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Archive for the ‘Regulated Clinical Trials: Design, Methods, Components and IRB related issues’ Category

Author:  Sreedhar Tirunagari, MD

Human subject recruitment is crucial for the success of any clinical trial and can be a challenging to Sponsors and investigators, hence they use four main strategies to recruit human subjects and encourage timely recruitment.

  •  Sponsors offer financial and other incentives to investigators to boost enrollment.
  •  Investigators target their own patients as potential subjects.
  •  Investigators seek additional subjects from other sources such as physician referrals and disease registries.
  •  Sponsors and investigators advertise and promote their studies.

To achieve timely recruitment for clinical trial the consent process may be undermined when, under pressure of quick recruitment like patients are influenced to participate in research due to their trust in their doctor. Some physicians searching medical records, disease registries, school records, or mailing lists by compromising confidentiality and then contacting a patient about participation. Some times there may be chance of enrollment of Ineligible Subjects in order to meet quotas and satisfy sponsors.

Most IRB’s are not reviewing many of the recruitment practices that they and others find most troubling. IRBs’ limited review of recruitment practices is in part due to their perceived lack of authority to review certain practices in their own oversight of research sites, sponsors pay minimal attention to how human subjects are recruited.

Role of IRB:
IRBs should concentrate on human subject recruitment consent process; how they are enrolled in to study and human subject protection and confidentiality is maintained. Few recommendations suggested by the Department of Health and Human Services in its report can be adopted to ensure essential human-subject protections without unnecessarily slowing the pace of research and discovery.

  •  IRB should be provided with direction regarding oversight of recruitment practices.

IRB should be given authority to review recruitment practices, Regulatory bodies should disseminate guidance explicitly stating this authority based on IRBs’ established authority to ensure informed consent and review anything related to human-subject protections.

Regulatory bodies should also suggest a recruitment question to the IRB’s that they should address in their protocol reviews and should foster discussion about these issues.

  •  Development of guidelines for all parties on appropriate recruiting practices :

Determination of appropriate recruiting practices would be helpful for all parties like; sponsors, investigators, and IRBs. It is essential that this determination be made cooperatively with industry and the research community. As part of their deliberations, these parties could explore such questions as:
• Is it acceptable for sponsors to offer bonuses to investigators for successfully recruiting subjects?
• Should physicians be allowed to receive fees for referring their patients as potential subjects for a clinical trial?
• Should the financial arrangements between sponsors and investigators be disclosed to potential subjects?
• Do searching medical records for potential subjects constitute a breach of confidentiality?

  •  IRBs and investigators should be adequately educated about human-subject protections :

• Investigators should be educated as a prerequisite for conducting research under regulatory guidelines.
• IRBs should develop training program for members.
• Require more extensive representation on IRBs of nonscientific and non- institutional members. Such members can help sensitize IRBs to patient concerns about recruitment practices.

• All the IRBs should be registered with the Country specific regulatory bodies.

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Author: Tilda Barliya PhD

Metastasis, the spread of cancer cells from a primary tumour to seed secondary tumours in distant sites, is one of the greatest challenges in cancer treatment today. For many patients, by the time cancer is detected, metastasis  has already occurred. Over 80% of patients diagnosed  with lung cancer, for example, present with metastatic  disease. Few patients with metastatic cancer are cured by surgical intervention, and other treatment modalities are limited. Across all cancer types, only one in five patients diagnosed with metastatic cancer will survive more than 5 years. (1,2).

Metastatic Cancer 

  • Metastatic cancer is cancer that has spread from the place where it first started to another place in the body.
  • Metastatic cancer has the same name and same type of cancer cells as the original cancer.
  • The most common sites of cancer metastasis are the lungs, bones, and liver.
  • Treatment for metastatic cancer usually depends on the type of cancer and the size, location, and number of metastatic tumors.

How do cancer cells spread (3)

  • Local invasion: Cancer cells invade nearby normal tissue.
  • Intravasation: Cancer cells invade and move through the walls of nearby lymph vessels or blood vessels.
  • Circulation: Cancer cells move through the lymphatic system and the bloodstream to other parts of the body.

The ability of a cancer cell to metastasize successfully depends on its individual properties; the properties of the noncancerous cells, including immune system cells, present at the original location; and the properties of the cells it encounters in the lymphatic system or the bloodstream and at the final destination in another part of the body. Not all cancer cells, by themselves, have the ability to metastasize. In addition, the noncancerous cells at the original location may be able to block cancer cell metastasis. Furthermore, successfully reaching another location in the body does not guarantee that a metastatic tumor will form. Metastatic cancer cells can lie dormant (not grow) at a distant site for many years before they begin to grow again, if at all.

Although cancer therapies are improving, many drugs are not reaching the sites of metastases, and doubt  remains over the efficacy of those that do. Methods  that are effective for treating large, well-vascularized tumours may be inadequate when dealing with small clusters of disseminated malignant cells.

We expect that the expanding capabilities of nanotechnology, especially in targeting, detection and particle trafficking, will enable  novel approaches to treat cancers even after metastatic dissemination.

 

Lymph nodes, which are linked by lymphatic vessels, are distributed throughout the body and have an integral role in the immune response. Dissemination of cancer cells through the lymph network is thought to be an important route for metastatic spread. Tumor proximal lymph nodes are often the first site of metastases, and the presence of lymph node metastases signifies further metastatic spread and poor patient survival.

As such, lymph nodes have been targeted using cell-based nanotechnologies

Lymph nodes are small, bean-shaped organs that act as filters along the lymph fluid channels. As lymph fluid leaves the organ (such as breast, lung etc) and eventually goes back into the bloodstream, the lymph nodes try to catch and trap cancer cells before they reach other parts of the body. Having cancer cells in the lymph nodes suggests an increased risk of the cancer spreading. It is thus very important to evaluate the involvement of lymph nodes when choosing the best possible treatment for the patient.

Although current mapping methods are available such as CT and MRI scans, PET scan, Endobronchial Ultrasound, Mediastinoscopy and lymph node biopsy, sentinel lymph node (SLN) mapping and nodal treatment in lung cancer remain inadequate for routine clinical use. 

Certain characteristics are associated with preferential (but not exclusive) nanoparticle trafficking to lymph nodes following intravenous administration.

Targeting is often an indirect process, as receptors on the surface of leukocytes bind nanoparticles and transfer them to lymph nodes as part of a normal immune response. Several strategies have been used to enhance nanoparticle uptake by leukocytes in circulation. Coating iron-oxide nanoparticles with carbohydrates, such as dextran, results in the increased accumulation of these nanoparticles in lymph nodes. Conjugating peptides and antibodies, such as immunoglobulin G (IgG), to the particle surface also increases their accumulation in the lymphatic network. In general, negatively charged particles are taken up at faster rates than positively charged or uncharged particles. Conversely, ‘stealth’ polymers, such as polyethylene glycol (PEG), on the surface of nanoparticles, can inhibit uptake by leukocytes, thereby reducing accumulation in the lymph nodes.

Lymph node targeting may be achieved by other routes of administration. Tsuda and co-workers reported that non-cationic particles with a size range of 6–34nm, when introduced to the lungs (intrapulmonary administration), are trafficked rapidly (<1 hour) to local lymph nodes. Administering particles <80 nm in size subcutaneously also results in trafficking to lymph nodes. Interestingly, some studies have indicated that non-pegylated particles exhibit enhanced accumulation in the lymphatics and that pegylated particles tend to appear in the circulation several hours after administration.

Over the last twenty years, sentinel lymph node (SLN) imaging has revolutionized the treatment of several malignancies, such has melanoma and breast cancer, and has the potential to drastically improve treatment in other malignancies, including lung cancer. Several attempts at developing an easy, reliable, and effective method for SLN mapping in lung cancer have been unsuccessful due to unique difficulties inherent to the lung and to operating in the thoracic cavity.

An inexpensive method offering rapid, intraoperative identification of SLNs, with minimal risk to both patient and provider, would allow for improved staging in patients. This, in turn, would permit better selection of patients for adjuvant therapy, thus reducing morbidity in those patients for whom adjuvant treatment is inappropriate, and ensuring that those who need this added therapy actually receive it. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/)

Current methods for SLN identification involve the use of radioactivity-guided mapping with technetium-99m sulfur colloid and/or visual mapping using vital blue dyes. Unfortunately these methods can be inadequate for SLN mapping in non-small cell lung cancer (NSCLC) The use of vital blue dyes is limited in vivo by poor visibility, particularly in the presence of anthracotic mediastinal nodes, thereby decreasing the signal-to-background ratio (SBR) that enables nodal detection. Similarly, results with technetium-99m sulfur colloid have been mixed when used in the thoracic cavity, where hilar structures and aberrant patterns of lymphatic drainage make detection more difficult.

Although Nomori et al. have reported an 83% nodal identification rate following a preoperative injection of technetium-99 colloid, there is an associated increased risk of pneumothorax and bleeding with this method. Further, the recently completed CALGB 140203 multicenter Phase 2 trial investigating the use of intraoperative technetium-99m colloid found an identification rate of only 51% with this technique.  Clearly a technology with greater accuracy, improved SBR, and less potential risk to surgeon and patient would be welcome in the field of thoracic oncology.

Near-infrared (NIR) fluorescence imaging has the potential to meet this difficult challenge.

Near-Infrared Light

NIR light is defined as that within the wavelength range of 700 to 1000 nm. Although NIR light is invisible to the naked eye, it can be thought of as “redder” than UV and visible light.

  • Absorption, scatter, and autofluorescence are all significantly reduced at redder wavelengths. For instance, Hemoglobin, water, lipids, and other endogenous chromophores, such as melanin, have their lowest absorption within the NIR spectrum, which permits increased photon depth penetration into tissues
  • In addition, imaging can also be affected by photon scatter, which describes the reflection and/or deflection of light when it interacts with tissue. Scatter, on an absolute scale, is often ten-times higher than absorption. However, the two major types of scatter, Mie and Rayleigh, are both reduced in the NIR, making the use of NIR wavelengths especially important for the reduction of photon attenuation.
  • living tissue has extremely high “autofluorescence” in the UV and visible wavelength ranges due to endogenous fluorophores, such as NADH and the porphyrins. Therefore, UV/visible fluorescence imaging of the intestines, bladder, and gallbladder is essentially precluded. However, in the NIR spectrum, autofluorescence is extremely low, providing the black imaging background necessary for optimal detection of a NIR fluorophore within the surgical field
  • Additionally, optical imaging techniques, such as NIR fluorescence, eliminate the need for ionizing radiation. This, combined with the availability of a NIR fluorophore already FDA-approved for other indications and having extremely low toxicity (discussed below), make this a potentially safe imaging modality.

The main disadvantage is that it’s invisible to the human eye, requiring special imaging-systems to “see” the NIR fluorescence.

Currently there are three intraoperative NIR imaging systems in various stages of development:

  • The SPY system (Novadaq, Canada) – utilizes laser light excitation in order to obtain fluorescent images. The Spy system has been studied for imaging patency of vascular anastamoses following CABG and organ transplantation
  • The Photodynamic Eye(Hamamatsu, Japan) – is presently available only in Japan
  • The Fluorescence-Assisted Resection and Exploration (FLARE) system ()- developed by the authors’ laboratory utilizes NIR light-emitting diode (LED) excitation, eliminating the need for a potentially harmful laser. Additionally, the FLAREsystem has the advantage of being able to provide simultaneous color imaging, NIR fluorescence imaging, and color-NIR merged images, allowing the surgeon to simultaneously visualize invisible NIR fluorescence images within the context of surgical anatomy.

Near-Infrared Fluorescent Nanoparticle Contrast Agents

The ideal contrast agent for SLN mapping would be anionic and within 10–50 nm in size in order to facilitate rapid uptake into lymphatic vessels with optimal retention within the SLN.

Due to the lack of endogenous NIR tissue fluorescence, exogenous contrast agents must be administered for in vivo studies. The most important contrast agents that emit within the NIR spectrum are the heptamethine cyanines fluorophores, of which indocyanine green (ICG) is the most widely used, and fluorescent semiconductor nanocrystals, also known as quantum dots (QDs).

  • ICG is an extremely safe NIR fluorophore, with its only known toxicity being rare anaphylaxis. The dye was FDA approved in 1958 for systemic administration for indicator-dilution studies including measurements of cardiac output and hepatic function. Additionally, it is commonly used in ophthalmic angiography. When given intravenously, ICG is rapidly bound to plasma albumin and cleared from the blood via the biliary system. Peak absorption and emission of ICG occur at 780 nm and 830 nm respectively, within the window where in vivo tissue absorption is at its minimum. ICG has a relatively neutral charge, has a hydrodynamic diameter of only 1.2 nm, and is relatively hydrophobic. Unfortunately, this results in rapid transport out of the SLN and relatively low fluorescence yield, thereby decreasing its efficacy in mapping techniques. However, noncovalent adsorption of ICG to human serum albumin (HSA), as occurs within plasma, results in an anionic nanoparticle with a diameter of 7.3 nm and a three-fold increase in fluorescence yield markedly improving its utility in SLN mapping.
  • QDs consist of an inorganic heavy metal core and shell which emit within the NIR spectrum. This structure is then surrounded by a hydrophilic organic coating which facilitates aqeuous solubility and lymphatic distrubtion. QDs have been extensively studied and are ideal for SLN mapping as their hydrodynamic diameter can be customized to the appropriate size within a narrow distribution (15–20 nm), they can be engineered to have an anionic surface charge, and exhibit an extremely high SBRs with significant photostability. Unfortunately, safety concerns due to the presence of heavy metals within the QDs so far have precluded clinical application

Human Clinical Trials and NIR SLN mapping

Several studies have investigated the clinical use of indocyanine green without adsorption to HSA for NIR fluorescence-guided SLN mapping in breast and gastric cancer with good success (9-13).

Kitai et al. first examined this technique in 2005 in breast cancer patients, and was able to identify a SLN node in 17 of 18 patients using NIR fluorescence rather than the visible green color of ICG (9). Sevick-Muraca et al. reported similar results using significantly lower microdoses of ICG (10 – 100 μg), successfully identifying the SLN in 8 of 9 patients (11). Similar to these subcutaneous studies, 56 patients with gastric cancer underwent endoscopic ICG injection into the submucosa around the tumor 1 to 3 days preoperatively or injection directly into the subserosa intraoperatively with identification of the SLN in 54 patients (13).

Recently, Troyan et al. have completed a pilot phase I clinical trial examining the utility of NIR imaging the ICG:HSA nanoparticle fluorophore for SLN mapping/biopsy in breast cancer using the FLAREsystem. In this study, 6 patients received both 99mTc-sulfur colloid lymphoscintigraphy along with ICG:HSA at micromolar doses. SLNs were identified in all patients using both methods. In 4 of 6 patients the SLNs identified were the same, while in the remaining two, lymphoscintigraphy identified an additional node in one patient and ICG:HSA identified an additional SLN in the other. Irrespective, this study demonstrates that NIR SLN mapping with low dose ICG:HSA is a viable method for intraoperative SLN identification.

Nanotechnology and Drug Delivery in Lung cancer

We previously explored Lung cancer and nanotechnology aspects as polymer nanotechnology has been an area of significant research over the past decade as polymer nanoparticle drug delivery systems offer several advantages over traditional methods of chemotherapy delivery

see: (15) http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/                (16) http://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

As the importance of micrometastatic lymphatic spread of tumor becomes clearer, there has been much interest in the use of nanoparticles for lymphatic drug delivery. The considerable focus on developing an effective method for SLN mapping for lung cancer is indicative of the importance of nodal spread on overall survival.

Our lab is investigating the use of image-guided nanoparticles engineered for lymphatic drug delivery. We have previously described the synthesis of novel, pH-responsive methacrylate nanoparticle systems (14). Following a simple subcutaneous injection of NIR fluorophore-labeled nanoparticles 70 nm in size, we have shown that we can deliver paclitaxel loaded within the particles to regional draining lymph nodes in several organ systems of Yorkshire pigs while simultaneously confirming nodal migration using NIR fluorescent light. Future studies will need to investigate the ability of nanoparticles to treat and prevent nodal metastases in animal cancer models. Additionally, the development of tumor specific nanoparticles will potentially allow for targeting of chemotherapy to small groups of metastatic tumor cells further limiting systemic toxicities by narrowing the delivery of cytotoxic drugs.

Ref:

1. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

2. http://www.nature.com/nrc/focus/metastasis/index.html

3. http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic

4. http://www.cancerresearchuk.org/cancer-help/about-cancer/what-is-cancer/body/the-lymphatic-system

5. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lymphnodessecondary/Secondarycancerlymphnodes.aspx

6. Khullar O, Frangioni JV and Colson YL. Image-Guided Sentinel Lymph Node Mapping and Nanotechnology-Based Nodal Treatment in Lung Cancer using Invisible Near-Infrared Fluorescent Light. Semi Thorac Cardiovasc Surg 2009 :21 (4);  309-315. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/

7. Stacker SA, Achen MG, Jussila L,  Baldwin ME and Alitalo K. Metastasis: Lymphangiogenesis and cancer metastasis.  Nature Reviews Cancer 2002 2, 573-583. http://www.nature.com/nrc/journal/v2/n8/full/nrc863.html

8. Schroeder A., Heller DA., Winslow MM., Dahlman JE., Pratt GW., Langer R., Jacks T and Anderson DG.. Nature Reviews Cancer 2012; 12(1), 39-50. Treating metastatic cancer with nanotechnology. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/full/nrc3180.html

9. Kitai T, Inomoto T, Miwa M, et al. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer. 2005;12:211–215.

10. Ogasawara Y, Ikeda H, Takahashi M, et al. Evaluation of breast lymphatic pathways with indocyanine green fluorescence imaging in patients with breast cancer. World journal of surgery.2008;32:1924–1929.

11. Sevick-Muraca EM, Sharma R, Rasmussen JC, et al. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology.2008;246:734–741.

12. Miyashiro I, Miyoshi N, Hiratsuka M, et al. Detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging: comparison with infrared imaging. Ann Surg Oncol.2008;15:1640–1643.

13. Tajima Y, Yamazaki K, Masuda Y, et al. Sentinel node mapping guided by indocyanine green fluorescence imaging in gastric cancer. Ann Surg. 2009;249:58–62.

