August 2008

Effectiveness Summary Preparation Detailed in Guidance

FDA News Source

The integrated summary of effectiveness (ISE) required in NDAs and encouraged in BLAs should include a detailed analysis of study results rather than just a summary of individual trials, according to an FDA draft guidance.

FDA Wants More Information on J&J Antibiotic

FDA News Source

Johnson & Johnson (JNJ) received a complete response letter from the FDA requesting additional information before it approves the company's antibiotic Doribax as a treatment for hospital-acquired pneumonia, including the ventilator-related form of the disease.

Doribax (doripenem), which is in the carbapenem class of antibiotics, is approved in the U.S. for the treatment of complicated intra-abdominal infections and complicated urinary tract infections.

J&J is reviewing the letter and will work to resolve questions from the FDA, the company says in a written statement. Although the firm would not say whether it would have to conduct an additional clinical trial to secure approval, the outcome of an advisory committee meeting on the product earlier this year indicated new clinical data would be necessary.

In July, the FDA's Anti-Infective Drugs Advisory Committee voted 8-5 that the product was safe and 7-6 that it was effective. However, the committee voted 9-4 that there was not sufficient scientific justification for the design of noninferiority clinical trials J&J used to support approval of the indication. The design included a noninferiority margin of 20 percent, and the FDA said it needed to be roughly 10 percent.

During the meeting, committee member Thomas Fleming, professor of biostatistics at the University of Washington, said J&J might need to use other endpoints or conduct a superiority trial.

BioDelivery Sciences Anticipates First Half 2009 Approval of BEMA Fentanyl (ONSOLIS)

Business Wire Source

BioDelivery Sciences International, Inc. (Nasdaq:BDSI) today announced receipt of a Complete Response letter from the U.S. Food and Drug Administration (FDA) regarding the Company’s New Drug Application (NDA) for BEMA™ Fentanyl, which will be marketed in the United States as ONSOLIS (fentanyl buccal soluble film). The FDA has requested that the Company make modifications to the submitted risk management program. All aspects of the review were complete and no deficiencies were noted in chemistry, manufacturing and controls, nonclinical, or clinical efficacy/safety. The Company will submit the requested information and anticipates a first half 2009 approval.

The FDA requested conversion of the risk minimization action plan (RiskMAP) submitted as part of the NDA for ONSOLIS into a Risk Evaluation and Mitigation Strategy (REMS). REMS is a new term for a strategy and plan aimed at ensuring the benefits of a drug outweigh its risks. The REMS requested of BDSI is believed to be the result of the FDA's recent experience with other high-potency opioid products and the new authority granted under the Food and Drug Administration Amendment Act (FDAAA) enacted in March of 2008. This followed BDSI’s submission of its ONSOLIS NDA in October 2007.

"We are pleased with this significant and extremely positive development for our Company,” stated Dr. Mark A. Sirgo, President and Chief Executive Officer of BDSI. “We have been anticipating the REMS request and have been proactively evaluating a series of options that will enable us to mitigate any delay in approval. All other aspects of our ONSOLIS NDA were reviewed positively and with no deficiencies noted. I want to congratulate the entire team at BDSI for this tremendous accomplishment."

Dr. Sirgo continued, "We believe that FDA approval of ONSOLIS and its U.S. commercial launch should add considerable value to BDSI based on the aggregate $30 million in approval and launch milestone payments, sales-based milestone payments, and double-digit royalty on sales, which provide the means to accelerate development of our pipeline. In addition, the outcome of the ONSOLIS NDA review validates the BEMA drug delivery platform and should immediately enhance the value of other BEMA products in development, particularly BEMA Buprenorphine, our second pain product. We believe that the future of BDSI continues to be very promising."

According to Dr. Andrew Finn, Executive Vice President, Product Development, "We have been working over the last several months with Meda AB, our partner for the commercialization of ONSOLIS, to prepare for a potential REMS requirement. These activities have put us in a position to respond rapidly to FDA’s request. Depending on FDA review time, approval could occur as early as the first quarter or as late as 2Q09."

