Approval Process for New Drugs

The process of introducing new chemotherapy agents to the market – and to the oncologist’s toolbox – involves pharmaceutical companies, regulatory agencies, and the community of medical professionals. The journey from laboratory to approved medication, and the expansion of already approved medication for use in other illnesses, are expensive and can take many years.  The costly approval process is one of the driver of high chemotherapy prices.

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 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.

The FDA (and European Medicines Agency and other regulators) look for evidence before they grant approval of a new drug. These might include toxicity profile of the new medicine, realistic expected benefits, and the situation of the medical world with regard to the patient population in question – e.g. risk to untreated patients and other treatments available.

The sponsor files an Investigational New Drug (IND) application with the FDA before proceeding with clinical trials in human subjects.  By this time the new medicine has been tried on animals and researchers think they have enough data to convince the regulators the drug is safe enough to try it on people.

The drug developer presents a case to address some or all of these issues. Clinical trial data may address expected benefits and toxicity of the new medicine.  The sponsor also typically presents a dossier on other treatment options and prognosis for patients with the cancer in question.  In the United States, sponsors of new small molecule therapeutic compounds apply for an NDA (new drug application).  New biologics go through an analogous process called the Biologics License Application (BLA).

Within the FDA, the Center for Drug Evaluation and Research, or CDER, reviews applications, issues or denies approvals, and keeps tabs on approved drugs on the market. The Center for Biologics Evaluation and Research (CBER) does the same thing for biopharmaceuticals (biologics). 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 and CBER employ 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 FDA requests further information or research to be done.

The Orphan Drug Act of 1983 was intended to spur development of medicines that are projected to have a modest-sized market. These are often referred to as Rare Diseases, although some of them are not so rare. The act enables tax credits for clinical trials for drugs intended to treat rare diseases, and allows the FDA to grant periods of extended market exclusivity. Drugs identified as orphan drugs are more likely to get expedited review for approval. In 2021, 26 of the 50 drugs approved by the FDA (all drugs, not just cancer drugs) were considered orphan drugs.

The FDA also has special programs intended to make things easier for medicines with promise to have big impact. These are Accelerated Approval, Breakthrough Therapy, Fast Track, and Priority Review.  In June 2019 the FDA announced Project Facilitate, a pilot program to expand access to oncology drugs. The European Medicines Agency (EMA) likewise has the PRIME scheme which offers accelerated approval for promising medicines.

The Accelerated Approval program actually allows the FDA to lower the standard for proving efficacy.  The website Undark says “in cases where there is an unmet medical need for a serious condition…a drug manufacturer need not show that the drug works. It only needs to demonstrate some reasonable expectation that the drug ought to work. ”  This loosening of standards has brought criticism.

The FDA can designate a medicine under the Breakthrough Therapy program if the drug is intended to treat a serious condition, promises substantially better results than what is currently available, and for which there is some clinical evidence of its efficacy.  The evidence does not have to be as strong as is must be for other medicines on the to-be-approved list.  Medicines designated under this program get expedited review.  Over 220 drugs (oncology and other) have been approved under the Breakthrough Therapy program.

The Fast Track designation allows the sponsor to submit sections of the New Drug Application or Biologic License Application to the FDA for review before the entire application is complete.  Priority Review designation means the FDA aims to act on the application within six months, rather than the ten months goal for most applications.

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.

Oncology vs. Other Drugs

In the 15 years prior to 2017, the FDA approved 86 new cancer medicines, and 29 of them went through an accelerated approval process.  Oncology drugs accounted for over 20 percent of the new medicines approved during that period.

A 2007 study published by the American Society of Clinical Oncology stated that 71% of first FDA approvals of oncology drugs have been “priority reviews.” Only 40% of other drugs revised a FDA priority review in the period 1990 to 2005. One difference between oncology medicines and other new medicines is in which phase of the process the disapproved drugs struck out. Cancer drugs had higher rates of success getting through Phases 1 and 2 before striking out Phase 3. The extra time in clinical trials processes increases the cost of developing cancer drugs.  The Pharmaceutical Research and Manufacturers of America estimates US-based companies are running 8000 clinical trials for all branches of medicine.

However, there is concern that many clinical trials take place outside the United States and that the data may not be as reliable as when trials take place domestically. There are cost and regulatory avoidance reasons for doing the tests elsewhere, but the safety protocols may not be adequate.  An article in Scientific American pointed out that 90 percent of recently approved therapies involved trials outside the US and Canada.

Does the FDA ever un-approve drugs?

Yes, both prescription and over-the-counter drugs are occasionally pulled from the market if evidence builds as to them not being safe.  Medicines are approved for specific indications, but even those can be rolled back.  For instance Avastin (bevacizumab) was approved in 2004 and its labelling was expanded for breast cancer in 2008.  Then in 2011 an FDA review panel concluded that the risks outweigh the benefits for treatment of breast cancer and pulled approval for that disease.  There was considerable complainingOf course, drugs can still be given “off-label” but this action meant the drug maker could not advertise Avastin for breast cancer, perhaps that insurance plans would not cover it, and that a doctor who did administer it would lose some backing if he or she ever got sued for malpractice.

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.

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.

But an example of when the safety-first approach is better is Thalidomide: 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 deregulation fans put out is that data about 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 and distribution channels are used, when all these resources 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 the regulatory process makes that happen.

young cancer patient

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

See also: Regulation and Market Power

Opinion article in Nature: