The F.D.A. – The Federal Delay Administration?

The field of bioethics is filed with emotional and political landmines. And clearly, in a litigious society, side-effects and unintended consequences are ripe for greedy litigants and more greedy attorneys to file actions for the money. For others, “safety” is of little concern to them; they are the ones unfortunately diagnosed with terminal illnesses. If they take a not-yet-fully-vetted drug and die as a result – one that might alleviate or cure – “so what?” they ask.

But dangling a hopeful treatment in front of them that is in a vetting process that will easily exceed their most probable life expectancy… but not letting them try the treatment… seems needlessly cruel. Many are drawn by “treatments” overseas, some in nations where experimentation has proven valuable… and in others where quacks ply their trade to vulnerable and desperate people. For those who actually make it into clinical trials, there is the harsh reality that they just might be in the control group that is only being provided with a placebo… and no real treatment.

Currently, the United States, Europe and other well-developed countries are cooperating increasingly to develop comparable standards for testing and approving for use new drugs. The Federal Food and Drug Administration (FDA) has also accelerated its approval process from years to months, but drugs often cannot even be submitted for commercial approval unless they have already gone through years of mandatory clinical trials. Here’s where the FDA came from and how the drug testing/approval system operates:

“In 1820, the new era of USA drug regulation was started with the establishment of U.S. Pharmacopoeia. In 1906, Congress passed the original Food and Drugs Act, which require that drugs must meet official standards of strength and purity. However, in 1937, due to sulphanilamide tragedy, the Federal Food, Drug and Cosmetic Act (of 1938) was enacted and added new provisions that new drugs must be shown safe before marketing. Further, in 1962, the Kefauver-Harris Amendment Act was passed which require that manufacturers must prove that drug is safe and effective (for the claims made in labelling).

“The [FDA] is responsible for protecting and promoting public health. Like general drug approval process, FDA's new drug approval process is also accomplished in two phases: clinical trials (CT) and new drug application (NDA) approval. FDA approval process begins only after submission of investigational new drug (IND) application. The IND application should provide high quality preclinical data to justify the testing of the drug in humans. Almost 85% of drugs are subjected to clinical trials, for which IND applications are filed. The next step is phase I clinical trials (1-3 years) on human subjects (~100). The drug's safety profile and pharmacokinetics of drug are focused in this phase. Phase II trials (2 years) are performed if the drug successfully passes phase I. To evaluate dosage, broad efficacy and additional safety in people (~300) are the main objective of the phase II. If evidence of effectiveness is shown in phase II, phase III studies (3-4 years) begins. These phase III concerns more about safety and effectiveness of drug from data of different populations, dosages and its combination with other drugs in several hundred to about 3,000 people. A new drug application (NDA) can be filed only when the drug successfully passes all three phases of clinical trials and includes all animal and human data, data analyses, pharmacokinetics of drug and its manufacturing and proposed labelling. The preclinical, clinical reports and risk-benefit analysis (product's beneficial effects outweigh its possible harmful effects) are reviewed at the Center for Drug Evaluation and Research by a team of scientists. Generally approval of an NDA is granted within two years (on an average), however, this process can be completed from two months to several years. The innovating company is allowed to market the drug after the approval of an NDA and is considered to be in Phase IV trials. In this phase, new areas, uses or new populations, long-term effects, and how participants respond to different dosages are explored.” Pharmainfo.com, December 11, 2010.

Every moment that can be cut from the approval process matters. The recent shorter 5-6 month FDA approval process is significant. “That is a major acceleration in a pharmaceutical industry where every month’s delay can mean thousands of lives lost and sometimes hundreds of millions of dollars in sales that, given limited patent times, can never be recovered.” New York Times, January 2^nd. But for those “who are about to die,” the bigger question is whether or not there might not be another path to access drugs before those clinical trials are complete. There is a parallel question as to whether or not healthcare insurers should have to pay for such treatments, usually denied as “experimental.” It is, after all, much cheaper to let the patient die.

The issues at the FDA have gotten personal, it seems. Dr. Richard Pazdur, who has run the FDA’s oncology program for over a decade and a half, lost his wife to cancer last year. Her struggles with access to new treatments seems to have helped to accelerate the FDA’s internal approval process. “‘I have a much greater sense of urgency these days,’ Dr. Pazdur, 63, said in an interview. ‘I have been on a jihad to streamline the review process and get things out the door faster. I have evolved from regulator to regulator-advocate.’

