Taking a hit

What does the concept of 'safety' mean? Is anything 100 per cent safe? Certainly not. All drugs have risks as well as benefits. More often than not, the more serious the disease, the more serious the risks associated with the treatments available.

In the wake of genuine safety concerns, high-profile stories on counterfeiting and the successful rollout of the US Food and Drug Administration's (FDA) Part D drug benefit, foreign drug re-importation has lost much of its political allure and momentum. Most elected officials in the US who called previously for the legalisation of foreign drugs have since abandoned their incautious and dotty schemes.

In its place, the clarion call of 'safety'. After all, who could be against safety? As Dr Mark Goldberger, director of FDA's office of antimicrobial products commented: It's more complex than it seems at first glance. This is certainly true.

The media loves it because although the pressure point is different (issues of price and access are no longer as sexy as they once were), the victim is the same - the pharmaceutical industry. As everyone knows, it is more than okay to kick the stuffing out of big pharma (or, if you prefer, big piÒata). It's a free hit. Sanctimonious quotes and macho strutting results in terrific headlines.

A little harmless politicking? Hardly. Just ask the people who no longer have access to the medicines they need, or to those who will suffer needlessly because of a dearth of new 'unsafe' medicines in the pipeline.

RISK OF NO TREATMENT
Consider multiple sclerosis (MS) and Tysabri. In February 2005, Biogen Idec and Elan were pressured to suspend sales of Tysabri after two patients died from the rare neurological disease progressive multifocal leukoencephalopathy (PML).

Thousands of MS patients, who have learned a lesson from HIV/AIDS activists, descended on FDA hearings en masse. In June 2006, Tysabri was allowed back on the market, albeit with more stringent labelling. Subsequently, an exhaustive study of all patients who took the drug found no new cases of PML.

To put this into perspective, there is a 0.1 per cent risk of developing PML if you use Tysabri. That's half the risk of dying from aspirin. Meanwhile, MS causes about 53,000 relapses yearly and 5 per cent of relapses cripple or even kill their victims.

Patient advocates claim that all too often regulators ignore the risks to patients of not making a medicine available. Certainly, risks cannot be ignored, but the existing FDA approval process, in most cases, makes all of the information about a drug's benefits and risks available. Further testing does little to expand what is already known through initial certification and informed practice.

POLITICAL PRESSURE
Under pending US legislation, even those drugs that have successfully passed through the complicated, expensive and exhaustive FDA approval obstacle course will no longer be considered 'safe'. If a drug raises even the slightest concern, a new safety 'politburo' could demand further testing or prevent it from reaching the market.

If such decisions are made, the thousands or even millions of patients who derive real benefit from the drug will have little say. A new layer of drug czars will be given near absolute power to shut down otherwise successful programmes, with virtually no possibility of appeal.

Rather than waging a war against Alzheimer's, cancer and other illnesses, many members of Congress are formulating a battle plan to expand the regulatory reach of the FDA. It is neither science nor suffering but politics that is dominating this controversy. Some want another level of control: an independent Drug Safety Board could intervene and demand additional safety studies of any size and quantity at virtually any time before or after approval.

Others want the FDA to have the power to demand additional clinical trials to identify possible safety problems and to pull drugs off the market - regardless of their benefit - if the studies are not completed within a specific timeframe. Certainly, this would make the approval process far less efficient and limit a patient's access to new life-saving developments.

MORE TRIALS EQUAL MORE SAFETY?
Would the increased scrutiny at least improve drug safety? Unfortunately, the answer is no. It's simply not true that more studies make safer medicines. Over the past 40 years, the percentage of medicines withdrawn from the market because of dangerous side effects has been essentially constant at about 2-3 per cent, even as the number of required clinical studies - an average of 120 per drug approval - has mushroomed.

In fact, improper use of otherwise safe medicines remains the problem. Common over-the-counter painkillers, such as aspirin and ibuprofen, cause thousands of hospitalisations and hundreds of deaths each year.

With more advanced drugs, consider the now infamous Vioxx case, the proposed legislation would require studies involving 250,000 people, running several years and costing billions. There's also the additional cost of all the people who cannot access the drug. The millions who benefit would have no voice.

THE REAL ISSUE
The real problem with drug development is not loudly proclaimed drug safety, but the growing shortage of newer, more effective medicines which can treat or prevent the most costly and devastating diseases.

Despite the explosion in potential new targets for treating serious illnesses, fewer new medicines are being approved than ever before, and the number of drugs being withdrawn from development before they reach the market has increased. Why? Because the tools that allow scientists to tailor a drug to a disease are not being used to develop treatments around the patients who respond best to a medicine with the fewest side effects.

Such techniques can identify the mechanisms and individuals early in the development process, eliminating the need and risk of doing so once a drug is on the market. The effort to adopt these approaches to drug, device and diagnostic development, while increasing the number of products hitting the market to improve health, was dubbed the critical path initiative by the FDA. For example, the use of biomarkers (a biological measure of response to a drug or disease progress) with links to health outcomes could shave years and billions of dollars off drug development. What's more, drugs developed with newer methods are demonstrably safer. In addition, the new science produces medicines which are more personalised and better targeted to genetic profiles.

