Abstract
EMA Publishes Guidance for Biosimilar Monoclonal Antibodies
LONDON, UK 11/18/10—The Similar Biological Medicinal Products Working Party of the European Medicines Agency has released new guidelines for biosimilar monoclonal antibodies. The full document is available in this issue.
Separate sections outline the preclinical pharmaco-toxicological requirements and the requirements for clinical pharmacokinetic, pharmacodynamic, efficacy and safety studies, and pharmacovigilance (post-marketing monitoring). The necessary preclinical studies will differ according to the product and may include in vivo as well as in vitro assessment. The document discourages the use of non-human primates.
The focus of the clinical work is to be confirmation of biosimilarity to the originally licensed product from the legacy company. “Normally, similar clinical efficacy should be demonstrated in adequately powered, randomised, parallel group comparative clinical trial(s), preferably double-blind, normally equivalence trials. … The focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been shown for the reference product.” In deciding whether to approve the product, the EMA will pay special attention to immunogenicity data. Applicants may attempt to obtain approval for an indication not part of the labeling for the original product by providing appropriate clinical data.
The “Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues” (EMEA/CHMP/49348/05) and the “Guideline on Production and Quality Control of Monoclonal Antibodies and Related Substances” (CHMP/BWP/157653/07) will apply to these products as well, although the former document is being revised.
Second- or later-generation biologicals are not covered by these guidelines.
Government Issues Advice on Keeping Synthetic DNA Out of Terrorist Hands
WASHINGTON, DC 10/3/10—The US Department of Health and Human Services today issued a list of baseline measures companies will be required to take when they receive an order for synthetic double-stranded DNA. The goal is to prevent acquisition of such materials by terrorist groups, which could use them to create new pathogens.
Both the potential customers and the DNA sequences are to be screened.
At a time of concern about the potential of synthetic DNA in creating biological weapons, the HHS noted that synthetic DNA is becoming a “key material” in life science and biotechnology such that its development should “be encouraged in a safe and secure manner.”
According to
Avastin Will No Longer Be Indicated for Breast Cancer
BETHESDA, MD 12/16/10—The US Food and Drug Administration announced today that it is withdrawing approval of bevacizumab (Avastin; Genentech) in combination with paclitaxel (Taxol) for the treatment of advanced breast cancer.
Genentech has not agreed to change the labeling to remove breast cancer from the indications, so the FDA issued a Notice of Opportunity for a Hearing.
Bevacizumab received accelerated approval for breast cancer in Avastin 2008 after clinical trial E2100 in patients with metastatic HER2-negative breast cancer who had not yet received chemotherapy suggested the Mab retarded tumor growth for more than 5 months. However, four later trials showed the Mab had little effect on progression-free survival, inhibiting growth for no more than 3 months and failing to prolong patient survival. The FDA found this benefit insufficient to compensate for the significant risks of myocardial infarction, cardiac failure, hemorrhage, and tissue perforation associated with the product's use. Also associated with the Mab was reversible posterior leukoencephalopathy syndrome—severe high blood pressure, headaches, confusion, seizures, and vision loss secondary to swelling of the brain.
The vote by the Advisory Committee to rescind approval was 12-1.
Avastin retains its indications for use in cancers of the lung, colon, kidney, and brain and thus will still be available to physicians who wish to prescribe it for breast cancer. Oncologists were told to decide for each individual patient whether to continue administering the Mab to breast cancer patients.
Some members of Congress saw the decision as an attempt by the government to ration drugs.
Curiously, European regulators today affirmed their faith in the value of Avastin for breast cancer. Thus, payment for its prescription will continue.
In Europe, especially the UK, financial support for many new products, including biotechnology drugs, has been withdrawn or refused on the grounds that the cost–benefit ratio was too low to warrant expenditure of scarce government funds.
FDA Releases Regulatory Science Plan
BETHESDA, MD 11/2/10—The US Food and Drug Administration has released a plan to improve the safety of drugs and food. The agency notes that recent scientific and technology developments, such as nanotechnology, although likely to improve medical care, are creating complications for regulators.
“For these advances to reach their full potential … FDA must play an increasingly integral role as an agency not just dedicated to ensuring safe and effective products, but also to promote public health and participate more actively in the scientific research enterprise directed towards new treatments and interventions. We must also modernize our evaluation and approval processes to ensure that innovative products reach the patients who need them, when they need them,” the agency said.
The document, called Advancing Regulatory Science, has two sections: (1) the promise of regulatory science and (2) a collaborative implementation framework. The Regulatory Science Initiative, which builds on the earlier Critical Path Initiative, has a four-part base:
Leadership, coordination, strategic planning, and transparency to support science and innovation; Support for mission-critical applied research, both at FDA and collaboratively; Support for scientific excellence, professional development, and a learning organization; and Recruitment and retention of outstanding scientists.
The areas on which FDA intends to focus initially are:
Transforming product development: bringing progress to patients (e.g., methods for modernizing toxicology, biomarkers for personalized medicine, the stem cell initiative and updating drug review standards); Science to address emerging technologies in FDA-regulated products (e.g., nanotechnology and expertise to regulate new animal biotechnology products); Information sciences for health outcomes (e.g., medical device registry and scientific computing for data analyses); Addressing unmet public health needs (e.g., nutrition and public health).
