An important op-ed from today's Wall Street Journal, penned by our friend Mark Thornton.
By MARK THORNTON
The news did not make it to the front pages, but on Feb. 28 a powerful member of the U.S. Senate launched an attack on the Food and Drug Administration, the drug companies and the desperate cancer patients they treat.
Charles Grassley (R., Iowa), ranking member of the Senate Finance Committee, requested that the Government Accountability Office launch an inquiry into whether the FDA behaved appropriately in granting the "accelerated approval" of Avastin, a drug for treating women with metastatic breast cancer. Mr. Grassley's action will have a catastrophic effect on America's ability to develop new drugs.
At issue is the concept of "surrogate endpoints" and the FDA's "accelerated approval" regulations. In the 1980s, at the height of the AIDS epidemic, AIDS activists were livid at the slow pace of development of new drugs to fight HIV. They lobbied heavily for changes in the law to allow an expedited pathway for the approval of new drugs for any disease deemed serious or life-threatening. The historic results were new laws and regulations that created an accelerated approval mechanism by which a drug could be allowed on the market if it showed early evidence of an effect on a surrogate endpoint. For cancer, examples of surrogate endpoints are tumor shrinkage or a delay in the disease's progression.
This kind of measurement – as opposed to an assessment of a drug's impact on a patient's overall survival – has dramatically increased the pace of cancer clinical trials. It also has won near-universal acceptance within the cancer community. The FDA does require follow-on studies to assure that a surrogate finding shows clinical benefit. But if all cancer clinical trials were required to show a survival benefit from the get-go, progress in cancer-drug development would slow to an absolute crawl.
Enter Mr. Grassley. It seems not a week goes by without him making a public accusation of evil doings within the drug industry or the FDA. Yes, Mr. Grassley did some good after the Vioxx episode, by focusing on the woeful manner in which postmarketing drug safety is managed and regulated by the FDA. But he and his staff should have kept their eyes on the ball. In the case of Avastin, the senator implied in his GAO request that something sinister occurred during the FDA's premarket deliberations, and that surrogate endpoints were the new bogeyman. Nothing could be further from the truth.
In February, the FDA approved Avastin despite a 5-4 vote by its Oncology Drugs Advisory Committee (ODAC) not to recommend approval. Meetings of this advisory committee address the most vexing issues that exist in cancer-drug development. The advice is usually helpful but never binding. Everyone who works at the FDA knows that the public only sees a fraction of what FDA insiders consider when they make their final decisions on products.
In the case of Avastin, additional data emerged late in the review process, after the ODAC meeting, that strongly supported accelerated approval. It became clear that Avastin had an enormous impact on the surrogate endpoint known as "progression-free survival." PFS is such a powerful measure that it is actually used as the basis for full approval in many cancer indications.
As part of the accelerated approval letter, the FDA also placed some of the most stringent postmarketing requirements in history for the drug's sponsor to gain full approval. No standards were lowered, and many women may now live much longer without their disease progressing.
The damage done by Mr. Grassley's decision to make an issue of this decision cannot be understated. Having served at the FDA during the Congressional hearings over the Imclone/Martha Stewart insider trading scandal, I can attest to how an action like this GAO inquiry will resonate within the halls of FDA. An extremely cautious and protective bureaucracy will respond to such intimidation by being even more protective.
The senator is demanding a full-scale review of each and every product ever approved, and is asking for a rejudgment by GAO "to ensure that drugs approved on surrogate endpoints are both safe and effective."
You can bet these bully tactics will have an effect. Look for greater demands by the FDA for cancer programs to not use the accelerated approval pathway. Just a few weeks ago, Medarex Inc. announced that the FDA will renege on a commitment to grant accelerated approval of a new product for skin cancer if its clinical trial showed benefit using the PFS endpoint. The FDA ordered a change toward the much stricter endpoint of overall survival, adding years to the time it will take to evaluate the drug's efficacy.
U.S. cancer-drug development stands on a precipice overlooking a new dark age in which each new product's development is longer and costlier than the last. Companies may decide it is not financially viable to even bother developing new drugs, and the pipeline for new products to treat cancer could slow even more. Mr. Grassley's legacy could be thousands of additional cancer deaths.
Advocates for all patients affected by Mr. Grassley's antidrug company demagoguery – including cancer patients, Alzheimer's patients, AIDS patients – must make their voices heard.
Dr. Thornton is a former medical officer in the Office of Oncology Products at the Food and Drug Administration. He volunteers as president of the Sarcoma Foundation of America.
