Pharmaceutical Physician - Life, Living and Medicine

HUMAN CONNECTOME PROJECT

2010-09-21T12:09:00.000-07:00

Map of Resting Brain is thought to be the Key to the diagnosis of the diseases of central nervous system and recently NIH has given out $40 million grant just to research that further. Finally there is a forward movement in the real research of the BRAIN. The term “Resting Brain” is in a way a misnomer because brain actually is never at rest. If and when it really does, the life ceases to exist unless otherwise supported.
Currently the resting brain is defined by the scientific community as the inactive state of the brain when it is supposedly doing "nothing" specific; some of us may call it daydreaming. This area has been one of the busiest areas of neuroscience in recent years thankfully. Mapping the complete wiring of the living human brain at rest has become almost a scientific equivalent of Holy Grail for lack of better expression.
Knowledge gained through the help of MRI (magnetic resonance imaging) has given us the understanding that altered activity in the resting brain circuitry can be a sign of brain disorders- neurological/psychiatric.
Fifteen years ago, in 1995 resting-state functional MRI (r-fMRI) was used to show that the brain is in continuous activity of chatting within its own regions even when there is no ongoing physical or mental activity. Similarly the differences in the chatting patterns can also be detected and tracked by fMRI during resting state. It can potentially help determine the response to auditory and tactatory stimuli in a patient that is in coma or in a vegetative state. This would open up the wonderful world of connecting the disease symptoms to the changes in chatting patterns…and we would have the first win; a diagnosis based on objective evidence, a rarity in many CNS disorders. Here the bigger picture of our hope is to be able to have definite diagnoses of depression, bipolar disorder, schizophrenia, ADHD, MCI, Alzheimer’s even autism based on fMRI. Then come the next step; our ability to measure the response to a treatment objectively. It would be a major MILESTONE in CNS research, a victory so many scientists have been dreaming of. The possibilities are endless.
National Institutes of Health grant of $40 million is to map out the neurons and synapses in the human brain – in high resolution. It is called the "HUMAN CONNECTOME PROJECT”.
The first grant of this is given to 2 collaborating research groups: one to the group at Washington University in St. Louis and the University of Minnesota in Minneapolis and the other to a group at Harvard and UCLA.
Under this project brains from 1,200 healthy adults from twin pairs and siblings in 300 families will be mapped along with the collection of their behavioral and genetic information.
Approximately 350 scientists are met at the conference last weekend at the Medical College of Wisconsin to share their research and thoughts about the brain mapping.
A wealth of information has already been collected by several scientists. One scientist from New Jersey Medical School has put together a not so sophisticated “connectome” using the fMRI scans of 2,000 individuals from 33 countries. A scientist from University College in London, has been studying connections in the brains of people in coma comparing them to those under general anesthesia. A lot of research has already been under works with Alzheimer’s disease.
Majority of CNS disorders, especially that are clumped under psychiatric disorders are still diagnosed and treated on symptoms and the tests that are mostly subjective. The hopeful in me thinks that all this research that would eventually come together cohesively and will lead to correct diagnoses and treatment of these tough CNS diseases by simple non invasive fMRI scans.

Link to Human Connectome Project web site:
http://www.humanconnectomeproject.org/

New Broad Spectrum Antibiotics

2010-09-10T14:00:00.000-07:00

It is great to see the approval of ceftaroline a novel, bactericidal, broad-spectrum injectable cephalosporin by FDA’s Anti-Infective Drugs Advisory Committee with a vote of 21 - 0 for the treatment of CABP (community acquired bacterial pneumonia) and 18 - 0 in favor of approval for cSSSI (complicated skin and skin structure infections) against both gram positive pathogens, (that include MRSA [methicillin-resistant Staphylococcus aureus] and MDRSP [multi-drug resistant Staphylococcus pneumonia] and common gram negative pathogens.
The new drug application (NDA) for ceftaroline is based on the data from 2 Phase III clinical studies in CABP (FOCUS I and FOCUS II) and 2 Phase III studies in cSSSI (CANVAS I and CANVAS II).
Paratek Pharmaceuticals in collaboration with Novartis is developing their broad spectrum antibiotic, PTK 0796, a first in class AMC (aminomethylcycline) a broad spectrum once daily, oral and IV antibiotic for single-agent treatment of life threatening infections such as cSSSI and CABP, with activity against resistant bacteria such as MRSA, MDRSP and VRE (vancomycin-resistant enterococci). They are currently conducting Phase III studies.
Cempra Pharmaceuticals announced moving ahead with their dual approach: CABP and cSSSI of the development of their first of a new generation macrolide-ketolide- a fluoroketolide CEM -101 (solithromycin). It is the first fluoroketolide that belongs to the macrolide class and is the first macrolide since azithromycin with the potential for both IV and oral administration and has potent in vitro activity against respiratory pathogens such as pneumococci, including those resistant to macrolides and quinolones
Pfizer (previously Wyeth) has an FDA approved indication of CABP, cIAI (complicated intra-abdominal infections) and cSSSI in adults for TYGACIL® (tigecycline).
There are several other different broad spectrum antibiotics currently under development by different companies from different countries. Check the following web link.
http://www.pharmainformatic.com/html/future_drugs.html#AC98-6446
I may have missed several other entities currently under development. I am glad to see the new trend in antibiotic development by the pharmaceutical companies and the new guidelines being set by FDA for the development of antibiotics for CABP, cSSSI and other infections.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm123686.pdf
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071185.pdf

Yet the balancing act of use of appropriate antibiotics for a specific indication is crucial. That is the only way to slow the rate of fast developing resistant strains and prevent the development of resistant strains.

FIBROMYALGIA - a syndrome and a conundrum....

2010-07-31T12:16:00.000-07:00

Fibromyalgia is a neuro sensory disorder-a central sensitivity syndrome, estimated to be affecting 2-4% of general population in the US, more common in young to middle age females.
Historically, fibromyalgia has been considered either a musculoskeletal or a neuropsychiatric condition.
People suffering from fibromyalgia have persistent widespread pain (muscle, bone, connective tissue), allodynia (heightened painful response to pressure), paresthesias, joint stiffness, fatigue, sleep disturbances, cognitive problems – all leading to impaired activities of daily living. In addition to that they may have depression, anxiety, post traumatic stress disorder.
Fibromyalgia appears to overlap with other central nervous sensitivity syndromes such as chronic fatigue syndrome, irritable bowel syndrome, chronic pelvic pain syndrome, tension headaches, and restless leg syndrome among others. The coexistence with autoimmune inflammatory disorders such as RA (Rheumatoid Arthritis), SLE (Systemic Lupus Erythematosus) makes us wonder if there is a strong correlation between fibromyalgia and the autoimmune inflammatory disorders as well.
What is pain anyway?
International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". The threat of pain is what drives everything. According to neuropsychology, experience of pain comes from a complex mechanism of sensation-perception interaction involving the simultaneous parallel nociceptive signal input processing from the spinal cord to and within multiple regions of brain-emotional [includes motivational], discriminative, autonomic, motor [includes reflex]. In fibromyalgia there is a generalized decrease in the pain perception threshold which may reduce the discrimination between nociceptive and nonnociceptive quality to touch, pressure and temperature reflecting in altered processing of the signals at the central level. Stress plays a major role. Stress response is usually adaptive with 2 effectors; hypothalamic-pituitary-adrenocortical axis and the sympathetic nervous system. The stress perception and response may become maldaptive in chronic pain and fatigue syndromes such as fibromyalgia. Negative emotional, psychological, and cognitive factors can become real stressors and may even dominate the clinical picture of the syndrome which may potentially lead to a neuroendocrine cascade - depressed mood, fatigue, flu like symptoms with muscle aches, cognitive and sleep related problems. The neuroendocrine cascade includes the neuroendocrinal axis, HPA axis, immune system signals through cytokines, the autonomic nervous system, even growth-hormone and may be other things that we currently are not aware of.
There are several abnormalities in pain processing in Fibromyalgia. Major observable abnormalities include:
• Elevation of levels of excitatory neurotransmitters - substance P and glutamate
• Decreased levels of Inhibitory neurotransmitters - as serotonin and norepinephrine in descending antinociceptive pathways in the spinal cord
• Dysregulation of dopamine
• Alteration of endogenous opioid analgesic activity that play a major role in pain modulation in several brain regions
So far the pharmacological approaches of fibromyalgia are targeted towards these observable abnormalities. Examples of agents that can increase serotonin and norepinephrine levels – SSRIs, SNRIs and SSNRIs, and the agents that can reduce the substance P and /or glutamate.

In 1990 American College of Rheumatology (ACR) put together the diagnostic criteria for fibromyalgia.

http://www.nfra.net/Diagnost.htm

The main criteria are:
• Presence of widespread pain for more than 3 months
• Pain, not just tenderness, that can be elicited by manual pressure of approximately 4 kg/cm2 at 11 or more of 18 defined tender points.
These criteria are used mostly for research study subject selection rather than for the clinical diagnosis.

A guidance document has been put together for the diagnosis, pharmacological and non pharmacological interventions, the syndrome in children, etc. The guidance document can be located by clicking the following link.

http://www.guideline.gov/content.aspx?id=7298

The guidance is based on an expert committee consensus, weighting according to a rating scheme. The evidence for recommendations was collected and ranked from I to V as:
• Meta-analysis of multiple well-designed controlled studies
• Well-designed experimental studies
• Well-designed, quasi-experimental studies, such as nonrandomized controlled, single-group pre-post, cohort, time series, or matched-case controlled studies
• Well-designed nonexperimental studies, such as comparative and co relational descriptive and case studies
• Case reports and clinical examples

Diagnosis and assessment should be based on:

• Complete history and physical examination (including joints, muscle strength and neurological), focusing on illnesses that complicate the disease (hypothyroidism, ankylosing spondylitis), that occur concurrently (tendonitis, SLE, RA, osteoarthritis).
• Observation of excess tenderness on manual palpation of at least 11/18 muscle-tendon sites.
• Presence of widespread pain for at least 90 consecutive days- assessment of pain on the type, quality, source, location, duration, time course, pain affect, and finally the effect on quality of life with self-report as primary source.