“There is no single discovery—no magic bullet—to address our unique set of modern scientific regulatory challenges,” the Executive Summary concludes. “But one thing is clear: if we are to solve the most pressing public health problems we face today, we need new approaches, new collaborations, and new ways to take advantage of 21st Century technologies. And we need them now.”
Guidance on Treating Heart Disease with Cell Therapy
BETHESDA, MD 10/10—The US Food and Drug Administration has issued a Guidance for Industry on the use of cellular therapy in patients with heart disease, an update of “Guidance for Industry: Somatic Cell Therapy for Cardiac Disease,” which was published in April 2009. The text is available in the documents section of this issue.
The Guidance covers manufacture and quality control of the products as well as preclinical and clinical studies and indicates what information FDA wants to receive about the delivery system to be used for the cells. The agency expects cellular therapies to qualify as combination products under 21 CFR 3.2(e) and thus to require only a single investigational and one marketing application rather than one for the cells and another for the delivery technology.
“One common processing step for cellular products is the use of immunomagnetic selection by means of monoclonal antibodies and paramagnetic microspheres to yield a cell population enriched for a specific cell surface antigen. Antibodies used in this process should be demonstrated to be free of adventitious agents and of appropriate quality to function as intended.”
Preclinical studies generally will be required to determine:
biological response to the products; the durability of response; toxicology (e.g., potential for the product to cause local and systemic adverse findings of the product, including tumorigenicity); dose–response.
Studies needed for the delivery system are those that assess:
damage to the site of delivery system introduction/retrieval, the access vasculature, the site(s) of product delivery, and any significant intermediate structures; delivery system handling characteristics; and damage to the delivery system as a result of simulated use.
“We recommend that all protocols for the use of cellular therapies in the treatment of cardiac disease contain stopping rules. These stopping rules should address the considerations discussed in this section (i.e., safety monitoring), as well as those issues unique to the product and its method of delivery.”
“FDA recognizes that it may be difficult for sponsors to develop a clinical study design with a sham control arm that investigators, institutional review boards, and patients believe is ethical. For this reason, studies involving a sham control arm should be carefully considered and planned.”
An Appendix discusses in vitro testing of the catheter or other delivery device.
Epo Still Indicated for Patients in Earlier Stages of Renal Disease
BETHESDA, MD 10/18/10—The Cardiovascular and Renal Drugs Advisory Panel of the US Food and Drug Administration today said that Amgen's Aranesp, a long-lasting formulation of recombinant human erythropoietin, is safe for patients with mild to moderate renal disease who do not require dialysis. The question arose when a doubling of the risk of stroke was seen in this population in the TREAT trial.
Erythropoietin, a hormone that stimulates the creation of red blood cells, is synthesized by the kidneys and thus is reduced in patients with renal disease. Aranesp and earlier formulations have been used for several years to help restore erythrocyte volume in patients in renal failure, was well as in patients with anemia because their bone marrow has been damaged by chemotherapy. Recent safety concerns have led to dosage reductions, with changes in product labeling.
The Committee voted 15-1 to allow continued use of Epo in patients with less severe kidney disease (i.e., those not yet needing dialysis) and 9-5 against reducing the dose for patients with serum hemoglobin concentrations below 9 g/dL. Hemoglobin, the oxygen-carrying protein in red blood cells, is used as a measure of cell volume and is present in a concentration of 14 to 15 g/dL in healthy men and 12 to 15.6 g/dL in healthy women. The target concentration in patients receiving recombinant Epo is 10 to 12 g/dL. Until recent reevaluations suggested risks of cardiovascular events and stimulation of cancer growth by the protein, the recommended hemoglobin target was 13 to 14 g/dL.
FDA Threatens Criminal Charges in Off-Label Promotions
BETHESDA, MD 10/13/10—
Misdemeanor violations of the Drug and Cosmetic Act are covered by the Park Doctrine, which can subject an executive to as long as a year in prison, a fine of as much as $100,000, and being banned from the pharmaceutical industry. It does not matter whether the executive knew of the violation.
US Attempting to Expand Responsibilities of Generic Drug Makers
WASHINGTON, DC 11/15/10—Acting Solicitor General Neal Katyal has filed an amicus curiae brief with the Supreme Court arguing that a generic drug manufacturer is required to warn consumers of an adverse effect not described in the labeling for the original drug.
Current law requires a package insert for a generic drug to duplicate that of the legacy manufacturer; the US is now arguing that a generic manufacturer that becomes aware of a previously unrecognized risk must modify its package insert. The case involves the drug metoclopramide.
The Eighth Circuit Court of Appeals recently found a generic manufacturer liable for patient injuries because it did not appeal to the Food and Drug Administration for a revision of the labeling to accommodate a new finding of harm and because it could have taken other steps to warn physicians and consumers of the adverse reaction.
