TCS Daily

Drug Regulation: The Worst Has Become the Norm

By Henry I. Miller - September 26, 2007 12:00 AM

The pendulum swings back and forth about what ails the regulation of drug development. Thirty years ago, the concerns were primarily about "drug lag" - indolent reviews and approvals by the FDA that put Americans at disadvantage to consumers in other countries. In recent years, however, there have been repeated accusations about what might be called "drug leap" - a supposedly "too cozy" relationship between regulators and industry, along with too little attention paid to drug safety, possibly as the result of regulators' pressing to meet arbitrary deadlines.

The reality is that over the past decade or so the FDA has become more progressively risk-averse and defensive in its decision-making. Regulators have been encouraged "drug safety" but no longer are called to account for the unnecessary suffering and deaths of patients who don't get the new drugs they need in a timely way.

This asymmetry will be further worsened by the tragically misnamed FDA Revitalization Act, which was passed by Congress and is expected to be signed by the president. The bill focuses on providing regulators with more sticks with which to flog drug developers, while what is needed are more ways to get regulators to be more efficient, effective and smart. It also contains an important giveaway to plantiffs' trial lawyers: No longer will the FDA's very close and stringent regulation of drug labeling pre-empt state juries from second-guessing new safety warnings imposed by drug companies and the FDA. Drug development, already in dire straits, will become even more difficult, slow and expensive.

In spite of increasingly more powerful and precise technologies for drug discovery, purification and production during the past twenty years, development costs have skyrocketed. On average it takes 12-15 years and costs over a billion dollars to bring a drug to market. Of that amount, capitalized out-of-pocket preclinical costs and clinical testing each account for about half.

Why the huge costs and lengthy development times, which exceed even those for conventional drugs? Regulatory excesses, for the most part. Regulators are inflexible and inconsistent and keep raising the bar for approval, especially for innovative, high-tech products. Another factor is user fees (nothing more than a discriminatory tax) paid to FDA by drug companies - raised to almost $400 million in the new legislation.

Several highly publicized events have heightened public and congressional concern about drug safety during the past few years: inadequate warnings on the labels of anti-depressants and the discovery of previously unknown side effects from non-steroidal anti-inflammatory drugs (NSAIDS) and from the multiple sclerosis drug Tysabri.

However, contrary to perceptions that regulatory oversight might have become lax, drug regulation in the United States in recent years has actually become progressively more risk-averse, as the FDA has steadily made it more difficult to initiate and perform the clinical testing of new drugs. Recent criticism from Congress, the media and others regarding drug safety has caused an already risk-averse agency to become even more conservative and defensive in its decision-making. The FDA has been requiring ever larger numbers of patients in clinical trials; its demands for post-marketing clinical trials have proliferated wildly; and "risk management" plans for newly approved drugs have been inconsistently applied, punitive and often more appropriate for weapons-grade plutonium than prescription drugs.

Regulators' moving the goalposts in the middle of the game is particularly vexing for drug developers. In September 2006, Genentech announced that approval of its colon cancer drug Avastin for breast cancer would be delayed at least a year because of requests from the FDA for additional data. The company said that regulators appeared to be increasing the stringency of requirements for certain types of clinical trials and had arbitrarily demanded that its trials be "audited and summarized" in a way different from that earlier agreed upon with regulators.

Another recent and particularly problematic example involves Somaxon Pharmaceuticals' testing of an already-approved drug, doxepin, for a new indication. The drug, approved for the treatment of depression since 1969, is being tested in very low doses for use as a sleeping pill. The FDA initially assured the company that it could begin human clinical trials without first doing animal tests because of doxepin's long history of use in people and because Somaxon was using a dose less than one-tenth that used to treat depression. However, in May 2006, after having completed several clinical trials, while the company was meeting with the FDA to discuss the submission of a New Drug Application, regulators unexpectedly asked for a full battery of testing in animals. Animal testing is usually considered to be "pre-clinical," so it is difficult to understand the logic of animal testing for an almost forty-year-old drug that is undergoing trials for a new indication, and at a far lower dose than it is normally used.

In addition, a number of drugs previously granted marketing approval in Europe have received "approvable," instead of approval, letters from the FDA, meaning that additional data is required before the drug can be marketed. These include Sanofi-Aventis' Acomplia for weight loss and cessation of smoking, NPS Pharmaceuticals' Preos for osteoporosis and Encysive Pharmaceuticals' Thelin for pulmonary hypertension.

Many new targeted therapies are difficult to assess with traditional clinical trial designs or endpoints. For example, a drug intended to arrest or eliminate cancer by boosting the patient's immune system might be most efficacious in early stage cancers when the tumor load is low and the patient is not debilitated. Thus, if the company were to adopt a clinical design that called for recruiting and treating only patients with advanced cancers, one would expect to see sub-optimal efficacy. This kind of situation, in which there is a high level of novelty and uncertainty, argues for greater flexibility both in clinical trial design and in reaching agreement on what constitutes "efficacy," but instead the FDA has been risk-averse and defensive, sometimes intransigent. In the review of cancer drugs in particular, FDA reviewers and managers frequently are characterized as inadequately prepared for meetings with industry scientists and insensitive to the needs of dying patients.

