Target Health Champions the Paperless Clinical Trial



A very Senior VP of a major pharmaceutical company said to THI the other day, “you do it first and we will follow.” Therefore, as part of Target Health’s commitment to the world of the paperless clinical trial, we are “putting our money where our mouth is.”


We have now begun our 3rd direct data entry (DDE) phase 2 clinical trial under two separate US INDs. The clinical sites are using Target e*CRF® fully integrated with our eSource software, Target e*CTR® (US Patent 8,041,581 “System and Method for Collecting, Processing, and Storing Discrete Data Records Based Upon a Single Data Input”). Phase 3 will start in Q2 2012 and NDA submission planned for Q1 2013.


Target Document® is being used by both the clinical sites and the Sponsor for the entire eTMF, including eSignatures in lieu of all paper signatures.


Target Monitoring Reports™ allows for the CRAs to generate, review and sign off of onsite and remote monitoring reports that are fully integrated with Target e*CRF.


Target e*Pharmacovigilance™ allows for the clinical sites to populate and for the medical monitor to review, generate, and sign off FDA Form 3500A and CIOMS1 forms that are fully integrated with Target e*CRF.


Target Encoder® allows the medical coder, at any time and any place to code adverse events, medications, and medical history, all within the Target eCRF database.


Target e*CTMS® allows the project manager and sponsor to view the progress of study startup and project management features such as deliverables, clinical team, clinical sites, IRBs/ECs etc.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at

Alzheimer’s Disease


NOTE: Alzheimer’s Disease (AD) is a rampant global concern, of emergency proportions. Because there has been encouraging research in February 2012, this ON TARGET weekly newsletter is focusing mainly on this  issue. Most of our readers, have had a colleague, friend, or relative stricken by Alzheimer’s, have their own personal story to tell, and are interested in being kept current.


In Alzheimer’s disease, changes in tau protein lead to the disintegration of microtubules in brain cells.



Although Alzheimer’s disease (AD) develops differently for every individual, there are many common 1) ___. Early symptoms are often mistakenly thought to be ‘age-related’ concerns, or manifestations of stress.In the early stages, the most common symptom is difficulty in remembering recent events. When AD is suspected, the diagnosis is usually confirmed with tests that evaluate behavior and thinking abilities, often followed by a brain scan if available. Most often, AD is diagnosed in people over 65 years of age, although the less-prevalent early-onset AD can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. AD is predicted to affect 1 in 85 people globally by 2050. By the midway point of this century the planet is predicted to have 9 billion people, which means there will be 90 million 2) ____ with AD at that time, presenting each country with alarming healthcare challenges.


AD has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid. Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron’s membrane. APP is critical to neuron growth, survival and post-injury repair. In AD, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis.One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile 3) ___. In AD, changes in tau protein lead to the disintegration of microtubules in brain cells.


AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. The protein called 4) ___ stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron’s transport system.


Comparison of a normal aged brain (left) and the brain of a person with AD (right). Differential characteristics are pointed out



The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell’s calcium ion homeostasis, induces programmed cell death, called, 5) ___.  Various inflammatory processes and cytokines may also have a role in the pathology of AD. 6)___ is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.


Feb 1, 2012 UpdateAD seems to spread like an infection from brain cell to brain 7) ___, two new studies find. But instead of viruses or bacteria, what is being spread is the distorted protein known as tau. The surprising finding answers a longstanding question and has immediate implications for developing treatments. It is now suspected that other degenerative brain diseases like 8) ___ may spread in a similar way.


AD researchers have long known that dying, tau-filled cells first emerge in a small area of the brain where memories are made and stored. The disease then slowly moves outward to larger areas that involve remembering and reasoning. But for more than a quarter-century, researchers have been unable to decide between two explanations. One is that the spread may mean that the disease is transmitted from neuron to 9) ___, perhaps along the paths that nerve cells use to communicate with one another. Or it could simply mean that some brain areas are more resilient than others and resist the disease longer. The new studies provide an answer. And they indicate it may be possible to bring AD to an abrupt halt early on by preventing cell-to-cell transmission, perhaps with an antibody that blocks tau.