"With respect to our financial position, we have managed our cash prudently over the course of 2008 and have a few months of cash in reserve," said Dr. Sirgo. "We have a financial plan that includes several choices to bridge the gap to approval and the receipt of milestone payments from Meda totaling $30 million. Importantly, we will seek to only raise the capital required to reach the anticipated approval, with little or no dilution to our stockholders. It should be noted that the costs associated with finalization and implementation of the REMS for ONSOLIS™ will be the responsibility of Meda."

BDSI’s lead product under development is ONSOLIS (fentanyl buccal soluble film) a potential treatment for "breakthrough" pain (i.e., episodes of severe pain which "break through" the medication used to control the persistent pain) in opioid tolerant patients with cancer. ONSOLIS consists of a small, dissolvable, polymer film, formulated with the opioid narcotic fentanyl for application to the buccal mucosa (inner lining of the cheek). Fentanyl belongs to the group of medicines called narcotic analgesics, which are used to relieve pain. The BEMA delivery technology is particularly well suited for the delivery of products where rapid onset of activity and convenient administration are important. BDSI believes there is a clear need and growing market for additional narcotic agents in alternative dosage forms to provide rapid and convenient pain relief.

BDSI is a specialty pharmaceutical company that is focused on developing innovative products to address growing market opportunities, including conditions such as pain. The company utilizes its owned and licensed patented drug delivery technologies to develop, partner, and commercialize new products using proven therapeutics. BDSI’s pain franchise currently consists of two products in development utilizing the company's patented BEMA oral adhesive film technology: ONSOLIS, a potential treatment for "breakthrough" pain in opioid tolerant patients with cancer, and BEMA Buprenorphine, a second analgesic with at least one potential target indication for the treatment of moderate to severe pain. The company is working with its BEMA technology and its patented Bioral cochleate technology on products targeted at conditions common to oncology and surgical patients such as pain and infections. The company headquarters is located in Raleigh, North Carolina, and its principal laboratory is located in Newark, New Jersey. For more information please visit www.bdsinternational.com.

Heparin Contamination Has Wide Scope

Philadelphia Injury Board Source

Contamination of the blood thinner heparin was discovered earlier this year. One of the largest US suppliers of heparin is Baxter International, and Baxter recalled most of its heparin in February 2008 after patient deaths were linked to the product. Accorinding to the FDA, US deaths linked to contaminated heparin has increased to 81, up from the earlier count of 62. Twelve companies in China are the sources of the contaminated raw product that was part of the heparin linked to deaths. According to Chinese officials, even though the contaminated product came from China, they do not believe that the contamination caused the deaths. The contaminated product affected several countries, including France, Germany, Canada, Italy, and the US. According to the FDA, the contaminated product entered the global market in 2007. Testing has found contaminated heparin in IV drug products and some diagnostic tests. It is still unclear how the contaminated raw product became mixed with heparin.

Cytokinetics Announces Completion of Interim Safety Analysis in Ongoing Phase IIa Clinical Trial of CK-1827452

Market Wire Source

Cytokinetics, Incorporated (NASDAQ: CYTK) announced the completion of a protocol-defined interim analysis in an ongoing Phase IIa clinical trial evaluating the safety of CK-1827452 in patients with ischemic cardiomyopathy and angina. Based on the Safety Review Committee's review of safety data from the first cohort of patients, the Committee has recommended that the company open the second cohort of this clinical trial for enrollment. To date, no serious adverse events have been reported in this ongoing clinical trial. Cytokinetics also reiterated that it expects to conclude this trial by the end of 2008. CK-1827452, a novel cardiac myosin activator, is being developed for the potential treatment of patients with either acutely decompensated or chronic heart failure. CK-1827452 is the subject of a collaboration and option agreement between Cytokinetics and Amgen Inc.

"Based on our careful review of safety data from this trial, I am comfortable recommending that the trial proceed to enroll patients in the second cohort, in which patients randomized to treatment with active CK-1827452 will receive a higher dose than in Cohort 1," stated Barry H. Greenberg, M.D., Chair of the Safety Review Committee for this clinical trial and Director, Advanced Heart Failure Treatment Program, University of California, San Diego Medical Center.