14. Griset AP, Walpole J, Liu R, et al. Expansile nanoparticles: synthesis, characterization, and in vivo efficacy of an acid-responsive drug delivery system. J Am Chem Soc. 2009;131:2469–2471

15. http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/

16.  http://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

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Nitric Oxide and it’s impact on Cardiothoracic Surgery

Author, curator: Tilda Barliya PhD

 

In the past few weeks we’ve had extensive in-depth series about nitric oxide (NO) and it’s role in renal function and donors in renal disorders, coagulation, endothelium and hemostasis. This inspired this new post regarding the impact of NO on cardiothoratic surgery.  You can read and follow up on these posts here: http://pharmaceuticalintelligence.com/category/nitric-oxide-in-health-and-disease/

Atherosclerosis in the form of peripheral arterial disease (PAD) affects approximately eight million Americans, which includes 12 to 20% of individuals over the age of 65.  Approximately 20% of patients with PAD have typical symptoms of lower extremity claudication, rest pain, ulceration, or gangrene, and one-third have atypical exertional symptoms. Persons with PAD have impaired function and quality of life even if they do not report symptoms and experience a decline in lower extremity function over time. Cardiovascular disease is the major cause of death in patients with intermittent claudication; the annual rate of cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes) is 5 to 7%.  Thus, PAD represents a significant source of morbidity and mortality. (1) (http://www.medscape.com/viewarticle/569812).

Several options exist for treating atherosclerotic lesions, including:

  • percutaneous transluminal angioplasty with and without stenting,
  • endarterectomy
  • bypass grafting

Unfortunately, patency rates for each of these procedures continue to be suboptimal secondary to the development of neointimal hyperplasia. A universal feature of all vascular surgical procedures is the removal of or damage to the endothelial cell monolayer that occurs whether the procedure performed is endovascular or open. This endothelial damage leads to a decreased or absent production of nitric oxide (NO) at the site of injury.

noendoschematic

he relationship between NO and the cardiovascular system has proven to be a landmark discovery, and the scientists credited for its discovery were awarded the Nobel Prize in Medicine in 1998. Since its discovery, NO has proven to be one of the most important molecules in vascular homeostasis. In fact, the term endothelial dysfunction has now become synonymous with the reduced biologic activity of NO.

NO produced by endothelial cells has been shown to have many beneficial effects on the vasculature.

As described above,

  • NO stimulates vascular smooth muscle cells (VSMC) relaxation, which leads to vessel vasodilatation.  
  • NO has opposite beneficial affects on endothelial cells compared with VSMCs.
  • Whereas NO stimulates endothelial cell proliferation and prevents endothelial cell apoptosis,  it inhibits VSMC growth and migration  and stimulates VSMC apoptosis.  
  • NO also has many thromboresistant properties, such as inhibition of platelet aggregation, adhesion, and activation;  inhibition of leukocyte adhesion and migration;  and inhibition of matrix formation

 As stated before, the endothelial cell monolayer is often removed or damaged during the time of vascular procedures, which leads to a local decrease in the production of NO. It is now understood that this loss of local NO synthesis by endothelial cells at the site of vascular injury is one of the inciting events that allows platelet aggregation, inflammatory cell infiltration, and VSMC proliferation and migration to occur in excess, which, taken together, leads to neointimal hyperplasia.

Reendothelialization of the injured artery can restore proper function to the artery and potentially halt the restenotic process. Many studies have attempted to improve the patency of bypass grafts and stents by coating them with endothelial cells in the hope that this would restore the thromboresistant nature of native blood vessels.

Unfortunately, although it has been possible to coat these devices with endothelial cells, these cells do not behave like normal endothelial cells and their NO production is often diminished or absent. Because the vasoprotective properties of endothelial cells are largely carried out by NO alone, investigators are engaged in research to improve the bioavailability of NO at the site of vascular injury in an attempt to reduce the risk of thrombosis and restenosis after successful revascularization. The overall goal of using a NO-based approach is to reproduce the same thromboresistive moiety observed with normal NO production.

Why of delivering NO to the injured site:

  • Systemic delivery
  • Local delivery

Systemic Delivery

One simple mechanism by which to deliver NO to the body is via inhalational therapy. Inhaled NO has been used clinically in the past to selectively reduce pulmonary vascular resistance in patients with pulmonary hypertension, as well as a potential therapy for patients with acute respiratory distress syndrome. Because the gas is delivered only to the pulmonary system and has a very short half-life, it was thought that there would be no systemic effects of the drug. Subsequently, studies in the mid- to late 1990s suggested that inhaled NO had beneficial antiplatelet and antileukocyte properties without adverse systemic side effects (2,3)

To test if inhaled NO had any beneficial systemic properties specifically on the vasculature, Lee and colleagues evaluated the effect of inhaled NO on neointimal hyperplasia in rats undergoing carotid balloon injury, Unfortunately, the treatment was required for the full 2 weeks to see any difference between the treatment and the control group, thereby limiting its clinical utility.

Despite some of the early animal studies, investigations with healthy human volunteers failed to reproduce these findings.I t was speculated that despite the obvious effects of inhaled NO on the pulmonary vasculature, systemic bioavailability could not be reliably achieved because of the immediate binding and depletion of NO by hemoglobin as soon as it entered the systemic circulation.

Hamon and colleagues tested the ability of orally supplementing l-arginine (2.25%), the precursor to NO, in the drinking water of rabbits to reduce the formation of neointimal hyperplasia after injuring the iliac arteries with a balloon.  This amount of l-arginine is approximately sixfold higher than normal daily intake. When the arteries were studied 4 weeks after injury, the l-arginine-fed group exhibited less neointimal hyperplasia and greater acetylcholine-induced relaxation compared with the control animals. The authors speculated that the improved outcomes were due to increased bioavailability of NO secondary to the l-arginine-supplemented diets. To test the ability of this supplemented diet to reduce neointimal hyperplasia in a vein bypass graft model, Davies and colleagues fed rabbits l-arginine (2.25%) 7 days prior to and 28 days after common carotid vein bypass grafts. A 51% decrease in the formation of neointimal hyperplasia was demonstrated in the l-arginine-fed groups, and their vein grafts exhibited preserved NO-mediated relaxation.

Despite some of the positive findings in animals, similar studies in humans have failed to show any benefit with l-arginine supplementation. Shiraki and colleagues studied the effects of short-term high-dose l-arginine on restenosis after PTCA.  Thirty-four patients undergoing cardiac catheterization and PTCA for angina pectoris received 500 mg of l-arginine administered through the cardiac catheter immediately prior to PTCA and 30 g per day of l-arginine administered via the peripheral vein for 5 days after PTCA. No significant statistical differences in restenosis were observed between the two groups (34% vs 44%). The authors speculated that the lack of effect was secondary to the fact that although the levels of l-arginine in the plasma increased significantly, NO and cyclic guanosine monophosphate (cGMP) did not. (4)

Table 1.  Comparison of Different Nitric Oxide Donor Drugs Currently Used for Clinical or Research Purposes
Drug Mechanism of NO Release Unique Properties
Diazeniumdiolates Spontaneous when in contact with physiologic fluidsNO release follows first-order kinetics Stable as solidsVarious reliable half-lives depending on the structure of the nucleophile it is attached to
Nitrosamines can form as by-products
S-Nitrosothiols Copper ion-mediated decomposition Stable as a solid
Direct reaction with ascorbate Must be protected from light
Homeolytic cleavage by light Present in circulating blood
Potential for unlimited NO release
Sydnonimines Requires enzymatic cleavage by liver esterases to form active metabolite Stable as a solidMust be protected from light
Requires molecular oxygen as an electron acceptor Requires alkaline pHReleases superoxide as a by-product, which may have negative effects
l-Arginine Substrate for NOS genes Stable as a solid
Ease of administration
Dependent on presence of NOS for NO production
Sodium nitroprusside Requires a one-electron reduction to release NO Stable as a solid
Must be protected from light
Light can induce NO release Must be given intravenously
Releases cyanide as a by-product
Organic nitrates Either by enzymatic cleavage or nonenzymatic bioactivation with sulfhydryl or thiol groups Stable as a solid
Must be protected from light
Ease of administration
Development of tolerance limits efficacy
NO-releasing aspirin Require enzymatic cleavage to break the covalent bond between the aspirin and the NO moiety Stable as a solid
Ease of administration
Inherent benefits of aspirin also
Does not affect systemic blood pressure

Despite the ease of administration, the reliability of drug delivery, and the relative safety of these NO-donating drugs, there are limitations associated with systemic administration. One such limitation is that NO is rapidly inactivated by hemoglobin in the circulating blood, resulting in limited bioavailability. Furthermore, in attempts to increase the amount of drug delivered to obtain the desired clinical effect, unwanted systemic circulatory effects (eg, vasodilation) and unwanted hemostatic effects (eg, bleeding) often preclude administration of biologically effective doses of NO.

Because NO produces systemic side effects, lower doses of NO have been used in many of the human studies. One of the reasons for the differences observed between the animal studies and the human studies was the 10- to 50-fold lower doses of drugs used in the human studies compared with the animal studies. Thus, local delivery of NO may achieve improved results.

Local Delivery

The local delivery of drugs allows for the administration of the maximally effective dose of a drug without the unwanted systemic side effects. Because the target vessels are easily accessible during most vascular procedures, a local pharmacologic approach to administer a drug during the intervention can be easily performed.

Suzuki and colleagues performed a prospective, randomized, single-center clinical trial. (7)

The study population consisted of patients with symptomatic ischemic heart disease who were undergoing coronary artery stent placement. After stent deployment, l-arginine (600 mg/6 mL) or saline (6 mL) was locally delivered via a catheter over 15 minutes. The patients were followed with serial angiography and intravascular ultrasonography to assess for neointimal thickness for up to 6 months. The authors found that in the l-arginine-treated groups, there was slightly less neointimal volume, but this was not statistically significant.

Because it was not known if the addition of l-arginine actually translated to increased NO production, several studies have focused on the addition of NO donors directly to the site of injury.However, Critics of some of the highlighted animal studies point out that the evaluation of neointimal hyperplasia was performed radiographically, which could be subjectively biased. Furthermore, infusing the drug through a catheter for an extended period of time during the procedure to achieve an effect is not clinically feasible. Because of this, other studies have aimed to develop a clinically applicable approach to deliver NO locally to the site of injury.

  • Hydrogels
  • Vascular grafts
  • Gene therapy

represents another method by which to locally increase the level of NO at the site of vascular injury, tested in different multiple creative animal models. Thought, most of this studies shown great preliminary results, only the gene therapy moved forward into randomized clinical trial in humans using gene therapy to reduce neointimal hyperplasia.

In December 2000, the Recombinant DNA Advisory Committee at the National Institutes of Health voted unanimously to proceed with the first phase of clinical evaluation of iNOS lipoplex-mediated gene transfer, called REGENT-1: Restenosis Gene Therapy Trial. (8). The primary objective of this multicenter, prospective, single-blind, dose escalation study was to obtain safety and tolerability information of iNOS-lipoplex gene therapy for reducing restenosis following coronary angioplasty. As of 2002, 27 patients had been enrolled overseas and the process had been determined to be safe. To date, no results have been published as it appears that this trial lost its funding and closed. On April 5, 2002, a notification was issued that the trial had been closed without enrolling any individuals in the United States.

Unfortunately, despite the promising findings shown with NOS therapy, the field of gene therapy has been mottled by two widely known complications. One case occurred as the result of administering a large viral load that led to the death of a patient. In addition, in France, there were at least two cases of malignancy following retroviral gene therapy.  (9)

Summary

Atherosclerosis in the form of coronary artery disease and peripheral vascular disease continues to be a major source of morbidity and mortality. Unfortunately, the procedures and materials that are currently used to alleviate these disease states are temporary at best because of the inevitable injury to the native endothelium and the subsequent impairment of NO release. Since the discovery of NO and its role in vascular biology, a main focus in vascular research has been to create novel mechanisms to use NO to combat neointimal hyperplasia. To date, numerous animal studies have restored NO production to the vasculature and have shown that this inhibits neointimal hyperplasia, improves patency rates, and is safe to the animal. Clinical studies using these novel NO-releasing compounds in humans are on the horizon.

Ref:

1. Daniel A. Popowich, Vinit Varu, Melina R. Kibbe. Nitric Oxide: What a Vascular Surgeon Needs to Know. Vascular. 2007;15(6):324-335. (http://www.medscape.com/viewarticle/569812).

2.  Gries A, Bode C, Peter K, et al. Inhaled nitric oxide inhibits human platelet aggregation, P-selectin expression, and fibrinogen binding in vitro and in vivo Circulation 1998;97:1481-7.

3.  Lee JS, Adrie C, Jacob HJ, et al. Chronic inhalation of nitric oxide inhibits neointimal formation after balloon-induced arterial injury Circ Res 1996;78:337-42.

4.  Shiraki T, Takamura T, Kajiyama A, et al. Effect of short-term administration of high dose l-arginine on restenosis after percutaneous transluminal coronary angioplasty J Cardiol 2004;44:13-20.

5. David A. Fullerton, MD, Robert C. McIntyre, Jr, MD. Inhaled Nitric Oxide: Therapeutic Applications in Cardiothoracic Surgery. Ann Thorac Surg 1996;61:1856-1864. http://ats.ctsnetjournals.org/cgi/content/abstract/61/6/1856

6. Owen I.Miller,Swee Fong Tang, Anthony Keech,Nicholas B.Pigott, Elaine Beller and David S. Celemajer.  Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. The Lancet,2000:356; 9240 Pages 1464 – 1469,  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02869-5/abstract

7. Suzuki T, Hayase M, Hibi K, et al. Effect of local delivery of l-arginine on in-stent restenosis in humans Am J Cardiol 2002;89:363-7.

8. von der Leyen HE, Chew N. Nitric oxide synthase gene transfer and treatment of restenosis: from bench to bedside Eur J Clin Pharmacol 2006;62:83-89

9.  Barbato JE, Tzeng E. iNOS gene transfer for graft disease Trends Cardiovasc Med 2004;14:267-72.

10. E. Matevossian, A. Novotny, C. Knebel, T. Brill, M. Werner, I. Sinicina, M. Kriner, M. Stangl, S. Thorban, and N. Hüser. The Effect of Selective Inhibition of Inducible Nitric Oxide Synthase on Cytochrome P450 After Liver Transplantation in a Rat Model. Transplantation Proceedings 2008, 40, 983–985. http://211.144.68.84:9998/91keshi/Public/File/29/40-4/pdf/1-s2.0-S0041134508004181-main.pdf

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Reporter: Aviva Lev-Ari, PhD, RN

Demonstrate Biosimilarity with 100% confidence. Everytime

While offering greater flexibility, new FDA biosimilar guidelines lack specificity, nothing in the development can be taken for granted.

Develop biosimilars that exhibit comparability in every required category and avoid ever having a biosimilar application rejected. With so much at stake, are you 100% confident of demonstrating comparability every time? 

Demonstrate Biosimilarity is your opportunity to get first hand case studies from the leading biosimilar and generic drug developers as well as the FDA on the best approaches to…

  1. Interpret regulatory ambiguity and determine how much similarity must be demonstrated to gain approval and achieve interchangeability
  2. Ensure stability and analytical comparability as well as comparability in safety and PK/PD by optimizing your quality assessment strategy
  3. Reduce the impact of immunogenicity in your biosimilar drug and discover how to translate this regulatory expectation into a clinical trial concept
  4. Optimize your approaches to protein characterization with practical guidance from industry leading analytical scientists and service providers

Demonstrate Biosimilarity will tackle burning issues surrounding naming and pricing policiesoriginators defence strategiesmanufacturing challenges andhow to identify the best target for biosimilar development. Achieve technical insights and obtain cutting edge intelligence from 16 pharma case studies showcasing biosimilar best practise.

Attend and gain first hand testimony from the FDA, that combined with this depth of insight will give you the information you need to move quickly and decisively to get your biosimilar approved.

What you will learn? 

Attend Demonstrate Biosimilarity to:

  • Learn how to effectively monitor the higher-order structure and associated structural dynamics of your biosimilar drug molecules by optimizing your approach to comparability studies with practical guidance from Biogen Idec
  •  Expand your knowledge of how protein aggregates interact with the immune system and how this understanding can be used to reduce immunogenicitywith the Chief Medical Research Officer at the FDA
  •  More effectively determine the extent of physiochemical, pre-clinical and clinical characterization required to demonstrate biosimilarity and gain approval with case studies from Novartis and Sandoz
  • Enhance harmonization of your biosimilar data with a comprehensive comparison of the EMEA Vs USA regulatory landscape with Sandoz, Pfizerand Wokhardt
  • Get insight from MedImmune to achieve comparability when test methods are changed during the product life cycle and a non-inferior, equivalent, or superior replacement study model has been selected
  • Understand fully the applications of bioassays to determine product potency, aid biological characterization, test comparability, and determine stability with expert advice and clinical data from Teva Pharmaceuticals
  • Get a first hand guide from the FDA regarding quantitation and characterization of protein aggregates in biosimilars to ensure quality and safety of products,consistency of manufacture between lots and comparability when the manufacturing process has been changed

Does the FDA biosimilar guidance go far enough? Not if you want to operate with 100% confidence.

In fact the FDA still wants to take a cautious case by case approach. Complex biosimilar comparability studies are inherently risky and the consequences of a rejected submission are dramatic. This means that an open dialogue with FDA & other developers is essential.

Our recent industry survey highlighted two key desires for drug developers:

 

To know exactly how other drug developers are tackling challenges such as structural comparability, immunogenicity and interchangeability

What the FDA is currently thinking and how this would apply to their development programs

In response to this demand for insight and support we’ve assembled the FDA alongside the industry’s best at Demonstrate Biosimilarity Washington DC (13-14th February).

 

Learn from the testimony of 18 industry speakers including Sandoz, Teva, Wokhardt, GSK, Pfizer, MedImmune, Biogen Idec, Amgen, Novartis, Merck and senior FDA representatives dedicated to answering these questions.  This will ensure that you can effectively achieve comparability , demonstrate biosimilarity and avoid costly failed submissions. View the agenda now.

Overcome challenges such as:

 

  • How do I assess the level of biological purity needed to match my innovator product and avoid making several submission to regulators?
  • Is it truly possible to achieve interchangeability and how can I convince patients and physicians of the equivalence of my biosimilar and ensure market access?
  • What are the best practises to decrease immunogenicity risk to increase my chances of achieving comparability?
  • Where can I obtain a suitable reference product to allow me to begin characterization?
  • What is the FDA’s current thinking on the criteria for analytical, stability, safety and PK/PD comparability?

Download the brochure now to view the full agenda, workshops & speaker line up.

http://demonstrate-biosimilarity.com/download-brochure?utm_campaign=2924FIERCE&utm_medium=email&utm_source=Eloqua&elq=268b14bad28e4a9f979fc60b45a9c3c6&elqCampaignId= 

This meeting will provide you with unrivalled access to 15 case study lead presentations from pioneering biosimilar and generic drug developers sharing their innovative new approaches.

Learn how your peers are decreasing the clinical work required, minimising the impact of immunogenicity, achieving interchangeability and how they define targets for biosimilar development.

If that isn’t enough, the FDA will be giving keynote presentations on the regulatory expectations regarding aggregates and comparability as well as minimizing the impact of immunogenicity by understanding the role of protein aggregates in unwanted immunogenicity.