The studies, done independently by researchers at Columbia and Harvard, involved genetically 10) ___ mice that could make abnormal human tau proteins, predominantly in the entorhinal cortex, a sliver of tissue behind the ears, toward the middle of the brain, where cells first start dying in AD. As expected, tau showed up there. And, as also expected, entorhinal cortex cells in the mice started dying, filled with tangled, spaghetti-like strands of tau. Over the next two years, the cell death and destruction spread outward to other cells along the same network. Since those other cells could not make human tau, the only way they could get the protein was by 11) ___ from nerve cell to nerve cell.


Although the studies were in mice, researchers say they expect that the same phenomenon occurs in 12) ___ because the mice had a human tau gene and the progressive wave of cell death matched what they see in people with AD. One study, by Karen Duff and Dr. Scott A. Small and their colleagues at the Taub Institute for Research on AD and the Aging Brain at Columbia University Medical Center, was published on Wednesday in the journal PLoS One. The other, by Dr. Bradley T. Hyman, director of the AD Research Center at Massachusetts General Hospital, and his colleagues, is to be published in the journal Neuron. Both groups of researchers were inspired by the many observations over the years that AD starts in the entorhinal cortex and spreads. But, said Dr. Small, “what do we mean by spreads?”


Researchers knew that something set off AD. The most likely candidate is a protein known as beta amyloid, which accumulates in the brain of AD patients, forming hard, barnacle-like plaques. But beta amyloid is very different from tau. It is secreted and clumps outside cells. Although researchers have looked, they have never seen evidence that amyloid spreads from cell to cell in a network. Still, amyloid creates what amounts to a bad neighborhood in memory regions of the brain. Then tau comes in — some researchers call it “the executioner” – piling up inside cells and killing them. If some cells take longer than others to succumb to the bad neighborhood, that would explain the spread of the disease in the brain, and there would be no need to blame something odd, like the spread of tau from cell to cell.


Studies in humans, though, could not determine whether that hypothesis was correct. They involved autopsy and brain imaging studies and were “indirect and inconclusive,” Dr. Small said. Looking at the 13) ___ of people who have died of the disease, Dr. Duff said, is like looking at a wrecked car and trying to figure out the accident’s cause. Faulty brakes? Broken struts?


The question of which hypothesis was correct – tau spreading cell to cell, or a bad neighborhood in the brain and cells with different vulnerabilities to it — remained, unanswerable. Dr. Hyman said he tried for 25 years to find a good way to address it. One of his ideas was to find a patient or two who had had a stroke or other injury that severed the entorhinal cortex from the rest of the brain. If the patient developed AD in the entorhinal cortex — and it remained contained there — he would have evidence that the disease spread like an 14) ___. But he never found such patients.


The solution came when researchers were able to develop genetically engineered mice that expressed abnormal human tau, but only in their entorhinal cortexes. There is another advantage, too. The mice give provide a tool to test ways to block tau’s spread. But if tau spreads from neuron to neuron, Dr. Hardy said, it may be necessary to block both beta amyloid production, which seems to get the disease going, and the spread of tau, which continues it, to bring AD to a halt. He and others are also asking if other degenerative diseases spread through the brain because proteins pass from nerve cell to nerve cell.


Dr. Hardy thought he saw provocative human evidence that it might be happening in Parkinson’s disease. Two Parkinson’s patients being treated by a colleague had fetal brain cells implanted to replace dead and dying neurons. When the patients died, years later, 15) ___ showed they still had the fetal cells, but they had balls of a Parkinson’s disease protein, synuclein, inside. The most obvious way that could happen, the researchers reasoned, was if the toxic protein had spread from the patient’s diseased cells to the healthy fetal cells. But they could not rule out the bad-neighborhood hypothesis. Now, Dr. Hardy said, with the mouse studies, the issue of a bad neighborhood is settled. The answer in AD, he said, “is that isn’t possible.”