“Many factors are driving him, he continued. ‘Was Mary’s illness one of them? Yes,’ he said. But in 2012, he added, Congress also passed a law that gave the F.D.A. more money and a new pathway to work more closely with drug makers when a medicine may save lives. Another important change in the same period, he said, was a surge in advances in genetic research that made some medications more effective and easier to test… ‘The drugs simply got better,’ Dr. Pazdur said.

“A year ago, when a clinical trial showed that a skin cancer medicine called Opdivo could also extend survival in lung cancer patients, Dr. Pazdur got the results directly from the trial’s overseers weeks before executives at the Bristol-Myers Squibb Company, the maker of Opdivo, saw the numbers. That allowed him to approve the drug for lung cancer patients three months ahead of schedule.

“In 2014, Dr. Pazdur approved a drug for widespread use against ovarian cancer that an expert advisory panel had previously voted, 11 to 2, against authorizing. Ms. Pazdur did not take the drug, Dr. Pazdur said, because it was targeted at a form of cancer that was genetically different from hers.” NY Times. But particularly in the world of aggressive cancer drugs, some of the treatments may indeed be worse than the disease itself. Much, much worse. Many also see accelerating the approval process as catering to the pharma industry, not consumers.

“‘The F.D.A. is more beholden to industry now than at any time since I became a close observer of the agency in 1971,’ said Dr. Sidney Wolfe, who with Ralph Nader founded Public Citizen’s Health Research Group. ‘Too many decisions F.D.A. now makes are driven by industry concerns, and as a result people are getting hurt.’

“Cancer medicines not only often fail to save patients but can accelerate their deaths and make their last weeks far more painful, and critics, like Public Citizen, argue that the F.D.A. focuses far too much on saving the few at the cost of cutting short the lives of many.

“Robert Hazlett, a research analyst with Ladenburg Thalmann, an investment firm, said the F.D.A.’s greater urgency — particularly in cancer drug approvals — had led to a boom in biotechnology shares.” NY Times. Even Mrs. Pazdur faced her own reality with an experimental drug that failed. “Ms. Pazdur suffered terribly from taking [an] experimental drug in a clinical trial, in which Dr. Pazdur had no role, at the National Institutes of Health. Her heart swelled to near bursting, her blood pressure soared, and she became so tired that she could barely walk to the bathroom. That experience was one of many reasons that Dr. Pazdur has also pushed for better research into drug side effects, an effort the F.D.A. began in earnest last year.” NY Times.

While cancer is certain a big force in medical research, there are other forces afoot. Does the pharma world, for example, really want a cure for diabetes? Billions and billions of investments in diabetes treatments and mitigators, an entire field of healthcare professionals, would vaporize. Many of the new treatments involve and will increasingly involve genetic manipulation with equally powerful bioethical issues. Can trials accelerate with increasingly sophisticated computer simulations?

And here’s the future of genetic engineering treatments that will test the FDA like no other: “[One new] technology that came into the mainstream was CRISPR [clustered regularly-interspaced short palindromic repeats] gene modification.  Discovered by scientists only a few years ago, CRISPRs are elements of an ancient system that protects bacteria and other single-celled organisms from viruses, acquiring immunity to them by incorporating genetic elements from the virus invaders.  Via CRISPRs, DNA can be edited, either removing unwanted sequences or inserting payload sequences, the genetic and chemical components necessary costing as little as $100.

“CRISPR modification introduces many new risks if used wrongly—to edit human embryos, for example.  But it could also be used to correct faulty DNA that’s responsible for genetic diseases such as cystic fibrosis, sickle-cell anemia, and Alzheimer’s, and to edit the genes of plants to produce more-nutritious food and require less water.  Labs all over the world are working with this technology to solve a wide range of problems, and we will see breakthroughs.” Washington Post, December 28^th. How should the testing rules change to meet this challenge? And exactly what is a “terminal” disease anyway?

For those like Mrs. Pazdur, diagnosed with ovarian cancer rate, her disease was not 100% fatal; the five year survival rate for those with the disease is 45%. Was her disease sufficiently likely to result in her near-term death to qualify as “terminal”? Where do we draw the lines? We do we make the “nothing left to lose” decision? Do we need panels of specialists to determine a patient as facing a high possibility of death before more extreme treatments are allowed? Do we then let the patient decide? Do we place these treatments outside of normal insurance coverage or allow them to a cap once that panel specialists have made their determination? Is it a matter of rich versus poor?

I’m Peter Dekom, and it is time we starting asking these questions at a legislative level to deal with pain and suffering that just might be prevented.