Same methods should be used at the initial examination and at subsequent assessments.
Assess the severity of other symptoms -fatigue, sleep problems, and mood and cognitive disturbance; refer the patients with suspected mood and cognitive disorders for formal testing; measure the impact of fibromyalgia on physical and emotional function and overall quality of life by assessing functional status at the initial and subsequent assessments.
Lab tests include a complete blood count, ESR, LFTs, TFT and other muscle enzymes.
Once diagnosis is confirmed, treatment should begin with complete explanation and education of the syndrome to the patients. Use multiple strategies and include both pharmacological and nonpharmacological therapies for the treatment.
Educate the patients with basic information about the disease, treatment options, pain management and self-management programs upfront.
Pharmacological therapies:
Start with a tricyclic antidepressant to help sleep (amitriptyline or cyclobenzaprine) at bedtime, SSRIs alone or in combination with tricyclics for pain with individualized dose based on the concurrent mood disturbances. NSAIDs, COX-2 selective agents and acetaminophen by themselves are not known to be effective for pain in fibromyalgia unless they are combined with other medications. Tramadol may help the pain, but it needs to be tapered up or down slowly; it can be used alone or in combination with acetaminophen. Opioids should be considered only when all the other pharmacological and nonpharmacological modalities have been exhausted. If sleep disturbances are prominent (restless leg syndrome etc) sleep aids/anxiolytics (trazodone, benzodiazepines, nonbenzodiazepine sedatives, L-dopa and carbidopa) need to be considered. Unless there is concurrent joint/bursa/tendon inflammation, corticosteroids should not have a role in the treatment.
Consider cognitive-behavioral therapy, biofeedback, aerobic and muscle strengthening exercises (avoid exercise that induces pain), and other supporting treatments.
When it comes to assessment of pain in children with juvenile fibromyalgia syndrome (JFMS), it should be based on developmental stage of the child and include both child and parent components that involves pain history, observations of behavior, physiological changes, comorbid mood disorders, psychosocial distress, and functional status such as school attendance.
The child and the family needs to be educated on the diagnosis, associated diseases, management of the symptoms of JFMS in addition to self-care skills, and help them understand the relationship between pain, mood, stress, exercise, and the factors associated with parental and family environment.
Pharmacotherapy with nonpharmacological approaches that focus on functional maximization, regular school attendance, and functional goals with the child and family, CBT to reduce pain and psychological disability, aerobic exercise to minimize pain, improve sleep quality enhance self-efficacy and increase positive mood. Emphasize sleep hygiene, address anxiety and depression with both pharmacological and nonpharmacological techniques.
Current pharmacological treatment choices are fairly limited. SSRIs and SNRIs are commonly used along with the tricyclics. As far as the FDA approval goes, there are only three; Lyrica (pregabalin- Pfizer), Cymbalta (duloxetine-Eli Lilly) and Savella (milnacipran-Forest labs).
Jazz pharmaceuticals(sodium oxybate), Adeona pharmaceuticals ( flupirtine), Chelsea Therapeutics (droxidopa), UCB pharma (lacosamide), Pfizer (reboxetine), GSK, Sanofi Aventis and others are working on the development of new drugs including nabilone is based on the active ingredient in cannabis for the treatment of fibromyalgia syndrome.
Fibromyalgia is polygenic. Chances of one drug or type of treatment working for all or majority of fibromyalgia patients are very slim. Genetic testing to customize the treatment may be the way to go eventually.
In addition to the efforts to develop the treatment modalities for fibromyalgia, there are several websites, patient support organizations and groups available that provide information, support for the patients.

THERE IS A HOPE FOR POSSIBLE NEW DRUGS IN PSYCHIATRY…after all

2010-07-26T07:24:00.000-07:00

Close to 3 decades; 1980s, 90s and the 2000 pharmaceutical/medical device industry worked feverishly to bring in tremendous number of new drugs in the CNS area. SSRIs, SNRIs and brain stimulation for depression, anxiety, new class of antipsychotics for schizophrenia, related disorders, bipolar disorders and autism, different mood stabilizers for bipolar disorders, cholinesterase inhibitors for Alzheimer’s, several formulations of beta interferon, glatiramer, natalizumab, and now the recent oral fingolimod for MS, and several different replacement therapies for rare genetic disorders, even for a chronic neurological form of Nieman Picks disease, type C (a glycosphingolipid synthesis inhibitor) though none for type A- an acute neurological form.

Lately we had seen a slowdown in the development of medications in the CNS area except for Alzheimer’s, multiple Sclerosis, ALS and rare genetic disorders and feel that the drug development in psychiatric conditions appears to have taken a back seat. News is indicating that many major Pharma companies are closing down doors on their CNS related operations. Examples that come to mind right now are GSK and Pfizer. There is a lingering question in the curious minds of at least some medical professionals why the interest to develop new medications for psychiatric conditions is dwindling and what could be the potential reasons?

Recently PhRMA released an update for 2010 that “Pharmaceutical Research Companies Are Developing More Than 300 Medicines to Treat Mental Illnesses (see the link)”

Among them we can see quite a few are for alcohol, nicotine and other drug dependence, anxiety, Alzheimer’s and several others; the list is fairly inclusive of all conditions. Are they all new compounds? Not really; some are old with same formulations, some new formulations, some with new route of administration. But overall, this is good news; out of 313 newer developmental programs here there are quite a few new chemical entities. It is quite encouraging…..though that number may be far behind the current programs in oncology and diabetes.

http://www.phrma.org/sites/phrma.org/files/attachments/Mental_2010.pdf

IS LOVENOX a DRUG or a BIOLOGIC?

2010-07-23T12:37:00.000-07:00

Today the 23 July 2010, Sandoz and Momenta received the marketing approval by FDA for their version of enoxaparin (Lovenox). Lovenox is a leading anticoagulant manufactured by Sanofi Aventis. Sandoz/Momenta have been working with the FDA since 2003 with substantial data on their version of enoxaparin showing the bio equivalence and potential immunogenicity issues.

Enoxaparin (Lovenox) is a low molecular weight heparin made from the heparin extracted from pig intestines. It is technically a biologic and more (may be not entirely) similar to naturally occuring biologics such as IgG, albumin, alpha 1 antitrypsin etc- major players-CSL Behring, Baxter, Talecris, Grifols that are extracted and purified from human plasma. The basic proteins are same, because they all come from human plasma; but the purification and the concentration process of those proteins is proprietary for an individual company which allows them specific trade names. Example: 10% IgG is called Privigen (CSL Behring), Gamunex (Talecris), Gammagard (Baxter). These products are approved through different pathway. They do not call them generics when a new brand is approved.

I am not sure through which pathway this “GENERIC” from Sandoz is/Momenta approved. It is another version of the low molecular heparin derived from the pig intestine heparin –perhaps purified by different mechanism? The remarkable length of time it has taken to get the approval for this tells us that this is not a typical abbreviated NDA that is applicable to generics.

This pathway would probably be entirely different for BIOLOGICS and their BIOSIMILARS.

While we are talking about the low molecular weight heparin and their approvals, tainted heparin from China caused over 80 fatalities in the US between 2007 and 2008. There was assurance that Chinese regulatory authorities were looking into it. WSJ article on 22 July 2010 says that the Chinese government did not pursue an investigation into contaminated heparin sent to the U.S. in 2007 and 2008, despite repeated requests from the U.S. for help, according to a congressional probe by two House Republicans Reps. Joe Barton and Michael Burgess, both from Texas. They said FDA officials recently told them that the agency has been "severely hampered" by the lack of cooperation from China in finding those responsible. An FDA spokeswoman said that "there are serious limitations on what the FDA can do to pursue civil and criminal investigations in foreign countries, especially without the cooperation of the foreign government."

Yan Jiangying, spokeswoman for China's State Food and Drug Administration, said the congressmen's accusations are "not true" and her agency "did a very thorough investigation, including very detailed inspection and testing, and surveys of enterprises as well. “We signed an agreement with the FDA on drug safety in the end of 2007, and strengthened the monitoring of heparin."

The probe, comes as FDA Commissioner Margaret Hamburg prepares for her first trip to China since assuming her position in 2009.

http://online.wsj.com/article/SB10001424052748703954804575381540372921432.html

WHO issues the Model Formulary for Children 2010

2010-07-14T10:41:00.000-07:00

Model Formulary for Children 2010 is a 528 page document, based on the Second Model List of Essential Medicines for Children 2009.
The drug list includes anesthetics to vitamins and specific medicines for neonatal care.

It is edited by:

-Matthew Bidgood, PhD
-Elizabeth Donohoo, BSc
-Niroshni Gunewardhane, MD
-Allyson Harvey, RN
-Valerie Hoa, MPharm
-Sue Hunter, BVSc
-Sarah Keen, BPharm
-Olivia Wroth, BVSc, DipBEP

Clinical editing was provided by the members of The Royal Children’s Hospital, Melbourne, Department of Essential Medicines and Pharmaceutical Policies, World Health Organization- Geneva, Centre for International Child Health, Department of Pediatrics and The University of Melbourne

http://www.who.int/selection_medicines/list/WMFc_2010.pdf

VIRTUAL REALITY a successful APPROACH IN PTSD TREATMENT

2010-06-29T08:14:00.000-07:00

TV shows are getting fairly savvy in using latest treatment developments in their shows. Prime example: FOX TV show “Lie To Me” episode that was aired on 28th June, 2010 showed the use of the Virtual Reality (VR) based approach to trace back the root cause of the PTSD experienced by an Afghanistan war hero. The story is fairly well constructed around the use of the VR.

VR integrates real time computer graphics and visual displays that allow users to feel a sense of immersion in the virtual environments. VR offers a promising technological adjunct to traditional image based exposure treatment of PTSD.
Internet based treatments have been proposed as a delivery method for the treatment of anxiety disorders, especially PTSD that may address some logistical impediments including geographic and fiscal constraints not surprisingly.
The research from the Executive Division of the National Center for PTSD (NCPTSD) has focused primarily on clinical trials testing different treatments for PTSD and on veterans' health. One of the areas they are working on; Computer-based prolonged exposure for PTSD. This Depart Of Defense funded project aims to develop an interactive media program incorporating nascent technologies to enhance treatment delivery to military personnel in primary care settings.

According to US Navy investigators who are studying the approach in service members returning from Iraq and Afghanistan, virtual reality exposure with arousal control (VRE-AC) may be more effective than prolonged exposure therapy with simulation for the treatment of combat-related posttraumatic stress disorder (PTSD), ,
Robert McLay, MD, PhD, of the Naval Medical Center, San Diego, California, described the early success of VRE-AC at the American Psychiatric Association (APA) 2010 Annual Meeting. For the treatment of combat-related PTSD, VRE-AC may be more effective than prolonged exposure therapy with simulation, according to US Navy investigators who are studying the approach in service members returning from Iraq and Afghanistan.
The study was conducted at 2 military hospitals in Southern California. It compared VRE-AC with treatment as usual for combat PTSD in 20 active duty members diagnosed with PTSD related to their service in Iraq or Afghanistan. Majority of them had not responded to standard therapy.
Participants were randomly assigned to 10 weeks of VRE-AC treatment (n = 10) or standard therapy (n = 10), which was primarily traditional approaches to exposure. Outcomes were measured using the Clinician Administered PTSD Scale (CAPS). Treatment success was defined as a response that is 30% or higher. All participants in VRE-AC group and 9 members in the control group had all the assessments.
Nine participants (90%), in VRE-AC arm had 30% or greater improvement on CAPS as opposed to one participant in the control arm (11%) (P < .01). Participants treated with VRE-AC improved an average of 35 points on CAPS (decreasing from 83.4 to 48.1), whereas those receiving standard treatment averaged only a 9-point improvement (decreasing from 82.8 to 72.3) (P < .05). “Improvement was noted in both groups, but the gains with the virtual reality treatment were more impressive," Dr. McLay said. VRE-AC is perhaps most practical, cost effective and beneficial in the treatment of PTSD related to the war and other mass events. The images can be obtained from already available footage. No need for additional custom built images and reconstruction of the scenarios. It may be cost prohibitive to build it up for the PTSD related to other real life scenarios right now; but as the technology is advancing in leaps and bounds we may not be far off for the approach to be mainstream. Recent related publication: http://www.maps.org/mdma/clinical_psychology_ptsd_review.pdf

THANK GOODNESS- RARE GENETIC DISEASE TREATMENTS ARE FINALLY IN VOGUE ….

