I was at dinner with a former colleague, discussing new business opportunities. During the course of the conversation, it became apparent that the complexities of drug research and development are not understood in many quarters. We were discussing a new potential drug. Without revealing specific details, a small team owns the rights to a molecule. In trying to finance the development of drug – taking it through all phases in the clinical development process – the partners approached several large pharmaceutical companies. They did not like hearing that the process would take years, perhaps decades, and would cost millions upon millions of dollars. So they continue to“shop” the molecule around, looking for private equity funding.
They clearly hoped to hear much more modest estimates of time and costs, based on their own belief (fantasy???) that this drug is highly effective and virtually non-toxic. Maybe…but you have to prove it, and proof is a long and costly venture. So, what does it take to bring a drug to market?
As mentioned in one of my earlier postings, the drug development process starts its flow in the “upstream” basic science labs where likely therapeutic targets are identified, molecules are formulated to fit those targets and, ultimately, demonstrated by modeling, in vitro and in vivo animal testing, that the underlying physiology of a disease process is altered.
Teams of scientists will screen thousands of entities and engineer new “lead compounds,” and then make modifications to “optimize” these leads. During the process, the ideal route of delivery will be determined and researchers will estimate a range of doses that will be effective for the disease under study. Preclinical testing will include characterizing the pharmacokinetics (PK) of the drug include absorption, distribution, metabolism and excretion and developing methodologies to measure the drug and it metabolites. This pre clinical phase of development takes from 3-6 years…and this must be done before human trials begin.
Clinical testing involves registering the entity with FDA as an Investigational New Drug (IND) and proposing a clinical development plan to the agency for review. An Institutional Review Board (IRB) of independent consultants is formed to review the development plan and to assess the scientific and ethical quality of the planned studies, where the trials will be conducted. Then clinical trials can begin.
During Phase I, the drug is tested in a small group (20-100) of healthy volunteers to determine dosing, toxicity and PK. This phase of study usually takes 6-12 months. Phase II development may include a few or even hundreds of study subjects in a “proof of concept” trial to determine if the drug is effective and generally consumes another 6-12 months.
The real work comes in Phase III — the large randomized, placebo-controlled trials — with hundreds to thousands of study subjects (depending on the disease) in hospitals, clinics or other study sites. Meanwhile, back at the ranch, the statisticians and others are processing the data and sometimes generating interim reports that may be reviewed by a data safety monitoring board. Phase III clinical trials may run just a few weeks or may cover many years. Why this great range of variation? A headache study may take a month or two, but a cholesterol lowering drug used for primary prevention to reduce the rate of heart attacks needs to include thousands of people and will take years to run. (http://www.phrma.org/research-development)
While these human trials are underway, other studies are being run, including long term animal toxicity studies and drug stability studies. Other teams are engaged in document preparation, package and labeling design, and FDA filing preparation, no small task. A typical New Drug Application (NDA) is 100,000 pages.
The FDA often convenes an advisory committee to review the drug. This committee will include independent experts in the field who analyze the analysis done by the FDA reviewers, along with presentations prepared by the pharmaceutical sponsor for the drug. The committee then votes and recommends for or against approval. But ultimately, the decision rest with the authorities at FDA.
After approval, the agency may require adverse event registries (e.g. birth defects with use of retinoids), or ask for additional post market studies. One drug I worked on was approved, but the PK data was rejected by FDA, owing to a long storage time before testing. FDA approved the drug with the proviso that the company redo their PK studies to complete their FDA submission.
The team involved in the process is vast — an expansive population of pre-clinical scientists, clinicians, clinical trial management personnel, statisticians, regulatory personnel, and more, and ultimately a team of marketing experts.
Review at FDA averages 16.9 months, but crucial drugs may receive rapid review.
Estimates are that of 10,000 New Chemical Entities that are characterized pharmacologically, only 10% will have an appropriate efficacy and safety profile to warrant entry into clinical study. From that 1,000 entities approved for clinical study, only 1% will prove to have adequate therapeutic efficacy and acceptable toxicity across the population at risk. So, 10 entities out of 10,000 make it through the entire process. Most of the attrition occurs before human use. But between Phase I and NDA, 90% of drugs are thrown out. In 2011, the FDA approved 23 drugs, and in 2010 only 21 drugs.
Kola and Landis, Nature Review Drug Discovery, 2004 (3):711-715
So, back to the drug I was asked to look at. What will it take to bring this drug to market? 12-15 years and 800 million- $1 billion.
In an effort to streamline and improve the drug development process, the FDA developed the Critical Path Initiative, with 76 proposed areas to potentially improve the drug development process, and provide great efficiencies and higher productivity. The projects fall into six general areas:
1. Biomarker development
2. Streamlining clinical trials
5. Antibiotics and countermeasures to combat infection and bioterrorism
6. Developing therapies for children and adolescent
As these initiatives become actualized, the hope is that unlikely entities will be identified sooner in the process, since late stage failures are extremely costly. The initiatives also will strive to help shorten time lines and lower development costs.
In conclusion, there are opportunities in private, academic and governmental institutions working on upstream and downstream drug research. As our understanding of the fundamental physiology involved in disease expands, there will be expanded work opportunities for talented life science grads.