An often-quoted statement is that new drug development may take over ten years from the lab to Food and Drug Administration (FDA) approval, and that cost of that research and development may be over a billion dollars. These numbers understandably upset people, especially those suffering from a disease for which treatments are inadequate, or the condition is fatal. During the early days of the AIDS epidemic for example, activists called for the FDA to speed approval of drugs they believed would be life-saving. And, the FDA has developed four ways to speed up approval for drugs to treat serious disease (1):
priority review: FDA attempts to take action on an application within six months
breakthrough therapy: a process to expedite the development of new drugs which may be a significant improvement over available treatment
accelerated approval: a drug for a serious condition, filling an unmet need, and based on a surrogate endpoint, such as improvement in a lab, imaging finding, or physical sign, that is used to predict benefit
fast track: a process to facilitate development and expedite review of drugs for a serious condition, and fill an unmet need
There is also a special consideration for orphan drugs (those drugs intended to treat conditions which affect fewer than 200,000 U.S. citizens) (2) (see the interview with Dr. Moore in this issue on DUOPA). Orphan drug designation allows for incentives to the developer, such as tax credits. Even with these steps, the FDA’s role is that of safety, and the process may still take several years. Consider this 2018 statement from FDA commissioner Scott Gottlieb, M.D. on the mission of the agency (3):
“The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.”
This brief article is meant to summarize how drugs reach FDA approval (4), and hopefully give a better understanding of why it takes so long to safely bring a drug to the doctor’s office. I hope this writing will serve as a point of entry for other upcoming articles about the drug development pipeline in PD. The article is not meant to disentangle the problem of drug cost, which several authors have tackled (5-7) and is under consideration for a future topic in MPDN.
The FDA lists five steps in the new drug development process. Nested within these steps we find clinical trials. At first, the process may cumbersome to understand, but it can be summarized as follows:
Step 1: Discovery and development, research for a new drug beginning in the laboratory
Most commonly, researchers discover new drugs through a variety of mechanisms: new understanding of a disease process (how something happens in a disease); testing several different compounds to see if they help against a disease (test tube work); observing an unexpected benefit in an existing treatment (for example, a medication for the flu also prevents dyskinesia); or new technologies/ways to target medical products to specific sites within the body or manipulate genetic material. Thousands of compounds may be potential candidates, but most fail, and only a small number may warrant more study.
If a compound is to be tested, information must be learned about it, such as:
- how it is absorbed, distributed, metabolized, and excreted
- what are the potential benefits and mechanisms of action
- what is the best dosage
- what is the best way to deliver the drug (mouth, skin, injection)
- what are the possible side effects or toxicity
- how does it affect different groups of people (gender, race, age)
- how does it interact with other drugs or treatments
- how effective is it compared with similar drugs
Step 2: Preclinical research, drugs undergo laboratory and animal testing to answer basic questions about safety
The two types of preclinical research are: in vitro (outside of living organisms in test tubes or petri dishes, for example), and in vivo (in living organisms such as lab animals or people). These are usually small studies which are meant to find out about proper dosing: how much is enough, and how much is too much. This also helps researchers to decide if the compound should be tested in people.
Step 3: Clinical research, drugs tested on people to make sure they are safe and effective
The FDA makes the following statement (4):
“While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. ‘Clinical research’ refers to studies, or trials, that are done in people…”
The steps through human clinical trials may allow a drug to become FDA approved. Some compounds go through trials but never receive approval.
Clinical trials are often referred to as “translational research,” which brings a drug from the laboratory bench to the human being for testing. Trials at this stage are designed to answer very specific questions related to a drug or device, and follow a protocol that is written prior to starting the study. They must determine the selection criteria (who is included), how many people will be recruited, if there will be a control (placebo) group, how long the study will last, how to give drug, what dose will be given, what questions will be asked in the trial (what data collected), and how that data will be analyzed. Clinical trials proceed from small phase I to large phase III studies.