2010-06-15T16:00:00.000-07:00

Due to my odd way of learning, I had easy time learning and remembering the names and related information of rare genetic diseases while in medical school. As I started working in the pharmaceutical industry, I also learned that regulations categorize these rare genetic diseases as orphan diseases as the numbers of patients that inherit them are rather small. I used to think, "How appropriate; they are orphan diseases and no one wants to do much for them".
I often used to wonder about these orphan diseases and will there ever be a hope for possible treatment/cures for them. The regulatory pathway is rather simple for orphan indications and they are not as rigorous for all the right reasons. Until now the potential treatment development for the orphan diseases has not been looked at seriously. Because the pharmaceutical industry growth model did not have a place for these diseases that do not have a large market potential. Genzyme, can be called a pioneer in this area. Established in 1981, celebrated their 25th anniversary on June 8th, Genzyme is one of the pioneers in this field. They got the first approval for the purified, modified enzyme replacement Ceredase to treat Gaucher’s disease in 1991, and for a recombinant version - Cerezyme in 1994. In 2004 they got the approval for Fabrazyme (afgalsidase beta) to treat Fabry’s Disease. They partnered with the West coast biotech company Biomarin pharmaceuticals in the development of Aldurazyme (l aronidase) - an enzyme replacement therapy for the treatment of Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and got the approval in 2003. They are also working on the treatment for Pompe Disease and got the indication extension of Cerezyme (which is short supply currently due to GMP issues) for Type 3 Gaucher’s disease. Meanwhile Biomarin pharmaceuticals got the approval for Naglazyme (galsulfase - a recombinant version of lysosomal enzyme. N-cetylgalactosamine 4-sulfatase), an enzyme replacement therapy for the treatment of mucopolysaccharidosis VI - Maroteaux-Lamy syndrome (MPS VI) in 2005. Merck Serono and Biomarin partenered in the development of sapropterin dihydrochloride (Kuvan), a synthetic form of 6R-BH4, a naturally occurring enzyme cofactor that works in conjunction with the enzyme phenylalanine hydroxylase (PAH) to metabolize phenylalanine in the orphan disease, phenylketonuria. Some scientists are claiming that phenylketonuria is no longer an orphan condition (increase in the number of patients?- it not a good news…). They are also working on Duchenne Muscular Dystrophy (DMD). The other player in this, Shire Human Genetic Therapeutics got the approval for Elaprase (idursulfase), the first enzyme replacement treatment for individuals with Hunter Syndrome (MPS II) in 2006 and velaglucerase alfa (VPRIV) to treat children and adults with the most common form of Type I Gaucher disease in early 2010.

I am thrilled to see so many developments in the area of rare genetic diseases.
Now suddenly all the attention now is gearing towards the rare diseases. The big players are jumping on the band wagon of “finding the treatment for the rare diseases “rather quickly.

First it was GSK in Feb 2010.
In 2009, GSK entered into strategic alliance with 2 companies, Prosensa and Japnese Company- JCR Pharmaceuticals. With Prosensa the focus is on nucleic acid based therapeutics, correcting gene expression in diseases. It includes 4 RNA-based compounds to treat different specific subpopulations of Duchenne Muscular Dystrophy (DMD). In the agreement with JCR Pharmaceuticals, GSK has obtained global rights to a number of enzyme replacement therapies that could potentially be useful in the treatment of orphan diseases such as Hunter syndrome, Fabry disease and Gaucher disease.
Yesterday, June 14th, 2010, Pfizer announces the creation Of Rare Disease Research
http://media.pfizer.com/files/news/press_releases/2010/rare_disease_research_unit_061410.pdf

Orphan drug act was passed in the US in 1983. EU has similar rules but they are broader. Over 2100 orphan designations and 353 approvals were granted by FDA, since the act was passed and 19 of them reached a blockbuster status. FDA approved 17 drugs for orphan indications in 2009.

The most attractive aspects of the orphan indications include easier, faster approvals with low development costs and the high treatment costs. Some analysts are predicting that in the current market place, companies like Biomarin are potential takeover/acquisition targets.

Other developments in the rare genetic disease area.
Fifth European conference on rare diseases took place in mid May this year in Krakow with the passionate motto “We have a dream” , akin to the famous words uttered by the great MLK in a different context.

http://www.orpha.net/actor/EuropaNews/2010/100602.html

Around the same time frame the finalized the Rare Diseases Task Force Report April 2010.

http://www.eucerd.eu//upload/file/RDTFReportIndicatorsApril2010.pdf

Forbes article on world’s priciest drugs; majority of them are for rare diseases.

http://www.forbes.com/2010/02/19/expensive-drugs-cost-business-healthcare-rare-diseases.html

Recent good news in oncology arena and personalized treatment.

2010-06-05T17:07:00.000-07:00

Recent good news in oncology arena:

Pfizer analyzed early-stage results of crizotinib in lung cancer patients recently, and found that there was shrinkage in tumors in patients that have the ALK genetic fusion which is suggests the inhibition of ALK enzyme by crizotinib. In the expanded trial of twice daily oral crizotinib in 82 with ALK gene (ALK positive) lung-cancer patients, 82% patients showed either tumor shrinkage or stabilization of the tumor. According to a published study, the estimated genetic fusion is present in about 3% to 5% of people with nonsmall-cell lung cancer, or 40,000 patients diagnosed annually world-wide. Crizotinib is known to have the ability to inhibit C-met enzyme that feeds tumor growth and also affects ALK (anaplastic lymphoma kinase).

BMS study with ipilimumab (a monoclonal antibody, that works by increasing the activation of T-cells), found that the melanoma patients taking ipilimumab alone or in combination with the vaccine (A synthetic peptide cancer vaccine consisting of amino acid residues 209 through 217 of the glycoprotein 100 (gp100) melanoma antigen, with a methionine substitution at position 210 designed to improve immunogenicity.– used as control according to BMS) lived an average of 10 months, versus the average survival of 6.5 months noted in patients that received the vaccine alone. In other words, 45.6% of people that received ipilimumab were alive after one year, versus 25.3% in the vaccine group.

Amgen’s Prolia (denosumab) was observed to have reduced the risk of fractures in a study with cancer patients. Prolia was approved recently by FDA to reduce the risk of fractures in women with osteoporosis.

Personalized medicine theory appears to hold true in studies especially in cancer studies. It definitely holds true with Pfizer’s crizotinib in lung cancer patients.

Majority of oncology drug failures are due to lack of understanding of intricate mechanisms of the drugs, individual tumor/cancer characters, and patient genetic makeup. It is extremely important to discuss all the possibilities in the areas of mechanism of the drug, individual tumor/cancer characters, and patient genetic makeup with all the experts and scientists prior to setting up the patient selection criteria, dose/regimen of the drug and co-medications amongst the other important items, instead of rushing to start the program. That approach would help improve the success rate of these life saving drugs with better tolerability and of course better safety and efficacy.

Pharmacovigilance – All The Vigilance Required To Make Sure Of The Safety Of An Approved Product

2010-05-24T14:43:00.000-07:00

Pharmacovigilance is a simple and elegant Greek and Latin (literally) term. The process on the other hand is quite elaborate and scientific. It involves the detecting, assessing and understanding of the adverse events related to the drugs from the time they are in development (toxicology, clinical phases- though a lot can be found during this time, due to controlled conditions [dosing, exposure time, other drugs and other coexisting diseases] and the limited [over 1,000] exposure to the agents) to the marketing phase where the use is in real life conditions. Pharmacovigilance is not just limited to drugs. It encompasses devices, biologics, imaging products, blood derived products, herbals (not as much usually) - you name it. The main basic purpose of pharmacovigilance is to watch for any unusual stuff going on with the regulated marketed products, so that the patients/consumers can be protected by proper warnings (Black box-most common method for drugs) to voluntary- mandated withdrawal of the product from the market.
We generally tend to think that the pharmacovigilance is applicable just for the safety of human beings; it applies to veterinary medicinal products as well.
Let me start with a little bit of introductory info for the organizational structures of the regulatory bodies in the US, Europe and others.
Food and Drug Administration (FDA) has 3 main divisions: Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH). FDA has put together the pharmacovigilance guidance for the industry. See the link: http://www.pharmamanufacturing.com/Media/MediaManager/FDAGuidance_Pharmacovigilance.pdf
European Medicines Agency (EMEA) has 6 main divisions: Committee for Medicinal Products for Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP), Committee for Orphan Medicinal Products (COMP), Committee on Herbal Medicinal Products (HMPC), Pediatric Committee (PDCO), and Committee for Advanced Therapies (CAT)
EMEA established the Pharmacovigilance Working Party (PhVWP). They provide recommendations to the CHMP on all matters directly or indirectly related to pharmacovigilance - their way of constant monitoring of medicinal products on the market.
EMEA uses The EudraVigilance Clinical Trial Module (EVCTM) systems while the drugs are going through clinical trials and The EudraVigilance Post-Authorization Module (EVPM) during marketing phase of drugs.
In UK, Medicines and Healthcare products Regulatory Agency (MHRA), has Pharmacovigilance Inspectorate to assess pharmaceutical companies’ compliance with UK and EU legislation related to the safety monitoring of medicines given to patients. This is mainly achieved through carrying out inspections of UK Marketing Authorization Holders (MAHs) that are responsible for placing medicinal products on the market (which are usually the pharmaceutical companies).