SPEAKERS

http://demonstrate-biosimilarity.com/speakers?utm_campaign=2924FIERCE&utm_medium=email&utm_source=Eloqua&elq=268b14bad28e4a9f979fc60b45a9c3c6&elqCampaignId=

AGENDA:

Day One

13th February, 2013

8.00 Registration

8.55 Chair’s Opening Remarks 

Optimizing Quality Assessments: Biochemical and Physiochemical Properties

9.00 Regulatory Expectations Regarding Aggregates and Comparability

• A guide from the FDA regarding quantitation and characterization of protein aggregates to ensure quality and safety, consistency of manufacture and comparability when the manufacturing process is being changed

• Overcoming challenges associated with characterization of the aggregates’ full size range to maximize safety information

Ewa Marszal, Chemist, Laboratory of Plasma Derivatives, Division of Haematology, CBER, FDA

9.30 An Industry Perspective: Optimizing Approaches to Protein Characterization in the Development of Biosimilars

• Practical guidance for optimizing analytical characterization of commercial products

• Understanding the innovation required in both technical development and clinical development

• Devising a systematic engineering approach to match biosimilar to reference product

Roxana Butoi, Manager, Biosimilars, GSK

10.00 Solution Spotlight: Analytical methods for monitoring biosimilar glycosylation

Scott Barksdale, Director, Business Development, Procognia

10.15 Speed Networking & Morning Refreshments

11.45 CASE STUDY: Implementing Advanced Analytical Methods and Regulatory Approved Comparability Strategies

• Numerous case studies demonstrating when test methods are changed during the product life cycle and a non-inferior, equivalent, or superior replacement study model has been selected based on the intended use of the new test method

• How to set risk-based acceptance criteria from product specifications and existing manufacturing process knowledge

Stephan Krause, PDA Task Force Leader for Analytical Methods, and Principal Scientist, Analytical Biochemistry, MedImmune

12.15 Application of Hydrogen/Deuterium Exchange with Mass Spec Detection (H/DX-MS) to Assess Comparability 

• Applications of instrumental hardware and computer software to enable H/DX-MS to be employed in a practical and routine way to assess biosimilarity

• Optimizing comparability studies to monitor the higherorder structure and associated dynamics of biosimilar drugs

Steven Berkowitz, Principal Investigator, Analytical Development, Biogen Idec

12.45 Effective use of Bioassays to Streamline Biosimilar Development 

• Applications of bioassays to determine product potency, aid biological characterization, and test comparability

• Bioassays as a bioanalytical tool in support of pre clinical and clinical studies throughout the span of biosimilar development

• Developing an assay strategy and clear understanding of regulatory expectations, development and implementation of validated biological assays to ensure approval

Patrick Liu, Senior Director and Global Head of Bioassays, Teva Pharmaceuticals

1:15 Lunch & Networking

2.15 CASE STUDY: Correcting Biases in Light Obscuration and Light Scattering Measurements of Protein Particles 

• A demonstration of the applications of optical models for measuring of protein particles

• Several case studies involving protein aggregates, examining size errors and the practicality of corrections for biosimilar development

Dean Ripple, Leader, Bioprocess Measurements Group, National Institute of Standards and Technology

Demonstrating Biosimilarity: Biochemical and Physiochemical Properties

Roxana Butoi, Manager, Biosimilars, GSK 

Stephan KrausePDA Task Force Leader for Analytical Methods, and Principal Scientist, Analytical Biochemistry, MedImmune

Steven Berkowitz, Principal Investigator, Analytical Development, Biogen Idec

Patrick Liu, Senior Director and Global Head of Bioassays, Teva Pharmaceuticals

3.15 Afternoon Refreshments & Networking  

Achieving Interchangeability with a Biosimilar Product

3.45 Application of Biophysical Techniques in Comparability Exercises: Quantitative Assessment of Spectral Similarity

• Effective use of biophysical tools, including circular dichroism spectroscopy to provide qualitative assessment of the similarity in higher order structure for biological molecules

• Using statistical analysis to provide a more quantitative evaluation of spectral similarity

Qin Zou, Senior Principal Scientist, BioProcess Analytics, Pfizer  

4.15 The Momenta Approach to Developing Biosimilars and Potentially Interchangeable Biologics

• Establishing biosimilarity and potential interchangeability by focussing on “comparison” between RPP and biosimilar

• An overview of Momenta’s key takeaways from the recently issued FDA draft guidance

Jim Roach, SVP, Development and Chief Medical Officer, Momenta Pharmaceuticals

4.45 Comparability and Biosimilarity – Two Sides of the Same (or a Different) Coin? 

• Compare and contrast the comparability and biosimilarity paradigms, with consideration for the impact of Quality by Design on these product development strategies

• The challenges and future directions of product characterization for biosimilars

Brent Kendrick, Director of Analytical Sciences, Amgen

5.15 Chair’s Closing Remark

 

Day Two

14th February, 2013

8.15 Registration

9.10 Chair’s opening remarks

9.15 Analysis of the Biosimilar Development Pipeline

• Gain a better understanding of how the biosimilar market will develop and evolve in light of the biosimilarity guidelines

• Understand when products will begin entering the U.S. and European markets

• What different development approaches are companies taking?

• What will be the involvement of companies in the US/EU

vs. those in developing countries?

Ronald Rader, President, Biotechnology Information Institute

9.45 Minimizing the Impact of Immunogenicity Understanding the Role of Protein Aggregates in Unwanted Immunogenicity

• How subvisible protein aggregates may interact with the immune system, their potential impact on product safety and efficacy

• An FDA perspective on the current regulatory considerations pertaining to the control of these particulates

Jack Ragheb, Chief Medical Research Officer, CDER, FDA

10.15 Morning Refreshments & Networking

Navigating the Regulatory and Legal Environment for Biosimilars

11.00 Comparison of the EMEA and USA Regulation for Biosimilar Development

• A review of the current state of initiatives for biosimilars in both EMEA and USA

• Perspective on how regulatory uncertainty could be reduced in the implementation of quality by design arguments

• A comprehensive comparison of the EMEA Vs USA landscape an the intricacies of harmonization

Ajaz Hussain, Chief Scientific Officer, Workhardt

11.30 An Industry Perspective: USA Current and Future Regulatory Setting for Biosimilars 

• Understanding the need to maximize productivity of FDA biosimilars development meetings

• Identifying and justifying differences between structural and functional characterization

• Negotiating regulatory landscape for clinical development and determining the required magnitude of the program

• Pursuing interchangeability for your biosimilar product without FDA guidance

John Pakulski, Senior Director and Head US Biopharmaceutical Regulatory Affairs, Sandoz

12.00 Biosimilar Regulation Roundtable Session 

• An opportunity for delegates to discuss with the regulators and regulatory experts the recent FDA biosimilar guidelines

• Collaboratively discuss the impact of the regulation and strategies to comply with it

12.45 Lunch & Networking

2.00 A Practical Guide and Overview of Current Strategies of Biocomparability and Biosimilarity 

• Industry perspective on the current guidance from EMEA and FDA for biocomparability

• Current strategies to assess the the extent of physiochemical, pre-clinical and clinical characterization based on the stage of development

• Emerging guidance on biosimilarity and the implications on the pre-clinical and clinical development programs for biosimilars

• Use of biomarkers in the biocomparability exercise: Are we there yet?

Shefali Kakar, Senior Fellow, Clinical Pharmacology, Oncology Business Unit, Novartis

2.30 Understand the Nuances and Implications of the FDA Guidelines on Biosimilars

• A detailed examination of the content of the recently released FDA guidelines and how to best understand the requirements for quantity of data, sources of material and types of studies permitted

• What kind of potential exists for increased efficiency, collaboration and cost-effectiveness in the U.S?

• The repercussions of important FDA decisions that have been made regarding user fees to be paid by companies in order to submit an application for a biosimilar

Helen Hartman, Regulatory Affairs Strategist, Pfizer

3.00 Afternoon Refreshments & Networking

Optimizing Approaches for Biosimilar Production and Manufacture

3.30 CASE STUDY: Evaluation of Comparability due to Changes in Scale-up, Process, Manufacturing Site, and Formulation 

• A case study of a preliminary comparability study used to evaluate the changes due to scale-up, manufacturing site, process and formulation of batches used in phases I/II and III

• A detailed overview of the extended characterization results from this study

• Preliminary assessment of comparability studies to establish the type of analytical testing required to correlate manufacturing changes to the product characteristics in the final comparability testing

Soundara Soundararajan, Principal Scientist, Bioprocess Development, Merck

4.00 Biosimilars: The Age of Post-Patent Medicine

• How will the thorny issues of safety, efficacy and cost (and in that order) impact the role of biosimilars in 21st century healthcare

• A detailed look at the challenges associated with demonstrating biosimilarity to the relevant regulatory bodies

Peter Pitts, President, Center for Medicine in the Public Interest

4.30 Chair’s Closing Remarks

 

Workshops

Pre Conference Workshops: 12th February 2013

Workshop A) 08.00 – 11.00: Measurement, Characterization and Impactof Impurities for Biosimilars

Biotechnology and biosimilar products have substantial differences fromchemical entities in their starting materials, manufacturing processes, productcharacteristics, stability profiles, and interactions with containers and closures.Each of these can impact the nature of the impurities present in the finalproduct.

This workshop will provide an overview of these differences with links tothe current regulatory expectations and notes on current ‘best practices’for impurities assessment during development.

  • Impurities in Biotechnology/Biosimilar Products – What Makes themCritical?

– What are the specific guidance requirements for biosimilar productimpurities?

– What elements impact meaningful, reliable specifications for processand product impurities?

– How are the risks of impurities managed during development?

  • Example of Critical Process-Related Impurities: Host Cell Proteins

– What are the key requirements for measuring host cell proteins fromvarious expression systems?

– How should host cell protein assays be selected, optimized, and validated?

  • Example of Critical Product-Related Impurities: Particulates

– What types of particulates are of concern?

– How do we measure particulates?

  • Example of Critical Container/Closure Related Impurities: Extractables/Leachables

– How do we identify the extractables and leachables?

– How can extractables or leachables affect the product?

You will leave this workshop with a detailed understanding of the impact of key impurities in biosimilar development, through case study examples ofeach, to review the current and emerging issues for biotechnology productsassociated with each.

Led By: Nadine Ritter, Senior CMC Consultant, Biologics Consulting Group

 

Workshop B) 12.00 – 15.00: Strategies for an Abbreviated Clinical Programfor Biosimilar mAbs

This workshop is designed to give you a practical guide to develop theoptimum clinical strategy for developing a biosimilar to minimize the size ofthe clinical program require to demonstrate biosimilarityIn this workshop you will:

  • Understand how to design an abbreviated clinical program for biosimilardrugs
  • Learn to optimize phase I by developing a streamlined FIM PK study usingreference product and PK equivalence as endpoints
  • Discuss best practices for phase III dose and time response design
  • Develop solutions to challenges associated with safety, immunogenicity, interchangeability and extrapolation across multiple indications

You will leave this workshop with a step by step guide to taking a biosimilarthrough clinical development that will minimize the amount of clinical workrequired without compromising the quality or quantity of clinical evidence.

Led by: Partha Roy, Principle Consultant, PAREXEL Consulting

Please note that workshop B runs at the same time as workshop C – so you cannot attend both.

Workshop C) 12.00 – 15.00: Biosimilars: Is the Risk worth the Reward?

This workshop will demonstrate how you can capitalize on the recentregulatory developments, and offer all of the information you need tomove quickly and decisively to turn the streamlined biosimilars processinto a lucrative commercial opportunity.In this workshop you will:

  • Gain an understanding of the potential of the biosimilar market andassess the potential entry routes available for your business
  • Get an overview via numerous case studies of the latest progress inthe biosimilar field and discover how you can capitalize on the latestdevelopments
  • Understand the complex issue of biosimilar ROI and discusspractical strategies to maximize your return
  • Hear both provider and payer perspectives to gain a betterunderstanding of how you can cater to both of their needs

You will leave this workshop with all the information you need todevelop an effective commercially viable biosimilar development strategy.

Led by: James Harris, Chief Executive Officer, Healthcare Economics LLC

Please note that workshop B runs at the same time as workshop C – so you cannot attend both.

 

Workshop D) 15.30 – 18.30: Gain a Biosimilar Market Overview:Present and Future Challenges

Biosimilars present a new set of challenges for regulatory authoritieswhen compared with conventional generics. After many years in theslow lane, changes are driving new momentum in the market forbiosimilarsIn this workshop you will:

  • Analyze with industry leaders the present and future actions of themain players in biosimilar market in different regions of the world tohelp identify best practises from varying geo-specific approaches
  • Get an understanding of the patents used for the first generation ofapproved biopharmaceuticals and discover how to capitalize onpatents about to expire to open up new opportunities in the biosimilarmarket
  • Understand the critical issues for healthcare professionals surroundingthe use of biosimilars to make informed treatment decisions

You will leave this workshop with a greater understanding of thebiosimilar market place and an actionable biosimilar strategyincorporating the best practises discussed during this case study anddiscussion lead workshop.

Led by: Leandro Mieravilla, Global Market Manager mAbs, Cassara Biotech

 

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Telling NO to Cardiac Risk

DDAH Says NO to ADMA(1); The DDAH/ADMA/NOS Pathway(2)

Author-Writer-Reporter:  Stephen J. Williams, PhD

Endothelium-derived nitric oxide (NO) has been shown to be vasoprotective.  Nitric oxide enhances endothelial cell survival, inhibits excessive proliferation of vascular smooth muscle cells, regulates vascular smooth muscle tone, and prevents platelets from sticking to the endothelial wall.  Together with evidence from preclinical and human studies, it is clear that impairment of the NOS pathway increases risk of cardiovascular disease (3-5).

This post contains two articles on the physiological regulation of nitric oxide (NO) by an endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) and ADMA metabolism by the enzyme DDAH(1,2).  Previous posts on nitric oxide, referenced at the bottom of the page, provides excellent background and further insight for this posting. In summary plasma ADMA levels are elevated in patients with cardiovascular disease and several large studies have shown that plasma ADMA is an independent biomarker for cardiovascular-related morbidity and mortality(6-8).

admacardiacrisk

admaeffects

Figure 1 A. Cardiac risks of ADMA B. Effects of ADMA (Photo credit: Wikipedia)

ADMA Production and Metabolism

Nuclear proteins such as histones can be methylated on arginine residues by protein-arginine methyltransferases, enzymes which use S-adenosylmethionine as methyl groups.  This methylation event is thought to regulate protein function, much in the way of protein acetylation and phosphorylation (9).  And much like phosphorylation, these modifications are reversible through methylesterases.   The proteolysis of these arginine-methyl modifications lead to the liberation of free guanidine-methylated arginine residues such as L-NMMA, asymmetric dimethylarginine (ADMA) and symmetrical methylarginine (SDMA).

The first two, L-NMMA and ADMA, have been shown to inhibit the activity of the endothelial NOS.  This protein turnover is substantial: for instance the authors note that each day 40% of constitutive protein in adult liver is newly synthesized protein. And in several diseases, such as muscular dystrophy, ischemic heart disease, and diabetes, it has been known since the 1970’s that protein catabolism rates are very high, with corresponding increased urinary excretion of ADMA(10-13).  Methylarginines are excreted in the urine by cationic transport.  However, the majority of ADMA and L-NMMA are degraded within the cell by dimethylaminohydrolase (DDAH), first cloned and purified in rat(14).

endogenous NO inhibitors from pubchem

Figure 2.  Endogenous inhibitors of NO synthase.  Chemical structures generated from PubChem.

DDAH

DDAH specifically hydrolyzes ADMA and L-NMMA to yield citruline and demethylamine and usually shows co-localization with NOS. Pharmacologic inhibition of DDAH activity causes accumulation of ADMA and can reverse the NO-mediated bradykinin-induced relaxation of human saphenous vein.

Two isoforms have been found in human:

  • DDAH1 (found in brain and kidney and associated with nNOS) and
  • DDAH2 (highly expressed in heart, placenta, and kidney and associated with eNOS).

DDAH2 can be upregulated by all-trans retinoic acid (atRA can increase NO production).  Increased reactive oxygen species and possibly homocysteine, a risk factor for cardiovascular disease, can decrease DDAH activity(15,16).

  • The importance of DDAH activity can also be seen in transgenic mice which overexpress DDAH, exhibiting increased NO production, increased insulin sensitivity, and reduced vascular resistance  (17).  Likewise,
  • Transgenic mice, null for the DDAH1, showed increase in blood pressure, decreased NO production, and significant increase in tissue and plasma ADMA and L-NMMA.

amdanosfigure

Figure 3.  The DDAH/ADMA/NOS cycle. Figure adapted from Cooke and Ghebremarian (1).

As mentioned in the article by Cooke and Ghebremariam, the authors state: the weight of the evidence indicates that DDAH is a worthy therapeutic target. Agents that increase DDAH expression are known, and 1 of these, a farnesoid X receptor agonist, is in clinical trials

http://www.interceptpharma.com

An alternate approach is to

  • develop an allosteric activator of the enzyme.  Although
  • development of an allosteric activator is not a typical pharmaceutical approach, recent studies indicate that this may be achievable aim(18).