Phase I trials provide information about how drugs work in the body. These trials typically involve from 20-100 healthy people, or people with the disease being considered for treatment. The study may go on for several months. People are closely monitored to learn how a drug interacts with the human body, how to adjust dosing (usually based on animal data), how much of a drug the body can tolerate, and side effects at the doses given. Per the FDA, about 70% of drugs move to phase II.
Phase II may involve up to several hundred people with the disease or condition, and the study might last years (though the FDA reports it is usually no more than 2 years). These studies aren’t large enough to show whether a drug will be beneficial, and are instead designed to give additional safety data, refine research questions, develop research methods, and design new phase III protocols. Per the FDA, about 33% of drugs move to phase III.
Phase III trials may include thousands of people who have the disease or condition, and the study may last for years. The purpose of a phase III study is to learn how effective a treatment is and to monitor for side effects or adverse reactions (which may be more evident with a longer study and a larger population). These studies may recruit very specific populations of people, and are sometimes known as pivotal studies. Completing a successful phase III trial moves a drug along to what the FDA refers to as step 4 in the overall process.
Step 4: FDA Review, teams “thoroughly examine all of the submitted data related to the drug or device and make a decision to approve or not to approve it”
If FDA approved, it is available for prescription from a doctor. Per the FDA about 25-30% of drugs move to phase IV.
Phase IV studies may include several thousand volunteers with the disease or condition, and are meant to learn even more about safety and effectiveness. These studies are collected after the drug or device has been approved by FDA, and give post-market safety monitoring, also known as step 5 in overall process.
Step 5: “FDA monitors all drug and device safety once products are available for use by the public”
At this point many thousands of patients may be using a drug, and for much longer periods of time than trials were able to cover. This means hidden or rare problems may become more obvious, some of them very serious. A consequence is that many drugs found to be unsafe have been removed from the market over the years. A key issue is that we humans can have very different reactions to medications. What is life-saving for one person may be deadly for another. That is not to say a certain drug which is dangerous for some will always be removed. Instead, it might be the case that it can used by the right person, in the right way. That distinction takes a lot of clarity about the medicines, and about the differences between us. As my second grade teacher used to say, “people are like snowflakes, no two are the same.” It is so true, and it applies to medicine in a deep way. That is why safety is so hard to establish. This applies to “natural” products as well. We are told constantly by advertisers that if something is natural, it is better, or safer. That is not always the case. Natural remedies may be very potent, or they may be very harmful. Just as much scrutiny and care should be taken to make sure any substance given to treat or prevent illness is safe for people. However, in the United States vitamins and supplements are not required to go through the steps above. Sometimes giving these compounds to people results in a bad outcome, and those reports are not rare in the medical literature. For more information on that topic, see the MPDN article “Dietary supplements,” Fall 2016. For more information on drugs in development, stay tuned.
REFERENCES
- https://www.fda.gov/ForPatients/Approvals/Fast/default.htm
- https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/howtoapplyfororphanproductdesignation/ucm364750.htm
- https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm594009.htm
- https://www.cdc.gov/ForPatients/Approvals/Drugs/default.htm
- Marcia Angell, M.D. The Truth About the Drug Companies: How They Deceive Us and What to Do About It. New York: Random House, 2004, 291 pages(A lengthy and well-cited appraisal of the pharmaceutical industry and laws affecting it in 2004 by an internist and 20 year editor of the New England Journal of Medicine.)
- Robert Love, editor in chief AARP Bulletin. Why Our Drugs Cost So Much: Nothing stops drug companies from charging the highest price the market will bear, AARP Bulletin May 2017 https://www.aarp.org/health/drugs-supplements/info-2017/rx-prescription-drug-pricing.html
- Gina Shaw. The Price Isn’t Right: Breakthrough drugs for rare neurologic diseases are staggeringly expensive. We explain why and how to effect change. Neurology Now, February/March 2018 – Volume 14 – Issue 1 – p 40–45 or https://journals.lww.com/neurologynow/Fulltext/2018/14010/The_Price_Isn_t_Right__Breakthrough_drugs_for_rare.15.aspx
