease
Tysabri^® was approved January 14, 2008 for treatment of Crohn’s disease, which is a chronic, inflammatory bowel disease characterized with diarrhea, fever, rectal bleeding, malnutrition, narrowing of the intestinal tract, obstructions, abscesses, cramping and abdominal pain. The disease affects approximately 1 million individuals worldwide. Tysabri is indicated as a second line medication prescribed for patients that do not respond to other biologics such as Remicade or Humira^®.

Tysabri may only be administered for Crohn’s disease patients by Tysabri Outreach: Unified Commitment to Health (CD-TOUCH) approved providers. Under the TOUCH™ program all infusion sites, pharmacies, physicians and patients must adhere to strict monitoring guidelines. Coram is committed to the TOUCH program and its infusion suites are TOUCH approved for the administration of Tysabri.

Common ICD-9 Codes
Specific to Gastroenterology, Dermatology and Hematology

Below is a list of potential gastroenterology, dermatology and hematology diagnoses associated with treatment infusions typically driven to an AIS setting.

Bug of the Month: Lyme Disease

Borrelia burgdorferi; image courtesy of the CDC.

Lyme disease is an acute inflammatory response to invasion by the spirochete Borrelia burgdorferi. It is the most common vector-borne disease in the United States, with greater than 20,000 cases reported annually, primarily from the northeast and upper midwest states, with greatest risk of infection in the spring and summer, when ticks are feeding.

The most at-risk populations are those aged 5–14 years old and 50–59 years old who reside in areas where Lyme disease is endemic. Two additional factors that have led to an increase of Lyme disease are the growing population of deer that support the ixodes tick vector and an increase in the residential development of wooded areas resulting in tick dispersal to new areas.

The Life-cycle of a Tick
Eggs that are laid in the spring hatch in late summer. Once the ticks are born they start searching for their first blood meal, which is usually from a white-footed mouse. The ticks eat and then lie in the leaves of the forest throughout the fall and winter. During the next spring and late summer, the nymphs feed again, and in the late summer or early fall they begin to mature and the adult ticks search for a host.

Transmission
The reservoir of Borrelia burgdorferi is the white-footed mouse. The typical vector is the deer tick Ixodes scapularis. The tick acquires the spirochetes by feeding on the mouse. The disease is transferred to humans when the infected tick attaches. Transmission of infection typically requires attachment for 24–48 hours.

As noted, the cycle of infection starts by a tick feeding on an asymptomatic, infected host (mouse), thus becoming infected itself. The tick then feeds on an uninfected host (human). The spirochete can then enter the blood stream. Once the bacteria is transmitted, the spirochete will either be destroyed by the host’s immune system resulting in no disease, cause local inflammation or disseminate hematogenously to such sites as the skin, heart, nervous system, joints and other organs resulting in a disseminated disease.

Common Symptoms

Diagnosis
Diagnosis is primarily based on clinical assessment and findings:

• History of exposure to tick bite(s)
• Clinical symptoms
• Serological testing may include:
  • Indirect immunoflourescence assay (IFA) or enzyme-linked
    immunosorbent assay (ELISA)
  • Western blot to detect IgM or IgG
  • Polymerase chain reaction (PCR) to detect spirochete-specific DNA
• EKG if cardiac involvement is suspected
• Cerebrospinal fluid evaluation if neurological involvement is suspected

Treatment and Prognosis
Prompt recognition and treatment of Lyme disease usually leads to rapid improvement with little likelihood of later complications. Treatment with tetracyclines (typically doxycycline) or beta-lactam antibiotics for 10 to 20 days is associated with a high degree of success. Most patients do well with oral antibiotics. For those who do not respond or have multi-systemic effects, IV antibiotics may be prescribed.

In patients whose symptoms are incompletely relieved or develop months later, long-term IV antibiotics may be required. If left untreated, Lyme disease may lead to often irreversible nervous system and joint effects, also requiring long-term antibiotics.