The company announced that 46 patients were enrolled and completed treatment in the first cohort of this trial and that, as per protocol, safety data from the first 31 of these patients were presented to the committee. No serious adverse events were reported for any patients in the first cohort and analyses of safety data from patients included in the interim analysis revealed no additional safety concerns.

"We look forward to sharing these data with the medical community at an appropriate scientific and medical forum and are now pleased to proceed forward with the next stage of this clinical trial," stated Andrew A. Wolff, M.D., F.A.C.C., Cytokinetics' Senior Vice President of Clinical Research and Development and Chief Medical Officer. "We believe these data, and data reported recently from other clinical trials, support the advancement of CK-1827452 in continuing trials."

In June 2008, at the Heart Failure Congress, the annual meeting of the Heart Failure Association of the European Society of Cardiology in Milan, Italy, Cytokinetics announced results from an interim analysis of its first and ongoing Phase IIa clinical trial of CK-1827452 in patients with stable heart failure. At the time of the analysis, 22 patients had been evaluated in this clinical trial. The safety data from this analysis suggested that CK-1827452 was well-tolerated with no serious adverse events reported in heart failure patients exposed to the intended range of doses and plasma concentrations. A pharmacodynamic-pharmacokinetic analysis of data from these 22 patients showed that when compared to placebo, CK-1827452 produced statistically significant and clinically relevant increases in Doppler-derived stroke volume and fractional shortening as a consequence of statistically significant prolongations of systolic ejection time. In this interim analysis, statistically significant correlations were observed between the increases in the three indices of cardiac ventricular function and increases in the plasma concentration of CK-1827452. Doppler-derived systolic ejection time and stroke volume measured during the second hour of infusion were the most sensitive indicators of effect. Changes in left ventricular ejection fraction, a measurement with high variability in patients with ventricular disease, did not reach statistical significance in that dataset. Across the range of plasma concentrations evaluated, the pharmacokinetics of CK-1827452 were generally linear with respect to dose and similar to those observed in the healthy volunteers in the first-time-in-humans Phase I trial of CK-1827452. Heart rate declined slightly at higher concentrations and there were no dose-related changes in blood pressure in this interim analysis. Cytokinetics plans to present additional data from these same 22 patients at the European Society of Cardiology 2008 Congress in Munich, Germany and also plans to present interim data including additional patients who have completed treatment in this ongoing trial in as part of the Late Breaking Clinical Trials Session at the Annual Meeting of the Heart Failure Society of America in Toronto, Ontario, Canada.

In addition to these two ongoing Phase IIa clinical trials, in April 2008, Cytokinetics opened enrollment in an open-label, non-randomized Phase IIa clinical trial designed to evaluate an intravenous formulation of CK-1827452 administered to patients with stable heart failure undergoing clinically indicated coronary angiography in a cardiac catheterization laboratory. Cytokinetics has conducted five Phase I clinical trials of CK-1827452 in healthy subjects: a first-time-in-humans study evaluating an intravenous formulation, an oral bioavailability study evaluating both intravenous and oral formulations, and three studies of oral formulations: a drug-drug interaction study, a dose proportionality study and a study evaluating modified-release formulations. Data from each of these trials have been reported previously.