INNOVATIVE THINKING
Innovations like biomarkers and the critical path initiative require cooperation between regulators and the pharmaceutical industry. But politicians and self-styled public advocates continue to demonise pharma and accuse the FDA of being too 'cosy' with those it regulates. But introducing new science is impossible without significant collaboration between the public sector pharma companies, academia, disease organisations and public policy institutions.

With partnerships, we could improve standardisation and automation of clinical research. We could also develop novel and improved clinical trial designs, and analytical methods for evaluation of safety and effectiveness to reduce costs. Currently, 50 per cent of drugs that undergo large-scale phase III trials turn out to be too unsafe or not effective enough for marketing - an unsustainable model for the 21st Century.

Today's newest computer models and imaging tools can predict not only the onset of illnesses, such as Alzheimer's disease, but also which drugs will work best for which patients.

Such information can be captured with no invasion of privacy, using the electronic records of existing patients, or from other health information technology platforms, such as those being developed by the not-for-profit integrated managed care organisation, Kaiser Permanente. The result would be medicines that reach market faster, are safer and better targeted to individual patient needs.

Do post-approval safety issues arise? Of course, and pharma companies themselves have a huge interest in monitoring on- and off-label events. But instituting hasty measures on the back of media headlines which demonise pharma more often than not have the effect of halting new research.

THE WAY FORWARD
The current system of drug regulation involves a careful balancing of drug benefits and risks based on the best possible scientific data that can be discovered about a new drug's safety profile.

Is reform needed? Certainly. But we do not need hasty measures which harm public health by slowing down the availability of new and better medicines. Our elected officials should remain mindful of these concerns when they consider how best to continue to provide the resources which make the US drug approval system the world's gold standard.

The US has, and should continue to have, the best medical research in the world. Congress should do everything it can to keep it that way.

PRESSURE TO PERFORM
The society we live in is being pulled in two directions at once when it comes to drug safety. On one hand, we want treatments to cure our ills, but on the other we expect these treatments to be 100 per cent safe. Consider the case of GlaxoSmithKline's (GSK) diabetes drug Avandia. It was linked to heart problems in an article published by the Journal of American Medical Association (JAMA) in May 2007.

The FDA asked GSK to change the labelling, effectively warning doctors not to prescribe the drug. The published JAMA study described a meta-analysis of post-marketing studies for Avandia, which is how the author arrived at his conclusions. GSK defended itself by saying that a meta-analysis was not as scientifically rigorous as its own large-scale, long-term clinical trials. All possible side effects of a drug cannot be anticipated by pre-approval studies alone, as they involve only several hundred to several thousand patients. So how much active post-marketing surveillance of Avandia was performed? Enough for GSK and the FDA, or the drug would not have reached the market. But how large should sample sizes be? How long should a study run? There is very little consensus on the matter in industry or among regulatory agencies.

In the US, the FDA maintains a system of post-marketing surveillance and risk assessment programmes to identify adverse events which did not appear during the drug approval process. The agency has, however, been under significant pressure from the US federal government to increase its own evaluations of drug safety. This has resulted in reduced prescriptions and ultimately reduced costs. The public is caught in the middle of a war between the pharma industry and the regulatory bodies of government. One wants to produce more drugs to make profits to make more drugs, while the other sees safety as a convenient way to take these expensive drugs off the market and save money.

REGULATORY AGENCIES CRITICISED
In a July 2007 speech to Congress, Senator Chuck Grassley criticised the FDA's handling of Avandia and expressed his concerns similar to those seen in the Vioxx case, where the FDA ignored its own post-marketing safety experts and once again left the public in the dark regarding potential risk.

Not only did the FDA disregard the concerns and recommendations from the office responsible for post-marketing surveillance, but I have found that it also attempted to suppress scientific dissent. As I've said many times before, FDA employees dedicated to post-marketing drug safety should be able to express their opinions in writing and independently without fear of retaliation, reprimand or reprisal, said Grassley.

Where these internal pressures come from is a topic of much debate, but the pharmaceutical industry is a very powerful group and actively lobbies governments, backed up by large budgets. For example, GSK spent more than $3.6m to lobby on issues related to patent reform legislation, pharma regulation and foreign investment in the US, according to a company disclosure.

Pharma is under great pressure from investors to protect its investments and keep drugs on the market. Conversely, while regulatory bodies may pat themselves on the back for being seen to take drug safety seriously, patient groups lament the loss of useful treatments.

The recent withdrawal of Novartis' Prexige in some EU countries is a case in point. A spokesperson for the Arthritis Research Campaign said the loss of the drug was a major blow for osteoarthritis sufferers and represented the end of the line for COX-2 inhibitors, which have helped a large number of patients, despite their short-comings.

Being risk-averse is one thing, but the current preoccupation with trying to attain a 100 per cent safety record has resulted in products that have given symptom relief to many being withdrawn from the market and could threaten the future of other much-needed medicines reaching the market.

The Author
Peter J Pitts is senior vice-president for global health affairs at Manning Selvage & Lee and is also director of the Center for Medicine in the Public Interest