Prevention

• Avoid areas that are likely to be infested with ticks, especially in the spring and summer
• Wear appropriate clothing that includes:
  • Light colors and long sleeves
  • Pants tucked into socks and high boots
• After outdoor activities, run clothes through the dryer on high heat
• Use insect repellants containing N,N-Diethyl-meta-toluamide (DEET).
  • Adults - 35% DEET
  • Children - 10% DEET
  • Infants - No DEET
• Self-inspect for ticks and remove any ticks appropriately and promptly
• Remove brush and leaf litter or create a buffer zone of wood chips or gravel between forest and lawn

Do You Know?

Based on the pre-clinical time, and the four phases of clinical trials, the FDA reports that the new drug development timeline averages how many years to complete?

1. a) 4 years
2. b) 6.5 years
3. c) 7.5 years
4. d) 9 years

Answer – c) 7.5 years
The FDA reports that the new drug development timeline is anywhere from 3–17 years, with an average of 7.5 years. Considering these long-range requirements, the successful recruitment and retention of patients is critical to maintain the development timeline.

Resource Center

The Drug Information Association (DIA) serves more than 30,000 professionals involved in the discovery, development, regulation, surveillance or marketing of pharmaceuticals or related products worldwide. DIA's annual meeting was held on June 22-26, 2008, in Boston, Mass. Coram Clinical Trials, formerly CTI Network, Inc., exhibited during this year's meeting. To learn more about Coram Clinical Trials and their valuable services for clinical research projects in all phases of pharmaceutical development, either visit the booth at the show or visit coramclinicaltrials.com. To learn more about DIA, visit their website at diahome.org.

Coram Clinical Trials provides in-home and alternate site clinical research services for phase I through IV clinical trials. With more than 1,200 affiliated home care agencies and 660 full-time registered nurse employees, Coram Clinical Trials can bring the trial services to a patient’s home, workplace or to one of their ambulatory infusion suites. Coram Clinical Trials has the expertise and geographic reach in the U.S., Canada and Puerto Rico required to foster patient retention. For information, visit coramclinicaltrials.com.

CoramAIS.com offers patient, physician and payor resources for those seeking to learn more about Coram’s ambulatory infusion suite model and available services. Coram’s infusion suites offer a safe and convenient alternative to infuse specialty drugs. Their experienced infusion nurses and pharmacists provide consistent, expert care for complex therapies every day. Visit coramais.com to learn more.

The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary federal agency for conducting and supporting medical research. Helping to lead the way toward important medical discoveries that improve people’s health and save lives, NIH scientists investigate ways to prevent disease as well as the causes, treatments, and even cures for common and rare diseases. The NIH provides leadership and financial support to researchers in all fifty states and throughout the world. To learn more about clinical research studies, visit the NIH website at clinicaltrials.gov.

The American Lyme Disease Foundation, Inc. (ALDF) is dedicated to the prevention, diagnosis and treatment of Lyme disease and other tick-borne infections. ALDF plays a key role in providing reliable and scientifically accurate information to the public, medical community and government agencies about tick-borne diseases and their effects on human health and quality of life. Particular emphasis is placed on the importance of prevention and early intervention in avoiding complicated, expensive and potentially debilitating long-term illness. To learn more, visit aldf.com.

Bibliography

• Abstract from Business Insights, Patient Recruitment And Retention In Clinical Trials: Emerging Strategies In Europe,
  The Us And Asia, June 1, 2007
• Sullivan, Jean. “Subject Recruitment and Retention: Barriers to Success.” Applied Clinical Trials. April 1, 2004.
• Wormser, GP, Dattwyler, RJ, Shapiro, ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical practice guidelines by the Infectious Disease Society of America. Clinical Infectious Diseases, 2006; 43:1089-1134.
• Lyme Disease. http://en.wikipedia.org/wiki/Lyme_disease. Retrieved on 2008-03-14.
• CDC (2006-10-02). Reported cases of Lyme disease by year, United States, 1991-2005 (http://www.cdc.gov.ncidod/dvbid/lyme/ld_UpClimbLymeDis.htm). Retrieved on 2007-08-20 and 2008-04-02.