Not long ago, critics of the U.S. Food and Drug Administration seemed to outnumber those who supported its leadership. But under the administration of Commissioner Mark McClellan, MD, PhD — one of the shortest and surely one of the most activist in FDA history — those who griped about the agency’s slow approval process and risk-averse tendencies found little to complain about.
“Having studied FDA regulation and leadership within the FDA for nearly two decades, I would say there’s never been a commissioner quite like Mark McClellan,” says Kenneth Kaitin, PhD, director of the Tufts Center for the Study of Drug Development. “He had the unique background of being a physician and an economist, which gave him a perspective on both the critical importance and the enormous challenge of bringing new products to market.”
McClellan, whom Congress has approved as administrator of the Centers for Medicare and Medic-aid Services, made no bones about the importance of a healthy financial environment for pharmaceutical companies, because the cost, time, and risk involved in bringing new drugs to market is ultimately a public health concern. Few, if any, FDA commissioners have couched the economics of drug development in terms of public health.
The FDA’s remaining critics claim that McClellan was too cozy with industry; in fact, McClellan was liked by pharmaceutical manufacturers, partly because he was politically savvy. He came to the FDA from the White House Council of Economic Advisors and had free rein to talk about topics that FDA commissioners typically don’t address, such as international price controls and economic evaluations of pharmaceuticals.
Mark McClellan, MD, PhD
An early McClellan initiative was to consolidate the review process for chemical and biological therapeutic products by transferring the review of therapeutic proteins from the Center for Biologics Evaluation and Research to the Center for Drug Evaluation and Research. “The review process for monoclonal antibodies, recombinant proteins, and oligosaccharides is pretty straightforward; evaluating those products is not significantly different than evaluating chemical drugs,” says Kaitin. “That fact is supported by the FDA’s decision to move the review of these and other products to CDER.”
McClellan also spearheaded several patient-safety initiatives. A final FDA rule requiring bar codes on the labels of human drugs and biological products was released February 20. Separately, one of McClellan’s most significant legacies, says Kaitin, is the risk management program he instituted at the FDA. “This was a way for him to say, on behalf of the FDA, that the agency is taking steps to ensure that the current public focus on drug safety will not slow up FDA’s approval of important new medicines. No amount of clinical testing is going to enable sponsors to detect rare events; the FDA instead will beef up the system for detecting adverse events in the general population, so that drugs that have unexpected safety problems can be removed from the market before they do much damage.”
A permanent replacement for McClellan is expected to be named after the presidential election. Kaitin believes a new standard has been set. “It will be hard to go back to an FDA commissioner who has only a medical background but does not understand the economics of pharmaceutical development.”
New Approvals
Two high-profile products for colorectal cancer have received FDA approval. Bevacizumab (Avastin), has been approved as first-line treatment for metastatic colorectal cancer. Bevacizumab, a monoclonal antibody (mAb), prevents the formation of new blood vessels, and was shown to extend patients’ lives when given intravenously along with standard chemotherapy.
Days earlier, cetuximab (Erbitux), ImClone Systems’ mAb for patients whose colorectal cancer has spread, received an FDA indication as combination treatment with irinotecan. According to the FDA, there is no evidence that Erbitux extends lives, but tumors of some patients taking Erbitux decreased in size or grew more slowly, particularly when cetuximab had been combined with irinotecan.
Elsewhere, the FDA approved ZLB Bioplasma’s liquid Rho(D) immune globulin intravenous (Rhophylac) for sale. Rhophylac is used to prevent hemolytic disease of the fetus and in newborns…. Ciprofloxacin for intravenous infusion, the generic equivalent of Bayer’s Cipro IV, has received tentative FDA approval. The drug is used to treat lower respiratory, bone, and joint infections.
Fast Tracks and NDAs
The FDA has granted fast-track status to alvimopan (Entereg), a new drug used to treat ileus, a temporary postoperative bowel condition. Adolor will complete a new drug application for alvimopan by the end of June…. Ramoplanin, Genome Therapeutics’ treatment for Clostridium difficile-associated diarrhea, is in a phase 2 clinical trial and has been granted fast-track status.
An injectable form of azacitidine (Vidaza) for treating the bone marrow disease myelodys-plastic syndrome will get faster review from the FDA, with a decision expected by the end of June. Pharmion licensed the drug, which had already received orphan drug status, from Pfizer.
Biogen Idec and Elan, partners in the development of natalizumab (Antegren), announced that they they will file for FDA approval of their new treatment for multiple sclerosis one year ahead of schedule. According to Biogen Idec, data from a two-year clinical trial of Antegren is strong enough to win FDA approval.
U.S. Clinical Trials
Psoriasis and psoriatic arthritis therapies has been a hotbed of activity, with the results of three trials released recently.
In a phase 3 study of a step-down dosing regimen, 49 percent of patients with psoriasis achieved PASI-75 after 12 weeks when given a loading dose of 50 mg of etanercept (Enbrel) twice weekly, compared to 34 percent of those whose therapy was initiated at 25 mg. Of patients who achieved PASI 75, 77 percent maintained this response when stepped down to 25 mg during weeks 13 to 24.
A phase 2 study of infliximab (Remicade) for patients with severe plaque psoriasis found that 84 and 91 percent of patients receiving 3 mg/kg and 5 mg/kg doses, respectively, achieved PASI-75 after 10 weeks. Etanercept is marketed by Amgen, and infliximab by Centocor.
Xoma and Genentech’s efalizumab (Raptiva), already on the market for psoriasis, failed to reach a primary endpoint of symptom reduction of psoriatic arthritis in a phase 2 trial. Genentech says the results confirm that psoriatic arthritis and psoriasis are distinct conditions.
In news of other trials, hyperhidrosis (excessive sweating) was reduced in 75 percent of patients given botulinum toxin A in a phase 3 study, compared to 25 percent of patients given a placebo. The study was funded by Allergan…. The modified release form of indiplon helped elderly patients with chronic insomnia fall asleep sooner and stay asleep longer, according to a second long-term phase 3 trial. Neurocrine Biosciences is collaborating with Pfizer on two forms (modified and immediate release) of the drug…. In its phase 2b trial, Alteon’s dimethyl-3-phenacylthiazolium chloride (ALT-711) showed significant lowering of systolic blood pressure in patients with a baseline systolic reading of 140 mm Hg or greater, with little concurrent effect on diastolic blood pressure readings.
The National Institutes of Health has begun a phase 2 clinical trial of Guilford Pharmaceuticals’ neuroimmunophilin ligand GPI-1485. It’s part of a broader investigation of four experimental neuroprotective therapies for Parkinson’s disease.
Also of Interest…
The FDA will review a supplemental NDA to use Celgene’s thalidomide (Thalomid) as a treatment for multiple myeloma. Thalomid is already approved for treating cutaneous moderate to severe erythema nodosum leprosum…. Proposals for manufacture of an anthrax vaccine were due to the Department of Health and Human Services on April 16.
Supported by the National Institute of Allergy and Infectious Diseases of the NIH, the first U.S. tuberculosis vaccine trial in 60 years will be conducted by Seattle biotech Corixa and GlaxoSmith-Kline Biologicals, a vaccine manufacturer headquartered in Belgium. The recombinant vaccine-adjuvant combination will be tested on 20 volunteers in a single-site phase 1 trial. The available TB vaccine, BCG, is not very effective against pulmonary TB, the most contagious form of the disease.