“That is what is different between these papers and all the others,” Dr. Hardy said. “It isn’t a bad neighborhood. It is contagion from one neuron to another.”


Feb. 10, 2012, GOOD NEWS UPDATE–A skin-cancer drug could offer hope for the millions of patients coping with the debilitating effects of AD.


Scientists at Case Western Reserve University led a study of the drug bexarotene on mice and found that it helped wipe out a protein linked to AD. The study, published last Thursday, in the journal Science, showed that the drug reduced the amount of amyloid beta by as much as 75%. The protein damages 16) ___ cells. The mice returned to normal behaviors three days after treatment with bexarotene, which is marketed as Targretin. “No one, ourselves included, would have ever imagined that any drug would have worked with this speed,” said Gary Landreth, a Case neuroscientist and lead researcher. “It’s stunning.” There are an estimated 5.4 17) ___ people with AD in the US.


Amyloid beta is a common substance in human brains, but AD patients lose the ability to clear it from synapses. The researchers suspected that bexarotene’s effect on brain activity might help with AD. If not cleared, the protein builds up as plaque and blocks synapses, ultimately 18) ___ nerve cells, said Dr. Doug Scharre, director of cognitive neurology at the Ohio State University Medical Center. “The fact that this agent gets rid of the amyloid is very positive,” said Scharre, who was not involved in the study. Scharre said many researchers speculate that by the time drugs are used in human trials of AD patients, it’s too late to halt serious problems. “We can’t revive a 19) ___ nerve cell,” Scharre said. “If we could attack this at the very early stages of memory loss, we could have much better results.” Other studies of drugs that showed promise in mice produced little change in human 20) ___, said Maria Carrillo of the AD Association, which has helped fund some of Landreth’s research. “We’re not sure that this is going to actually show the desired clinical benefits,” Carrillo said. “We owe it to ourselves and our constituents to follow every lead that we have.” Landreth said he hopes to begin human trials soon. Source: The New York Times, February 2012, by Gina Kolata


ANSWERS: 1) symptoms; 2) people; 3) plaques; 4) tau; 5) apoptosis; 6) inflammation; 7) cell; 8) Parkinson’s; 9) neuron; 10) engineered; 11) transmission; 12) humans 13) brains; 14) infection; 15) autopsies; 16) nerve; 17) million; 18) killing 19) dead; 20) patients

Aloysius Alzheimer MD (1864-1915)



The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. Up to the end of the 19th century, dementia was a much broader clinical concept, which included mental illness and any type of psychosocial incapacity, including those which could be reversed. Dementia at this time simply referred to anyone who had lost the ability to reason, and was applied equally to psychosis of mental illness, “organic” diseases like syphilis which could destroy the brain, and to the dementia associated with old age, which was held to be caused by “hardening of the arteries.”


Aloysius “Alois” Alzheimer was a German psychiatrist and neuropathologist and a colleague of Emil Kraepelin, the “Linnaeus of psychiatry.” Alzheimer is credited with identifying the first published case of “presenile dementia”, which Kraepelin would later identify as Alzheimer’s disease. Alzheimer received a medical degree at Wurzburg University in 1887. In the following year, he spent five months assisting mentally ill women, before he took an office in the city mental asylum in Frankfurt am Main known as the Asylum for Lunatics and Epileptics. Emil Sioli was the dean of that asylum (1852-1922). Another neurologist, Franz Nissl (1860-1919), began to work in that same asylum with Alzheimer, and they knew each other. Much of Alzheimer’s later work on brain pathology made use of Nissl’s method of silver staining of the histological sections.