References:

1.            Cooke, J. P., and Ghebremariam, Y. T. : DDAH says NO to ADMA.(2011) Arteriosclerosis, thrombosis, and vascular biology 31, 1462-1464

2.            Tran, C. T., Leiper, J. M., and Vallance, P. : The DDAH/ADMA/NOS pathway.(2003) Atherosclerosis. Supplements 4, 33-40

3.            Niebauer, J., Maxwell, A. J., Lin, P. S., Wang, D., Tsao, P. S., and Cooke, J. P.: NOS inhibition accelerates atherogenesis: reversal by exercise. (2003) American journal of physiology. Heart and circulatory physiology 285, H535-540

4.            Miyazaki, H., Matsuoka, H., Cooke, J. P., Usui, M., Ueda, S., Okuda, S., and Imaizumi, T. : Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis.(1999) Circulation 99, 1141-1146

5.            Wilson, A. M., Shin, D. S., Weatherby, C., Harada, R. K., Ng, M. K., Nair, N., Kielstein, J., and Cooke, J. P. (2010): Asymmetric dimethylarginine correlates with measures of disease severity, major adverse cardiovascular events and all-cause mortality in patients with peripheral arterial disease. Vasc Med 15, 267-274

6.            Kielstein, J. T., Impraim, B., Simmel, S., Bode-Boger, S. M., Tsikas, D., Frolich, J. C., Hoeper, M. M., Haller, H., and Fliser, D. : Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans.(2004) Circulation 109, 172-177

7.            Kielstein, J. T., Donnerstag, F., Gasper, S., Menne, J., Kielstein, A., Martens-Lobenhoffer, J., Scalera, F., Cooke, J. P., Fliser, D., and Bode-Boger, S. M. : ADMA increases arterial stiffness and decreases cerebral blood flow in humans.(2006) Stroke; a journal of cerebral circulation 37, 2024-2029

8.            Mittermayer, F., Krzyzanowska, K., Exner, M., Mlekusch, W., Amighi, J., Sabeti, S., Minar, E., Muller, M., Wolzt, M., and Schillinger, M. : Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease.(2006) Arteriosclerosis, thrombosis, and vascular biology 26, 2536-2540

9.            Kakimoto, Y., and Akazawa, S.: Isolation and identification of N-G,N-G- and N-G,N’-G-dimethyl-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine. (1970) The Journal of biological chemistry 245, 5751-5758

10.          Inoue, R., Miyake, M., Kanazawa, A., Sato, M., and Kakimoto, Y.: Decrease of 3-methylhistidine and increase of NG,NG-dimethylarginine in the urine of patients with muscular dystrophy. (1979) Metabolism: clinical and experimental 28, 801-804

11.          Millward, D. J.: Protein turnover in skeletal muscle. II. The effect of starvation and a protein-free diet on the synthesis and catabolism of skeletal muscle proteins in comparison to liver. (1970) Clinical science 39, 591-603

12.          Goldberg, A. L., and St John, A. C.: Intracellular protein degradation in mammalian and bacterial cells: Part 2. (1976) Annual review of biochemistry 45, 747-803

13.          Dice, J. F., and Walker, C. D.: Protein degradation in metabolic and nutritional disorders. (1979) Ciba Foundation symposium, 331-350

14.          Ogawa, T., Kimoto, M., and Sasaoka, K.: Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney. (1989) The Journal of biological chemistry 264, 10205-10209

15.          Ito, A., Tsao, P. S., Adimoolam, S., Kimoto, M., Ogawa, T., and Cooke, J. P.: Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. (1999) Circulation 99, 3092-3095

16.          Stuhlinger, M. C., Tsao, P. S., Her, J. H., Kimoto, M., Balint, R. F., and Cooke, J. P. : Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine.(2001) Circulation 104, 2569-2575

17.          Sydow, K., Mondon, C. E., Schrader, J., Konishi, H., and Cooke, J. P.: Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity. (2008) Arteriosclerosis, thrombosis, and vascular biology 28, 692-697

18.          Zorn, J. A., and Wells, J. A.: Turning enzymes ON with small molecules. (2010) Nature chemical biology 6, 179-188

Other research papers on Nitric Oxide and Cardiac Risk  were published on this Scientific Web site as follows:

The Nitric Oxide and Renal is presented in FOUR parts:

Part I: The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide

Part II: Nitric Oxide and iNOS have Key Roles in Kidney Diseases

Part III: The Molecular Biology of Renal Disorders: Nitric Oxide

Part IV: New Insights on Nitric Oxide donors

Cardiac Arrhythmias: A Risk for Extreme Performance Athletes

What is the role of plasma viscosity in hemostasis and vascular disease risk?

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

Nitric Oxide Function in Coagulation

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Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

Curator: Aviva Lev-Ari, PhD, RN

 

 

In the field of Cancer Research, Translational Medicine  will become Personalized Medicine when each of the cancer type, below will have a Genetic Marker allowing the Clinical Team to use the marker for:

  • prediction of Patient’s reaction to Drug induction
  • design of Clinical Trials to validate drug efficacy on small subset of patients predicted to react favorable to drug regimen, increasing validity and reliability
  • Genetical identification of patients at no need to have a drug administered if non sensitivity to the drug has been predicted

Current urgent need exists for Identification of Genetic Markers to predict Patient’s reaction to Drugs Induction for the following types of Cancer:

The executive task of the clinician remains to assess the differentiation in Tumor Response to Treatment.

Review of limitations for the current existing Tools used by clinicians in to be found in:

Brücher BLDM, Bilchik A, Nissan A, Avital I & Stojadinovic A. Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment?  Future Oncology 2012; 8(8): 903-906 , DOI 10.2217/fon.12.78 (doi:10.2217/fon.12.78)   The heterogeneity is a problem that will take at least another decade to unravel because of the number of signaling pathways and the crosstalk that is specifically at issue.

Future Oncology August 2012, Vol. 8, No. 8, Pages 903-906 ,

It is suggested that the new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ characteristics. The new modality should be based on empirical evidence that translates into relevant and meaningful clinical outcome data.

Cancer is in particular a difficult to treat tissue type pathology. In “Tumor response criteria: are they appropriate?” that concern is addressed as follows:

“This becomes a conundrum of sorts in an era of ‘minimally invasive treatment’. One frequently encountered example is that of a patient with chronic gastric reflux and an ultrasound-staged T3N1 distal esophageal adenocarcinoma, who had complete sonographic tumor response to neoadjuvant chemoradiation. The physician may declare that, the tumor having disappeared, the patient requires no further treatment. The surgical oncologist recommends resection, recognizing the fact that up to 20% or more of these complete responders will have identifiable nests of tumor beyond the mucosal scar within the specimen – in other words: residual tumor. In other cases, patients with clinical, sonographic, functional (PET) and histopathological ‘complete’ tumor response to induction therapy experience recurrence within the first 2 years of resection, reminding us of the intricacy and enigma of tumor biology. We have yet to develop the tools needed to consistently delineate the response of a tumor to multimodality therapy.”

This described reality in the Oncology Operating Room is coupled with new trends in invasive treatment of tumor resection.

Minimally Invasive Surgery (MIS) vs. conventional surgery dissection applied to cancer tissue with the known pathophysiology of recurrence and remission cycles has its short term advantages. However, in many cases MIS is not the right surgical decision, yet, it is applied for a corollary of patient-centered care considerations. At present, facing the unknown of the future behavior of the tumor as its response to therapeutics bearing uncertainty related to therapy outcomes.

An increase in the desirable outcomes of MIS as a modality of treatment, will be strongly assisted in the future, with anticipated progress to be made in the field of Cancer Research, Translational Medicine and Personalized Medicine, when each of the cancer types, above,  will already have a Genetic Marker allowing the Clinical Team to use the marker(s) for:

  • prediction of Patient’s reaction to Drug induction
  • design of Clinical Trials to validate drug efficacy on small subset of patients predicted to react favorable to drug regimen, increasing validity and reliability
  • Genetical identification of patients at no need to have a drug administered if non sensitivity to the drug has been predicted by the genetic marker.

REFERENCES

Tumor response criteria: are they appropriate?

Björn LDM Brücher*1,2, Anton Bilchik2,3, Aviram Nissan2,4, Itzhak Avital2,5 & Alexander Stojadinovic2,6

Treatment for cure is not the endpoint, but the best that can be done is to extend the time of survival to a realistic long term goal and retain a quality of life.
Brücher BLDM, Piso P, Verwaal V et al. Peritoneal carcinomatosis: overview and basics. Cancer Invest.30(3),209–224 (2012).
Brücher BLDM, Swisher S, Königsrainer A et al. Response to preoperative therapy in upper gastrointestinal cancers. Ann. Surg. Oncol.16(4),878–886 (2009).
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer47(1),207–214 (1981).

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

What can we expect of tumor therapeutic response?

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Nanotechnology Tackles Brain Cancer

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Personalized medicine-based cure for cancer might not be far away

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Cancer Innovations from across the Web

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

mRNA interference with cancer expression

Search Results for ‘cancer’ on this web site

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

mRNA interference with cancer expression

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Crucial role of Nitric Oxide in Cancer

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

 

See comment written for:

Knowing the tumor’s size and location, could we target treatment to THE ROI by applying…..

http://pharmaceuticalintelligence.com/2012/10/16/knowing-the-tumors-size-and-location-could-we-target-treatment-to-the-roi-by-applying-imaging-guided-intervention/

24 Responses

  1. GREAT work.

    I’ll read and comment later on

  2. Highlights of The 2012 Johns Hopkins Prostate Disorders White Paper include:

    A promising new treatment for men with frequent nighttime urination.
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    Should you have a PSA screening test? Answers to important questions on the controversial USPSTF recommendation.
    Watchful waiting or radical prostatectomy for men with early-stage prostate cancer? What the research suggests.
    A look at state-of-the-art surveillance strategies for men on active surveillance for prostate cancer.
    Locally advanced prostate cancer: Will you benefit from radiation and hormones?
    New drug offers hope for men with metastatic castrate-resistant prostate cancer.
    Behavioral therapy for incontinence: Why it might be worth a try.

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    What’s your Prostate Symptom Score? Here’s a quick quiz you can take right now to determine if you should seek treatment for your enlarged prostate.
    Your surgical choices: a close look at simple prostatectomy, transurethral prostatectomy and open prostatectomy.
    New warnings about 5-alpha-reductase inhibitors and aggressive prostate cancer.

  3. Promising technique.

    INCORE pointed out in detail about the general problem judging response and the stil missing quality in standardization:

    http://www.futuremedicine.com/doi/abs/10.2217/fon.12.78?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov

    I did research in response evaluation and prediction for about 15y now and being honest: neither the clinical, nor the molecular biological data proved significant benefit in changing a strategy in patient diagnosis and / or treatment. I would state: this brings us back on the ground and not upon the sky. Additionally it means: we have to ´work harder on that and the WHO has to take responsibility: clinicians use a reponse classification without knowing, that this is just related to “ONE” experiment from the 70′s and that this experiment never had been rescrutinized (please read the Editorial I provided – we use a clinical response classification since more than 30 years worldwide (Miller et al. Cancer 1981) but it is useless !

  4. Dr. BB

    Thank you for your comment.
    Dr. Nir will reply to your comment.
    Regarding the Response Classification in use, it seems that the College of Oncology should champion a task force to revisit the Best Practice in use in this domain and issue a revised version or a new effort for a a new classification system for Clinical Response to treatment in Cancer.

  5. I’m sorry that I was looking for this paper again earlier and didn’t find it. I answered my view on your article earlier.

    This is a method demonstration, but not a proof of concept by any means. It adds to the cacophany of approaches, and in a much larger study would prove to be beneficial in treatment, but not a cure for serious prostate cancer because it is unlikely that it can get beyond the margin, and also because there is overtreatment at the cutoff of PSA at 4.0. There is now a proved prediction model that went to press some 4 months ago. I think that the pathologist has to see the tissue, and the standard in pathology now is for any result that is cancer, two pathologist or a group sitting together should see it. It’s not an easy diagnosis.

    Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital, & Alexander Stojadinovic. Tumor response criteria: are they appropriate? Future Oncol. (2012) 8(8), 903–906. 10.2217/FON.12.78. ISSN 1479-6694.

    ..Tumor heterogeneity is a ubiquitous phemomenon. In particular, there are important differences among the various types of gastrointestinal (GI) cancers in terms of tumor biology, treatment response and prognosis.

    ..This forms the principal basis for targeted therapy directed by tumor-specific testing at either the gene or protein level. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal.

    ..Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment?

    ..In 2000 theNCI with the European Association for Research and Treatment of Cancer, proposed a replacement of 2D measurement with a decrease in the largest tumor diameter by 30% in one dimension. Tumor response as defined would translate into a 50% decrease for a spherical lesion

    ..We must rethink how we may better determine treatment response in a reliable, reproducible way that is aimed at individualizing the therapy of cancer patients.

    ..we must change the tools we use to assess tumor response. The new modality should be based on empirical evidence that translates into relevant and meaningful clinical outcome data.

    ..This becomes a conundrum of sorts in an era of ‘minimally invasive treatment’.

    ..integrated multidisciplinary panel of international experts – not sure that that will do it

    Several years ago i heard Stamey present the totality of his work at Stanford, with great disappointment over hsPSA that they pioneered in. The outcomes were disappointing.

    I had published a review of all of our cases reviewed for 1 year with Marguerite Pinto.
    There’s a reason that the physicians line up outside of her office for her opinion.
    The review showed that a PSA over 24 ng/ml is predictive of bone metastasis. Any result over 10 was as likely to be prostatitis, BPH or cancer.

    I did an ordinal regression in the next study with Gustave Davis using a bivariate ordinal regression to predict lymph node metastasis using the PSA and the Gleason score. It was better than any univariate model, but there was no followup.

    I reviewed a paper for Clin Biochemistry (Elsevier) on a new method for PSA, very different than what we are familiar with. It was the most elegant paper I have seen in the treatment of the data. The model could predict post procedural time to recurrence to 8 years.

    • I hope we are in agreement on the fact that imaging guided interventions are needed for better treatment outcome. The point I’m trying to make in this post is that people are investing in developing imaging guided intervention and it is making progress.

      Over diagnosis and over treatment is another issue altogether. I think that many of my other posts are dealing with that.

  6. Tumor response criteria: are they appropriate?
    Future Oncology 2012; 8(8): 903-906 , DOI 10.2217/fon.12.78 (doi:10.2217/fon.12.78)
    Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital & Alexander Stojadinovic
    Tumor heterogeneity is a problematic because of differences among the metabolic variety among types of gastrointestinal (GI) cancers, confounding treatment response and prognosis.
    This is in response to … a group of investigators from Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada who evaluate the feasibility and safety of magnetic resonance (MR) imaging–controlled transurethral ultrasound therapy for prostate cancer in humans. Their study’s objective was to prove that using real-time MRI guidance of HIFU treatment is possible and it guarantees that the location of ablated tissue indeed corresponds to the locations planned for treatment.
    1. There is a difference between expected response to esophageal or gastric neoplasms both biologically and in expected response, even given variability within a class. The expected time to recurrence is usually longer in the latter case, but the confounders are – age at time of discovery, biological time of detection, presence of lymph node and/or distant metastasis, microscopic vascular invasion.
    2. There is a long latent period in abdominal cancers before discovery, unless a lesion is found incidentally in surgery for another reason.
    3. The undeniable reality is that it is not difficult to identify the main lesion, but it is difficult to identify adjacent epithelium that is at risk (transitional or pretransitional). Pathologists have a very good idea about precancerous cervical neoplasia.

    The heterogeneity rests within each tumor and between the primary and metastatic sites, which is expected to be improved by targeted therapy directed by tumor-specific testing. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal.

    The heterogeneity is a problem that will take at least another decade to unravel because of the number of signaling pathways and the crosstalk that is specifically at issue.

    I must refer back to the work of Frank Dixon, Herschel Sidransky, and others, who did much to develop a concept of neoplasia occurring in several stages – minimal deviation and fast growing. These have differences in growth rates, anaplasia, and biochemical. This resembles the multiple “hit” theory that is described in “systemic inflammatory” disease leading to a final stage, as in sepsis and septic shock.
    In 1920, Otto Warburg received the Nobel Prize for his work on respiration. He postulated that cancer cells become anaerobic compared with their normal counterpart that uses aerobic respiration to meet most energy needs. He attributed this to “mitochondrial dysfunction. In fact, we now think that in response to oxidative stress, the mitochondrion relies on the Lynen Cycle to make more cells and the major source of energy becomes glycolytic, which is at the expense of the lean body mass (muscle), which produces gluconeogenic precursors from muscle proteolysis (cancer cachexia). There is a loss of about 26 ATP ~Ps in the transition.
    The mitochondrial gene expression system includes the mitochondrial genome, mitochondrial ribosomes, and the transcription and translation machinery needed to regulate and conduct gene expression as well as mtDNA replication and repair. Machinery involved in energetics includes the enzymes of the Kreb’s citric acid or TCA (tricarboxylic acid) cycle, some of the enzymes involved in fatty acid catabolism (β-oxidation), and the proteins needed to help regulate these systems. The inner membrane is central to mitochondrial physiology and, as such, contains multiple protein systems of interest. These include the protein complexes involved in the electron transport component of oxidative phosphorylation and proteins involved in substrate and ion transport.
    Mitochondrial roles in, and effects on, cellular homeostasis extend far beyond the production of ATP, but the transformation of energy is central to most mitochondrial functions. Reducing equivalents are also used for anabolic reactions. The energy produced by mitochondria is most commonly thought of to come from the pyruvate that results from glycolysis, but it is important to keep in mind that the chemical energy contained in both fats and amino acids can also be converted into NADH and FADH2 through mitochondrial pathways. The major mechanism for harvesting energy from fats is β-oxidation; the major mechanism for harvesting energy from amino acids and pyruvate is the TCA cycle. Once the chemical energy has been transformed into NADH and FADH2 (also discovered by Warburg and the basis for a second Nobel nomination in 1934), these compounds are fed into the mitochondrial respiratory chain.
    The hydroxyl free radical is extremely reactive. It will react with most, if not all, compounds found in the living cell (including DNA, proteins, lipids and a host of small molecules). The hydroxyl free radical is so aggressive that it will react within 5 (or so) molecular diameters from its site of production. The damage caused by it, therefore, is very site specific. The reactions of the hydroxyl free radical can be classified as hydrogen abstraction, electron transfer, and addition.
    The formation of the hydroxyl free radical can be disastrous for living organisms. Unlike superoxide and hydrogen peroxide, which are mainly controlled enzymatically, the hydroxyl free radical is far too reactive to be restricted in such a way – it will even attack antioxidant enzymes. Instead, biological defenses have evolved that reduce the chance that the hydroxyl free radical will be produced and, as nothing is perfect, to repair damage.
    Currently, some endogenous markers are being proposed as useful measures of total “oxidative stress” e.g., 8-hydroxy-2’deoxyguanosine in urine. The ideal scavenger must be non-toxic, have limited or no biological activity, readily reach the site of hydroxyl free radical production (i.e., pass through barriers such as the blood-brain barrier), react rapidly with the free radical, be specific for this radical, and neither the scavenger nor its product(s) should undergo further metabolism.
    Nitric oxide has a single unpaired electron in its π*2p antibonding orbital and is therefore paramagnetic. This unpaired electron also weakens the overall bonding seen in diatomic nitrogen molecules so that the nitrogen and oxygen atoms are joined by only 2.5 bonds. The structure of nitric oxide is a resonance hybrid of two forms.
    In living organisms nitric oxide is produced enzymatically. Microbes can generate nitric oxide by the reduction of nitrite or oxidation of ammonia. In mammals nitric oxide is produced by stepwise oxidation of L-arginine catalyzed by nitric oxide synthase (NOS). Nitric oxide is formed from the guanidino nitrogen of the L-arginine in a reaction that consumes five electrons and requires flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) tetrahydrobiopterin (BH4), and iron protoporphyrin IX as cofactors. The primary product of NOS activity may be the nitroxyl anion that is then converted to nitric oxide by electron acceptors.
    The thiol-disulfide redox couple is very important to oxidative metabolism. GSH is a reducing cofactor for glutathione peroxidase, an antioxidant enzyme responsible for the destruction of hydrogen peroxide. Thiols and disulfides can readily undergo exchange reactions, forming mixed disulfides. Thiol-disulfide exchange is biologically very important. For example, GSH can react with protein cystine groups and influence the correct folding of proteins, and it GSH may play a direct role in cellular signaling through thiol-disulfide exchange reactions with membrane bound receptor proteins (e.g., the insulin receptor complex), transcription factors (e.g., nuclear factor κB), and regulatory proteins in cells. Conditions that alter the redox status of the cell can have important consequences on cellular function.
    So the complexity of life is not yet unraveled.

    Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment?
    The goal is not just complete response. Histopathological response seems to be related post-treatment histopathological assessment but it is not free from the challenge of accurately determining treatment response, as this method cannot delineate whether or not there are residual cancer cells. Functional imaging to assess metabolic response by 18-fluorodeoxyglucose PET also has its limits, as the results are impacted significantly by several variables:

    • tumor type
    • sizing
    • doubling time
    • anaplasia?
    • extent of tumor necrosis
    • type of antitumor therapy and the time when response was determined.
    The new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ characteristics, a greater challenge in an era of ‘minimally invasive treatment’.
    This listing suggests that for every cancer the following data has to be collected (except doubling time). If there are five variables, the classification based on these alone would calculate to be very sizable based on Eugene Rypka’s feature extraction and classification. But looking forward, time to remission and disease free survival are additionally important. Treatment for cure is not the endpoint, but the best that can be done is to extend the time of survival to a realistic long term goal and retain a quality of life.

    Brücher BLDM, Piso P, Verwaal V et al. Peritoneal carcinomatosis: overview and basics. Cancer Invest.30(3),209–224 (2012).
    Brücher BLDM, Swisher S, Königsrainer A et al. Response to preoperative therapy in upper gastrointestinal cancers. Ann. Surg. Oncol.16(4),878–886 (2009).
    Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer47(1),207–214 (1981).
    Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst.92(3),205–216 (2000).
    Brücher BLDM, Becker K, Lordick F et al. The clinical impact of histopathological response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer106(10),2119–2127 (2006).

    • Dr. Larry,

      Thank you for this comment.

      Please carry it as a stand alone post, Dr. Ritu will refer to it and reference it in her FORTHCOMING pst on Tumor Response which will integrate multiple sources.

      Please execute my instruction

      Thank you

    • Thank you Larry for this educating comment. It explains very well why the Canadian investigators did not try to measure therapy response!

      What they have demonstrated is the technological feasibility of coupling a treatment device to an imaging device and use that in order to guide the treatment to the right place.

      the issue of “choice of treatment” to which you are referring is not in the scope of this publication.
      The point is: if one treatment modality can be guided, other can as well! This should encourage others, to try and develop imaging-based treatment guidance systems.

  7. The crux of the matter in terms of capability is that the cancer tissue, adjacent tissue, and the fibrous matrix are all in transition to the cancerous state. It is taught to resect leaving “free margin”, which is better aesthetically, and has had success in breast surgery. The dilemma is that the patient may return, but how soon?

    • Correct. The philosophy behind lumpectomy is preserving quality of life. It was Prof. Veronesi (IEO) who introduced this method 30 years ago noticing that in the majority of cases, the patient will die from something else before presenting recurrence of breast cancer..

      It is well established that when the resection margins are declared by a pathologist (as good as he/she could be) as “free of cancer”, the probability of recurrence is much lower than otherwise.

  8. Dr. Larry,

    To assist Dr. Ritu, PLEASE carry ALL your comments above into a stand alone post and ADD to it your comment on my post on MIS

    Thank you

  9. Great post! Dr. Nir, can the ultrasound be used in conjunction with PET scanning as well to determine a spatial and functional map of the tumor. With a disease like serous ovarian cancer we typically see an intraperitoneal carcimatosis and it appears that clinicians are wanting to use fluorogenic probes and fiberoptics to visualize the numerous nodules located within the cavity Also is the technique being used mainy for surgery or image guided radiotherapy or can you use this for detecting response to various chemotherapeutics including immunotherapy.

    • Ultrasound can and is actually used in conjunction with PET scanning in many cases. The choice of using ultrasound is always left to the practitioner! Being a non-invasive, low cost procedure makes the use of ultrasound a non-issue. The down-side is that because it is so easy to access and operate, nobody bothers to develop rigorous guidelines about using it and the benefits remains the property of individuals.

      In regards to the possibility of screening for ovarian cancer and characterising pelvic masses using ultrasound I can refer you to scientific work in which I was involved:

      1. VAES (E.), MANCHANDA (R), AUTIER, NIR (R), NIR (D.), BLEIBERG (H.), ROBERT (A.), MENON (U.). Differential diagnosis of adnexal masses: Sequential use of the Risk of Malignancy Index and a novel computer aided diagnostic tool. Published in Ultrasound in Obstetrics & Gynecology. Issue 1 (January). Vol. 39. Page(s): 91-98.

      2. VAES (E.), MANCHANDA (R), NIR (R), NIR (D.), BLEIBERG (H.), AUTIER (P.), MENON (U.), ROBERT (A.). Mathematical models to discriminate between benign and malignant adnexal masses: potential diagnostic improvement using Ovarian HistoScanning. Published in International Journal of Gynecologic Cancer (IJGC). Issue 1. Vol. 21. Page(s): 35-43.

      3. LUCIDARME (0.), AKAKPO (J.-P.), GRANBERG (S.), SIDERI (M.), LEVAVI (H.), SCHNEIDER (A.), AUTIER (P.), NIR (D.), BLEIBERG (H.). A new computer aided diagnostic tool for non-invasive characterisation of malignant ovarian masses: Results of a multicentre validation study. Published in European Radiology. Issue 8. Vol. 20. Page(s): 1822-1830.

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  10. totally true and i am very thankfull for these briliant comments.

    Remember: 10years ago: every cancer researcher stated: “look at the tumor cells only – forget the stroma”. The era of laser-captured tumor-cell dissection started. Now , everyone knows: it is a system we are looking at and viewing and analyzing tumor cells only is really not enough.

    So if we would be honest, we would have to declare, that all data, which had been produced 13-8years ago, dealing with laser capture microdissection, that al these data would need a re-scrutinization, cause the influence of the stroma was “forgotten”. I ‘d better not try thinking about the waisted millions of dollars.

    If we keep on being honest: the surgeon looks at the “free margin” in a kind of reductionable model, the pathologist is more the control instance. I personally see the pathologist as “the control instance” of surgical quality. Therefore, not the wish of the surgeon is important, the objective way of looking into problems or challenges. Can a pathologist always state, if a R0-resection had been performed ?

    The use of the Resectability Classification:
    There had been many many surrogate marker analysis – nothing new. BUT never a real substantial well tought through structured analysis had been done: mm by mm by mm by mm and afterwards analyzing that by a ROC analysis. BUt against which goldstandard ? If you perform statistically a ROC analysis – you need a golstandard to compare to. Therefore what is the real R0-resectiòn? It had been not proven. It just had been stated in this or that tumor entity that this or that margin with this margin free mm distance or that mm distance is enough and it had been declared as “the real R0-classification”. In some organs it is very very difficult and we all (surgeons, pathologists, clinicians) that we always get to the limit, if we try interpretating the R-classification within the 3rd dimension. Often it is just declared and stated.

    Otherwise: if lymph nodes are negative it does not mean, lymph nodes are really negative, cause up to 38% for example in upper GI cancers have histological negative lymph nodes, but immunohistochemical positive lymph nodes. And this had been also shown by Stojadinovic at el analyzing the ultrastaging in colorectal cancer. So the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology.

    AS we see: cancer has multifactorial reasons and it is necessary taking the challenge performing high sophisticated research by a multifactorial and multidisciplinary manner.

    Again my deep and heartly thanks for that productive and excellent discussion !

    • Dr. BB,

      Thank you for your comment.

      Multidisciplinary perspectives have illuminated the discussion on the pages of this Journal.

      Eager to review Dr. Ritu’s forthcoming paper – the topic has a life of its own and is embodied in your statement:

      “the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology.”

    • Thank you BB for your comment. You have touched the core limitation of healthcare professionals: how do we know that we know!

      Do we have a reference to each of the test we perform?

      Do we have objective and standardise quality measures?

      Do we see what is out-there or are we imagining?

      The good news: Everyday we can “think” that we learned something new. We should be happy with that, even if it is means that we learned that yesterday’s truth is not true any-more and even if we are likely to be wrong again…:)

      But still, in the last decades, lots of progress was made….

  11. Dr. Nir,
    I thoroughly enjoyed reading your post as well as the comments that your post has attracted. There were different points of view and each one has been supported with relevant examples in the literature. Here are my two cents on the discussion:
    The paper that you have discussed had the objective of finding out whether real-time MRI guidance of treatment was even possible and if yes, and also if the treatment could be performed in accurate location of the ROI? The data reveals they were pretty successful in accomplishing their objective and of course that gives hope to the imaging-based targeted therapies.
    Whether the ROI is defined properly and if it accounts for the real tumor cure, is a different question. Role of pathologists and the histological analysis they bring about to the table cannot be ruled out, and the absence of a defined line between the tumor and the stromal region in the vicinity is well documented. However, that cannot rule out the value and scope of imaging-based detection and targeted therapy. After all, it is seminal in guiding minimally invasive surgery. As another arm of personalized medicine-based cure for cancer, molecular biologists at MD Anderson have suggested molecular and genetic profiling of the tumor to determine genetic aberrations on the basis of which matched-therapy could be recommended to patients. When phase I trial was conducted, the results were obtained were encouraging and the survival rate was better in matched-therapy patients compared to unmatched patients. Therefore, everytime there is more to consider when treating a cancer patient and who knows a combination of views of oncologists, pathologists, molecular biologists, geneticists, surgeons would device improvised protocols for diagnosis and treatment. It is always going to be complicated and generalizations would never give an answer. Smart interpretations of therapies – imaging-based or others would always be required!

    Ritu

    • Dr. Nir,
      One of your earlier comments, mentioned the non invasiveness of ultrasound, thus, it’s prevalence in use for diagnosis.

      This may be true for other or all areas with the exception of Mammography screening. In this field, an ultrasound is performed only if a suspected area of calcification or a lump has been detected in the routine or patient-initiated request for ad hoc mammography secondery to patient complain of pain or patient report of suspected lump.

      Ultrasound in this field repserents ascalation and two radiologists review.

      It in routine use for Breast biopsy.

    • Thanks Ritu for this supporting comment. The worst enemy of finding solutions is doing nothing while using the excuse of looking for the “ultimate solution” . Personally, I believe in combining methods and improving clinical assessment based on information fusion. Being able to predict, and then timely track the response to treatment is a major issue that affects survival and costs!

Judging the ‘Tumor response’-there is more food for thought

http://pharmaceuticalintelligence.com/2012/12/04/judging-the-tumor-response-there-is-more-food-for-thought/

13 Responses

  1. Dr. Sanexa
    you have brought up an interesting and very clinically relevant point: what is the best measurement of response and 2) how perspectives among oncologists and other professionals differ on this issues given their expertise in their respective subspecialties (immunologist versus oncologist. The advent of functional measurements of tumors (PET etc.) seems extremely important in the therapeutic use AND in the development of these types of compounds since usually a response presents (in cases of solid tumors) as either a lack of growth of the tumor or tumor shrinkage. Did the authors include an in-depth discussion of the rapidity of onset of resistance with these types of compounds?
    Thanks for the posting.

  2. Dr. Williams,
    Thanks for your comment on the post. The editorial brings to attention a view that although PET and other imaging methods provide vital information on tumor growth, shrinkage in response to a therapy, however, there are more aspects to consider including genetic and molecular characteristics of tumor.
    It was an editorial review and the authors did not include any in-depth discussion on the rapidity of onset of resistance with these types of compounds as the focus was primarily on interpreting tumor response.
    I am glad you found the contents of the write-up informative.
    Thanks again!
    Ritu

  3. Thank you for your wonderful comment and interpretation. Dr.Sanexa made a brilliant comment.

    May I allow myself putting my finger deeper into this wound ? Cancer patients deserve it.

    It had been already pointed out by international experts from Munich, Tokyo, Hong-Kong and Houston, dealing with upper GI cancer, that the actual response criteria are not appropriate and moreover: the clinical response criteria in use seem rather to function as an alibi, than helping to differentiate and / or discriminate tumor biology (Ann Surg Oncol 2009):

    http://www.ncbi.nlm.nih.gov/pubmed/19194759

    The response data in a phase-II-trial (one tumor entity, one histology, one treatment, one group) revealed: clinical response evaluation according to the WHO-criteria is not appropriate to determine response:

    http://www.ncbi.nlm.nih.gov/pubmed/15498642

    Of course, there was a time, when it seemed to be useful and this also has to be respected.

    There is another challenge: using statistically a ROC and resulting in thresholds. This was, is and always be “a clinical decision only” and not the decision of the statistician. The clinician tells the statistician, what decision, he wants to make – the responsibility is enormous. Getting back to the roots:
    After the main results of the Munich-group had been published 2001 (Ann Surg) and 2004 (J Clin Oncol):

    http://www.ncbi.nlm.nih.gov/pubmed/11224616

    http://www.ncbi.nlm.nih.gov/pubmed/14990646

    the first reaction in the community was: to difficult, can’t be, not re-evaluated, etc.. However, all evaluated cut-offs / thresholds had been later proven to be the real and best ones by the MD Anderson Cancer Center in Houston, Texas. Jaffer Ajani – a great and critical oncologist – pushed that together with Steve Swisher and they found the same results. Than the upper GI stakeholders went an uncommon way in science: they re-scrutinized their findings. Meanwhile the Goldstandard using histopathology as the basis-criterion had been published in Cancer 2006.

    http://www.ncbi.nlm.nih.gov/pubmed/16607651

    Not every author, who was at the authorlist in 2001 and 2004 wanted to be a part of this analysis and publication ! Why ? Everyone should judge that by himself.

    The data of this analysis had been submitted to the New England Journal of Medicine. In the 2nd review stage process, the manuscript was rejected. The Ann Surg Oncol accepted the publication: the re-scrutinized data resulted in another interesting finding: in the future maybe “one PET-scan” might be appropriate predicting the patient’s response.

    Where are we now ?

    The level of evidence using the response criteria is very low: Miller’s (Cancer 1981) publication belonged to ”one single” experiment from Moertel (Cancer 1976). During that time, there was no definition of “experiences” rather than “oncologists”. These terms had not been in use during that time.

    Additionally they resulted in a (scientifically weak) change of the classification, published by Therasse (J Natl Cancer Inst 2000). Targeted therapy did not result in a change so far. In 2009, the international upper GI experts sent their publication of the Ann Surg Oncol 2009 to the WHO but without any kind of reaction.

    Using molecular biological predictive markers within the last 10years all seem to have potential.

    http://www.ncbi.nlm.nih.gov/pubmed/20012971

    http://www.ncbi.nlm.nih.gov/pubmed/18704459

    http://www.ncbi.nlm.nih.gov/pubmed/17940507

    http://www.ncbi.nlm.nih.gov/pubmed/17354029

    But, experts are aware: the real step breaking barriers had not been performed so far. Additionally, it is very important in trying to evaluate and / predict response, that not different tumor entities with different survival and tumor biology are mixed together. Those data are from my perspective not helpful, but maybe that is my own Bias (!) of my view.

    INCORE, the International Consortium of Research Excellence of the Theodor-Billroth-Academy, was invited publishing the Editorial in Future Oncology 2012. The consortium pointed out, that living within an area of ‘prove of principle’ and also trying to work out level of evidence in medicine, it is “the duty and responsibility” of every clinician, but also of the societies and institutions, also of the WHO.

    Complete remission is not the only goal, as experts dealing with ‘response-research’ are aware. It is so frustrating for patients and clinicians: there is a rate of those patients with complete remission, who develop early recurrence ! This reflects, that complete remission cannot function as the only criterion describing response !

    Again, my heartly thanks, that Dr.Sanexa discussed this issue in detail.
    I hope, I found the way explaining the way of development and evaluating response criteria properly and in a differentiated way of view. From the perspective of INCORE:

    “an interdisciplinary initiative with all key stake¬holders and disciplines represented is imperative to make predictive and prognostic individualized tumor response assessment a modern-day reality. The integrated multidisciplinary panel of international experts need to define how to leverage existing data, tissue and testing platforms in order to predict individual patient treatment response and prognosis.”

  4. Dr. Brucher,

    First of all thanks for expressing your views on the ‘tumor response’ in a comprehensive way. You are the first author of the editorial review one of the prominent people who has taken part in the process of defining tumor response and I am glad that you decided to write a comment on the writeup.
    The topic has been explained well in an immaculate manner and that it further clarifies the need for the perfect markers that would be able to evaluate and predict tumor response. There are, as you mentioned, some molecular markers available including VEGF, cyclins, that have been brought to focus in the context of squamous cell carcinoma.

    It would be great if you could be the guest author for our blog and we could publish your opinion (comment on this blog post) as a separate post. Please let us know if it is OK with you.

    Thanks again for your comment
    Ritu

  5. Thank you all to the compelling discussions, above.

    Please review the two sources on the topic I placed at the bottom of the post, above as post on this Scientific Journal,

    All comments made to both entries are part of thisvdiscussion, I am referring to Dr. Nir’s post on size of tumor, to BB comment to Nir’s post, to Larry’ Pathologist view on Tumors and my post on remission and minimally invasive surgery (MIS).

    Great comments by Dr. Williams, BB and wonderful topic exposition by Dr. Ritu.

  6. Aviva,
    Thats a great idea. I will combine all sources referred by you, the post on tumor imaging by Dr. Nir and the comments made on the these posts including Dr. Brucher’s comments in a new posts.
    Thanks
    Ritu

    • Great idea, ask Larry, he has written two very long important comments on this topic, one on Nir’s post and another one, ask him where, if it is not on MIS post. GREAT work, Ritu, integration is very important. Dr, Williams is one of our Gems.

    • Assessing tumour response it is not an easy task!Because tumours don’t change,but happilly our knowlege(about them) does really change,is everchanging(thans god!).In the past we had the Recist Criteria,then the Modified Recist Criteria,becausa of Gist and other tumors.At this very moment,these are clearly insuficient.We do need more ,new validated facing the reality of nowadays.A great,enormoust post Dr Ritu!Congratulations!

 

 

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN

http://www.elsevierbi.com/mkt/conf/fda-cms/2012?elsca1=fda&elsca2=fdafierce112612&utm_source=fda&utm_medium=fda&utm_campaign=%20fierce112612

The FDA/CMS Summit For Biopharma Executives
2013: Year One For PDUFA V – And The Last Chance To Prepare For Health Reform

The Affordable Care Act is a go, after surviving Supreme Court review mostly intact—and especially after the re-election of Barack Obama as President. For the biopharma industry, that means preparing to reap the benefits of insurance market expansion that industry has already paid billions of dollars for in rebates, discounts and fees. The new markets start up in 2014. That means 2013 is the last chance to prepare.

