Chemotherapy Drug Discovery and Development

Over a quarter of new drugs approved by the FDA are for cancer.  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.
  • Pseudo-Copying existing biologic drugs.  This called the development of biosimilars.

Another avenue of discovery involves testing “old” drugs – ones that were developed in the past and made it through initial safety trials, but did not prove effective against the disease or indication their developers initially intended.  Testing these failed drugs against different diseases (e.g. cancer) could find some surprises.  Scientists at the Broad Institute used this approach and analyzed 4518 compounds using automated testing techniques.  They found several dozen had some anti-cancer activity, at least against malignant cells.  That doesn’t mean all of those compounds will turn into medicines that eventually make it to the clinic, but it gives researchers a shorter list of candidates to pursue.

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.  Oncology drugs wash out in clinical trials at a greater rate than any other drug classPatents 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.

Development encompasses pre-clinical research, clinical research, and post-clinical research (after the drug is approved.)

Forward pharmacology vs Reverse pharmacology

Forward pharmacology was the original way drugs were developed.  It was found, somehow, that a medicine or material worked against a disease.  Then scientists isolated the active compound (say from a plant source) and used it as the medicine or packaged it in another delivery system or they chemically modified it to make it better.  During or after this process the biochemical mechanism may be elucidated.  This was the main way drugs were found before modern laboratory equipment was developed; it is therefore sometimes called classic pharmacology.  This method (also called phenotypic drug discovery) is still employed today, but for the most part scientists have moved to reverse pharmacology.

Reverse pharmacology is called by its fans a more “rational drug discovery process”.  It involves identifying a biochemical pathway critical to disease progression and then finding a compound that disrupts that pathway.  Many compounds are screened in a drug discovery and the few that get through the screens are further investigated and perhaps chemically modified.  Using today’s laboratory techniques, developers can screen thousands of compounds.  Because the target is identified before an effective drug is found, this way of looking for medicines is called target-based discovery.  Compared to forward pharmacology, the reverse process is faster and cheaper.

In the early 21st Century, especially after data from the sequencing of the human genome became available, most researchers have been following the target-based approach.  Because of its popularity and its intellectual appeal, it has been called “rational drug design”.  This might appear snobbish – like the scientists of the past weren’t rational? – but it refers to use of modern scientific tools that permit a better understanding of disease etiology.

When using phenotypic drug discovery, scientists don’t have to understand, or even have a hypothesis about the cause of the malady at a molecular level.  While an effective drug may work by blocking or attacking or replacing one element of the body at a molecular level, the scientist and the clinician don’t necessarily need to understand the mechanics.

Classical pharmacology has attracted a little more attention in the past decade as improvements in screening technology has made identification of phenotypes at a cellular level easier.  There is also more recognition that diseases are multifactorial and have more than one biochemical source, so finding a target may not always be feasible.

Another secret is that rational drug design is not always particularly rational.  Cancer biology is complex, and sometimes a drug works but not through the mechanism scientist developers originally thought it would.  Rational drug discovery is not like the design of mechanical systems.

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 necessarily the same as increasing lifespan. 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.

development of cancer medicineNow, 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: 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 FDA website reports 39 of the new drugs approved in 2021 went through the Fast Track system.

The FDA approved 50 new drugs in 2021 (not just for cancer).  Of these 14 went through the Accelerated Approval system.  Also 14 new drugs were designated Breakthrough drugs.

The Government Accountability Office in 2016 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.”

Questions about chemotherapy going forward.