GxP Lifeline
The Importance of Knowing What You Don’t Know About Drug Development
I have seen it happen a dozen or more times - a first-time new drug sponsor with no industry experience gets good preclinical results and immediately assumes the road to approval of the drug will be short, well-landscaped, and smooth. They think a couple of clinical trials and — POOF — a biologics license application (BLA) is born, U.S. Food and Drug Administration (FDA) approval is imminent, and fame and fortune are on its heels.
Yeah, not so much.
The pathway from lab bench to approval more closely resembles the North Yungas Road in Bolivia — it is neither short nor smooth, and incredibly convoluted. On average, only one in 5,000 new compounds that makes it through nonclinical studies ends up as an approved drug.1 According to a BIO Industry Analysis, the overall likelihood of approval from Phase 1 for all developmental candidates is 9.6 percent - a bench-to-market total of 0.0192 percent! This means that of the 452 investigational new drug (IND) applications filed in 2017, only 43 will make it out of Phase 1 and move on to ultimately be approved. New drug development is a tough enterprise, and not for the faint of heart.
More than anything else, the single most important thing to know about new drug development is this: know what you don’t know. This is a phenomenally expensive enterprise, and mistakes are costly. One example of costly mistakes is incorrect design of a nonclinical study. In 2012, the average nonclinical program from early tox studies to first-in-man cost $6.5 million, with a range of $100,000 to $27 million.2 The FDA does not review most nonclinical protocols in advance; you will not always have the benefit of their advice. If nonclinical study design is not your area of expertise, get help. Picture spending $100,000 or more on a nonclinical trial, only to have the FDA tell you the data does not justify human clinical trials.
Clinical trial design and oversight is no place for amateurs, either. For most drugs, the costs range from $5 million to $50 million for a Phase 1 trial, and up to $50 million to $750 million for a Phase 3 trial.3 With that kind of money on the line, you want to be sure to get it right. Sure, the FDA will tell you if it is not right, but by the time they tell you that a lot of money has already been invested. Where the trials are conducted, by whom, and who monitors them are also very expensive and important to get right.
Get help and get it early. Talk to the FDA. They will seldom outright tell you what to do, but they will tell you if you are on the right track. Tell them what you propose to do, then ask “Does the agency agree?” You may be amazed at the help you will get. Don’t know how to go about talking with the FDA? Get a consultant who does.
Let us not forget drug manufacture. A few milliliters of new compound produced on a lab bench and used in an early tox study is generally pretty inexpensive, but that won’t get you through nonclinical and clinical trials. Larger quantities will require larger operations, and not everything scales up nicely, except for the costs — costs always scale up well.
Selecting a Contract Manufacturing Organization (CMO) should not be rushed – it is a complex process that can sink a startup if the wrong choice is made. You will need help. There are literally hundreds of CMOs in the world and finding the right one for your product can be daunting. You need to ask:
- How long has the CMO been in business and is it financially stable?
- What kind of projects has it completed in the past? Does it have experience with materials similar to yours?
- Does it have the capabilities, personnel and equipment to develop and manufacture your drug?
- Does it have experience with regulatory authorities? In what regions?
- Does it have a good regulatory inspection record?
- Is it currently manufacturing marketed products?
There are many more questions to ask, but it does not stop at the CMO selection process. The number and nature of decisions to be made will be indescribable because each biological drug is unique in its own way. No one person can anticipate all the questions that will need to be answered and all the details that will have to be addressed. The advance planning in terms of the development program and regulatory strategy requires a team of experts.
Get help. Get it early. There is a time and place to economize but making key decisions about a new drug development program is not it. By saving a few thousand dollars on an upstream development consultant, you could easily lose orders of magnitude more through mistakes, not to mention time to market. Trying to sort it all out on your own with the advice of inexperienced colleagues or, worst of all — the advice of inexperienced investors — is a recipe for failure.
Arvilla Trag, RAC, Consultant at BioProcess Technology Consultants, has 27 years of experience in new drug development. As president and principle consultant of Midwest Consulting Services (MCS) from 1997 to 2016, she prepared dozens of INDs, and several Module 3 and 2.3 sections for BLAs. In addition to detailed submissions preparation, Trag has conducted over 250 CGMP compliance audits of contract manufacturers and testing labs, performed due diligence audits for M&A, prepared several quality manuals, and done gap analyses of quality systems. She has a broad range of product type experience, participating in over two dozen development programs of several product types, including monoclonal antibodies, vaccines, small molecules, and combination products. Prior to forming MCS, Trag worked as a regulatory affairs manager at Biopure from 1994–1997, where she prepared the NADA CMC section for the hemoglobin-based oxygen carrier Oxyglobin. Before joining Biopure, Trag was regulatory affairs and quality assurance manager at Virogenetics, a vaccine research and development facility, where she was responsible for writing all submissions to the U.S. FDA CBER and CVM, and to USDA APHIS, maintaining SOPs and archives, and interfacing with local regulators. Prior to Virogenetics, she spent six years as a laboratory technician at the NYSDOH Department of Neurotoxicology doing mammalian tissue culture, primary tissue culture, and IEF and 2D-SDS-PAGE gels. Trag graduated magna cum laude from the College of St. Rose in Albany, New York, with bachelor’s degrees in biology and chemistry, and Regulatory Affairs Certified (RAC) since 1994.