But 2013 is also the first full year to adjust to the new rules for new drug reviews at FDA and adjust to important changes ushered in by the FDA Safety & Innovation Act of 2012. And it is also the year when deficit reduction will be tops on Congress’ agenda.

What will all this mean for you and your company? Come to The Pink Sheet and The RPM Report’s FDA/CMS Summit for Biopharma Executives on December 10-11 in Washington DC to hear from FDA and industry leaders about how health reform implementation will (and won’t) change the rules of the road for drug development and commercialization.

Our jam-packed two-day agenda will also tackle urgent topics like:

        • Drug reviews and PDUFA
        • The evolving biosimilars pathway in the US
        • The implementation of the FDA Safety & Innovation Act
        • The changing rules of pharmaceutical marketing
        • Creation of new generic drug and biosimilar user fee programs
        • And much, much more!

Don’t be caught unprepared. Join us at the eighth annual FDA/CMS Summit for Biopharma Executives.

Last year was standing room only and spaces are limited so please register now!

Key Benefits for Attending FDA/CMS Summit:

  • Hear about critical trends and changes so you can create successful strategies for dealing with FDA and CMS
  • Walk away with practical, real life lessons from some of the most experienced pharmaceutical and biotechnology executives on how they handle regulatory obstacles
  • Get face-to-face access to the top regulatory thought leaders and policy makers
  • Benchmark your regulatory strategy against all the major pharmaceutical and biotech companies

 

Here is what your peers have to say about FDA/CMS Summit:

“I would like to thank the whole Windhover/RPM team for putting together this conference. Conferences are made by its participants and the group assembled here today is so diverse and truly experienced.” – Mark McClellan, MD/PhD, Former FDA Commissioner and CMS Administrator

 

 

2012 FDA/CMS Summit Preliminary Agenda

December 10 & 11, 2012

Mayflower Hotel
1127 Connecticut Avenue NW
Washington, DC 20036

 

Monday, December 10, 2012
7:00-8:00am Registration and Continental Breakfast
8:00am Welcome and Opening Remarks

Michael McCaughan
Editor, The RPM Report
Founding Member, Prevision Policy LLC

8:15-9:00am  

KEYNOTE ADDRESS: Priorities for FDA’s Drug Center in 2012

Douglas Throckmorton, MD
Deputy Director
Center for Drug Evaluation & Research
Food & Drug Administration (FDA)

9:00-10:30am  

The New Rules of New Drug Reviews: A Roundtable

FDA’s top new drug and drug safety officials join industry leaders to discuss trends in the new drug review process and the changes enacted by the Prescription Drug User Fee Act reauthorization.

John Jenkins, MD
Director
Office of New Drugs
Food & Drug Administration (FDA)

Gerald Dal Pan, MD
Director
Office of Surveillance & Epidemiology
Food & Drug Administration (FDA)

Richard Pops
CEO
Alkermes

Francois Nader, MD
President and CEO
NPS Pharmaceuticals

Kay Holcombe
Senior Policy Advisor
Genzyme

Moderator: 
Kate Rawson
The RPM Report
Prevision Policy

10:30-11:00am  

Networking Break

11:00-12:00pm 2012 Elections: Implications for Pharma

What to expect from the new Administration and the new Congressional line-up for 2013.

John McManus
President
The McManus Group

Tracy Spicer
Partner
Avenue Solutions

Jeff Forbes
Partner
Forbes-Tate

Presenter/Moderator:

Marc Samuels
Founding Member & President
Hillco Health

12:00-1:00 pm  

Lunch

 

1:15-2:00pm

 

 

Fireside Chat

Jonathan Blum
Principal Deputy Administrator
Centers for Medicare & Medicaid Services (CMS)

 

2:00pm-3:30 pm

 

 

Hot Topics in Health Reform

The politics of health care reform aside, biopharma companies need to prepare for changes in the US health care system that emphasis quality and affordability of care. This session will feature presentations on different aspects of the upcoming changes in payment and delivery of care and how they will affect pharma.

 

Health Reform and The Climate for Innovation

Ron Cohen, MD
President and CEO
Acorda Therapeutics, Inc.What is Essential in Essential Health Benefits?

Ian Spatz 
Senior Advisor
Manatt Health Solutions

Medication Adherence in the Context of Health Reform

William Shrank, MD, MSHS 
Director
Rapid-Cycle Evaluation Group
Centers for Medicare & Medicaid Services (CMS)

 

Commercial Implications of Health Reform

Will Suvari
Vice President
Campbell Alliance

Moderator:
Michael McCaughan
Editor, The RPM Report
Founding Member, Prevision Policy LLC

 

3:30-4:00pm  

Networking Break

4:00-4:30pm  

Keynote: Implementing Reform
Joshua Sharfstein
Secretary
Maryland Department of Health
Former Deputy Commissioner
Food & Drug Administration (FDA)

4:30-5:00pm Closing Keynote: Reimbursable Labeling

Chuck Stevens
Vice President
PAREXEL

5:30-7:30pm Cocktail Reception
Tuesday, December 11, 2012
7:00-8:00am Registration and Continental Breakfast
8:00-8:30am  

 

KEYNOTE ADDRESS

Robert J. Hugin
Chairman and CEO
Celgene Corporation

8:30-9:45am  

Biosimilars Update

Mark A. McCamish, MD, PhD
Global Head of Biopharmaceutical Development
Sandoz International

Diem Nguyen
General Manager, Biosimilars
Emerging Markets/Established Products Business Unit
Pfizer Inc.

Leah Christl, PhD
Associate Director for Biosimilars
Office of New Drugs
Center for Drug Evaluation & Research
Food & Drug Administration (FDA)

9:45-10:00am Networking Break
10:00-11:15am  

Reinventing the Approval Pathway

PDUFA V makes important changes in drug regulation, but it doesn’t fundamentally change the standard for new drug approvals. Is it time for the US to consider moving to new models like progressive approval/adaptive licensing?

 

Mary Ellen Cosenza
Executive Director Regulatory Affairs and North America Regulatory Head
Amgen, Inc.

Steven Nissen, MD, MACC
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation

 

Barry Sickels, Ph.D.
Vice President, Regulatory Affairs and Wilmington R&D Site Leader
AstraZeneca

Moderator:
Cole Werble
Editor, The RPM Report
Founding Member, Prevision Policy LLC

 

11:15-12:00pm  

A Regulator’s Perspective

Robert Temple, MD
Deputy Director for Clinical Science
Center for Drug Evaluation & Research
Food & Drug Administration (FDA)

Moderator
Ramsey Baghdadi
The RPM Report
Founding Member, Prevision Policy

12:00-1:00pm Lunch – Sponsored by
1:00-1:45pm  

CMS Coverage Priorities: CED, NCDs and Parallel Reviews

The Medicare agency is moving forward with innovative models to use coverage policy to encourage development of better evidence for new technologies. Devices are the primary focus, but drugs won’t be far behind.

Louis Jacques, MD
Director
Coverage & Analysis Group Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services (CMS)

Tamara Syrek Jensen, JD 
Deputy Director
Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services (CMS)

Moderator
Ramsey Baghdadi
The RPM Report
Founding Member, Prevision Policy

1:45-3:00pm Right-Sizing the Demands for Evidence

FDA’s pre-market and post-market regulatory demands are increasing, and so are the expectations of public and private payors for “real world” comparative effectiveness data. How can policy makers and biopharmaceutical companies work together to assure that the need for evidence doesn’t overwhelm the capacity of innovators?

Jonathan Leff
Managing Director, Healthcare
Warburg Pincus

Martin Marciniak
Vice-President, US Health Outcomes
GlaxoSmithKline

Moderator:
Gillian Woollett

Vice President
Avalere Health

3:00-3:15pm Networking Break
3:15-4:30pm The New Generic Drug Era

The Generic Drug User Fee Act will usher in a new era for the generic drug industry, one with greater emphasis on global production quality and tough-to-copy products. What will the new era bring?

Gregory Geba
Director
Office of Generic Drugs
Food & Drug Administration (FDA) 

David Gaugh
VP-Regulatory Sciences
Generic Pharmaceutical Association

Gary Buehler
Vice President-Regulatory Strategic Operations
Teva Pharmaceuticals

Lara Ramsburg
VP-Government Relations
Mylan Inc.

Moderator:
Nancy Myers
President
Catalyst Healthcare

4:30-5:00pm A Fireside chat with:

Geno Germano
President
Pfizer Specialty Care and Oncology

2012 FDA/CMS Speakers

   
  Douglas Throckmorton, MD

Deputy Director, FDA Center for Drug Evaluation & Research

Food & Drug Administration (FDA)

Douglas C. Throckmorton, MD is the Deputy Director of the Center for Drug Evaluation and Research (CDER), FDA. In this role, he shares responsibility for overseeing the regulation of research, development, manufacture and marketing of prescription, over-the-counter and generic drugs in the U.S. Previously, he served as the Director of CDER’s Division of Cardiovascular and Renal Drug Products (DCRDP). Dr. Throckmorton joined DCRDP in 1997 as a Medical Officer, was promoted to Deputy Director in 2000 and to the Director position in 2002. Prior to joining FDA, he practiced medicine and held academic appointments at the Medical College of Georgia and the VA Medical Center in Augusta, GA. Dr. Throckmorton received an undergraduate degree in English and Chemistry from Hastings College and is Board-certified in Internal Medicine and Nephrology, having received his training at the University of Nebraska Medical School, Case Western Reserve University and Yale University.

   
  Robert J. Hugin

Chairman and CEO

Celgene Corporation

Mr. Hugin serves as Chairman and Chief Executive Officer of Celgene Corporation, a biopharmaceutical company focused on the discovery, development and commercialization of innovative therapies for unmet medical needs in cancer and immune-inflammatory disease. He joined Celgene in June 1999 and has been a Director of Celgene since December 2001. Mr. Hugin also serves as a Director of The Medicines Company, Atlantic Health System, Inc. and of Family Promise, a national non-profit network assisting homeless families. He serves on the Board of Trustees of Princeton University and is Chairman-Elect of The Pharmaceutical Research and Manufacturers of America. He also serves on the Board of Trustees of The Darden Foundation, University of Virginia as well as a founding Board member of Choose NJ. Prior to joining Celgene, Mr. Hugin was a Managing Director with J.P. Morgan & Co. Inc. Mr. Hugin received an AB degree from Princeton University in 1976 and an MBA from the University of Virginia in 1985 and served as a United States Marine Corps infantry officer during the intervening period. Bob and his wife Kathy have three children and live in Summit, New Jersey.

   
  John Jenkins, MD

Director, Office of New Drugs

Food and Drug Administration (FDA)

Dr. Jenkins is currently the Director of the Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration.  Dr. Jenkins received his undergraduate degree in biology from East Tennessee State University in 1979 and his medical degree from the University of Tennessee at Memphis in 1983.  Dr. Jenkins completed his postgraduate medical training in internal medicine, pulmonary disease, and critical care medicine at Virginia Commonwealth University/Medical College of Virginia from 1983 until 1988.  Dr. Jenkins is Board Certified in Internal Medicine and Pulmonary Diseases by the American Board of Internal Medicine.  Dr. Jenkins is also a Fellow of the American College of Chest Physicians.  Following completion of his medical training, Dr. Jenkins joined the faculty of MCV as an Assistant Professor of Pulmonary and Critical Care Medicine and as a Staff Physician at the McGuire VA Medical Center in Richmond.  Dr. Jenkins joined FDA as a medical officer in the Division of Oncology and Pulmonary Drug Products in 1992.  He subsequently served as Pulmonary Medical Group Leader and Acting Division Director before being appointed as Director of the newly created Division of Pulmonary Drug Products in 1995.  Dr. Jenkins became the Director of the Office of Drug Evaluation II in 1999 and served in that position until he was appointed to his current position in January 2002.

   
  John McManus

President

The McManus Group

John McManus is President and founder of The McManus Group, a consulting firm specializing in policy and political counsel for health care clients with issues before Congress and the Administration. The McManus Group services clients from the pharmaceutical, biotechnology and medical device industries, the physician organization and employee benefits managers.

Prior to founding The McManus Group in 2004, McManus served Chairman Bill Thomas as the Staff Director of the Ways and Means Health Subcommittee, where he led the policy development, negotiations and drafting of the Medicare Prescription Drug, Improvement and Modernization Act of 2003. The MMA provided a market-based, comprehensive prescription drug benefit, reformed Medicare and established Health Savings Accounts. McManus worked for Chairman Thomas for six years, where he also played an instrumental role in the Medicare Commission, Patients’ Bill of Rights and other Medicare legislation.

Before working for Chairman Thomas on Capitol Hill, McManus worked for Eli Lilly & Company as a Senior Associate from 1994-97 and for the Maryland House of Delegates from 1993-94 as a Research Analyst, briefing the Chairman of the Economic Matters Committee and the members of the Health Subcommittee.

McManus earned his Master of Public Policy from Duke University and Bachelor of Arts from Washington and Lee University.

   
  Tracy Spicer

Partner

Avenue Solutions

Avenue Solutions’ founding partner Tracy Spicer is a 20-year veteran of political campaigns at every level.  Ms. Spicer began her involvement in politics in 1992 in former U.S. Senator Edward M. Kennedy’s Senate office before transitioning to his campaign staff in 1994 to assist in his successful re-election campaign against Mitt Romney.  Since that time, she has worked with and coordinated numerous campaigns, ranging from municipal and state candidates to the U.S. Congress as well as the White House.

Ms. Spicer served as a longtime aide to former Senator Kennedy, quickly rising to Political Director and Deputy Chief of Staff.  During her decade of experience on Capitol Hill, she coordinated successful political and legislative strategies for Senator Kennedy.  Ms. Spicer managed Senator Kennedy’s legislative priorities in the areas of healthcare, education, labor and economic development and strategically worked with Democratic Senators and their political campaign committees to position legislative priorities for political success.

Ms. Spicer is widely recognized for her political acumen and expertise in designing legislative and regulatory strategies and her established network of long-standing professional contacts among elected officials, appointed policymakers and their staffs.  She draws on her vast political and legislative experience to help clients in navigate the labyrinth of Capitol Hill and government bureaucracy and to position them strategically to head off obstacles, find common ground and achieve success.

As founding partner of Avenue Solutions, Ms. Spicer advises a broad array of clients, including Fortune 100 companies, non-profit organizations, associations and coalitions.  She is particularly noted for her expertise in healthcare policy.  On behalf of her clients, Ms. Spicer has played a leading role in the consideration, negotiation and implementation of the Affordable Care Act (healthcare reform); Medicare and Medicaid legislation; healthcare information technology initiatives; mental health parity legislation; genetic non-discrimination legislation; small business incentive proposals; and prescription drug coverage legislation.

Ms. Spicer is a graduate of Hobart and William Smith Colleges in Geneva, NY where she earned her bachelor’s degree in Political Science.  She is married to George Spicer and has three children, Dylan, Tess and Callie and a loveable, albeit irreverent dog, Linus.

   
  Jeff Forbes

Partner

Forbes-Tate

Founding partner Jeff Forbes is a twenty-year veteran of political campaigns at every level.  Mr. Forbes began his involvement in politics in 1987 on then Senator Al Gore’s 1988 Presidential bid.  Since that time, he has worked with and coordinated more than nine different campaigns, ranging from municipal candidates to the US Congress as well as the White House.

Mr. Forbes served most recently as the Democratic Staff Director for the US Senate Committee on Finance in 2003.  Before assuming this role at the Committee, he served as chief of staff to Senator Max Baucus from 1999-2002.  Beyond his knowledge of the intricacies of tax and trade, Forbes is a veteran strategist for the Democratic National Committee.  From 1993-1995 he served as Midwest Political Director.  Mr. Forbes later served the national committee as Chief of Strategy in 1999.

A stalwart of Clinton-Gore Administration, Mr. Forbes was the New Hampshire Field Director for then Gov. Clinton’s 1992 Presidential campaign.  In President Clinton’s 1996 re-election bid, Forbes was Deputy Political Director and Director of Delegate Selection.  Following the campaign, Mr. Forbes went on to serve as a Special Assistant to the President and Staff Director for Legislative Affairs in 1997.  From 1998-99, Mr. Forbes served as the Deputy Assistant to President Clinton and was the Deputy Director of Scheduling at the White House.

Mr. Forbes is married to Linda Moore Forbes.  He earned a BA in Political Science with an Economics minor from Denison University in Granville, Ohio, in 1987.

   
  Gerald Dal Pan, MD

Director, Office of Surveillance & Epidemiology

Food and Drug Administration (FDA)

Gerald J. Dal Pan, MD, MHS is the Director of the Office of Surveillance and Epidemiology (formerly known as the Office of Drug Safety) in FDA’s Center for Drug Evaluation and Research, a position he has held since November 2005. From December 2003 through November 0225, he was the Director of the Division of Surveillance, Research, and Communication Support in CDER’s Office of Drug Safety. He received his medical degree from Columbia University, and his Master’s degree in clinical epidemiology from Johns Hopkins University. He trained in Internal Medicine at the Hospital of the University of Pennsylvania, and in Neurology at Johns Hopkins Hospital. He is board certified in Internal Medicine and Neurology. He was an instructor in the Neurology Department at Johns Hopkins. He next worked for Guilford Pharmaceuticals in Baltimore, and then for HHI Clinical Research and Statistical Services in Hunt Valley, MD. He joined the FDA in July 2000 as a medical officer in the Division of Anesthetic, Critical Care, and Addiction Drug Products.

   
  Louis Jacques, MD

Director, Coverage & Analysis Group Office of Clinical Standards and Quality

Centers for Medicare & Medicaid Services (CMS)

Dr Jacques joined CMS in 2003 and has been director of the Coverage and Analysis Group (CAG) since October 2009.  The group reviews evidence and develops Medicare national coverage policy. From 2004 through 2009 he was Director of the Division of Items and Devices within CAG.

Prior to his arrival at CMS, Dr. Jacques was the Associate Dean for Curriculum at Georgetown University School of Medicine, where he retains a faculty appointment.  He served on a number of university committees including the Executive Faculty, Committee on Admissions and the Institutional Review Board.  He previously worked in the Palliative Care program at Georgetown’s Lombardi Cancer Center where he covered the gynecologic oncology service and he made home visits as a volunteer physician for a rural hospice on the Maryland Eastern Shore.

   
  Steven Nissen
Chairman, Department of Cardiology
The Cleveland Clinic Foundation

Steven Nissen, MD, is the Chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine located on the main campus of Cleveland Clinic. He was appointed in 2006. Prior to this, he served nine years as Vice-Chairman of the Department of Cardiology and five years as Medical Director of the Cleveland Clinic Cardiovascular Coordinating Center (C5), an organization that directs multicenter clinical trials.

Dr. Nissen’s research during the last two decades has focused on the application of intravascular ultrasound (IVUS) imaging for the assessment of progression and regression of coronary atherosclerosis. He has served as International Principal Investigator for several large IVUS multi-center atherosclerosis trials.