FDA Approves Monoclonal Antibody for Prevention of Bone Pain and Fractures
THOUSAND OAKS, CAL. 11/18/10—Amgen announced today that it received marketing approval for denosumab for the prevention of skeletal-related events such as pain and fractures in patients with bone metastases from solid tumors such as prostate and breast cancer. The drug already has been approved for the treatment of postmenopausal osteoporosis. For that indication, it is sold as Prolia. Drug for cancer patients will be called Xgeva.
Use of different trade names for the same drug prescribed for different indications is not unusual, as it makes things easier for prescribers.
The newly approved Mab targets RANKL, which is involved in cancer-related bone destruction. It is given by injection once a month. This is a different mechanism than that used by other drugs now approved for prevention of complications of bone metastases.
The three clinical trials leading to today's approval enrolled more than 5700 patients. The endpoint was time to fracture or spinal cord compression. The comparator drug was Zometa.
In men with prostate cancer, the median time to a skeletal event was 21 months with Xgeva compared with 17 months with Zometa. For women with breast cancer, the median time had not yet been reached for Xgeva at the time the study was concluded, whereas it was 26 months for Zometa. The two drugs performed similarly in other cancers, such as renal and lung tumors. There also seemed to be benefit in patients with multiple myeloma, but the approval does not cover this cancer, leukemias, or lymphomas.
The most serious side effects experienced with Xgeva are a low calcium concentration in the blood (hypocalcemia) and osteonecrosis of the jaw, a serious complication that has been associated with other drugs used to treat osteoporosis.
Second Embryonic Stem Cell Trial Allowed to Proceed
BETHESDA, MD 11/22/10—The US Food and Drug Administration has granted Advanced Cell Technology (Santa Monica, Cal.) permission to conduct a clinical trial of embryonic stem cells in Stargardt disease, a genetic disorder that leads to visual loss beginning in the center of the visual field. In the worst cases, patients become blind.
The trial will entail implantation of scavenger cells derived from embryos. These cells remove toxic metabolites that kill other cells in the eye. Only one eye will be injected initially, as dosage finding and safety are the primary endpoints. It is hoped the technique also will work for persons with macular degeneration, a far more common disorder.
The approval marks only the second time the US government has granted permission to conduct a trial of embryonic stem cells. Although there is widespread enthusiasm for the procedure in the popular press, there is as yet no scientific evidence that such cells will be superior to stem cells acquired after birth, and there is concern about the formation of teratomas or teratocarcinomas when the cells are released from the controls that would be exerted on them by an embryo.
Research Institute at Odds with Employee on Stem Cell Funding
BOSTON, MASS. 11/22/10—The Boston Biomedical Research Institute has filed an amicus curiae brief in the suit seeking to overturn the halt on human embryonic stem cell research imposed by Judge Lamberth in August. The Institute argues that the ban interferes with development of new treatments, particularly those for muscular dystrophy.
“A university and a foundation have offered to provide BBRI with human embryonic stem cells with mutations conferring muscular dystrophy for its research, but BBRI has not accepted these materials as a result of the injunction,” the Institute said.
The filing of the brief is scarcely surprising but is interesting because
EU Raids Drug Company Offices
BRUSSELS, BELGIUM 12/3/10—European Union regulators have conducted raids on the offices of some drug companies as part of an investigation of measures used to delay entry of generic drugs into the marketplace. Many legacy companies have been found to have paid generic manufacturers to delay filing for marketing approval, generally in conjunction with settling patent litigation, the “pay-to-delay” strategy.
AstraZeneca PLC and Nycomed SCA were among the targets.
Regulators said they had “reason to believe that the companies concerned may have acted individually or jointly, notably to delay generic entry for a particular medicine.” The drug in this case is esomeprazole, which is used to prevent heartburn. It is sold by AstraZeneca under the trade name Nexium.
Nexium also faces competition from an earlier drug in the same chemical family, omeprazole. That drug is now available in several generic versions. Nexium costs more than 10 times as much, and some experts say it is no better.
How Much Data to Require for Approval of a Biosimilar Product
WASHINGTON, DC 12/1/10—A meeting convened at the Brookings Institution today heard experts say that the US Food and Drug Administration will have a difficult time crafting laws that would permit the introduction of “generic” biotechnology drugs; what are usually called “biosimilars.” The new healthcare law allows approval of such drugs after 12 years of patent exclusivity, but the law has been said by some critics to provide too much power to the FDA to decide what to require before approval is granted.
Considerable concern has surrounded biosimilars, as the products, being proteins rather than simple organic chemicals, could easily be modified unintentionally in ways that would reduce their efficacy and safety. Thus, there have been calls to require clinical trials before a biosimilar is approved, a costly measure.
Embryonic Stem Cell Scientist Calls for Comprehensive Research Policy
PHILADELPHIA, PENN. 11/22/10—As the courts deal with the question of whether federal funds can be used for human embryonic stem cell research, one of the first scientists to isolate such cells called for “a comprehensive national policy on all human embryo research with appropriate, unequivocal laws.” He said, however, that Congress “has no stomach” for tackling the issue.
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