International Conference on Harmonization (ICH) put together a draft Guidance for Pharmacovigilance Planning (PvP) for registration of pharmaceutical products for human use to aid industry and regulators in the planning pharmacovigilance activities, especially in preparation for the early postmarketing period of a new drug. FDA follows it as well.
http://www.fda.gov/OHRMS/DOCKETS/98fr/2004d-0117-gdl0001.pdf
Across the globe, there are several other organizations working separately and together in the process of pharmacovigilance. I listed some of them below. This gives us a glimpse of how pharmacovigilance is tackled.
World Health Organization (WHO) works with the WHO Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre) and promotes pharmacovigilance at the country level.
The International Society of Pharmacovigilance (ISoP) is an international non-profit scientific organization, aids in enhancing all aspects of the safe and proper use of medicines in all countries. It was first conceived as just a society in Europe, the European Society of Pharmacovigilance (ESOP) in 1992.
The terms Adverse Event (AE), Adverse Drug Reaction (ADR-though it says drug, it includes device, biologic, imaging product etc) are no strangers to anyone who is involved in clinical trials. Here is some clarity on AE vs ADR.
AE could be due to the disease the drug is treating, other medications, genetics, non compliance of medications, diet, environment and others factors along with the drug itself, where as ADR comes after the elimination of all the other factors and pretty close to be attributable to the drug itself (spontaneous reports are usually considered examples for this).
Here comes everyone’s favorite term “Serious Adverse Event (SAE)”. It is a regulatory term defined by ICH guidelines, guided by specific reporting timelines and is the most talked about component in GCP training; it is one of the most familiar tern to anyone that is involved in clinical trials.
SAE is defined as any untoward medical occurrence that at any dose that results in death, is life-threatening, requires inpatient hospitalization, or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
In almost all the scenarios, the events need to be reported immediately (week to 2 weeks) and the details are specified in the study protocols. Then we have the Suspected Unexpected Serious Adverse Reactions (SUSAR) that has not been seen, experienced, or expected. Reported timelines are between 7-14 days.
“Signal detection” is the catch phrase that is in vogue in addition to Risk Evaluation and Mitigation Strategy (REMS) right now. There is a big boom in the pharmacovigilance businesses and the providers that train and collect/analyze the signals.
Let us talk about the signal detection. The term sounds so spooky as though we are trying to detect the signals from the aliens or from the outer space.
The WHO defines a signal in pharmacovigilance as “reported information on a possible causal association between an adverse event and a drug, the relationship being unclear or incompletely documented previously”. Signal detection is thought to be one of the most important objectives of pharmacovigilance. Eventually, the entire process of risk/benefit evaluation is expected to depend on effective detection of signals. Information technology plays a key role in the process of successful signal detection and making it increasingly effective. Some believe that the days of automated methods to detect signals prospectively are not far away. One thing we all have to remember is that accuracy and logic are the key elements in creating the algorithms that help detecting the signals.
Signal detection is usually based on spontaneous reporting of adverse events. It involves looking for any new patterns or new findings that look significant in the safety database.
First identify the potential tentative signals, and then analyze how real they are. Most often, the signal can originate from the disease that the drug is treating: e.g. With an anti hypertensive, we would expect to see the reports of high blood pressure, and the consequences of high blood pressure itself such as kidney disease, stroke and heart failure. When these findings are frequent they need to be corroborated by checking the other diseases those patients have, other drugs they are taking along with checking the clinical trial database and toxicological study data (the way to tease out the ADR from AE).
If it is still looking suspect setting up a study to investigate that particular signal or safety concern would be necessary. There would be discussions between the companies and the regulatory bodies and regulatory bodies may advice different ways to deal with it based on the strength of the evidence. They can range from keeping the issue under review; propose a label or SPC (Summary of Product Characteristics) change, sending Dear Doctor letter about it etc. It might even lead to the voluntary withdrawal of the product by the license holder or suspension or revocation of the marketing authorization by the regulatory bodies. If it becomes apparent that the signal is a false alarm, then everyone involved in it will take a big sigh of relief and the issue is put to rest.
Although many companies have implemented signal detection systems, these systems alone do not automatically lead to improved risk management. There are several different structured signal management systems that, search, collaborate, analyze and document the risks and help improve pharmaceutical companies’ risk management capabilities. One of the most popular one is Oracle systems.
However sophisticated the software may be, they are as good as training received by the drug safety professional in the process. The theoretical basis and limitations of these methods should be understood by drug safety professionals, and automated methods should not be automatically accepted. Understanding the theoretical basis of these methods should enhance the effective assessment of the signals leading to effective and efficient pharmacovigilance process by the drug safety professionals.
Looking for patterns or clusters of reports that stand out; these clusters of events could be identified in the safety data tables within the company or in large databases at the regulatory authorities usually by using computerized systems. Examples: Bayesian Combination (Quantitative and automated numerator-based methods) Propagation Neural Network used by the WHO Uppsala Monitoring Centre, Proportional Reporting Ratio etc. Regulatory agencies such as FDA and MHRA use the Modified Gamma Poisson Shrinker method.
In July 2005 The Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has signed a license with Lincoln Technologies, Inc. for the installation of Lincoln's WebVDME pharmacovigilance signal detection and signal management software at MHRA. This Software will be a component of the Accenture-MHRA Sentinel Program.
Probably one of the biggest projects about signal detection in pharmacovigilance is FDA’s Sentinel Initiative. It is a national electronic system that will transform FDA’s ability to track the safety of drugs, biologics, medical devices–and ultimately all FDA-regulated products once they reach the market. . Launched in May 2008 by FDA, the Sentinel Initiative aims to develop and implement a proactive system that will complement existing systems that the agency has in place to track reports of adverse events linked to the use of its regulated products.
The Sentinel System would enable FDA to actively query diverse automated healthcare data holders such as electronic health record systems, administrative and insurance claims databases, and registries to evaluate possible medical product safety issues quickly and securely.
Sentinel will be developed and implemented in stages. As the system is envisioned, data would continue to be managed by its owners and questions would be sent to the participating data holders/generators. See the Link below:
http://www.fda.gov/Safety/FDAsSentinelInitiative/default.htm
Let us hope that we are heading towards a better safety vigilance for all the approved for our human use all around the world.
A personal cautionary note: However vigilant the industry and the regulatory bodies remain, following of the label is crucial unless there is evidence otherwise.

Personalized Medicine

2010-05-11T16:33:00.000-07:00

We all know NO drug works for everyone. As people we are all different not just the outward appearance and looks, but the core genetic makeup itself. Though we know a lot about the diseases, infections, human genetic makeup, the cumulative knowledge is still very little; almost like a drop in a bucket. Personalized medicine is an attractive concept. It is gaining popularity and fanfare. More and more scientists are finding plausible information and applicability of that information to the maladies in the human beings and the therapeutic approaches. The practicality and prospects of personalized medicine once thought to be gloomy are becoming evident. There would still be several hurdles before reaching the goal. But the scientific community is marching ahead. Some forward thinkers even believe that personalization of medicine will be the trend in the next decade.
There are several educational and promotional efforts are in progress for the concept of “Personalized Medicine”. Here are a couple of them.

PMC (Personalized Medicine Coalition), an independent, non-profit group that works to advance the understanding and adoption of personalized medicine for the ultimate benefit of patients. http://www.personalizedmedicinecoalition.org/
A publication “Personalized Medicine" http://www.futuremedicine.com/loi/pme

For the examples of recent progress of the personalized medicine:
The recent finding about the anti-clotting drug clopidogrel (Plavix), the second-biggest selling drug in the United States was observed to be not too effective in approximately 14% of studied people as they may not have the right genetic makeup for its activation. Some health practices are now using routine genetic testing for patients before they are giving the drug after receiving the stents. The tests are done either with blood or the saliva.
The other areas where the genetic testing is becoming useful prior to the right treatment are cancer therapies and the organ transplants.
In case of organ transplants, tests are being developed to assess a patient's genes, antibodies, proteins and cells with the hope that these tests will help in the assessment of what drugs they need for organ rejection balancing the vulnerability for infections and cancers.

In oncology the application is expected to be very helpful because of the innumerable variables.
My perspective on this approach is getting the right medicine to the patient as soon as they need it. Time and quality of the health are of the essence for the treatment.
In this type scenario the drugs are not expected to be blockbusters, but they will definitely going to be the targeted lifesavers we will all be getting the benefit from.
The flip side of this is the cost increase; additional cost of test kit plus the cost of time for test administration. The other very important aspect of it is the legality. We live in a litigious society. Unless there are preset legal limitations, this personalized medicine approach may prove to be disastrous for the makers of the drugs and test kits.

Is there a need for that much sensationalization in the news, really?

2010-05-05T10:50:00.000-07:00

Is it me, or lately we are seeing too much of sensationalization in the regular news.
“Glaxo Halts Red Wine Drug Study Enrollment on Safety Concern”. It is a fact, they did; it happened, agree. We see and read it again and again. Then the titles; they are extremely creative. Just look at one of them, “Is the Bloom Off the Resveratrol Rose?” It is the title of the health blog on the subject in WSJ.
This is about GSK halting the study of SIRT1 (GSK version of resveratrol) with Velcade in the treatment of Multiple Myeloma.
First of all I would like to clarify a simple matter. I neither have any fiduciary interest in GSK nor do I have any opinions (positive or negative) on resveratrol.
Here it is. Kidney failure due to cast nephropathy is the most common complication in Multiple Myeloma. It is called "myeloma kidney" and a characteristic of the disease. It occurs in approximately 28% of Multiple Myeloma patients (Dhodapkar et al. Biology and therapy of immunoglobulin deposition diseases. Hematol Oncol Clin North Am 1997). The problem is caused by the toxicity to the distal nephron due to accumulation of the immune protein (IgG, IgA and other light chains) and the associated inflammatory response.
The test drug SIRT1 is given with already approved Velcade in Multiple Myeloma patients. I am guessing the reason for choosing Multiple Myeloma to test the drug is because of the previously studied evidence that resveratrol suppressed the genes that protect myeloma cells from dying and it killed myeloma cells that were resistant to chemotherapy and enhanced the effects of bortezomib (Velcade) and thalidomide along with other related evidence. The study enrolled 24 patients so far and 5 of them developed cast nephropathy, very close to the expected rate of cast nephropahy occurrence in multiple myeloma patients; when you look at the pure numbers, it is in the ball park. I do admire GSK for halting the study. I believe they are trying to figure the observed findings out so far. There are quite a few other things that need to be considered here; stage of the disease in the enrolled patients, availability of pre dose data on renal involvement, use of corticosteroids, other coexisting diseases etc. In addition to that effect of Velcade on the renal tubular protein deposition and the effect of addition of SIRT1 to Velcade need to be evaluated as well amongst several other things.
While writing this, it occurred to me suddenly that however sensationalized some of these blog and news tidbit headings may sound and imply that there are problems with the drug and the company, this type of news tidbits and blogs will keep the momentum and the publicity going. Ultimately the efficacy and safety of the drug are the virtues that help get it into the market to help us.
What amazes me most at this point is, how quickly this particular blog got me going and made me a contributor to this flow, hmm….