Cytokinetics is a biopharmaceutical company focused on the discovery, development and commercialization of novel small molecule drugs that may address areas of significant unmet clinical needs. Cytokinetics' cardiovascular disease program is focused to cardiac myosin, a motor protein essential to cardiac muscle contraction. Cytokinetics' lead compound from this program, CK-1827452, a novel small molecule cardiac myosin activator, entered Phase II clinical trials for the treatment of heart failure in 2007. Under a strategic alliance established in 2006, Cytokinetics and Amgen Inc. are performing joint research focused on identifying and characterizing activators of cardiac myosin as back-up and follow-on potential drug candidates to CK-1827452. Amgen has obtained an option for an exclusive license to develop and commercialize CK-1827452, subject to Cytokinetics' development and commercial participation rights. Cytokinetics' cancer program is focused on mitotic kinesins, a family of motor proteins essential to cell division. Under a strategic alliance established in 2001, Cytokinetics and GlaxoSmithKline (GSK) are conducting research and development activities focused on the potential treatment of cancer. Cytokinetics is developing two novel drug candidates that have arisen from this program, ispinesib and SB-743921, each a novel inhibitor of kinesin spindle protein (KSP), a mitotic kinesin. Cytokinetics is sponsoring a Phase I/II clinical trial of ispinesib as monotherapy as a first-line treatment in chemotherapy-naïve patients with locally advanced or metastatic breast cancer. In addition, Cytokinetics is conducting a Phase I/II trial of SB-743921 in patients with non-Hodgkin or Hodgkin lymphomas. GSK has obtained an option for the joint development and commercialization of ispinesib and SB-743921. Cytokinetics and GSK are conducting collaborative research activities directed to the mitotic kinesin centromere-associated protein E (CENP-E). GSK-923295, a CENP-E inhibitor, is being developed under the strategic alliance by GSK; GSK began a Phase I clinical trial with GSK-923295 in 2007. In April 2008, Cytokinetics announced the selection of a potential drug candidate directed towards skeletal muscle contractility which may be developed as a potential treatment for skeletal muscle weakness associated with neuromuscular diseases or other conditions. All of these drug candidates and potential drug candidates have arisen from Cytokinetics' research activities and are directed towards the cytoskeleton. The cytoskeleton is a complex biological infrastructure that plays a fundamental role within every human cell. Additional information about Cytokinetics can be obtained at www.cytokinetics.com.

Cell Genesys Halts VITAL-2 GVAX Trial in Advanced Prostate Cancer

Business Wire Source

Cell Genesys, Inc. (Nasdaq:CEGE) today announced that it has terminated VITAL-2, the second of two Phase 3 clinical trials of GVAX immunotherapy for prostate cancer, which compares GVAX immunotherapy in combination with Taxotere® (docetaxel) to Taxotere plus prednisone in patients with advanced-stage prostate cancer. The Company ended the trial as recommended by its Independent Data Monitoring Committee (IDMC) which, in a routine safety review meeting held this week, observed an imbalance in deaths between the two treatment arms of the study. To date, VITAL-2 enrolled 408 patients. The IDMC based its recommendation on 114 deaths of which 67 occurred in the GVAX plus Taxotere combination treatment arm and 47 deaths occurred in the Taxotere control arm. At this time, a specific cause for the imbalance in deaths has not been identified and the IDMC reported no new safety issues for GVAX when administered in combination with Taxotere. The Company plans to fully analyze the clinical data from these patients to attempt to understand the potential cause for the higher rate of deaths observed in the GVAX immunotherapy plus Taxotere combination arm, including an assessment of potential imbalances between the two arms of the study such as baseline characteristics and prognostic factors, as well as other treatment variables. In light of the IDMC’s observation with respect to VITAL-2, the Company has requested that the IDMC perform a previously unspecified futility analysis of VITAL-1, the other Phase 3 clinical trial of GVAX immunotherapy for prostate cancer. The Company expects the results of the VITAL-1 futility analysis in approximately one month.

GVAX immunotherapy for prostate cancer is comprised of two prostate tumor cell lines that have been modified to secrete GM-CSF (granulocyte-macrophage colony-stimulating factor), an immune stimulatory cytokine that plays a key role in stimulating the body's immune response, and then irradiated for safety. GVAX immunotherapy for prostate cancer is designed to be administered through intradermal injections on an outpatient basis.

Cell Genesys (Nasdaq: CEGE) is focused on the development and commercialization of novel biological therapies for patients with cancer. The company's lead product platform is GVAX® immunotherapy for cancer, which holds the potential to treat multiple types of cancer including prostate cancer, leukemia, pancreatic cancer and lung cancer. Cell Genesys continues to hold an equity interest in its former subsidiary, Ceregene, Inc., which is developing gene therapies for neurodegenerative disorders. Cell Genesys is headquartered in South San Francisco, California, and has manufacturing operations in Hayward, California. For additional information, please visit the company’s website at www.cellgenesys.com.

China: What Does The Third Amendment To China's Patent Law Mean To Pharmaceutical Companies? - by Tony Chen and Ann W. Chen

Mondaq Source

Since its enactment in 1984, China's Patent Law has been amended twice, first in 1992 and then in 2000. The first amendment added pharmaceutical compositions to the list of patentable subject matter and inaugurated China's membership in the Patent Cooperation Treaty ("PCT"). The second amendment brought China's Patent Law into compliance with the Trade-Related Aspects of Intellectual Property Rights ("TRIPS") Agreement.

A third amendment to the Patent Law is widely expected to be approved by the People's Congress soon. The latest draft of the third amendment was released for public comment on March 5, 2008 (the "Draft"). This Commentary discusses several changes to the Patent Law in the proposed third amendment and their potential impact on pharmaceutical patent protection in China.

Tough Disclosure Rules for Inventions Relying on "Genetic Resources" or "Traditional Knowledge"

China is rich in genetic resources and traditional knowledge, and the Chinese government supports and encourages research to develop intellectual property derived from these assets. For inventions "completely relying" on genetic resources or traditional knowledge, the Draft for the first time imposes a requirement that the patent applicant disclose in the application the direct and original sources of the genetic resources or the source of the traditional knowledge.

Biotechnology companies need to pay close attention to this disclosure requirement because failure to comply could result in either the denial or invalidation of a Chinese patent. It should be noted that there is no equivalent requirement in the patent laws of Europe, Japan, or the United States.

The Draft also stipulates that no patent shall be granted to inventions "completely relying" on genetic resources or traditional knowledge if the acquisition or use of the underlying genetic resources or traditional knowledge violated Chinese law or regulation.

Because of the stiff penalty attached to noncompliance with the requirements in the Draft, the international business community has raised concerns with the Chinese government about the potential chilling effect of the new rules on commercial research and development related to "genetic resources" and "traditional knowledge."

Absolute Novelty Requirement for Patentability

Article 22.2 of China's existing Patent Law has a blended novelty standard for patentability—in assessing novelty of an invention, Chinese patent examiners consider publication anywhere in the world but not public use outside of China. This blended novelty standard occasionally allows "patent hijacking," i.e., the patenting in China of another party's invention witnessed at a public event (such as a trade show) outside of China. The Draft replaces this blended novelty standard with an absolute one, and it requires patent examiners to consider public use evidence from both inside and outside China in examining patent applications. Adoption of an absolute novelty standard will have the effect of reducing patent hijacking. The Draft does not state whether this absolute novelty requirement would be made retroactive. If so, it would open up the prior art space significantly for challenging the validity of existing Chinese patents.

Heavy Penalty for Foreign Filing Without a License

As international pharmaceutical companies set up research and development centers in China, they need to consider where to first file patent applications for inventions made in China. Today, Article 20.1 of China's Patent Law requires that a Chinese patent applicant for an invention made in China must first file a patent application in China before any foreign filing. However, the current law is silent about what a foreign applicant is required to do in the same situation. Consequently, some foreign-owned research labs in China assign the right to apply for patent to an entity outside of China and circumvent the foreign filing requirement of the current Chinese patent law.

The Draft blocks this "loophole" with a foreign filing license regime like the system in the United States. Under the new requirement, for any invention made in China, the applicant must obtain permission from the State Intellectual Property Office prior to filing a patent application in a foreign country. In most cases, the foreign filing license automatically will be granted shortly after the filing of a Chinese patent application. Violation of this requirement will result in loss of patent rights in China.

Because Chinese patent applications must be submitted in Chinese, this new rule will force international pharmaceutical companies to develop resources to draft original patent applications in Chinese to protect inventions made in China.