In 1901, Alzheimer observed a patient at the Frankfurt Asylum named Frau Auguste Deter. The 51-year-old patient had strange behavioral symptoms, including a loss of short-term memory. This patient would become his obsession over the coming years. In April 1906, Mrs. Deter died and Alzheimer had the patient records and the brain brought to Munich where he was working at Kraepelin’s lab. Together with two Italian physicians, he would use the staining techniques to identify amyloid plaques and neurofibrillary tangles. A speech given on 3 November 1906 would be the first time the pathology and the clinical symptoms of presenile dementia would be presented together. Through extremely fortunate circumstances the original microscope preparations on which Alzheimer based his description of the disease were rediscovered some years ago in Munich. Emil Kraepelin’s use of the term, AD in a textbook would make the name famous. By 1911, his description of the disease was being used by European physicians to diagnose patients in the US.


In mid-December 1915, Alzheimer died of heart failure at the age of 51. Alzheimer fell ill on the train on his way to the University of Breslau, where he had been appointed professor of psychiatry in 1912. Most probably he had a streptococcal infection and subsequent rheumatic fever and kidney failure.


For most of the 20th century, the diagnosis of Alzheimer’s disease (AD) was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on AD concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical. This eventually led to the diagnosis of Alzheimer’s disease independently of age. The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical AD being used for those younger. Eventually, the term AD was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.


Frau Auguste Deter (1850-1906) – First Patient Diagnosed with Alzheimer’s Disease



Auguste Deter was born May 1850 and died April 8th 1906. She is the first person to be diagnosed with AD. During the late 1890s, she started showing symptoms of dementia, such as: loss of memory, delusions, and even temporary vegetative states. She would have trouble sleeping, would drag sheets across the house, and even scream for hours in the middle of the night. Her husband could not handle the loss of sleep and the stress and finally brought her to the Institution for the Mentally Ill and for Epileptics where she was examined by Dr. Alzheimer. He asked her many questions, and later asked again to see if she remembered. He told her to write her name. She tried to, but would forget the rest and repeat: “I am lost.” He later put her in an isolation room for a while. When he released her, she would run out screaming, “I do not cut myself. I will not cut myself.” After many years, she became completely demented, and died on 8 April 1906. Her death was the result of sepsis caused by an infected bedsore. On examining her brain, he found the now well-known defining, senile plaques and neurofibrillary tangles.


In 1996, Dr. Konrad Maurer and his colleagues, Drs. Volk and Gerbaldo, rediscovered the medical record of Auguste Deter. In it Dr. Alzheimer had recorded his examination of his patient,


“What is your name?” “Auguste.”

“Family name?” “Auguste.”

“What is your husband’s name?” – she hesitates, finally answers: “I believe … Auguste.”

“How old are you?” “Fifty-one.”

“Where do you live?” “Oh, you have been to our place”

“Are you married?” “Oh, I am so confused.”

“Where are you right now?” “Here and everywhere, here and now, you must not think badly of me.”

“Where are you at the moment?” “This is where I will live.”

“What are you eating?” “Spinach.” (She was chewing meat.)

“What are you eating now?” “First I eat potatoes and then horseradish.”

“Write a ‘5’.” She writes: “A woman”

“Write an ‘8’.” She writes: “Auguste” (While she is writing she again says, “It’s like I have lost myself.”)


Alzheimer concluded that she had no sense of time or place. She could barely remember details of her life and frequently gave answers that had nothing to do with the question and were incoherent. Her moods changed rapidly between anxiety, mistrust, withdrawal and ‘whininess’. They could not let her wander around the wards because she would accost other patients who would then assault her. It was not the first time that Alzheimer had seen a complete degeneration of the psyche in patients, but previously the patients had been in their seventies. Deter piqued his curiosity because she was much younger. In the weeks following, he continued to question her and record her responses. She frequently responded, “Oh, God!”, and, “I seem to have lost myself”. She seemed to be consciously aware of her helplessness. Alzheimer called it the “Disease of Forgetfulness”


Enhancement and Deep-Brain Stimulation of the Entorhinal Area



According to an article published in the New England Journal of Medicine (2012; 366:502-510), a study was performed to test the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex (EC) alters memory performance.