Prescribing Medication a "Privilege"; not a Right...

2010-05-04T15:27:00.000-07:00

I just read the blog about psychologists’ wish to prescribe psychiatric medications by Dr. Ghaemi, on Medscape entitled "Psychologist prescribing: Lowest common denominator psychopharmacology".
Link: http://boards.medscape.com/forums?128@874.vlYYaUbLpbD@.29fd587b!comment=1
He says that “Perhaps we psychiatrists need to start taking disease seriously, and just as seriously realize when disease is not present, and drugs are not justified. Our ambivalence has led to symptom-oriented polypharmacy, criticisms about overtreatment, and calls by others to get in on the act. Our critics cannot have it both ways: They argue, rightly, that our practice of psychopharmacology is flawed, and then insist, wrongly, that we simply need to expand access to that treatment: Give us the prescription pad, they say, and we will prescribe drugs like you. Give us the prescription pad, they say, and we will prescribe drugs like you. To expand a faulty practice would seem an odd way to advance public health”.

I agree with the thought” let us not expand a faulty practice; it would seem like an odd way to advance public health”, I believe that my perspective on that may be somewhat different but simply fair.
As trained physicians first and psychiatrists afterwards, psychiatrists go through the medical training that does and should distinguish disease from non-disease first of all. Then they also understand and analyze the signs and symptoms and correlate them to patient examination findings and societal and environmental factors. So, before someone thinks that they should have the right to write a drug prescription for a patient, that someone needs to take a step back and ponder “have I done all that?” Writing a prescription is not a right. It is a privilege that comes with a lot of responsibility. Something to keep in mind whether one is a physician or not.

Multiple Sclerosis, can the cause of the disease be treated?

2010-05-01T11:26:00.000-07:00

Multiple Sclerosis is one of the most devastating and unpredictable diseases. Approximately 400,000 people in the US have MS and the world wide count is 2.1 million, mostly affecting the age group 20 to 50. The autoimmunity (immunity against one’s own myelin) de-myelinates the central nervous system (mainly brain and optic nerve) and spinal cord (CD4+ T cells and macrophages destroy oligodendrocytes that synthesize and maintain axonal myelin sheaths in the central nervous system).The disease course is variable; it could be relapsing remitting, primary progressive, secondary progressive, and progressive relapsing and the degree of severity can be mild, moderate and severe. To diagnose, specific guidelines using magnetic resonance imaging (MRI), visual evoked potentials (VEP) and cerebrospinal fluid analysis are set. All this is established so far
When it comes to treatment part of it, the autoimmune nature of the disease makes it quite un-reliable.
So far all we have are the disease modifying agents that work against demyelination, the effect of the disease. Most common and popular agents are Interferons; Interferon beta-1a (Avonex, Rebif), 1b (Betaseron, Extavia). The others include glateramer acetate (Copaxone- a 4 amino acid combination that is part of myelin basic protein which is expected to divert the immune system away from myelin) mitoxantrone (Novantrone -anti cancer drug used along with corticosteroids to suppress the autoimmunity), natalizumab (Tysabri-humanized monoclonal antibody against cellular adhesion molecule α4-integrin). Intravenous plasma derived IgG is also a popular treatment option amongst the neurologists across the globe. So far when we look at all the available/approved treatment options for MS, they are all injectables; nothing oral.
There is an oral drug once a day dose (fingolimod) is tested and completed the clinical trials and submitted for FDA approval. It is a chemical derivative of myriocin, a metabolite of the fungus Isaria sinclairii, which has been used in Chinese traditional medicine for a long time. When fingolimod enters the circulation, it is rapidly phosphorylated closely resembling the lysophospholipid sphingosine-1-phosphate (S1P- has 5 known receptors 1 to 5 that are involved in multiple physiologic activities, including neurogenesis, cardiovascular development, vasoregulation, endothelial-cell function, and leukocyte migration. The data on the efficacy of the drug is quite encouraging. When approved, the hope is that it would help the MS patients in the management of their medication effectively and efficiently.
The scientific community is now relentless and so many theories and approaches are being looked into. Lingo-1 is believed to stop myelin production in adults after axons are well covered. Work is going on an antibody that can safely turn off Lingo-1, and allow myelin regeneration and trials on that are expected to be launched soon. Some researchers are trying to direct oligodendrocytes to damaged areas. Stem cell transplantation is another approach. There are some ways now aimed at shutting down the early part of the disease process rather than repairing the damage as well.
Surgical approach for MS, that too cutting of the root cause?
Poor venous drainage from the small veins around the brain, Jugular and even the Azygos vein is pointed and theorized as indirectly responsible for MS. Surgical correction of the problem has been tested and it may even end up to be at least one of the treatment modalities.
Dr. Paolo Zamboni, a former vascular surgeon and professor at the University of Ferrara in Northern Italy, looked for the causes of MS when his wife was diagnosed with the disease. He noticed that the brains of MS patients had higher levels of iron, not accounted for by age. The iron deposits had a unique pattern, mostly in the brain core, clustered around the veins that normally drain blood away from the head. Everyone thought that the excess iron is a toxic byproduct of MS. When Zamboni started ultrasound examination of MS patients he found partial or full, blockage of the veins that are draining the blood from the brain in almost all of them compared to the ultrasound of the brains of the healthy people. In the MS patient brains there was noticeable regurgitation of the impure blood. He feels that this venous insufficiency in the brain is contributing to the breaking down of Blood Brain Barrier in addition to the built up iron that acts as free radical. Zamboni called the condition CCSVI (Chronic Cerebrospinal Venous Insufficiency). Soon he noted that the level and extent of venous blockage was directly proportionate to the severity of MS. Dr. F. Salvi, at Bellaria Hospital in Bologna, was intrigued by the concept and began sending MS patients to Zamboni for CCVIS testing. Patient after patient, the images of narrowed or blocked veins (strictures in veins) were evident. Then Zamboni, sought the help of vascular surgeon Dr. R. Galeotti, also at the University of Ferrara and Santa Anna Hospital and began a study 3 yrs ago; they did endovascular surgery on the strictured veins of 65 MS patients to restore blood flow. Preliminary results of the study show decrease in the number of relapses, reduction in the number of brain lesions, and improved quality of life. It was noted that symptoms returned for the patients when the veins re-narrowed (like an un intended re-challenge) . Full results will be published end of this year in Journal of Vascular Surgery. Another small study in the US and Canada showed similar results. A new study is under way for which they are recruiting 1,600 adults and 100 children with 50% of them MS patients. Zamboni’s wife who had the most severe form of the MS went through the endovascular surgery of her Azygos vein and she has been symptom free ever since. Zamboni says that it is the best prize of his research.
This sounds too good to be true, doesn’t it? They say most remarkable scientific breaktroughs happen because of coincidence. Hope this is one of them.

Generic drugs and the issues….

2010-04-15T14:54:00.000-07:00

General rule of thumb for the generic drugs: Generic drugs should be identical and bioequivalent to the brand-name originals. They should contain the same active substances and have the same quality, efficacy and safety. Generics may contain different inactive ingredients as additives and fillers that do not have therapeutic effect. Patent expiry of a brand-name drug triggers the assessment and introduction of generic version of that drug.

Generics are expected to be as safe and as effective as the brand-name drugs. They should have the same pharmacological and clinical effects, and have the same risks and benefits as the brand-name drugs and manufactured by Good Manufacturing Practice (GMP) certified manufacturing facilities. Price is the most attractive part of the generics. The insurance companies insist on generics because they are cheaper. Are they that much cheaper. It is hard to tell. The prices are supposed to be 30%-80% lower than the price of the equivalent brands. The high price variability is not a general knowledge. As more and more famous brand drugs are losing patents, generic market is going higher. According to IMS Health, the global sales of generics have increased from $29 billion in 2003 to $78 billion in 2008 and it is growing as we speak. To change with times, all the big pharma companies are jumping on the band wagon of generics.

Now let us look at the bioequivalency requirement for oral drugs. Australian pharmacologist Don Birkett, wrote (1998 and 2002) that the criterion that should be used to measure the bioequivalence of 2 similar products is that the ratio of their AUC should be in the range of 0.8-1.25 (Relative bioavailability= AUC test/AUC reference). The guidance for generics is written based on this across all the regulatory bodies. The definition goes like this "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards."
The FDA guidance for oral generics says: Confidence interval (CI) values should not be rounded off; therefore, to pass a CI limit of 80 to125, the value should be at least 80.00 and not more than 125.00. (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM154838.pdf)

EMEA/CPMP (European Medicines Evaluation Agency and Committee for Proprietary Medicinal Products) has similar approach. Two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. This is considered demonstrated if the 90% Confidence Intervals (CI) of the transformed natural log ratios, between the two preparations, of Cmax (The maximum or "peak" concentration) and AUC (Area Under the Curve-measures the total drug exposure) lie in the range 0.80-1.25.
The Therapeutics Goods Administration (TGA) of Australia has the same approach. They consider generic preparations to be bioequivalent if the 90% confidence intervals (90% CI) of the transformed natural log ratios, between the two preparations, of Cmax and AUC lie in the range 0.80-1.25. Tmax (time to reach the maximum concentration) should also be similar between the products. Their requirements for drugs with a narrow therapeutic index and/or saturable metabolism are very strict. That is why Australian market does not have generics for drugs such as digoxin or phenytoin.
Between 2000 and 2008, the number of new generic drugs put forth for FDA approval went up 40% and approvals doubled, with approximately 600 of them approved for sale in 2009. “Capitol Hill likes Generic companies because the industry is powerful and voters are anxious for cheaper drugs. There is always pressure on us to reduce barriers to entry for generics” says ex-deputy commissioner for medical and scientific affairs for the FDA from 2005 to 2007, Scott Gottlieb, M.D. As the brand-name medications have already been clinically tested for safety and efficacy, generic companies don’t have to repeat that process with their generic versions when they apply for FDA approval. Most of the time, all they have to do is to test their generic version of medicine on a minimum of 20 healthy people with a single dose. Some require multiple dose testing to get to a steady state in blood, and prove the bioequivalence per their definition to get it approved.
Patients are finding stark differences among drugs the FDA has deemed equivalent. The complaints from the patients are enormous. The worst problems seem to occur when the patients are being switched from the branded drugs to generics and given different brand of generics (sounds contradictory-brand of generic) each time as there might be bioavailability variation between them.
There are so many stories of the generics related to lack of efficacy, odd side effects, over dose to name a few. There are blogs and forums by and for people that are taking the generic drugs. To name a few: Fosamax, Topamax, Wellbutrin, Lamictal. Long acting or extended release formulations are much more prone for these issues. If the drugs have a narrow therapeutic index then with the wider allowable margin makes it down right risky and dangerous.