Times are tough for drug development, and they are getting worse. Beleaguered regulators are hunkered down and in go-slow mode. The Congress has once again shirked its responsibility to appropriate sufficient funds for the FDA or to perform the kind of informed, intelligent oversight that promotes innovation and ingenuity in drug development. The absence of outrage means that the worst has become the norm.

Henry I. Miller, a physician and fellow at Stanford University's Hoover Institution, headed the FDA's Office of Biotechnology from 1989 to 1993. He is the author, most recently, of "The Frankenfood Myth."



abandon fed regulation
Perhaps it is time to consider abandoning a system that has never worked in favor of private, free market certification. Of course, even the drug companies don't want this, even as they complain about regulation, because they are accustomed to using the fed as a restraint on their competitors and potential competitors.

There is nothing so sweet as the mess that the state can create by its incessant interference.

To Zero
The FDA is one of the most tyrannical bureaucracies in the federal government, routinely and with malice of forethought trampling the rights of free speech and free trade in the supplement and drug industries. It should be demolished immediately, and its leading administrators tried and convicted of the numerous crimes they have committed.

FeDerAl jackasses
The National Cancer Institute has said that it is virtually guaranteed that some potentent treatments for, and probably cures for, cancer have been lost entirely because the FDA blocked their distribution after the medicines sickened or killed lab mice, even though they would have benefitted human beings.

It is absurd to suddenly order a whole battery of testing on what is clearly a tried and true drug by using animals as models for humans.

What a world, what a world! The (incompetent)Nanny State cometh.

Competition will surely come into this market...
Just like nearly every other high-tech product with a broad consumer market medicines should be commodities. They are developed and marketed aggressively under brand names. The major players typically have competitive products for every application. Prices for mature products should be astoundingly low. Because unit production costs approach zero. The large pharmaceutical companies should be happy to fight for share points and earn plenty of money with immense volumes.

The reason this has not happened yet is that the rest of the world depends on the FDA to do its drug approvals and the industry looks to the US market for the largest part of its profit margin.

As the other 95% of the world catches up regarding their interest in health care and their ability to afford such a luxury the foolishness of the FDA will simply fade away. Other governments will deal with drug approvals for their own markets in a more reasonable (and completely responsible) manner. And the pharmaceutical houses will decide, more and more, to skip the US market unless FDA stops with the stupidity.

Clearly, what is going on with the FDA is unsustainable and the cost of Health Care generally for Americans continues to grow in such a manner that fundamental change is inevitable.

It does seem astounding that such government behavior (defeating the normal process of competition) is so obviously wrong yet no one seems able to make it stop.

This is the result of politics in a pretend democracy, two-party republic. If we had a real democracy then someone might be able to get elected on a platform to fix this thing before we hit the wall. As it is both parties are terrified to lose votes by bringing reasonable management to the sacred process of approving life-saving medicines.

At least in a place like China their one-party government is free to do the right thing without concerning itself with political fall out on both sides of such an issue.

no competition possible
Even if other countries approve drugs that aren't approved by the FDA it won't help the US patient and worker.
Those drugs won't be available in the US because they lack FDA approval and without such approval they're not legal for US doctors and pharmacies to prescribe and distribute.

And btw, the way other countries are dealing with it right now is not the best either.
Many countries have regulatory authorities that are an even worse mess than is the FDA, though there the problem is more often an ingrained culture of bribery and fraud rather than glacial and inconsisten decisionmaking by incompetent bureaucrats in ivory towers.
If the US system is too slow and opaque, the system in many other countries is often too rapid, paying scant attention to dangers (and beneficial effects) of drugs before they're approved for the market.
As a result drugs that are ineffective get approved over drugs that would work because their manufacturers offered higher bribes. Contaminated drugs enter the market, killing patients. Etc. etc.

Of couse, competition is possible...
No one can stop the other economies of the world from competing against the US health care paradigm for their own domestic consumption. No matter what we are doing here they can do things differently over there...if they want to.

The point is that America does health care better than anyone else, today, in spite of certain known "fatal flaws" built into our health care delivery system.

Just as we once had the finest autmobile industry in the world, eventually other nations started making really good cars. Ultimately such competition overcame Detroit with "better, faster and cheaper" design and manufacturing methods.

There is a lot of money in health care products and services. And a lot of premium margins to be earned. Business players all over the world look at this industry and imagine how they might get into the game. And, given the opportunity, they will. In the end this must benefit American consumers as such competiton will (at least) demonstrate to us how the health care industry must certainly evolve.

What we are doing is clearly unsustainable and (by that definition) it will not continue uncorrected into perpetuity. If the health care industries indeed "hit the wall" here in the US, Americans will, nevertheless, continue to demand such goods and services. And we will still constitute an attractive enough market that someone, somewhere will want to fill that demand. Our own industrial entities will correct themselves or the government will be forced to allow foreign players into our markets. The irresistable benefits of competition.

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