The EC is located in the medial temporal lobe and functions as a hub in a widespread network for memory and navigation. The EC is the main interface between the hippocampus and neocortex. The EC-hippocampus system plays an important role in autobiographical/declarative/episodic memories and in particular spatial memories including memory formation, memory consolidation, and memory optimization in sleep. The EC is also responsible for the pre-processing (familiarity) of the input signals in the reflex nictitating membrane response of classical trace conditioning, the association of impulses from the eye and the ear occurs in the entorhinal cortex.


For the study, intracranial depth electrodes were implanted in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an after-discharge (i.e., a neuronal discharge that occurs after termination of the stimulus).


Results showed that entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations in that the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.


According to the authors, stimulation of the entorhinal region enhanced memory of spatial information when applied during learning.

High Blood Levels of Cadmium and Lead Delay Pregnancy



Cigarette smoke is the most common source of exposure to cadmium, a toxic metal found in the earth’s crust, which is used in batteries, pigments, metal coatings and plastics. Smokers are estimated to have twice the levels of cadmium as do non-smokers. Exposure also occurs in workplaces where cadmium-containing products are made, and from the air near industrial facilities that emit cadmium. Airborne cadmium particles can travel long distances before settling on the ground or water. Soil levels of cadmium vary with location. Fish, plants, and animals absorb cadmium from the environment, and all foods contain at least low levels of the metal.


Lead, a toxic metal also found in the earth’s crust, is used in a variety of products, such as ceramics, pipes, and batteries. Common sources of lead exposure in the United States include lead-based paint in older homes, lead-glazed pottery, contaminated soil, and contaminated drinking water.


Exposure to these metals is known to have a number of effects on human health, but the effects on human fertility have not been extensively studied, especially when studying both partners of a couple.


As a result, a study published in Chemosphere (2011;85:1742–1748), was performed to evaluate whether higher blood levels of cadmium in females, and higher blood levels of lead in males, could lead to delayed pregnancy.


For the investigation, 501 couples were enrolled in the study from four counties in Michigan and 12 counties in Texas, from 2005 to 2009. The women ranged from 18 to 44 years of age, and the men were over 18. Couples provided blood samples for the analysis of three heavy metals and nearly every study participant had some exposure to these common metals, although blood levels of the metals varied across participants. Women kept journals to record their monthly menstrual cycles and the results of home pregnancy tests. The couples were followed until pregnancy or for up to one year of trying.


The probability that a couple would achieve pregnancy by levels of blood cadmium and lead with a statistical measure called the fecundability odds ratio. The measure estimates couples’ probability of pregnancy each cycle, by their blood concentration of metals. A ratio less than one suggests a longer time to pregnancy, while a ratio greater than one suggests a shorter time to pregnancy. Results from the study showed that the blood cadmium concentration of the female participants was associated with a ratio below 1 (0.78), which meant that the probability of pregnancy was reduced by 22% with each increase in the level of cadmium. Blood lead exposure in males also was associated with a ratio below 1 (0.85) with increasing levels, or about a 15% reduction in the probability of pregnancy for each increase in the level of blood lead concentrations.


The study also calculated a fecundability odds ratio based on both partners’ combined lead, cadmium and mercury concentrations. When this was done, it was found a ratio of 0.82 for male lead exposure, represented approximately a 28% reduction in the probability of pregnancy for each menstrual cycle, with increasing male blood lead concentration.


According to the authors, the findings highlight the importance of assessing couples’ exposure jointly, in a single, combined measure and that “males matter”, because chances of becoming pregnant per cycle were also reduced with increasing blood lead concentrations in men.