Contributions to scientific literature include more than 350 journal articles and 60 book chapters including many manuscripts in NEJM andJAMA. In recent years, he has also written on the subject of drug safety and was the author of manuscripts highlighting concerns about the COX-2 inhibitors (Vioxx™), muraglitazar and rosiglitazone (Avandia™).

Other contributions include current service as editor of Current Cardiology Report, and senior consulting editor to the Journal of the American College of Cardiology.

Dr. Nissen’s national positions include:

One-year term as president of the American College of Cardiology (ACC) from March 2006 to March 2007. He served on the ACC Executive Committee 2004-2008. He served 10 years as a member of Board of Trustees of the ACC. He has served several terms on the Program Committee for ACC Annual Scientific Sessions.

Dr. Nissen served as a member of the CardioRenal Advisory Panel of Food and Drug Administration (FDA) for five years, and as chair of the final year of his membership. He continues to serve as a periodic advisor to several FDA committees as a Special Government Employee.

Dr. Nissen is a frequent lecturer before national and international meetings. He has served as visiting professor, or provided Grand Rounds, at nearly 100 institutions.

   
  Richard Pops 

CEO

Alkermes

Richard Pops serves as Chairman and Chief Executive Officer of Alkermes. He joined Alkermes as CEO in 1991. Under his leadership, Alkermes has grown from a privately held company with 25 employees to an international, publicly traded biopharmaceutical company with more than 1,200 employees and a portfolio of more than 20 commercial products. Mr. Pops currently serves on the Board of Directors of Neurocrine Biosciences, Acceleron Pharma, Epizyme, the Biotechnology Industry Organization (BIO), the Pharmaceutical Research and Manufacturers of America (PhRMA) and is also a member of the Harvard Medical School Board of Fellows.

   
  Francois Nader, MD

President and CEO

NPS Pharmaceuticals

Francois Nader, MD, has been president and chief executive officer of NPS Pharmaceuticals since March 2008. During his tenure he transformed NPS into a leading biopharmaceutical company focused on orphan treatments for patients with rare diseases.

Dr. Nader is a 25-year veteran of the healthcare industry. Dr. Nader joined NPS in 2006 as chief medical and commercial officer. He was promoted to chief operating officer in 2007 and named a director in January 2008. Previously, he was a venture partner at Care Capital, LLC and chief medical officer of its Clinical Development Capital unit. He was also senior vice president, integrated healthcare markets and North America medical and regulatory affairs with Aventis Pharmaceuticals, serving on the North America Leadership Team (NALT), and held senior executive positions at its predecessor companies, Hoechst Marion Roussel and Marion Merrell Dow. Prior, Dr. Nader served as head of global commercial operations at the Pasteur Vaccines division of Rhone-Poulenc.

Dr. Nader served as director for Noven Pharmaceuticals and currently serves as treasurer and trustee of Bio NJ, New Jersey’s trade association for the biotechnology community and as trustee of the Healthcare Institute of New Jersey (HINJ), a trade association for the research-based pharmaceutical and medical technology industry in New Jersey.

Dr. Nader received a French State Doctorate in Medicine from St. Joseph University (Lebanon) and a Physician Executive MBA from the University of Tennessee.

   
  Diem Nguyen
General Manager, Biosimilars

Emerging Markets/Established Products Business Unit

Pfizer Inc.

Diem Nguyen is General Manager, Biosimilars for the Emerging Markets/Established Products Business Units. As General Manager Biosimilars, Diem Nguyen is the driving a core component of the EPBU strategy through the development and commercialization of a portfolio of post-LOE biologics through close collaboration with WRD’s Biosimilars Development Unit. Prior to this position, Diem held the position of VP, Strategy for EPBU where she was responsible for developing growth strategies for the off patent market.

Before Pfizer, Diem was a consultant for Danaher, a leading industrial and life sciences company. In 2004, she was appointed Senior Director of Corporate Development and Biotechnology at Serologicals Corporation, where she worked directly with the CEO, CFO and the Board of Directors and led enterprise level strategic planning and external development efforts. Her responsibilities included strategic planning, leading corporate development efforts and investor relations. In 2003, she took on the role of Director of Strategic Marketing, Research and Biotechnology at the Upstate Group, Inc. Diem has also previously held positions at Deloitte Consulting as a life sciences consultant and the University of Virginia Health Sciences Center as a medical researcher.

Diem received a B.A. and a Ph.D. in Biochemistry and Molecular Genetics from the University of Virginia. She attended Darden Graduate School of Business Administration, where she earned her MBA.

   
  Jonathan Blum

Principal Deputy Administrator

Centers for Medicare & Medicaid Services (CMS)

Jonathan Blum, Acting Principal Deputy Administrator and Director of the Center for Medicare at the Centers for Medicare and Medicaid Services (CMS), is responsible for overseeing the regulation and payment of Medicare fee-for service providers, privately-administered Medicare health plans, and the Medicare prescription drug program.  The benefits pay for health care for approximately 45 million elderly and disabled Americans, with an annual budget in the hundreds of billions of dollars.

Over the course of his career, Jonathan has become an expert in the gamut of CMS programs.  He served as an advisor to Senate Finance Committee members and its current chairman, Sen. Max Baucus, where he worked on prescription drug and Medicare Advantage policies during the development of the Medicare Modernization Act.  He focused on Medicare as a program analyst at the White House Office of Management and Budget.  Prior to joining CMS, Jonathan was a Vice President at Avalere Health, overseeing its Medicaid and Long-Term Care Practice.

Most recently, Jonathan served as a health policy advisor to the Obama-Biden Transition Team.  He holds a Master’s degree from the Kennedy School of Government and a BA from the University of Pennsylvania.

   
  Ian Spatz
Senior Advisor

Manatt Health Solutions

Mr. Spatz is a Senior Advisor in the national healthcare practice of Manatt, Phelps & Phillips, LLP and Manatt Health Solutions.  Mr. Spatz provides highly experienced insights into ongoing health reform efforts, helps develop public and private strategies and guidance on a broad array of issues affecting healthcare providers and insurers, pharmaceutical companies, the consuming public and U.S. healthcare initiatives generally, as well as the development and implementation of communication and advocacy efforts at the federal and state levels. Among his areas of expertise are national healthcare policies and programs; pharmaceutical pricing, including Medicare and Medicaid; intellectual property protection; and policies related to the U.S. Food and Drug Administration’s regulation of the research, approval, manufacturing and marketing of medicines.

Mr. Spatz is also the founder and principal of the policy consulting firm Rock Creek Policy Group, LLP.  Beforefounding Rock Creek Policy Group, Mr. Spatz served for 15 years in increasingly responsible positions with Merck & Co., Inc., one of the world’s leading research-based pharmaceutical and vaccine companies.  As Merck’s Vice President for Global Health Policy, he directed U.S. public policy and related public affairs activities and represented the company before Congress, the Administration, and to the media.  He also directed grassroots, employee communications and political action programs.

While at Merck, Mr. Spatz led the successful five-year campaign that helped to develop and gain enactment of the Medicare prescription drug benefit, providing millions of American elderly and persons with disabilities with drug insurance for the first time.  He promoted legislation to create the highly successful program of market exclusivity incentives for research on the pediatric uses of medicines and guided company efforts that resulted in resolution of international trade dispute on the licensing of medicines in the developing world.

Before joining Merck, Mr. Spatz served as Legislative Director for U.S. Senator Frank Lautenberg (D-NJ).  In that role, he directed the Senator’s legislative staff including developing and supervising the implementation of legislative strategies, proposal drafting and floor action.  During his tenure, he coordinated the successful development and passage of two transportation appropriations bills.  He began his career in the nonprofit sector where he led the public policy and government affairs activities of the National Trust for Historic Preservation, the nation’s leading heritage conservation organization. While with the National Trust, he conceived the highly successful Eleven Most Endangered Historic Places list that has served as a model public relations tool for many conservation organizations.  He advocated successfully for the creation of the transportation enhancements funding in the Intermodal Surface Transportation Act (ISTEA) that has resulted in more than $8 billion in spending on conservation projects.

   
  Kate Rawson
The RPM Report
Prevision Policy LLC

Kate Rawson is a Senior Editor at The RPM Report. She was formerly an editor at “The Pink Sheet” where she covered drug regulation and reimbursement issues. During her ten-year tenure at FDC Reports and Elsevier Business Intelligence, she helped launch “The Pink Sheet DAILY,” and served as Managing Editor of “The Rose Sheet,” which covers regulatory and business news of the cosmetics industry.

   
  Michael McCaughan
Founding Member
Prevision Policy LLC

Michael McCaughan is a founding member of Prevision Policy LLC and an editor with The RPM Report. He was formerly editor-in-chief of EBI’s biopharma editorial group. McCaughan has 20 years of experience providing analysis and insight for EBI’s products, including The Pink Sheet, The Pink Sheet DAILY and The RPM Report. He speaks frequently on regulatory and policy developments affecting the industry.

   
  Ramsey Baghdadi
Founding Member
Prevision Policy LLC

Ramsey Baghdadi is a founding member of Prevision Policy and an editor with The RPM Report.

   
  Marc Samuels
CEO
HillCo HEALTH

Widely regarded as “effective,” “resourceful,” “tireless,” well prepared” and “irreplaceable,” by clients and colleagues alike Marc Samuels is CEO of HillCo HEALTH, a boutique group of seasoned principals providing advisory services to leading health care delivery, financing, manufacturing, and service entities.

Samuels joined HillCo in 2001 and became a partner in 2004, working both in Austin and Washington, DC. He co-founded HillCo HEALTH soon thereafter. From 1998 to 2000, Samuels served as founder of and a partner in the Health Policy Group, a Washington, D.C.-based healthcare public policy and business strategy firm, along with J. Michael Hudson, former Deputy (and Acting) Administrator of the Centers for Medicare and Medicaid Services (CMS). Prior to that, he held various positions within state and federal government, including advising both former President George Herbert Walker Bush and then-Texas Governor George W. Bush on healthcare issues, as well as serving as Executive Assistant to the Texas Health and Human Services Commission (HHSC).

Samuels is a graduate of The University of Texas School of Law, Yale School of Medicine and the University of Michigan. His comments and analyses have appeared in Medical Economics, Health Systems Review, Journal of Health Care Finance, Disease Management News, the Fort Worth Star-Telegram, the Dallas Morning News, and Texas Medicine. He is a contributor to the third edition of the Managed Care Answer Book and the second edition of the HMO and Capitation Answer Book, published by Panel Publishers, New York.

   
  Ron Cohen, MD
President and CEO
Acorda Therapeutics, Inc

Ron Cohen, M.D., President and CEO, founded Acorda Therapeutics, Inc. in 1995. Previously he was a principal in the startup and an officer of Advanced Tissue Sciences, Inc., a biotechnology company engaged in the growth of human organ tissues for transplantation. Dr. Cohen received his B.A. with honors in Psychology from Princeton University, and his M.D. from the Columbia College of Physicians & Surgeons. He completed his residency in Internal Medicine at the University of Virginia Medical Center, and is Board Certified in Internal Medicine.

Dr. Cohen is a member of the Executive Committee of the Board of the Biotechnology Industry Organization (BIO) and is Chairman of the Emerging Company Section of BIO. He previously served as Director and Chairman of the New York Biotechnology Association (NYBA). He also serves as a member the Columbia-Presbyterian Health Sciences Advisory Council and was awarded Columbia University’s Alumni Medal for Distinguished Service.

Dr. Cohen was named NeuroInvestment’s CEO of the Year and was recognized by PharmaVoice Magazine as one of the 100 Most Inspirational People in the Biopharmaceutical Industry. He is a recipient of the Ernst & Young Entrepreneur of the Year Award for the New York Metropolitan Region and is an inductee of the National Spinal Cord Injury Association’s “Spinal Cord Injury Hall of Fame.” In 2010, Dr. Cohen was recognized by the New York Biotechnology Association as the NYBA “The Cure Starts Here” Business Leader of the Year.

   
  Tamara Syrek Jensen, JD, 
Deputy Director Coverage and Analysis Group (CAG)
CMS

Tamara Syrek Jensen is the deputy director for the Coverage and Analysis Group (CAG) at the Centers for Medicare & Medicaid Services (CMS). CAG develops, interprets, communicates, and updates evidence based national coverage policies. These policies help provide timely access to reasonable and necessary services and technologies to improve health outcomes for Medicare beneficiaries.

Before her current position at CAG, she was the Special Assistant for the CMS Chief Medical Officer and Director of Office of Clinical Standards and Quality (OCSQ). Prior to working at CMS, she worked as a legislative assistant in the U.S. House of Representatives. Tamara is an attorney, licensed in Maryland.

   
  Mark A. McCamish, MD, PhD
Global Head of Biopharmaceutical Development
Sandoz International

Dr. McCamish is the Global Head of Biopharmaceutical Development for Sandoz International, a Division of Novartis. He leads research and development of all biologics at Sandoz Biopharmaceuticals, which is the world leader in development and commercialization of follow-on biologics or biosimilars. His responsibilities include leadership involving selection of the target, cloning, technical development, scale-up, pre-clinical and clinical development and interfaces with regulatory authorities worldwide. He is a senior executive with extensive therapeutic and commercial experience in global pharmaceutical and biotechnology companies. Previously he was Senior VP and Chief Medical Officer at three biotechnology companies and held senior positions at Amgen and Abbott Laboratories. He has held professorships and maintained academic practices at the University of California, Davis and The Ohio State University.He has published broadly in several therapeutic areas in multiple journals including The New England Journal of Medicine, Journal of the American Medical Association, and Lancet.

He earned his bachelor’s and master’s degrees in exercise physiology from the University of California, Santa Barbara. His PhD is in human nutrition from Penn State University and his M.D. is from the University of California, Los Angeles. Dr. McCamish is Board Certified in Internal Medicine and Nutrition and Metabolism and he is licensed as a physician and surgeon in California.

He has published broadly in several therapeutic areas in multiple journals including The New England Journal of Medicine, Journal of the American Medical Association, and Lancet. He earned his bachelor’s and master’s degrees in exercise physiology from the University of California, Santa Barbara. His PhD is in human nutrition from Penn State University and his M.D. is from the University of California, Los Angeles. Dr. McCamish is Board Certified in Internal Medicine and Nutrition and Metabolism and he is licensed as a physician and surgeon in California.

   
  William Shrank, MD, MSHS
Director of the Rapid-Cycle Evaluation Group
CMS

William Shrank, MD, MSHS, is the Director of the Rapid-Cycle Evaluation Group at the Center for Medicare and Medicaid Innovation at the Centers for Medicare and Medicaid Services. In this capacity, Dr. Shrank leads the evaluation efforts of programs supported by the Innovation Center to reduce the cost and improve the quality of care in the U.S. He also leads the intramural research enterprise at CMS.
Dr. Shrank has served as an Assistant Professor of Medicine at Harvard Medical School and an Associate Physician in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital. His research is focused on improving the safe, appropriate and cost-effective use of prescription medications. His research interests also include evaluating quality in pharmacologic care, enhancing adherence to chronic medications, and improving prescription drug labels.

Dr. Shrank serves or has served on national advisory committees for the FDA, AHRQ, CMS, USP, and the American College of Physicians Foundation. He attended Brown University, received his M.D. from Cornell University, and trained in Internal Medicine at Georgetown University. He finished a health services research fellowship at UCLA, Rand, and the West Los Angeles VA Hospital where he earned an M.S. in Health Services.

   
  Geno Germano 
President
Pfizer Specialty Care and Oncology

Geno Germano is President and General Manager of Specialty Care and Oncology, Pfizer Inc.

The Specialty Care Business Unit (SCBU) works closely with specialty physicians and stakeholders to provide medicines to help treat a variety of serious and life-threatening conditions. Specialty Care holds leadership positions in vaccines and in key disease areas such as inflammation, infectious disease, hemophilia and ophthalmology. SCBU’s current portfolio includes more than 20 medicines in 11 disease areas, and the pipeline contains more than 25 compounds in late-stage development.

The Oncology Business Unit (OBU) is focused on improving the standard of care for cancer patients globally. With the full scale and scope of Pfizer support, the OBU has made rapid progress, with more than 20 molecules in development for various tumors including lung, breast, prostate, liver, kidney, colon and gastric diseases.

Geno joined Pfizer from Wyeth, where he was President, U.S. and Pharmaceutical Business Units for Wyeth Pharmaceuticals, responsible for its U.S. based Pharmaceuticals, Biologics and Vaccines businesses. In addition, he led Global Strategy for the Pharmaceutical and Institutional business units for major products in Neuroscience, Gastroenterology, Women’s Health, Infectious Diseases and Immunology.

In his more than 25 years in the pharmaceutical industry, Geno has held diverse positions, including Executive Vice President and General Manager for Wyeth Global Vaccines; Managing Director, Wyeth Australia and New Zealand; and Executive Vice President and General Manager of the Pharmaceutical Business Unit. He led numerous key product launches in primary and specialty care in gastroenterology, arthritis, infectious diseases, hemophilia, transplantation and oncology. Prior to joining Wyeth, Geno held leadership positions at several Johnson & Johnson companies.

Geno serves on the Advisory Board of the Healthcare Businesswomen’s Association, is a member of the Board of the Biotechnology Industry Organization and is a Trustee of the Albany College of Pharmacy, where he received his Bachelor of Science degree in Pharmacy in 1983.

   
  Joshua Sharfstein 
Secretary
Maryland Department of Health
Former Deputy Commissioner
Food & Drug Administration

Dr. Joshua M. Sharfstein was appointed by Governor Martin O’Malley as Secretary of the Maryland Department of Health and Mental Hygiene in January 2011.

In March 2009, President Obama appointed Dr. Sharfstein to serve as the Principal Deputy Commissioner of the U.S. Food and Drug Administration. He served as the Acting Commissioner from March 2009 through May 2009 and as Principal Deputy Commissioner through January 2011.

From December 2005 through March 2009, Dr. Sharfstein served as the Commissioner of Health for the City of Baltimore, Maryland. In this position, he led efforts to expand literacy efforts in pediatric primary care, facilitate the transition to Medicare Part D for disabled adults, engage college students in public health activities, increase influenza vaccination of healthcare workers, and expand access to effective treatment for opioid addiction. In 2008, Dr. Sharfstein was named Public Official of the Year by Governing Magazine.

Dr. Sharfstein is a 1991 graduate of Harvard College, a 1996 graduate of Harvard Medical School, a 1999 graduate of the combined residency program in pediatrics at Boston Children’s Hospital and Boston Medical Center, and a 2001 graduate of the fellowship in general pediatrics at the Boston University School of Medicine.