Co hosts of public radio show “ The People’s Pharmacy” Joe and Terry Graedon who are well known for their non biased opinions are talking about generics and generics related problems a lot lately. One sure thing is that the generics are not being monitored as they should be for their bioequivalence, efficacy and related adverse events. Being cheap alternative does not automatically translate into efficacy and usability.
Generics could be important alternatives for many patients especially economically, but they may need more monitoring for safety and efficacy in some diseases. The prime example: antiepileptic drugs (AEDs). Some in the US neurology community and the patient advocacy groups are questioning the current regulatory requirements for both establishing bioequivalence as well as product substitution. Recent data also questions the actual cost savings associated with generic substitution in this unique patient population. (Barry E. Gidal, Bioequivalence of antiepileptic drugs: How close is close enough? Current Neurology and Neuroscience Reports, June, 2009). In one large survey conducted in the United States, 75% of physicians and 65% of patients reported having concerns about the safety of generic AEDs. A number of physicians reported several cases of patients with previously well-controlled epilepsy had a loss of seizure control when their AEDs are substituted with generics. AEDs are just an example.

The manufacturing of generic drugs has improved over the past 20 years. Patients need to pay attention if suddenly they are not getting the same response to the drug they have been taking, or if they are experiencing more or different side-effects, they may need to check if their prescription/pill looks the same as before or not because the pharmacy may have changed manufacturers. Lately some (very few) pharmacies are informing the patients if there is a switch.

The other side of all of it is an issue that is not so small is the trial lawyers and their constant advertisement supporting the “helpless American patients and their efforts in getting the compensation the patients deserve”. It makes you wonder when you hear them say “American consumers are entitled to have safe and effective drugs.” Does that mean that the rest of the people in the world do not deserve the safe and effective drugs?

Update: Now FDA's Pharmaceutical Science and Clinical Pharmacology Advisory Committee agrees with the Office of Generic Drugs that bioequivalence standards should be tighter for generic versions of "critical dose" or "narrow therapeutic index" drugs. I believe that it should be for all drugs and for the "critical dose" or "narrow therapeutic index" drugs; it should be absolute bioequivalence (not relative which is the current acceptability standard). This will lead to higher costs and of course, higher prices for the generics.

Pink Sheet daily says: The Pharmaceutical Science and Clinical Pharmacology Advisory Committee doesn't see the additional criteria as necessary, but FDA could still impose narrower bioequivalence margins over its objections....

I have not even touched the safety monitoring and pharmacovigilance for generics. It is entirely another topic by itself.

OBESITY- a disease?

2010-04-09T16:03:00.000-07:00

Obesity is a BIG business. It is now called a chronic “disease”. There is so much of research, statistics, websites, societies, support groups, you name it. Obesity society is popular and meets annually. The most important of all, obesity has a major impact on economy. The treatment/cure business of obesity is huge.

A small example of the available data goes something like this:
In the US the data collected by the Behavioral Risk Factor Surveillance System (BRFSS) in 2007suggests that
• 25.6% of American population is obese, 26.4% of men and 24.8% of women.
• The obesity prevalence: 19.1% for men and women age group 18—29 and 31.7% and 30.2%, respectively for men and women age group 50--59.
• Prevalence was highest for non-Hispanic black women (39.0%) followed by non-Hispanic black men (32.1%). Geographically the prevalence is higher in the South (27.3%) and Midwest (26.5%) and lower in the Northeast (24.4%) and West (23.1%).
Obesity should not be such a generic term, but it is made into one. By definition obesity is an excessive amount of adipose tissue in the body. On the other hand, “overweight” has more specific definition. It means excessive body weight that may come from muscles, bone, fat tissue, and water. The term” excessive” is very arbitrary especially now; Look what we are doing; we are still following the Metropolitan Life Insurance Company’s ideal height weight chart from 1943. Though it was updated a little in 1983, it is antiquated. People are taller, bigger and the bone structures are evolving; genetics are evolving as far as the metabolism, response to foods and even the air we are breathing. There is a lot more to overweight and obesity than meets the eye (literally). When it comes to measuring the level of obesity and overweight, it is not a simple matter.
The most common and widely accepted measuring the level of obesity and overweight seems to be Body Mass Index (BMI= Weight (kg)/Height Squared (m2). Per CDC, an individual is obese, if that individual has a BMI over 30. There are so many other varieties of complicated measurements. Even with the bare minimum understanding of the human anatomy and physiology, we know that all the methods are different and they do not work the same with all individuals. We are all built, act and behave so differently. That is the beauty and intrigue of being a human.
Basic understanding of body function suggests that the body weight is maintained when calories eaten equals the number of calories the body “burns.” When more calories are consumed than burned, energy balance is tipped toward weight gain. We are finding out that “It is not that simple “. Not all foods and calories are created and burned equal. Not everyone burns the foods the same way. Too many variables play at least some role in all this; genetics, environmental, behavioral, and socioeconomic factors, urbanization, modernization so on and so forth.
The bigger and worrisome issues that are linked to overweight and obesity are diabetes, hypertension, heart disease etc. There are several groups and scientists researching these issues, trying to come up with several combinations and permutations with diet (don’t we hate that word?), exercise (the thought itself makes me cringe), behavior modification (“you have got to be kidding me!”), and sometimes weight-loss drugs (“that sounds easy and do-able”) and bariatric surgery (not too attractive, feeling bloated all the time).

The treatment aspect of obesity comes next.
There is staggering number of advertisements online and on TV for weight reduction support. They are not approved by any regulatory body anywhere in the world. Sale of anti obesity drugs reached close to $500 million in 1997, then fallen to half of that in 1998 and expected to stay there for a while according to a book on Business Ethics: Case studies. Majority of these things are drugs, supplements, food additives and an occasional device (electronic belts to sweat”?’ is one of them). That is not all; many self help books and blogs with alternative therapies, foods, external devices are also part of it.

The regulated obesity drug arena had seen a lot of “downs”, litigations but very few “ups”. Mostly because no one wants to follow the label (everyone wants the pounds off right away). Fen-Phen (fenfluramine and phentermine) is a great example. Still the continued enthusiasm and interest leading the way to tremendous activity in the pharma/biotech world, I believe mostly because of the size of the market.
The mode of action for each and every one of these drugs is different. Currently Xenicol (orlistat) is being promoted over the counter as Alli. It is a fat blocker in the gut. Meridia (sibutramine) is an centrally acting appetite suppressant.

Several new drugs are being developed for obesity currently. Some are already submitted for approval, and some are still in early stages. In the following information, I would only talk about the names of the drugs mainly without including mode of action for weight loss.

Orexigen pharma submitted the NDA (new drug application) for Contrave (combination: bupropion SR and naltrexone SR). They are also working on another combination formula: Empatic/Excalia (combination of bupropion and zonisamide). Arena pharmaceuticals submitted the NDA for Lorcaserin (selective 5-HT2C agonist). Vivus pharmaceuticals submitted the NDA for Qnexa (pentermine and topiramate). Novo Nordisk is working on their recently approved anti-diabetic drug Victoza (liraglutide) for weight loss.

Some companies are jointly working on these endeavors. Alizyme/Takeda - working on metabolic product Cetilistat. Amylin/Takeda - working on combination formula of pramlintide, an analog of the natural hormone amylin, and metreleptin, an analog of the natural hormone leptin. Amylin is also working on davalinitide (a second-generation analog of amylin). J&J is working on a type 2 diabetes drug called Canagliflozin (SGLT-2), a gut-specific MTP Inhibitor for obesity. 7TM Pharma is working on obinepitide, (a Y receptor peptide) and TM 30339 (natural satiety hormone, Pancreatic Polypeptide (PP). Bristol-Myers Squibb is working on BMS 830216. Shionogi is working on velneperit (a novel neuropeptide Y). Kissei of Japan with GSK is working on serglifozin etabonate (a novel selective inhibitor of low-affinity sodium glucose cotransporter). Phytopharm/Council for Scientific and Industrial Research and Unilever are working on Hoodia Gordonii Extract and Kyorin is working on KRP 204 (a highly selective ß3-agonist).

Sanofi-Aventis scrapped the research on rimonabant, an investigational drug aimed at weight loss and smoking cessation and Clobenzorex, a stimulant, not available in the US.

In addition to these, there are a bunch of early stage compounds from Astrazeneca, Biovitrum, Compellis, Emisphere, Epix, Genaera, GW Pharmaceuticals, Neurogen, OSI, Pfizer, Sirtris,, TransTech, Zydus Cadila are in the works.

When it comes to surgical approaches there is Roux-en-Y gastric bypass (RGB), the most common gastric bypass surgery performed in the U.S. With this first, a small stomach pouch is created by stapling part of the stomach together or by vertical banding, which limits the amount of food one can eat. Then, a Y-shaped section of the small intestine is attached to the pouch to allow food to bypass the duodenum as well as the first portion of the jejunum which reduces calorie and nutrient absorption. This procedure can be done with a laparoscope in some. The other one is extensive gastric bypass (biliopancreatic diversion). The lower portion of the stomach is removed and the remaining small pouch is connected directly to the final segment of the small intestine, completely bypassing both the duodenum and jejunum. This is not a widely used method because it leads to severe nutritional deficiencies. There is another device (Lap-band) based surgery that is simpler and adjustable and can be done laparoscopically.
The insurance coverage seems to be improving for obesity/overweight, though frequently objected and questioned.
Looking at all these approaches the world is undertaking to address OBESITY, I may need to refrain from voicing my strong objection calling it a “disease”

