Chemotherapy Drug Discovery and Development

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 pharmaceutical industry lives and dies on new products; this is why it spends more than any other industry on research and development. And that research can be like finding a needle in a haystack. Only one in five thousand compounds discovered reaches the market.

Patents on drugs last twenty years. Drug developers apply for patents early, before the medicines have garnered regulatory approval. It takes years for the medicine to go through testing, clinical trials, and approval, so by the time the drug is approved, the period of patent protection remaining is under twenty years. US law allows the FDA to give developers a 5-year market exclusivity period after approval. Sometimes the remaining patent life and this period of exclusivity overlap.

Speeding it up

The clinical trials process is very long – many years. It takes that long to show that the medicine works and to get a handle on its risks and side effects. When news of a potential new drug gets out, there are often cries to make everything go faster.

Who wants faster drug approval? Many stakeholders do, including individual patients, patient activist groups, elected officials, and the drug companies. The FDA is under great pressure and that’s part of the reason the Accelerated Approval and similar programs were created.

Stories of patients going to extremes and often outside the law to get medicines they suspect will work abound: home chemistry labs set up in attempts to synthesize or extract drugs, traveling to other countries, getting fraudulent prescriptions, and buying medicines from gray markets through the internet.

Good Enough Drugs

What is the measure of a medicine? How do we know a medicine works for a given disease? It used to be we kept track of patients in trials as they took the drug.  Results were measured by macro evaluation of patient health. Did the patient survive? Were the side effects tolerable? Did the disease disappear? Were there complications?

Slowing tumor growth is not the same as guaranteeing longer life. Sometimes drugs get approved because they have shown they can slow tumor growth.

Nowadays there is a greater emphasis on surrogates for macro health. Progression-free survival is a goal used in a lot of cancer trials. Maybe the cancer did not go into remission, but did it seem to be arrested?Biochemical signs are also used. Often new medicines are approved based largely on surrogate endpoint data.

Now, this allows the drug to go to market and be used by patients outside of clinical trials. The manufacturer can advertise and promote the new medicine. However, the manufacturer is usually required to administer Phase 4 trials for these drugs, meaning they are supposed to monitor patients. Survival data gathered is later submitted to the FDA and the approval of the medicine can be altered.

This process has been criticized by observers who feel that speed and certainty are in conflict and that the old way of proving medicines have clinical benefits is preferable.

The FDA has four programs for expediting new drugs through the process: This webpage lists them: https://www.fda.gov/forpatients/approvals/fast/default.htm Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review

Fast Track. This program was created in 1997 to allow quicker approval of drugs that have the potential to meet an “unmet need”. Clinical trials website Centerwatch reported that in 2016 pharmaceutical companies asked for fast track approval of 187 products. And that 131 of those were accepted into the fast track system.  Acceptance to Fast Track does not necessarily mean the medicine will be approved.

The Government Accountability Office in 2106 reported that “about a quarter of the drug applications CDER approved for the U.S. market from October 1, 2006, to December 31, 2014, used at least one expedited program.”