Drug Halts Organ Damage in Rare Inflammatory Genetic Disorder



Neonatal-onset multisystem inflammatory disease (NOMID) affects numerous organs and body systems, including the skin, joints, eyes, and central nervous system. The first sign of the disease is often a rash that develops within the first weeks of life. Other problems, including fever, meningitis, joint damage, vision and hearing loss, and mental retardation, can follow. Kineret, one of a relatively new class of drugs known as biologic response modifiers or biologics, blocks the activity of interleukin-1 (IL-1), a protein made by cells of the immune system. IL-1 is overproduced in NOMID and a number of other diseases, leading to damaging inflammation. Previous research showed that blocking IL-1 was effective in relieving symptoms of NOMID. However, this is the first study to show that Kineret works over the long-term and, at higher doses, can also control damage that often results in vision and hearing loss, and brain lesions. According to lead author Dr. Raphaela Goldbach-Mansky of the NIAMS Translational Autoinflammatory Disease Section, “Inflammation prolonged over many years will eventually cause irreversible damage and loss of function.” For example, inflammation of the cochlea — a tiny structure of the inner ear — was found to be responsible for hearing loss in people with NOMID. Thinning of the optic nerve caused by inflammation-related pressure in the brain has been identified as a cause of vision loss.


A new study, published online in Arthritis & Rheumatism (10 February 2012), showed that Kineret (anakinra), a medication approved for the treatment of rheumatoid arthritis, is effective in stopping the progression of organ damage in people with NOMID. For the study, participants, who ranged in age from 10 months to 42 years, were treated with daily doses of Kineret based on body weight — 1 to 5 milligrams of Kineret per kilogram of body weight (1 to 5 mg/kg/day) — for at least 36 months and as long as 60 months. Disease activity was monitored with blood tests to measure C-reactive protein, a marker for inflammation in the body, and by daily diaries kept by the patients or their parents. The study also used sensitive MRI imaging methods to assess inflammation in the inner ear and brain. The study found that the initial Kineret doses used were insufficient to control organ inflammation, but by increasing the dose, they were able to do so. By preventing organ inflammation, organ function was preserved in most patients. In addition, ways were found to predict who is at greatest risk of hearing and vision loss.


It was observed that the few patients in the study who had hearing loss were also the ones who continued to have inflammation in the inner ear. It was also found that people who had thin optic nerves when their vision was assessed, were more likely to lose vision than those who had thick optic nerves. According to the authors, this was most likely because they had already lost fibers due to untreated disease and, therefore, started with a huge disadvantage. The authors added that the findings point to the importance of early diagnosis and treatment to keep organ damage from developing.


Because IL-1 is needed to fight infections, there has been concern that blocking it with high doses of Kineret might leave the body vulnerable to infections. But overall, the study drug was well tolerated.


While Kineret is not a cure for NOMID — its effects last only as long as the drug is taken — the study offers hope for people with the disease. “Without Kineret, people with NOMID are at risk of progressive organ damage that results in hearing and vision loss, cognitive impairment and, in many cases, early death. As many as 20% of children with this genetic disorder do not live to adulthood,” said Goldbach-Mansky. “This study shows that treatment over five years is safe and effective, and can prevent organ damage.”

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.



FDA Issues Draft Guidances on Biosimilar Product Development



Biological products are therapies used to treat diseases and health conditions. They include a wide variety of products including vaccines, blood and blood components, gene therapies, tissues, and proteins. Unlike most prescription drugs made through chemical processes, biological products generally are made from human and/or animal materials.


A biosimilar is a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.


The Patient Protection and Affordable Care Act, signed into law by President Obama on March 23, 2010, amended the Public Health Service Act to create an abbreviated approval pathway — under section 351(k) — for biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product.


The FDA has issued three draft guidance documents on biosimilar product development to assist industry in developing such products in the United States. Through this new approval pathway, biological products are approved based on demonstrating they are biosimilar to, or interchangeable with, a biological product that is already approved by the FDA, which is called a reference product.