AIDS today

2010-03-31T12:50:00.000-07:00

AIDS it is a strange acronym for a disease that is so deadly. Does this disease aid the mankind (sorry, I deviated from political correctedness), human kind in any way? I wonder how the name evolved!?
Contrary to its name it has been a destroyer of human spirit for two and half decades. It separated the religious faith, tore the lives and relationships apart; created new hatred, new guilt that has been lying dormant for centuries in people’s hearts. All because it has been perceived as a disease of “homosexual men”; “SINFUL”, lifestyle gotten to that “doom”etc. “It does not and should not touch us non sinners. We are ‘normal’ people. We do not have to worry about it all” was the general consensus. Then we found out that IV drug addicts are more prone for the infection due to use of dirty needles and needle sharing and other related behavior. Our defense was “they are drug addicts; they deserve it. We don’t do drugs; we do not need to worry”. Oops! We found out people that received blood transfusions are getting infected…”oh their health is compromised, I am healthy, and it wouldn’t affect me. We are fine because we are morally, habitually and physically superior”. Then we found out that several people that are normal (?), heterosexual, healthy people found to be infected. We simply ran out of excuses. It came clear to us that this is not a disease affecting the sinners or weaklings anymore. It is simply a compromising, humbling, deadly disease. No one is immune (scientifically there may be some, we do not know exactly yet) and any one can get it within the realm of normal human relationships.
When president Regan expressed a viewpoint about AIDS that it was not a disease of regular people certain groups were irate. Italian clothier Bennetton even ran shock ads showing him as an AIDS victim with a fake obituary, blasting his administration on AIDS in June 1994. They did that to sensationalize their brand rather than showing their anguish about the view point of the administration on AIDS at that time. The view point was not unique to just a few politicians but pretty much everyone who believed that they were normal; “AIDS or whatever we call it comes only to those sinful, blasphemous people”. How many parents, siblings we see are ready to admit the homosexuality of their kin even today?
Like any disease, especially that of viral origin “AIDS” does not discriminate who it is going to attack or destroy. It has no racial, gender, regional, religious, or sexual orientation bias. It is simply an illness caused by a virus with an unbelievable capacity to mutate and attack the core of our existence, our precious immune system that protects us from all kinds of bugs (bacterial, fungal, viral, you name it, even emotional). The virus is a tricky one; it is a retro virus, can replicate itself using human DNA. Mutating capacity of this virus fairly rules out immunization route; several bright scientists are working on it; though we have not been able to find the way to immunize ourselves against cold.
Gosh, we need a cure for it as soon as we can get it. The disease that started in the interiors of Africa made its way into mainstream. Countries like India where people hide behind the public façade of moral authority facing the problem head on. The disease is spreading like wild fire in red light districts. Governments turn away and deny it vehemently; but facts speak for themselves. Denial is part of human defense and it is not any different in this scenario. Moral standards are gender based in Eastern countries. Men are getting infected and bringing it home spreading it across. The denial phase is not going to cover it any more.The affected people are not just the young girls from the brothels in metropolitan cities anymore. The “super men” visit them, go back home, lead their lives as perfect gentlemen, slowly passing it along to their innocent spouses. Plenty of educational efforts are being made by different means, but these efforts may not even scratch the surface due to deep seated ignorance and blind beliefs. The spread is not just limited to certain geographical areas; it is happening all over may be with a degree of difference.
The issues surrounding AIDS make the lives of AIDS victims more complicated. There are folks who would make a buck even if it means stealing from a baby. Washington DC is has the highest AIDS rate in the nation; they received millions of dollars in grants to distribute to nonprofits that are supposed to help AIDS patients. Some of these nonprofit organizations (?) are so greedy , they set up bogus operations and pocket that money according to a recent Washington Post report. The District directed more than $500,000 to a program that was supposed to provide housing for AIDS patients. Apparently the executive director of that program was convicted for theft, drugs and forgery and what not; the local inspector general’s office could not find any evidence of that person operating an AIDS nonprofit group. Obviously the funding was cancelled but they could not get the money that was already given out to that person in the name of that organization. The local health department in Washington DC awarded more than $25 million to nonprofit groups. Majority of them fail to show records, tangible care, and in some cases the existence of that nonprofit organization itself. They (mostly individuals) are pocketing the money that is so kindly and generously given by regular people like you and I that are making an honest living.
Several new drugs and drug cocktails are discovered and approved to breathe new life into this near death situation. All these drugs in combination are supposedly making the human T cells stronger and preventing them from being fatally attacked by the deadly retrovirus. These drugs are expensive. Rightfully so because they are approved only after the pharma companies spent millions of dollars researching them and ready them for human use. The companies should be able to make that money back even though they are not expected to make any profit. The term “cocktails” angers some. They do not provide any pleasure to the users like our heavenly potions of cocktails. But they do aid the AIDS patients live longer, stronger, with dignity like they are supposed to; not as haunted, scared, feeling angry, guilty worried “ what is going to happen tomorrow” souls. With these cocktails they can look forward to “tomorrow”. But this is creating an uncertainty, sort of conundrum for tomorrow. “I did not think I was going to live; I did not care to prepare for future; did not care to improve my relationships; I was not going to be there long, preparing for tomorrow did not make sense”. That convenient thought of not thinking about tomorrow is proving to be problematic for a lot of AIDS patients and making their post treatment survival difficult as they need to re-prepare for life, not give up on the relationships, people, future and the emotions that could make or break the future. It is a major hardship many of them who are getting a new lease on life are facing. The confusion for them could be overwhelming for some of them compared to the original choices of fairly simple “life” or “death”. The choices are far apart, equally difficult to face. In general, we as human beings tend to believe that life is more beautiful than the unknown “death”. We have choices, beauty, kindness, warmth, and most of all abundant humanity however diminishing that might be. Skeptics are always there, but as human beings we should lean on humanity and go with its AID to fight AIDS and make the world a little less confusing, a bit more protected, livable space.

Every December 1, we commemorate World AIDS Day.
The facts and figures of HIV and AIDs
The UN just released its latest global estimates on AIDs.
The rate of new infections has been falling for more than a decade, but there is no decline in the total number of people infected with HIV.
2.7 million People are newly infected with HIV in 2008, compared to 3.2 million in 2001
33.4 million People are living with HIV in 2008, compared to 29 million in 2001
2.0 million Deaths from AIDs in 2008, compared to 1.9 million in 2001
According to Associated press, in the past few years, the number of people living with HIV has remained essentially flat. It estimates that 33.2 million people had HIV in 2007.

Psychiatry and Neurology Should Merge as a Single Discipline.

2010-03-23T13:03:00.000-07:00

On August 27, 2009, at SUNY Upstate Medical University in Syracuse, NY, the Department of Psychiatry Grand Rounds featured a debate titled “Resolved: Psychiatry and Neurology Should Merge as a Single Discipline.” Professor Chaitanya Haldipur, MD, organized the conference. The principal presentations were by Ronald Pies, MD, for the affirmative, and Robert Daly, MD, for the negative. Also participating were Jeremy Shefner, MD, PhD (chairman, department of neurology) for the affirmative, and Mantosh Dewan, MD (chair, department of psychiatry) for the negative. This debate is published in March 2010 issue of Psychiatric times (see the attached link).

http://www.psychiatrictimes.com/display/article/10168/1532271?p_p_id=EXT_4&p_p_action=1&p_p_state=normal&p_p_mode=view&p_p_col_id=column-2&p_p_col_pos=1&p_p_col_count=2&_EXT_4_struts_action=%2Farticles_display%2Fview_article#add-comment

I am in support of merger of neurology and psychiatry (no bias here which one is first; I just placed them alphabetically). I am first and foremost a physician and then a psychiatrist that has been involved in clinical development of drugs, biologics and devices for a long time.
To begin with I tend to look at every symptom with body as “WHOLE”. It is not a surprise that I always thought and continue to think that psychiatry and neurology are inseparable, except for the social aspects of it, which is responsible for the creation of the separation. This separate approach has been global, not just regional. In my mind I simply cannot separate the two entities with tangible differences and I bet neither can anyone else. My simple minded take on this; it has been simply the approach of “CAUSE and EFFECT”. “CAUSE” is neurological and the “EFFECT” is psychiatric. Generally when the symptoms are manageable neurologists are happy to deal with them (don’t get upset with me, my dear neurologist colleagues and friends; isn’t it true really?) but when the behavioral symptoms surface the management of them falls into psychiatry (the social and human aspects of it).
It is true that the split between neurology and psychiatry as professions became more prominent as Freud’s psychoanalytic approach gained ground, and I agree with Dr. Pies that it is essentially an artifact of professional rivalries and turf battles. But after staying separate for this long and established terminology, combining them into a single entity is no small task especially with respect to terminology.
I like the 4 different approaches put together by Dr. Pies combining neurology and psychiatry. As a comprehensive approach in combining the 2 entities, I support the approach in Figure 4 (somehow I am unable to transport the picture; it can be accessed by using the link above). It suggests one way in which the 2 fields (neurology and psychiatry) might successfully merge—by becoming, in effect, a new and unified field, “encephiatrics,” or “brain healing. To accomplish this, however, we will need to develop a linguistic framework that allows us to “translate,” as it were, from psychiatrese to neurologese and vice versa.
It is all about language; development of “bridging terms” or “transformative language” would be of great help to come to a common ground between the practicing neurologists and psychiatrists, hopefully soon. The bottom-line is; however we argue and whatever we argue about, ultimately we all work for the patient and the patient in all of us.

Antibiotic resistant bugs: causes and effects and what to expect in future!!!!!

2010-03-22T16:41:00.000-07:00

According to the National Institute of Allergy and Infectious Diseases, the number of germs resistant to antibiotics is growing. The Institute, which is part of NIH, will publish an article in the April 15 issue of the Journal of Infectious Diseases, stating that one in 5 of the 94,360 patients who developed an invasive MRSA infection in 2005 died; in addition to that, 20% of tuberculosis cases worldwide are drug-resistant, with 10% of them "extensively" drug resistant. Most importantly, as of 2002: 14% of certain systemic infections were resistant to antibiotics, up from 4% in 1993.

Methicillin-resistant Staphylococcus aureus (MRSA) is the strain that does not react to regular antibiotics. It usually attacks the skin, but can also cause other infections— including pneumonia. According to CDC, in 1974, MRSA infections accounted for 2% of the total number of staph infections; it increased to 22% in 1995, 63% in 2004. CDC estimated that 94,360 invasive MRSA infections occurred in the US in 2005; 18,650 of these resulted in death. MRSA is resistant to very strong antibiotics extending from penicillin, amoxicillin, oxacillin to methicillin, hence also acquired the name “Multidrug-Resistant Organisms (MDROs)”. Often MRSA infects people that are in hospitals and healthcare facilities (such as nursing homes and dialysis centers) that have weakened immune systems. The spread of infection is multi modal; skin-to-skin contact, sharing or touching personal items of infected people, touching an area or item that has been in contact with someone infected with MRSA.
As far as the health economics are concerned, hospitalized patients that are infected with MRSA, had an average of 3 additional weeks of hospitalization along with an additional $60,000 per patient cost than patients who were never infected. Patients with MRSA-related surgical wound infections also were 35 times more likely to be re-hospitalized and 7 times more likely to die within 90 days compared to patients that did not have it.
To prevent the spread of MRSA and other hospital associated infections, guidelines and best practices are being sought and put into practice. They include but not limited to: the use of UV light to illuminate all the nooks and crannies where deadly bacteria lurk, use of Bioquell Z, a little machine that looks like R2D2 in Star Wars and can be wheeled into a patient's room and seal the door as it sprays a disinfecting hydrogen-peroxide vapor and after about 90 minutes, the room and all the equipment inside are disinfected without residual smell, regular cleaning of the patients' mouth, gums and teeth to keep the bacteria to a minimum, detecting the bacteria early by quick swab and study, and some hospitals going to extreme measures by implementing a harsh punishment of giving out pink slips for the staff that do not practice hand hygiene.
As if the MRSA threat in the hospitals is not enough, it seems to have extended to the communities as well earning a new name: Community Associated methicillin-resistant Staphylococcus aureus (CA-MRSA).
A new strain of MRSA (USA600) is reported be emerging according to researchers at Henry Ford Hospital. It is partially immune to vancomycin, the drug that has thus far proved to be effective against MRSA. According to research presented at the annual meeting of the Infectious Diseases Society of America, half of the USA600-infected patients in the study died within a month, a death rate that is 5 times that of known MRSA strains.
MRSA does not appear to be the only threat for patients in healthcare facilities today. As hospitals get better handle on MRSA, an epidemic of Clostridium difficile (C. diff) is emerging to be a threat for patients in hospitals, leading to unusual complications including perforated bowels, ruptured colons, kidney failure and death.