Strengthening Patent Co-Ownership Rights

As pharmaceutical companies enter into research collaborations with Chinese universities and companies, they need to understand how Chinese law governs the commercialization of jointly developed and owned patent rights. In that regard, the Draft includes provisions that prevent unilateral use of the patent rights without the consent of co-owners.

Specifically, the Draft states that unless agreed upon otherwise, consent by all co-owners is required for (1) assigning the right to apply for a patent; (2) assigning or withdrawing the patent application; (3) assigning, abandoning, or pledging the patent right; and (4) licensing others to exploit the patent. Under such rules, pharmaceutical companies should draft collaborative research agreements in ways to ensure that commercial use of the patent rights arising from the joint research efforts will not be blocked by the default veto power of the co-owner.

Road Map for Compulsory Licenses

No compulsory license has ever been granted in China even though Chapter VI of China's current Patent Law contains compulsory license provisions. However, the Draft contains new rules that will make it more feasible and likely for compulsory licenses to be granted in China.

First, the Draft provides that the government may grant a compulsory license to a party qualified to exploit the patent if the patent owner, without justification, has not exploited or sufficiently exploited the patent three years after the patent grant. The Draft also provides that a compulsory license may be granted if it is judicially or administratively determined that the patent owner used the patent right in an anticompetitive fashion.

In addition, the Draft authorizes the grant of a compulsory license "where the public interest so requires" and where a developing country with no or insufficient capacity to manufacture a patented drug for treating an epidemic disease "hopes to import the drug from China."

International pharmaceutical companies have voiced serious concerns about the breadth and ambiguity of the compulsory license provisions in the Draft. The shaping of these provisions in the final stages of the lawmaking process deserves careful monitoring by the pharmaceutical research community.

Formalization of the Regulatory Review Exemption

China's Patent Law does not expressly exempt activities related to regulatory review from patent infringement. Such an exemption currently exists as a judicial interpretation of the broad experimental use exception provided in Chinese patent law. The Draft codifies the judicial interpretation by stating that it is not an act of infringement if a patented drug or patented medical apparatus is manufactured, used, or imported solely for the purposes of obtaining and providing information for administrative approval.

While the Draft formalizes the exemption for activities related to regulatory review, it does not provide any provision for patent term extension to compensate for regulatory delays in obtaining State Food and Drug Administration approval of drugs. Neither does the Draft provide a patent linkage system like the Hatch-Waxman patent certification and 30-month stay mechanism.

Conclusion

Strong patent protection in China for pharmaceutical inventions is a top priority for the international pharmaceutical industry as China's pharmaceutical market grows by leaps and bounds and China becomes a center of pharmaceutical research and development. The proposed amendment to China's Patent Law contains changes that will significantly affect how pharmaceutical companies will compete in this market. Recent examples in China show that the government will take note of comments from the international business community in making and amending laws. Pharmaceutical companies planning to be active in China should make their opinions heard.

According to Cutting Edge Information Research, Patient Recruitment Costs Having Greater Impact on Clinical Development

Market Wire Source

The difficulty of recruiting suitable patients for clinical trials has been a greater factor in rising trial costs, according survey data collected from pharmaceutical companies. A new study by pharmaceutical business intelligence leader Cutting Edge Information, "Streamlining Clinical Trials," finds that on a cost-impact scale of 1-5, patient recruitment received a mark of 4.1, a 6% increase from a similar study conducted in 2006.

The report explores reasons behind the growing challenge of patient recruitment and retention, such as more stringent FDA regulations, budgetary constraints, and timeline overrun. Another challenge that impacts recruitment is overlap of patients for various studies at a single site. The sample populations in this case are lowered, making it difficult to find the necessary candidates to conduct trials. This challenge results in cost increase.

David Richardson, project leader of the study said, "Companies are continuing to encounter development challenges, and increased patient recruitment costs make it more difficult to run a trial smoothly."

A complementary brochure is available for download at http://cuttingedgeinfo.com/clinicaltrialbenchmarking/index.htm#body.