The following three guidance documents provide the FDA’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to the agency. FDA is seeking public comment on these draft guidance documents:


Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:

This draft guidance is intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting an application, called a “351(k)” application, to the FDA. This draft guidance describes a risk-based “totality-of-the-evidence” approach that the FDA intends to use to evaluate the data and information submitted in support of a determination of biosimilarity of the proposed product to the reference product. As outlined in the draft guidance, FDA recommends a stepwise approach in the development of biosimilar products.


Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product:

This draft guidance provides an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product for the purpose of submitting a 351(k) application. This includes the importance of extensive analytical, physico-chemical and biological characterization in demonstrating that the proposed biosimilar product is highly similar to the reference product notwithstanding minor differences in clinically inactive components.


Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009:

This draft guidance provides answers to common questions from people interested in developing biosimilar products. The question and answer format addresses questions that may arise in the early stages of product development, such as how to request meetings with the FDA, addressing differences in formulation from the reference product, how to request exclusivity, and other topics.


FDA will seek public comment on the guidance documents and instructions on how to submit comments will be announced in an upcoming Federal Register notice. In finalizing the guidance documents, the agency will consider the information received from the public.

The Commerce Clause – Few Words With a Major Impact



By Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.



“…to regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes”


The Constitution’s Commerce Clause, those few words above, or more precisely their interpretation by the current Supreme Court which will hear arguments in late Winter or early Spring, may well determine the fate of the overwhelmingly lengthier and complex Affordable Care Act (ACA). It is, ironically, the terse and simple reference to the “several states” above from which Congress derives authority to enact the individual mandate to purchase health insurance, a mandate considered to be a cornerstone of the Affordable Care Act.


There is a vigorous ongoing and understandable debate in multiple media: print, television, radio, medical journals (and I’m certain in Legal Journals as well although I can’t confirm this from personal experience), about the constitutionality of the ACA. While it’s been a challenging set of discussions to follow, it’s more than a little disconcerting that the opinions of various authors about constitutionality seem to be driven by whether they support the law rather than constitutional fidelity; e.g., proponents seem to readily find Commerce Clause support for Congressional authority for a mandate, opponents don’t. In addition, and unlike Second Amendment discussions which often invoke the intent of the Founders, we don’t hear much about how our Founding Fathers felt about Health Insurance except, of course, for the Act for the Relief of Sick and Disabled Seamen of 1798, in which “the master or owner of every ship or vessel in the United States, arriving from a foreign port into any port of the United States,” was required to take out health insurance for every one of its seamen.


The uncertainty about the “constitutionality” of the ACA predicts a quite dramatic series of Court arguments and rulings where the Supreme Court may, in an extraordinarily highly charged political environment, determine the fate of the signature legislative achievement of the other branches, an achievement which includes a critically needed insurance safety net for many citizens. Ideally the Court and its members, as objective assessors of constitutionality, should render judgment on constitutional grounds alone, independent of their personal views of the law itself. A daunting and aspirational task, though it reflects the standard we should demand.


To date, the ACA has quite transparently worked its way through the Court system generating both interesting and controversial analyses which have been publicly available and highly educational. In addition, pressure has been put on several justices for recusal based upon potential conflicts of interest. The Chief Justice has intervened in support of his colleagues, supporting their ability to assess their personal objectivity in the case. Interestingly (and happily), this has impacted justices with presumed contradictory views about the law, disarming the partisans on both sides.


As Americans we must remain actively engaged in this process. Whatever one’s views on the ACA, opponents have the right to challenge the law, and it will receive a vigorous defense. We should demand, through public pressure and media engagement, that the process is transparent and that we receive a complete and understandable explanation of how constitutional principles are applied by the Court, including its analysis and application of precedents. If we understand why and how the decision is made and are confident that the process is transparent, fair, and constitutionally sound, we will have been well served, whatever the outcome.