C. diff. is a nasty bug, causes diarrhea, colon inflammation, and can be fatal for some patients and, resistant to some antibiotics. This bug spreads by spores in feces. The spores are difficult to kill with most conventional household cleaners or alcohol-based hand sanitizers, so some of the disinfection measures against MRSA don't work on C. diff.
Deaths from C-diff are rare; but apparently more dangerous forms have emerged in the last 10 years. C. diff. infections kill an estimated 5,000 people in the U.S. per year per CDC. Rates of C. diff are rising rapidly, and getting worse by virulent strains of the bug. According to the CDC, there are 500,000 cases of C. diff infection each year in the US, up from 150,000 in 2001. It is estimated that these 500,000 infections are contributing to between 15,000 and 30,000 deaths a year.

Antibiotic use is blamed for the spread of C. diff. Several different varieties of ways to control C. diff in hospitals are put in place; isolation of known and suspected C. diff patients, use antibiotics carefully, clean the rooms where C. diff patients have been thoroughly with high-intensity cleaners.
Findings presented at this year's American College of Gastroenterology annual meeting suggest that C. diff infections are growing outside of hospitals, nursing homes and similar facilities (where it used to be common and a threat to elderly and immune compromised). This spread makes it harder as the environment in the community is uncontrolled. Researchers examined 385 cases of C. diff. infection, dating from 1991 to 2005 and found that those who caught the bug outside of a hospital were younger, averaging about 50 years of age rather than the typical average age of 72 in the hospitals. Though these cases seem to be less severe than those in the hospital, experts are rather concerned by the trend and recommending that doctors and patients be aware of the bug and watch for symptoms of abdominal cramps and diarrhea.

What is next; only time will tell!? Perhaps the concentration of R&D should be the PREVENTION: of drug resistance in bugs & drug resistant bug infections, especially now the R&D of antibiotics is not so much in VOGUE.

The approved draft guidance for the Format and Content of proposed Risk Evaluation and Mitigation Strategy (REMS)

2010-03-21T18:33:00.000-07:00

The approved draft guidance for the Format and Content of proposed Risk Evaluation and Mitigation Strategy (REMS) is released. It can be located at the following weblink.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf

The FDA Amendments Act (FDAAA) of 2007 authorizes FDA to require persons submitting certain applications (NDA, ANDA, and BLA) to submit proposed REMS as part of such application if the FDA determines that a REMS is necessary to ensure that the benefits of a drug outweigh the risks of the drug. It also allows FDA to require the holders of covered applications approved without REMS to submit a proposed REMS if the FDA becomes aware of new safety information as defined in 505-1(b)(3) and determines that such a strategy is necessary. Once the holder of an approved covered application is notified by FDA that a REMS is necessary, the holder must submit a proposed REMS within 120 days, or within such other reasonable time as FDA requires to protect the public health.
An applicant may also submit proposed REMS voluntarily without having been required to do so by FDA though it will not be approved as a REMS unless and until the FDA determines that it is required and that it meets the FDAAA criteria.
Before FDAAA of 2007, FDA approved a small number of drugs and biologics with risk minimization action plans (RiskMAPs). A RiskMAP is a strategic safety program to meet specific goals and objectives to minimize the known risks of a product preserving its benefits and was developed for products that had risks that required additional risk management strategies in addition to describing the risks and benefits of the product in the label and reporting the safety. Labeling and routine safety reporting are thought to be sufficient to mitigate risks preserving benefits for majority of products. For a few, when additional measures were needed, FDA approved the drug with a RiskMAP based on the guidance issued by FDA in 2005. Now that FDAAA has given FDA the authority to require REMS when necessary, FDA anticipates that,
a) If a product that would previously have been approved with a RiskMAP, it will be approved with a REMS instead, if statutory requirements for a REMS are met
b) If the products that would previously have been approved with a Medication Guide or patient package insert that meet the statutory requirements for a REMS will now be required to have a REMS.
c) While certain products approved with RiskMAPs that included certain types of risk management tools have been deemed to have in effect an approved REMS, all other approved RiskMAPs and approved Medication Guides and patient package inserts that were in place when Subtitle A took effect will continue to be in effect, unless they are replaced by or included in a REMS. If information is identified after approval of the product, that a REMS is necessary to ensure that the benefits of the drug outweigh the risks.
As far as the ANDAs are concerned, if the reference listed drug has an approved RiskMAP, it will be approved with a comparable RiskMAP that includes the same essential elements and if the reference listed drug has a REMS, it will be approved with the elements of that REMS applicable to that ANDA. Revisions of existing Medication Guides or patient package inserts that meet REMS requirements will be approved as part of a REMS.
Majority of the principles of the RiskMAP guidance are essentially became part of REMs.
The guidance document has very detailed segments with reference to, Voluntary Assessments and Proposed Modifications and Required assessments as part of the Assessments and Modifications of Approved REMS.
Importantly, note the enforceability of REM: violation of a REMS requirement is subject to civil monetary penalties of up to $250,000/violation (limit of $1 million in a single proceeding); penalties double if more than 30 days after FDA notification passes, and continue to double for subsequent 30-day periods, up to $1 million per period and $10 million per proceeding including the efforts to correct the violation.
The guidance document is clear about the content of the proposed REMS. It needs to include Product and Contact Information, Goals, Medication Guide and/or Patient Package Insert, Communication Plan, elements to assure safe product use (this one is tricky and takes a lot of effort to set up and monitor: Health care providers who prescribe the drug need to have particular training/experience/are specially certified; pharmacies, practitioners, or health care settings that dispense the drug are specially certified; the drug be dispensed to patients only in certain health care settings, such as hospitals; the drug be dispensed only to patients with evidence or other documentation of safe-use conditions, such as laboratory test results; each patient using the drug be subject to certain monitoring and each patient using the drug be enrolled in a registry), followed by Implementation System, timetable for submission of Assessment of the REMS.
We will have to wait and see whether this elaborate setup and monitoring will be of help in the thorough monitoring of the drug/biologics safety.

The list of FDA approved REMS so far include biologics as well as drugs. The current list includes Actemra (tocilizumab) Injection to Zyprexa Relprevv (olanzapine) Extended-Release Injection alphabetically. The complete list can be found at the following web link:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

Can the MSLs bridge the knowledge gap?

2010-03-20T11:07:00.000-07:00

Can Medical Science Liaisons (MSLs) bridge the gap between the highly regulated and diverse pharmaceutical/biotech industry and the clinicians?

The roles of MSLs came a long way. They are not our ordinary day today scientific support to sales. They are highly educated and well trained individuals to discuss the current developments, evidence based safety and efficacy profiles of the drugs, upcoming studies, possibility of initiation of studies by the thought leaders and publications in the area within the ever changing regulatory guidelines from DDMAC (Division of Drug Marketing, Advertising, and Communications) of FDA and OIG (Office of Inspector General), though the direct concentration of OIG is on the integrity of Department of Health and Human Services (HHS) programs and the health and welfare of the beneficiaries of those programs. Meanwhile they have to play close attention to HIPAA (Health Insurance Portability and Accountability Act) rules. It is a ‘tight rope walk’ for the industry and their MSLs. Even with all the advanced scientific and regulatory training occasionally the scientific discussions and unique possibilities for research and development and the feedback from clinicians get missed. Industry is trying to minimize that through continuous education and training of the MSLs.

Today MSLs are the conduits of scientific information between the pharma industry and the treating physicians, that are too busy to do anything else other than taking care of their patients and dealing with insurance companies; they hardly ever have any time to read and follow the latest developments, though they try their best. The MSLs can be of some help in that matter through different modes of information given to them, such as drug information pamphlets, specific publications amongst other ways. The education and development of the MSL contributes to better education in the healthcare community indirectly resulting in better education of patient that eventually converts to better compliance.

MSLs may have other contributions as well; some may contribute in advanced clinical trials programs by using their expertise in ICH and GCP guidelines specific to how clinical trials are conducted and guide the clinical trial centers to assure the data that is of high quality and collected with integrity. This would be very helpful in today’s world where the post marketing observational studies are slowly being subjected to regulatory nod.

Hopefully through all this and future innovative approaches we as patients would get incremental benefit ultimately when the non-biased, scientific information from the industry is disseminated through the MSLs timely and effectively.

Possible changes to DTC advertising.....

2010-03-19T13:50:00.000-07:00

Generally people were not the original intended audience for the facts about drugs, but now as consumers they are as a matter of fact we all are….

Recently DDMAC instructed 3 companies to correct the communications (starting Dear doctor letters to TV ads) regarding their drugs. The most prominent one amongst them is Bayer for Yaz, the birth control pill. Even a sporadic TV watcher would notice that Bayer was instructed by the FDA to change the content.
Is FDA going to require the fact boxes as part of the review process for the new drugs so that they are reviewed prior to be part of DTC advertising? I am not talking about the Reuter’s FACTBOX. This is drug fact box; it presents the drug benefits and harms (facts) in a box.
It all started like this:
Dartmouth Medical School faculty published their study results about how a consumer sees the data. It suggests:
• Majority of consumers want benefit data in drug ads as they can understand the data, hence are influenced by them.
• Assessment of the drug benefits/harms (facts) box proved to be beneficial in contributing to the better understanding by the consumers even those with lower formal educational attainment.
• They suggested to FDA to make the fact boxes part of the review process for the new drugs so that they are reviewed as part of the submission package.

Based on that recommendation, it is also presumed that the fact boxes would be included in all print DTC ads, on product web sites, and provided with the drug when it is picked up at the pharmacy.
I am wondering how much of wordsmithing should go into it when that “ fact box” is submitted with the package; However and whatever way we say it in the language of English, the meanings and interpretation of those facts is going remain in the hands of reviewers and the consumers when it comes to understanding what is written there.
The guidance for the OTC drugs probably has more clarity for the label. In most cases, as part of the label, safety warnings are required and therefore must be included in the Drug Facts box according to FDA guidance to Industry. I wonder if majority of people that use these products actually read them……