Chemotherapy Drug Discovery and Approval Process

The process of introducing new chemotherapy agents to the market – and to the oncologist’s tool chest – involves pharmaceutical companies, regulatory agencies, and the medical community. The journey from laboratory to approved medication, and the expansion of already approved medication to use in other illnesses, is expensive and can take many years.

In the United States, the Food and Drug Administration (FDA) oversees the process and must approve all drugs – prescription and over-the-counter – before they get on the market.  The FDA is charged with making sure the drugs are both safe and effective.  Approved drugs are labeled – approved – for specific conditions.  The FDA does not approve a drug for a condition unless it has been shown to have some efficacy.  Some outsiders are mildly surprised by this stance – why not approve anything that doesn’t cause harm?  They ask.  But the FDA takes this seriously and will not authorize marketing of a drug that has not been shown to either prevent an illness or treat it with some effect.  The effect does not have to be large – many cancer drugs are approved only because they extend survival time a few months – but there has to be some medical benefit from the patient taking the drug.

Within the FDA is the Center for Drug Evaluation and Research (CDER) which reviews drug studies.  Note that the FDA doesn’t actually do any research.  Outsiders, usually the drug company that owns the rights to the compound or brand spends the money to do the research and present the findings if the results are good.  CDER employs professionals trained in medicinal chemistry, physiology, biochemistry, medicine, statistics, and law.  They are qualified to evaluate the applications that similarly trained professionals at the drug companies have prepared.  This is bureaucracy at its best – technocrats doing what they are supposed to do.  There is often back-and-forth as the CDER request further information or research to be done.

New chemotherapy drugs are found by several ways

  • Accident – the efficacy of nitrogen mustards – the first chemotherapy agents – was discovered after accidental exposure of soldiers to chemical weapons.
  • Bioprospecting – finding compounds in nature that have activity against cancer.  The most famous examples are paclitaxel (found in the bark of the Pacific Yew) and the vinca alkaloids (from the Madagascar periwinkle.)
  • Basic scientific research into cellular biology, physiology, biochemistry, and similar fields.  So-called rational drug design involves the creation of chemical compounds that trained and experienced scientists think might be effective against cancer.  This is the most common way of finding new drugs and big pharmaceutical companies and universities spend billions of dollars a year on these activities.

The FDA also conducts “post marketing surveillance” on drugs as part of their mandate to protect the public.  Doctors and other health care professionals are supposed to report adverse effects and other notable events suspected to be from the use of the drug to the manufacturer.  The manufacturers are required to collect reports and relay findings to the FDA.  The FDA also receives direct reports of adverse events and their people monitor the media and do selected surveys of patients to get a handle on what is going on.

Drug Regulation and Approval: Debate About the Role of Government

When the Food, Drug, and Cosmetic Act was passed in 1938, it required that sponsors prove drugs are safe before they go to market.  The drugs (and devices) didn’t actually have to work, so long as they were reasonably safe for adults.  In 1962 Congress passed a law that required new drugs be shown to be effective – that is, have at least some therapeutic benefit for some patients in some situations.  It’s a fairly low bar – many new cancer drugs get approved after showing they extend expected survival time by only a few months.  Nonetheless, after the 1962 law went through hundreds of products were withdrawn – essentially were unapproved – when reviews showed they provided no patient benefit.

The libertarian view is for looser regulation, and that the burden of regulation exceeds the benefits.  While it’s true that some unsafe drugs might get through a looser system, critics say, those unsafe drugs will be recognized quickly and pulled from the market by sellers.  For the drugs that are safe, avoiding the regulatory process and burden of proof gets them to patients who need them sooner.

Thalidomide is an example of a drug that caused tens of thousands of birth defects.  Under today’s testing process, scientists would have found the problem before thalidomide was used widely.

 

Another argument the deregulators put out is that data and efficacy and safety can be collected after the drug is being used: observational studies of patients on the medicine.

This system might work in detecting unsafe drugs, but outside the controlled clinical trial process it is less likely to identify medicines that are safe but ineffective.  (Many new medicines wash out of the clinical trials process not because they cause harm but because they don’t seem to help anybody.)

Is that so bad?  That we have ineffective drugs on the market?  Well, yes, it makes the entire health care system less efficient.  People and capital are employed to make the ineffective drug, and marketing channels are used when they could be used to make and distribute drugs that work.

The pro-regulation argument also points out that information has a cost.  In a competitive world, one drug company cannot afford to develop evidence for safety and reliability unless its competitors do so too.  If we as a society want good information (to inform medical and economic decisions), we must generate this information somehow, and regulations can do that.

Further, even the critics admit that the clinical trial process yields reliable information – more reliable and reproducible than post-market observational studies.

You sometimes see news stories about drugs being withdrawn from the marketplace, and this is usually a joint effort of the FDA and the drug manufacturer.   The press releases usually say the manufacturer is voluntarily withdrawing the medicine, although it is a safe bet they do so for fear the FDA will impose a mandatory withdrawal.  The reasons for withdrawal are usually safety-related, not because the medicine doesn’t work.

Opinion article in Nature: http://www.nature.com/news/show-drugs-work-before-selling-them-1.21582#/b7