   
  Gillian Woollett 
Vice President
Avalere Health

Gillian Woollett, Vice President, leads the FDA Practice within Avalere’s Center on Evidence-Based Medicine. She provides the “prequel” of scientific and regulatory strategic policy expertise that supports medicinal products gaining approval at the FDA in a manner that allows them to be successful in the public and private reimbursement world. She is building a bridge for Avalere clients from the FDA space into the traditionally separate Centers for Medicare & Medicaid Services and healthcare policy/business world.

Trained as a molecular biologist/immunologist before coming to Washington, Gillian still publishes in peer-reviewed literature on biotechnology topics, and is also a frequent speaker educating on the core prospects and promises of the emerging biosciences and their ability to support better and more focused therapies.

Immediately prior to joining Avalere, Gillian was Chief Scientist at Engel & Novitt, LLP. She was Vice President, Science and Regulatory Affairs at the Biotechnology Industry Organization (BIO), where she established and led a new department to support BIO companies’ interactions with regulatory agencies in all aspects of the discovery, development, and manufacture of biotechnology-based medicines. She joined BIO after being Associate Vice President at the Pharmaceutical Research and Manufacturers of America. She has been an appointee on federal advisory committees to the Centers for Disease Control and Prevention and the Department of Commerce.

Gillian earned her B.A., M.A. in the Natural Sciences Tripos (Biochemistry) from the University of Cambridge, and her D.Phil. in Immunology from the University of Oxford in the United Kingdom.

   
  Robert Temple, MD

Deputy Director for Clinical Science

Center for Drug Evaluation & Research

Food & Drug Administration (FDA)

Dr. Robert Temple is Deputy Center Director for Clinical Science of FDA’s Center for Drug Evaluation and Research and is also Acting Deputy Director of the Office of Drug Evaluation I (ODE-I).     Dr. Temple received his medical degree from the New York University School of Medicine in 1967.    In 1972 he joined CDER as a review Medical Officer in the Division of Metabolic and Endocrine Drug Products.  He later moved into the position of Director of the Division of Cardio-Renal Drug Products.  In his current position, Dr. Temple oversees ODE-1 which is responsible for the regulation of cardio-renal, neuropharmacologic, and psychopharmacologic drug products.  Dr. Temple has a long-standing interest in the design and conduct of clinical trials and has written extensively on this subject, especially on choice of control group in clinical trials, evaluation of active control trials, trials to evaluate dose-response, and trials using “enrichment” designs. He also has a long-standing interest in hepatotoxicity of drugs, having participated in the first detailed FDA-NIH-outside discussion of the subject in 1978.

   
  Jonathan S. Leff

Managing Director

Warburg Pincus

Jonathan S. Leff is a managing director with Warburg Pincus, where he has been a member of the firm’s HealthCare Group since 1996. Mr. Leff is currently a Director of InterMune, ReSearch Pharmaceutical Services, Rib-X Pharmaceuticals, Sophiris Bio and Talon Therapeutics. In addition, he serves on the Executive Committee of the Board of the National Venture Capital Association (NVCA) and leads the NVCA’s life sciences industry efforts as Chairman of NVCA’s Medical Innovation and Competitiveness Coalition, and serves as a member of the Board of the Biotechnology Industry Organization. He is also a member of the Boards of Friends of Cancer Research and the Spinal Muscular Atrophy Foundation and the Board of Advisors of Columbia University Medical Center. Mr. Leff received an A.B. in Government from Harvard University and an M.B.A. from Stanford University.

   
  Lara Ramsburg

Vice President, Government Relations

Mylan

Lara Ramsburg is Vice President of Government Relations for Mylan, the largest global generics company headquartered in the United States. During the Generic Drug User Fee (GDUFA) negotiation process, she participated on behalf of Mylan as a member of the Generic Pharmaceutical Association (GPhA) negotiating team. Lara also previously served as Chief of Staff in Mylan’s Office of the President.

Prior to joining Mylan, Lara was Director of Communications and then Director of Policy for the West Virginia Governor’s Office. She also worked previously for Rowan & Blewitt, an issue and crisis management consulting firm, and media outlet CNN, among other professional experiences. Lara holds a Bachelor of Science in communication from Ohio University and a Master of Science in corporate and professional communication from Radford University.

   
  Nancy Bradish Myers

President

Catalyst Healthcare

Nancy Bradish Myers, JD, is a Washington-based attorney with expertise in health care law and regulation, policy development, government relations and political analysis for investors. She is the President of Catalyst Healthcare Consulting, Inc., a niche consulting firm that provides clients with strategic regulatory insight and advice as they position biopharmaceutical and medical device companies, trade associations, and patient advocacy organizations on regulatory and health policy matters before the FDA and other regulatory agencies.

Ms. Myers has served in FDA’s Office of the Commissioner in various positions, including as Senior Strategic Advisor. She has also served as Special Counsel for Science Policy for PhRMA, Vice Presidential-level political healthcare analyst for a Wall Street financial services firm, Reimbursement Counsel and Director of Government Affairs for BIO, a lobbyist for the Blue Cross Blue Shield Association and staff person to a Member of Congress on Capitol Hill.

She is also an expert on FDA user fees and served as co-editor of the book PDUFA and the Expansion of FDA User Fees: Lessons from Negotiators, published by the Food and Drug Law Institute in 2011.

She is a founding Board member and past-President of the Alliance for a Stronger FDA. This 200-member coalition of former regulators, patient and consumer advocates and industry leaders works with the Administration and Congress to increase FDA federally appropriated funds. She is also a Board member of the FDA Alumni Association and is actively involved in the Food and Drug Law Institute (FDLI) and the Drug Information Association (DIA).

Ms. Myers is the 2012 recipient of FDA’s Distinguished Alumni Award, for outstanding contributions in advancing FDA’s mission, creating a strong coalition to advocate for agency resources, and establishing enduring connections between FDA alumni and staff.  Ms. Myers received her law degree from Temple University School of Law and her undergraduate degree from Duke University.

   
  Leah Christl, PhD

Associate Director for Biosimilars

Office of New Drugs

Center for Drug Evaluation & Research

Food & Drug Administration (FDA)

Dr. Christl is the Associate Director for Therapeutic Biologics in the Office of New Drugs (OND) in the FDA’s Center for Drug Evaluation and Research. Dr. Christl leads the Therapeutic Biologics and Biosimilars Team (TBBT) in OND. TBBT is responsible for ensuring consistency in the regulatory approach and guidance to sponsors regarding development programs for proposed biosimilar biological products and related issues regarding development programs for therapeutic biologics, for developing the procedures and staff training necessary to implement the Biologics Price Competition and Innovation Act of 2009 in a consistent manner across all OND review divisions, and for managing the CDER Biosimilar Review Committee.

Dr. Christl joined the FDA in 2003 as a Regulatory Project Manager in the Division of Over-the-Counter Drug Products. From 2004 – 2008, she was the Chief Regulatory Project Manager in the Division of Nonprescription Clinical Evaluation. Dr. Christl served as the Associate Director for Regulatory Affairs for the Office of Nonprescription Products, now the Office of Drug Evaluation IV, from 2005 – 2010. Prior to joining the FDA, Dr. Christl received her Ph.D. in Molecular and Cellular Biology and Pathobiology – Marine Biomedicine and Environmental Science from the Medical University of South Carolina in Charleston. She also spent 2 years at the University of South Carolina as an Associate Research Professor.

   
  Will Suvari
Vice President
Campbell Alliance

Will Suvari is a Vice President in Campbell Alliance’s Pricing & Market Access practice.  He focuses on commercialization strategy and organizational structure design within the context of the reform-driven evolution of provider and payer markets.   Will brings 20 years of research, industry and consulting experience from his work with life sciences firms, leading provider networks/institutions, as well as national payers.

Prior to joining Campbell Alliance, will was an Associate Partner at Oliver Wyman.  Before Oliver Wyman, Will worked in Deloitte Consulting’s Life Sciences practice.  He worked in various functions at Amgen prior to his career in consulting.

Will holds degrees from Northwestern University in Biochemistry and English Literature.  He has an MBA from The Kellogg Graduate School of Management.

   
  Barry Sickels, Ph.D.

Vice President, Regulatory Affairs and Wilmington R&D Site Leader

AstraZeneca

Barry Sickels is Vice President, Regulatory Affairs at AstraZeneca and the R&D Site Leader for the Wilmington, Delaware campus.  He has more than 25 years experience in the pharmaceutical industry and has worked in discovery research, clinical research and development and, for the past 18 years, Regulatory Affairs. Barry has worked in many therapy areas including oncology, infectious disease, central nervous system, respiratory disease, GI and diabetes. Prior to his current role, Barry served as Vice President and Global Regulatory Therapy Area Leader for Oncology and Infection projects at AstraZeneca.  Barry also previously served as Vice President, Regulatory Affairs, Global Therapy Areas and North America at Pfizer/Wyeth.   Barry earned his BS in biology from Rider University and holds an MS in toxicology/environmental science from Rutgers University. He also holds a Master of Jurisprudence and a Doctorate in Health Law from the Widener University School of Law’s Health Law Institute.

   
  Kay Holcombe

Senior Policy Advisor

Genzyme

Kay Holcombe is Senior Policy Advisor at Genzyme, a Sanofi Company.  From Genzyme’s Washington, DC, government relations office, Kay participates in developing and implementing corporate policies and responses to government regulatory and policy initiatives.  She works with members of Congress and their staffs and with officials of government agencies.

Before joining Genzyme, Kay was Executive Vice President of Policy Directions Inc., a government relations firm specializing in strategic planning and legislative and regulatory advocacy regarding health care and related issues.  She represented a variety of clients in academia and in the pharmaceutical and biotechnology, food, and consumer products industries.

Earlier, she served as professional health legislative staff and senior health policy advisor,  House of Representatives Committee on Energy and Commerce, and professional health staff, Senate Committee on Labor and Human Resources; Deputy Associate Commissioner for Legislative Affairs, Food and Drug Administration; Executive Vice President, Foundation for Biomedical Research; Associate Director for Public Health Legislation, Office of the Assistant Secretary for Legislation,  Department of Health and Human Services; Deputy Associate Administrator for Planning, Evaluation, and Legislation, Health Resources and Services Administration, U.S. Public Health Service; Special Assistant to the Director, Division of Legislative Affairs, National Institutes of Health; Executive Secretary, National Heart, Lung, and Blood Institute National Advisory Council; and researcher, National Institutes of Health.

Kay received her B.S. in chemistry education from the University of Illinois and her M.S. in chemistry from the University of Virginia.  She was elected to Phi Beta Kappa, Phi Kappa Phi, and Iota Sigma Pi.

   
  Martin Marciniak

Vice-President, US Health Outcomes

GlaxoSmithKline

Dr. Marciniak has 13 years of strategic and health outcomes research experience in the pharmaceutical industry, most recently with GlaxoSmithKline.  His experience and leadership has been both Global and US oriented, internally and externally facing, and has included specific therapeutic research focus in the areas of oncology, neurosciences, and cardiovascular disease.  Martin’s research has been published in scholarly journals, and has been presented at both national and international congresses.  In addition to his research activities, he also serves as an ad hoc peer reviewer for scientific journals and research foundations.  Currently, Martin is one of the nonvoting industry representatives to Medicare Evidence Development & Coverage Advisory Committee for the Centers for Medicare and Medicaid Services.

Dr Marciniak has a broad academic career which includes scientific and public policy research, as well as the tactical implementation and strategic management of observational research programs.  He received his Ph.D. in Health Services and Policy Analysis with a concentration in Health Economics from the University of California at Berkeley, and a Masters in Public Policy from the John F. Kennedy School of Government at Harvard University.  His B.S is in Pharmacy from Purdue University.  Additionally, Martin also holds an executive education certificate from the Sloan School of Management at the Massachusetts Institute of Technology focusing on innovation and management.

   
  Charles A. (Chuck) Stevens, JD, MBA

Vice President & General Manager, Commercialization Strategy

PAREXEL Consulting

Mr. Stevens is responsible for leading the practice including managing all reimbursement, market access and commercial strategy consulting, tactical reimbursement support help lines and PAP’s (Patient Assistance Programs) designed to provide workable solutions to support commercial success and patient access to therapy. Mr. Stevens has over 17 years of bio and pharma industry experience, including responsibility for strategic reimbursement, pricing, public and private payer strategy, product distribution/channel management and pharmaco-economics for both commercialized and non-commercialized products at the senior director level.

He has specialized expertise in Hematology, Oncology, HIV/AIDS, Addiction Medicine, Gastroenterology and Urology. He has worked extensively on issues involving the Patient Protection & Affordable Care Act (PPACA), the Medicare Modernization Act (MMA) of 2003, the Single Drug Pricer (SDP) system and obtaining product specific HCPCS codes. In 2006, he was the first person to be successful in obtaining an individual product HCPCS from CMS by making application in advance of FDA product approval, resulting in the specific code being available at time of product launch.

Chuck is a frequent presenter at national conferences, has authored articles on Comparative Effectiveness Research (CER) and has been quoted in publications such as PharmaVoice, FDA Week and the Grey Sheet.

   
  Gregory Geba

Director

Office of Generic Drugs

Food & Drug Administration (FDA)

After nearly a decade at Yale where he was a faculty member in Pulmonary and Critical Care in the School of Medicine, Dr. Geba served in senior-level clinical/managerial positions in the pharmaceutical industry for the past 15 years.  In his most recent position, he served as Deputy Chief Medical Officer for Sanofi US, where he provided medical and scientific leadership and managerial direction to multidisciplinary scientific and regulatory professionals engaged in drug development activities across all therapeutic areas, as well as to the company’s field medical group.

He has contributed to the registration of more than 20 currently marketed drugs or devices across multiple therapeutic areas. In so doing, he successfully employed his working knowledge and demonstrated practical application of drug manufacturing processes, current quality and risk management processes, and standards relevant to FDA’s laws and regulations. He brings extensive clinical research experience, including leading or serving as the key point in filing new drug applications, biologic license applications, and promotional studies comparing efficacy and effectiveness of novel biopharmaceuticals versus standard of care (including regimens containing branded or generic drugs), and has provided or supervised key safety updates and presentations to FDA Advisory Committees. Dr. Geba’s experience also includes leading medical affairs activities while serving in a variety of senior-level positions. His scope of responsibility in those activities included contribution to the design of experimental protocols and assessment of data from pre-clinical, animal, and first-in-human studies; design, implementation, analysis, and interpretation of phase 2a proof-of-concept and 2b dose ranging studies; and production of important comparative effectiveness and safety data when assessing benefit-risk relationships during phase 3, phase 3b, and phase 4 studies.

Dr. Geba received his medical degree from the University of Navarre and his M.P.H. from the Johns Hopkins Bloomberg School of Public Health. He joins OGD to lead the expanding generic program into a reorganization of both structure and process to improve coordination, communication, and efficiency, and to enhance the Office’s ability to ensure that all generic drugs-which make up nearly 80 percent of prescriptions filled in the United States-are safe, effective, of high quality, and interchangeable with the brand name drug product/reference listed drug.

   
  Mary Ellen Cosenza

Executive Director Regulatory Affairs and North America Regulatory Head

Amgen, Inc.

Mary Ellen Cosenza has almost 30 years experience in the Bio-Pharmaceutical Industry, with the last 17 years being at Amgen Inc. Mary Ellen is currently Executive Director of U.S. Regulatory Affairs with Amgen. Her role is to provide management and leadership by overseeing the execution and by providing advice on the development of regulatory strategy and plans for the FDA.  In addition, she supervises the Regulatory Promotion and Material Compliance Group, as well as supervising Amgen Regulatory policy activities and priorities in the U.S.

Prior to taking on the U.S. Regulatory team she managed the International Emerging Markets Regulatory team. She has also served at the Regulatory Therapeutic Area Head for Inflammation and Early Development and overseen the Global Regulatory Writing department.  Prior to joining Regulatory Affairs, Dr. Cosenza was Senior Director of Toxicology where she managed a department of scientists that are involved in the safety assessment of both traditional small molecules and biotechnology products.  She set policy concerning study type, study design, approval of contract laboratories and interacted with FDA and other Boards of Health.

Prior to joining Amgen (1995), Dr. Cosenza worked for the Medical Research Division of American Cyanamid Company (now Pfizer) in Toxicology Research as a Principal Scientist.  At Cyanamid, Dr. Cosenza held several positions including Group Leader of Regulatory Toxicology, Manager of the Quality Assurance Unit for GLPs and GMPs and later managed the Toxicology Operations group.

Mary Ellen received her PhD from St. John’s University, New York.  She recently received her MS in Regulatory Affairs from University Southern California, Los Angeles.  Mary Ellen also teaches a course on Food and Drug Toxicology at USC.

Dr. Cosenza is a Diplomat of the American Board of Toxicology, has her Regulatory Affairs Certification (US and EU) and is a member of the Society of Toxicology (SOT), the American College of Toxicology (ACT), Drug Information Association (DIA) and Regulatory Affairs Professional Society (RAPS).  Mary Ellen was the representative for BIO on the ICH M3 Expert working group for the most recent revision.

   
  David Gaugh

VP-Regulatory Sciences

Generic Pharmaceutical Association

David Gaugh has over 25 years of leadership experience in the Healthcare and Pharmaceutical business and has been an outstanding contributor to the industry over the years. He has been employed by GPhA since February 2012 as the Senior Vice President for Sciences and Regulatory, where he is responsible for the science, regulatory and professional liaison functions between member companies, agencies of the US Government and Legislative bodies. Prior to joining GPhA, David was the Vice President and General Manager of Bedford Laboratories, a Division of Ben Venue Laboratories (a wholly owned subsidiary of Boehringer Ingelheim). David was responsible for Strategic Planning, Financial Management, Business Development, Marketing and Sales for a $500 million multi-source injectable business.

Prior to joining Ben Venue, David was Senior Director, Pharmacy Contracting and Marketing at VHA/Novation; the largest Group Purchasing Organization in the US. Prior to Novation, he was System Director of Pharmacy for St. Luke’s Health-System, a tertiary-care hospital in Kansas City, MO.

David is a registered Pharmacist and is engaged in several pharmacy-related activities such as the ASHP Education and Research Foundation Board of Directors and various Pharmacy Internship and Residency Programs.

   
  Gary Buehler
Vice President-Regulatory Strategic Operations
Teva Pharmaceuticals

Mr.  Buehler is the VP for Regulatory Strategic Operations for Teva Pharmaceuticals.  Prior to joining Teva, he worked for 24 years at the US Food and Drug Administration, starting as a Project  Manager in OND’s Cardio Renal Division.  In 1999, he joined the Office of Generic Drugs as the Deputy Director.  In 2001, after serving for over a year as Acting Director, he became the Director of OGD and served in that position until 2010. Mr. Buehler retired from the U.S. Public Health Service in April of 2000 after serving in a variety of duty stations including Indian Health Service positions in Nevada and Montana.  He graduated from Temple University School of Pharmacy.

 

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